Sample records for endocannabinoid system activation

  1. Peripheral Endocannabinoid System Activity in Patients Treated With Sibutramine

    PubMed Central

    Engeli, Stefan; Heusser, Karsten; Janke, Jürgen; Gorzelniak, Kerstin; Bátkai, Sándor; Pacher, Pál; Harvey-White, Judith; Luft, Friedrich C.; Jordan, Jens

    2008-01-01

    Objective The endocannabinoid system (ECS) promotes weight gain and obesity-associated metabolic changes. Weight loss interventions may influence obesity-associated risk indirectly through modulation of the peripheral ECS. We investigated the effect of acute and chronic treatment with sibutramine on components of the peripheral ECS. Methods and Procedures Twenty obese otherwise healthy patients received randomized, double-blind, crossover treatment with placebo and 15 mg/day sibutramine for 5 days each, followed by 12 weeks open-label sibutramine treatment. We determined circulating anandamide and 2-arachidonoylglycerol and expression levels of endocannabinoid genes in subcutaneous abdominal adipose tissue biopsies. Results Body weight was stable during the acute treatment period and decreased by 6.0 ± 0.8 kg in those patients completing 3 months of sibutramine treatment (P < 0.05). Circulating endocannabinoids and the expression of ECS genes did not change with acute or chronic sibutramine treatment. Discussion The ECS is activated in obesity. We did not find any influence of 5% body weight loss induced by sibutramine on circulating levels of endocannabinoids and adipose-tissue expression of endocannabinoid genes in obese subjects. These data confirm our previous findings on dietary weight loss and suggest that the dysregulation of the ECS may be a cause rather than a consequence of obesity. PMID:18356837

  2. Endocannabinoid System in Neurological Disorders.

    PubMed

    Ranieri, Roberta; Laezza, Chiara; Bifulco, Maurizio; Marasco, Daniela; Malfitano, Anna M

    2016-01-01

    Several studies support the evidence that the endocannabinoid system and cannabimimetic drugs might have therapeutic potential in numerous pathologies. These pathologies range from neurological disorders, atherosclerosis, stroke, cancer to obesity/metabolic syndrome and others. In this paper we review the endocannabinoid system signaling and its alteration in neurodegenerative disorders like multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease and discuss the main findings about the use of cannabinoids in the therapy of these pathologies. Despite different etiologies, neurodegenerative disorders exhibit similar mechanisms like neuro-inflammation, excitotoxicity, deregulation of intercellular communication, mitochondrial dysfunction and disruption of brain tissue homeostasis. Current treatments ameliorate the symptoms but are not curative. Interfering with the endocannabinoid signaling might be a valid therapeutic option in neuro-degeneration. To this aim, pharmacological intervention to modulate the endocannabinoid system and the use of natural and synthetic cannabimimetic drugs have been assessed. CB1 and CB2 receptor signaling contributes to the control of Ca2+ homeostasis, trophic support, mitochondrial activity, and inflammatory conditions. Several studies and patents suggest that the endocannabinoid system has neuro-protective properties and might be a target in neurodegenerative diseases.

  3. The endocannabinoid system in brain reward processes.

    PubMed

    Solinas, M; Goldberg, S R; Piomelli, D

    2008-05-01

    Food, drugs and brain stimulation can serve as strong rewarding stimuli and are all believed to activate common brain circuits that evolved in mammals to favour fitness and survival. For decades, endogenous dopaminergic and opioid systems have been considered the most important systems in mediating brain reward processes. Recent evidence suggests that the endogenous cannabinoid (endocannabinoid) system also has an important role in signalling of rewarding events. First, CB(1) receptors are found in brain areas involved in reward processes, such as the dopaminergic mesolimbic system. Second, activation of CB(1) receptors by plant-derived, synthetic or endogenous CB(1) receptor agonists stimulates dopaminergic neurotransmission, produces rewarding effects and increases rewarding effects of abused drugs and food. Third, pharmacological or genetic blockade of CB(1) receptors prevents activation of dopaminergic neurotransmission by several addictive drugs and reduces rewarding effects of food and these drugs. Fourth, brain levels of the endocannabinoids anandamide and 2-arachidonoylglycerol are altered by activation of reward processes. However, the intrinsic activity of the endocannabinoid system does not appear to play a facilitatory role in brain stimulation reward and some evidence suggests it may even oppose it. The influence of the endocannabinoid system on brain reward processes may depend on the degree of activation of the different brain areas involved and might represent a mechanism for fine-tuning dopaminergic activity. Although involvement of the various components of the endocannabinoid system may differ depending on the type of rewarding event investigated, this system appears to play a major role in modulating reward processes.

  4. Endocannabinoids and the Cardiovascular System in Health and Disease.

    PubMed

    O'Sullivan, Saoirse Elizabeth

    2015-01-01

    The endocannabinoid system is widely distributed throughout the cardiovascular system. Endocannabinoids play a minimal role in the regulation of cardiovascular function in normal conditions, but are altered in most cardiovascular disorders. In shock, endocannabinoids released within blood mediate the associated hypotension through CB(1) activation. In hypertension, there is evidence for changes in the expression of CB(1), and CB(1) antagonism reduces blood pressure in obese hypertensive and diabetic patients. The endocannabinoid system is also upregulated in cardiac pathologies. This is likely to be cardioprotective, via CB(2) and CB(1) (lesser extent). In the vasculature, endocannabinoids cause vasorelaxation through activation of multiple target sites, inhibition of calcium channels, activation of potassium channels, NO production and the release of vasoactive substances. Changes in the expression or function of any of these pathways alter the vascular effect of endocannabinoids. Endocannabinoids have positive (CB(2)) and negative effects (CB(1)) on the progression of atherosclerosis. However, any negative effects of CB(1) may not be consequential, as chronic CB(1) antagonism in large scale human trials was not associated with significant reductions in atheroma. In neurovascular disorders such as stroke, endocannabinoids are upregulated and protective, involving activation of CB(1), CB(2), TRPV1 and PPARα. Although most of this evidence is from preclinical studies, it seems likely that cannabinoid-based therapies could be beneficial in a range of cardiovascular disorders.

  5. Acute resistance exercise induces antinociception by activation of the endocannabinoid system in rats.

    PubMed

    Galdino, Giovane; Romero, Thiago; Silva, José Felippe Pinho da; Aguiar, Daniele; Paula, Ana Maria de; Cruz, Jader; Parrella, Cosimo; Piscitelli, Fabiana; Duarte, Igor; Di Marzo, Vincenzo; Perez, Andrea

    2014-09-01

    Resistance exercise (RE) is also known as strength training, and it is performed to increase the strength and mass of muscles, bone strength, and metabolism. RE has been increasingly prescribed for pain relief. However, the endogenous mechanisms underlying this antinociceptive effect are still largely unexplored. Thus, we investigated the involvement of the endocannabinoid system in RE-induced antinociception. Male Wistar rats were submitted to acute RE in a weight-lifting model. The nociceptive threshold was measured by a mechanical nociceptive test (paw pressure) before and after exercise. To investigate the involvement of cannabinoid receptors and endocannabinoids in RE-induced antinociception, cannabinoid receptor inverse agonists, endocannabinoid metabolizing enzyme inhibitors, and an anandamide reuptake inhibitor were injected before RE. After RE, CB1 cannabinoid receptors were quantified in rat brain tissue by Western blot and immunofluorescence. In addition, endocannabinoid plasma levels were measured by isotope dilution-liquid chromatography mass spectrometry. RE-induced antinociception was prevented by preinjection with CB1 and CB2 cannabinoid receptor inverse agonists. By contrast, preadministration of metabolizing enzyme inhibitors and the anandamide reuptake inhibitor prolonged and enhanced this effect. RE also produced an increase in the expression and activation of CB1 cannabinoid receptors in rat brain tissue and in the dorsolateral and ventrolateral periaqueductal regions and an increase in endocannabinoid plasma levels. The present study suggests that a single session of RE activates the endocannabinoid system to induce antinociception.

  6. Acute Resistance Exercise Induces Antinociception by Activation of the Endocannabinoid System in Rats

    PubMed Central

    Galdino, Giovane; Romero, Thiago; da Silva, José Felippe Pinho; Aguiar, Daniele; de Paula, Ana Maria; Cruz, Jader; Parrella, Cosimo; Piscitelli, Fabiana; Duarte, Igor; Di Marzo, Vincenzo; Perez, Andrea

    2014-01-01

    Background Resistance exercise (RE) is also known as strength training, and it is performed to increase the strength and mass of muscles, bone strength and metabolism. RE has been increasingly prescribed for pain relief. However, the endogenous mechanisms underlying this antinociceptive effect are still largely unexplored. Thus, we investigated the involvement of the endocannabinoid system in RE-induced antinociception. Methods Male Wistar rats were submitted to acute RE in a weight-lifting model. The nociceptive threshold was measured by a mechanical nociceptive test (paw pressure) before and after exercise. To investigate the involvement of cannabinoid receptors and endocannabinoids in RE-induced antinociception, cannabinoid receptor inverse agonists, endocannabinoid metabolizing enzyme inhibitors and an anandamide reuptake inhibitor were injected before RE. After RE, CB1 cannabinoid receptors were quantified in rat brain tissue by Western blot and immunofluorescence. In addition, endocannabinoid plasma levels were measured by isotope dilution-liquid chromatography mass spectrometry. Results RE-induced antinociception was prevented by preinjection with CB1 and CB2 cannabinoid receptor inverse agonists. By contrast, preadministration of metabolizing enzyme inhibitors and the anandamide reuptake inhibitor prolonged and enhanced this effect. RE also produced an increase in the expression and activation of CB1 cannabinoid receptors in rat brain tissue and in the dorsolateral and ventrolateral periaqueductal regions and an increase of endocannabinoid plasma levels. Conclusion The present study suggests that a single session of RE activates the endocannabinoid system to induce antinociception. PMID:24977916

  7. The endocannabinoid system and nondrug rewarding behaviours.

    PubMed

    Fattore, Liana; Melis, Miriam; Fadda, Paola; Pistis, Marco; Fratta, Walter

    2010-07-01

    Rewarding behaviours such as sexual activity, eating, nursing, parenting, social interactions, and play activity are conserved strongly in evolution, and they are essential for development and survival. All of these behaviours are enjoyable and represent pleasant experiences with a high reward value. Remarkably, rewarding behaviours activate the same brain circuits that mediate the positive reinforcing effects of drugs of abuse and of other forms of addiction, such as gambling and food addiction. Given the involvement of the endocannabinoid system in a variety of physiological functions of the nervous system, it is not surprising that it takes part in the complex machinery that regulates gratification and perception of pleasure. In this review, we focus first on the role of the endocannabinoid system in the modulation of neural activity and synaptic functions in brain regions that are involved in natural and nonnatural rewards (namely, the ventral tegmental area, striatum, amygdala, and prefrontal cortex). Then, we examine the role of the endocannabinoid system in modulating behaviours that directly or indirectly activate these brain reward pathways. More specifically, current knowledge of the effects of the pharmacological manipulation of the endocannabinoid system on natural (eating, sexual behaviour, parenting, and social play) and pathological (gambling) rewarding behaviours is summarised and discussed. Copyright 2010 Elsevier Inc. All rights reserved.

  8. The brain endocannabinoid system in the regulation of energy balance.

    PubMed

    Richard, Denis; Guesdon, Benjamin; Timofeeva, Elena

    2009-02-01

    The role played by the endocannabinoid system in the regulation of energy balance is currently generating a great amount of interest among several groups of investigators. This interest in large part comes from the urgent need to develop anti-obesity and anti-cachexia drugs around target systems (such as the endocannabinoid system), which appears to be genuinely involved in energy balance regulation. When activated, the endocannabinoid system favors energy deposition through increasing energy intake and reducing energy expenditure. This system is activated in obesity and following food deprivation, which further supports its authentic function in energy balance regulation. The cannabinoid receptor type 1 (CB1), one of the two identified cannabinoid receptors, is expressed in energy-balance brain structures that are also able to readily produce or inactivate N-arachidonoyl ethanolamine (anandamide) and 2-arachidonoylglycerol (2AG), the most abundantly formed and released endocannabinoids. The brain action of endocannabinoid system on energy balance seems crucial and needs to be delineated in the context of the homeostatic and hedonic controls of food intake and energy expenditure. These controls require the coordinated interaction of the hypothalamus, brainstem and limbic system and it appears imperative to unravel those interplays. It is also critical to investigate the metabolic endocannabinoid system while considering the panoply of functions that the endocannabinoid system fulfills in the brain and other tissues. This article aims at reviewing the potential mechanisms whereby the brain endocannabinoid system influences the regulation energy balance.

  9. Distribution of the Endocannabinoid System in the Central Nervous System.

    PubMed

    Hu, Sherry Shu-Jung; Mackie, Ken

    2015-01-01

    The endocannabinoid system consists of endogenous cannabinoids (endocannabinoids), the enzymes that synthesize and degrade endocannabinoids, and the receptors that transduce the effects of endocannabinoids. Much of what we know about the function of endocannabinoids comes from studies that combine localization of endocannabinoid system components with physiological or behavioral approaches. This review will focus on the localization of the best-known components of the endocannabinoid system for which the strongest anatomical evidence exists.

  10. The Endocannabinoid Signaling System in the CNS: A Primer.

    PubMed

    Hillard, Cecilia J

    2015-01-01

    The purpose of this chapter is to provide an introduction to the mechanisms for the regulation of endocannabinoid signaling through CB1 cannabinoid receptors in the central nervous system. The processes involved in the synthesis and degradation of the two most well-studied endocannabinoids, 2-arachidonoylglycerol and N-arachidonylethanolamine are outlined along with information regarding the regulation of the proteins involved. Signaling mechanisms and pharmacology of the CB1 cannabinoid receptor are outlined, as is the paradigm of endocannabinoid/CB1 receptor regulation of neurotransmitter release. The reader is encouraged to appreciate the importance of the endocannabinoid/CB1 receptor signaling system in the regulation of synaptic activity in the brain. © 2015 Elsevier Inc. All rights reserved.

  11. The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages.

    PubMed

    Siniscalco, Dario; Bradstreet, James Jeffrey; Cirillo, Alessandra; Antonucci, Nicola

    2014-04-17

    Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein responsible for macrophage cell activation has demonstrated positive effects in the treatment of autistic children. In this current study, we investigated the in vitro effects of GcMAF treatment on the endocannabinoid system gene expression, as well as cellular activation in blood monocyte-derived macrophages (BMDMs) from autistic patients compared to age-matched healthy developing controls. To achieve these goals, we used biomolecular, biochemical and immunocytochemical methods. GcMAF treatment was able to normalize the observed differences in dysregulated gene expression of the endocannabinoid system of the autism group. GcMAF also down-regulated the over-activation of BMDMs from autistic children. This study presents the first observations of GcMAF effects on the transcriptionomics of the endocannabinoid system and expression of CB2R protein. These data point to a potential nexus between endocannabinoids, vitamin D and its transporter proteins, and the immune dysregulations observed with autism.

  12. The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages

    PubMed Central

    2014-01-01

    Background Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein responsible for macrophage cell activation has demonstrated positive effects in the treatment of autistic children. In this current study, we investigated the in vitro effects of GcMAF treatment on the endocannabinoid system gene expression, as well as cellular activation in blood monocyte-derived macrophages (BMDMs) from autistic patients compared to age-matched healthy developing controls. Methods To achieve these goals, we used biomolecular, biochemical and immunocytochemical methods. Results GcMAF treatment was able to normalize the observed differences in dysregulated gene expression of the endocannabinoid system of the autism group. GcMAF also down-regulated the over-activation of BMDMs from autistic children. Conclusions This study presents the first observations of GcMAF effects on the transcriptionomics of the endocannabinoid system and expression of CB2R protein. These data point to a potential nexus between endocannabinoids, vitamin D and its transporter proteins, and the immune dysregulations observed with autism. PMID:24739187

  13. Endocannabinoid system and mood disorders: priming a target for new therapies.

    PubMed

    Micale, Vincenzo; Di Marzo, Vincenzo; Sulcova, Alexandra; Wotjak, Carsten T; Drago, Filippo

    2013-04-01

    The endocannabinoid system (ECS), comprising two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuana's psychoactive principle ∆(9)-tetrahydrocannabinol [∆(9)-THC]), their endogenous small lipid ligands (namely anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and the proteins for endocannabinoid biosynthesis and degradation, has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during physiopathological conditions. In the brain activation of this system modulates the release of excitatory and inhibitory neurotransmitters and of cytokines from glial cells. As such, the ECS is strongly involved in neuropsychiatric disorders, particularly in affective disturbances such as anxiety and depression. It has been proposed that synthetic molecules that inhibit endocannabinoid degradation can exploit the selectivity of endocannabinoid action, thus activating cannabinoid receptors only in those tissues where there is perturbed endocannabinoid turnover due to the disorder, and avoiding the potential side effects of direct CB1 and CB2 activation. However, the realization that endocannabinoids, and AEA in particular, also act at other molecular targets, and that these mediators can be deactivated by redundant pathways, has recently led to question the efficacy of such approach, thus opening the way to new multi-target therapeutic strategies, and to the use of non-psychotropic cannabinoids, such as cannabidiol (CBD), which act via several parallel mechanisms, including indirect interactions with the ECS. The state of the art of the possible therapeutic use of endocannabinoid deactivation inhibitors and phytocannabinoids in mood disorders is discussed in this review article. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. The endocannabinoid system and multiple sclerosis.

    PubMed

    Baker, David; Pryce, Gareth

    2008-01-01

    Multiple sclerosis (MS) is a neurodegenerative disease that is characterised by repeated inflammatory/demyelinating events within the central nervous system (CNS). In addition to relapsing-remitting neurological insults, leading to loss of function, patients are often left with residual, troublesome symptoms such as spasticity and pain. These greatly diminish "quality of life" and have prompted some patients to self-medicate with and perceive benefit from cannabis. Recent advances in cannabinoid biology are beginning to support these anecdotal observations, notably the demonstration that spasticity is tonically regulated by the endogenous cannabinoid system. Recent clinical trials may indeed suggest that cannabis has some potential to relieve, pain, spasms and spasticity in MS. However, because the CB(1) cannabinoid receptor mediates both the positive and adverse effects of cannabis, therapy will invariably be associated with some unwanted, psychoactive effects. In an experimental model of MS, and in MS tissue, there are local perturbations of the endocannabinoid system in lesional areas. Stimulation of endocannabinoid activity in these areas either through increase of synthesis or inhibition of endocannabinoid degradation offers the positive therapeutic potential of the cannabinoid system whilst limiting adverse events by locally targeting the lesion. In addition, CB(1) and CB(2) cannabinoid receptor stimulation may also have anti-inflammatory and neuroprotective potential as the endocannabinoid system controls the level of neurodegeneration that occurs as a result of the inflammatory insults. Therefore cannabinoids may not only offer symptom control but may also slow the neurodegenerative disease progression that ultimately leads to the accumulation of disability.

  15. Supply and demand for endocannabinoids

    PubMed Central

    Alger, Bradley E.; Kim, Jimok

    2011-01-01

    The endocannabinoid system consists of G-protein coupled cannabinoid receptors that can be activated by cannabis-derived drugs and small lipids called endocannabinoids, plus associated biochemical machinery (precursors, synthetic and degradative enzymes, transporters). The endocannabinoid system in the brain primarily influences neuronal synaptic communication, and affects biological – functions including eating, anxiety, learning and memory, growth and development – via an array of actions throughout the nervous system. While many aspects of synaptic regulation by endocannabinoids are becoming clear, details of the subcellular organization and regulation of the endocannabinoid system are less well understood. This review focuses on recent investigations that illuminate fundamental issues of endocannabinoid storage, release, and functional roles. PMID:21507493

  16. Endocannabinoid regulation in white and brown adipose tissue following thermogenic activation

    PubMed Central

    Krott, Lucia M.; Piscitelli, Fabiana; Heine, Markus; Borrino, Simona; Scheja, Ludger; Silvestri, Cristoforo; Heeren, Joerg; Di Marzo, Vincenzo

    2016-01-01

    The endocannabinoids and their main receptor, cannabinoid type-1 (CB1), suppress intracellular cyclic AMP levels and have emerged as key players in the control of energy metabolism. CB1 agonists and blockers have been reported to influence the thermogenic function of white and brown adipose tissue (WAT and BAT), affecting body weight through the inhibition and stimulation of energy expenditure, respectively. The purpose of the current study was to investigate the regulation of the endocannabinoid system in WAT and BAT following exposure to either cold or specific agonism of β3-adrenoceptors using CL316,243 (CL), conditions known to cause BAT activation and WAT browning. To address this question, we performed quantitative PCR-based mRNA profiling of genes important for endocannabinoid synthesis, degradation, and signaling, and determined endocannabinoid levels by LC-MS in WAT and BAT of control, cold-exposed, and CL-treated wild-type mice as well as primary brown adipocytes. Treatment with CL and exposure to cold caused an upregulation of endocannabinoid levels and biosynthetic enzymes in WAT. Acute β3-adrenoceptor activation increased endocannabinoids and a subset of genes of biosynthesis in BAT and primary brown adipocytes. We suggest that the cold-mediated increase in endocannabinoid tone is part of autocrine negative feed-back mechanisms controlling β3-adrenoceptor-induced BAT activation and WAT browning. PMID:26768656

  17. The endocannabinoid system mediates aerobic exercise-induced antinociception in rats.

    PubMed

    Galdino, Giovane; Romero, Thiago R L; Silva, José Felipe P; Aguiar, Daniele C; de Paula, Ana Maria; Cruz, Jader S; Parrella, Cosimo; Piscitelli, Fabiana; Duarte, Igor D; Di Marzo, Vincenzo; Perez, Andrea C

    2014-02-01

    Exercise-induced antinociception is widely described in the literature, but the mechanisms involved in this phenomenon are poorly understood. Systemic (s.c.) and central (i.t., i.c.v.) pretreatment with CB₁ and CB₂ cannabinoid receptor antagonists (AM251 and AM630) blocked the antinociception induced by an aerobic exercise (AE) protocol in both mechanical and thermal nociceptive tests. Western blot analysis revealed an increase and activation of CB₁ receptors in the rat brain, and immunofluorescence analysis demonstrated an increase of activation and expression of CB₁ receptors in neurons of the periaqueductal gray matter (PAG) after exercise. Additionally, pretreatment (s.c., i.t. and i.c.v.) with endocannabinoid metabolizing enzyme inhibitors (MAFP and JZL184) and an anandamide reuptake inhibitor (VDM11) prolonged and intensified this antinociceptive effect. These results indicate that exercise could activate the endocannabinoid system, producing antinociception. Supporting this hypothesis, liquid-chromatography/mass-spectrometry measurements demonstrated that plasma levels of endocannabinoids (anandamide and 2-arachidonoylglycerol) and of anandamide-related mediators (palmitoylethanolamide and oleoylethanolamide) were increased after AE. Therefore, these results suggest that the endocannabinoid system mediates aerobic exercise-induced antinociception at peripheral and central levels. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. The Endocannabinoid System as an Emerging Target of Pharmacotherapy

    PubMed Central

    PACHER, PÁL; BÁTKAI, SÁNDOR; KUNOS, GEORGE

    2008-01-01

    The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson’s and Huntington’s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB1 receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB1 receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB2 receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The

  19. Updates in Reproduction Coming from the Endocannabinoid System

    PubMed Central

    Bradshaw, Heather B.

    2014-01-01

    The endocannabinoid system (ECS) is an evolutionarily conserved master system deeply involved in the central and local control of reproductive functions in both sexes. The tone of these lipid mediators—deeply modulated by the activity of biosynthetic and hydrolyzing machineries—regulates reproductive functions from gonadotropin discharge and steroid biosynthesis to the formation of high quality gametes and successful pregnancy. This review provides an overview on ECS and reproduction and focuses on the insights in the regulation of endocannabinoid production by steroids, in the regulation of male reproductive activity, and in placentation and parturition. Taken all together, evidences emerge that the activity of the ECS is crucial for procreation and may represent a target for the therapeutic exploitation of infertility. PMID:24550985

  20. Endocannabinoid signaling and synaptic function.

    PubMed

    Castillo, Pablo E; Younts, Thomas J; Chávez, Andrés E; Hashimotodani, Yuki

    2012-10-04

    Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors. As experimental tools advance, the repertoire of known endocannabinoid-mediated effects at the synapse, and their underlying mechanism, continues to expand. Retrograde signaling is the principal mode by which endocannabinoids mediate short- and long-term forms of plasticity at both excitatory and inhibitory synapses. However, growing evidence suggests that endocannabinoids can also signal in a nonretrograde manner. In addition to mediating synaptic plasticity, the endocannabinoid system is itself subject to plastic changes. Multiple points of interaction with other neuromodulatory and signaling systems have now been identified. In this Review, we focus on new advances in synaptic endocannabinoid signaling in the mammalian brain. The emerging picture not only reinforces endocannabinoids as potent regulators of synaptic function but also reveals that endocannabinoid signaling is mechanistically more complex and diverse than originally thought. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. The endocannabinoid system and the brain.

    PubMed

    Mechoulam, Raphael; Parker, Linda A

    2013-01-01

    The psychoactive constituent in cannabis, Δ(9)-tetrahydrocannabinol (THC), was isolated in the mid-1960s, but the cannabinoid receptors, CB1 and CB2, and the major endogenous cannabinoids (anandamide and 2-arachidonoyl glycerol) were identified only 20 to 25 years later. The cannabinoid system affects both central nervous system (CNS) and peripheral processes. In this review, we have tried to summarize research--with an emphasis on recent publications--on the actions of the endocannabinoid system on anxiety, depression, neurogenesis, reward, cognition, learning, and memory. The effects are at times biphasic--lower doses causing effects opposite to those seen at high doses. Recently, numerous endocannabinoid-like compounds have been identified in the brain. Only a few have been investigated for their CNS activity, and future investigations on their action may throw light on a wide spectrum of brain functions.

  2. Endocannabinoid system in neurodegenerative disorders.

    PubMed

    Basavarajappa, Balapal S; Shivakumar, Madhu; Joshi, Vikram; Subbanna, Shivakumar

    2017-09-01

    Most neurodegenerative disorders (NDDs) are characterized by cognitive impairment and other neurological defects. The definite cause of and pathways underlying the progression of these NDDs are not well-defined. Several mechanisms have been proposed to contribute to the development of NDDs. These mechanisms may proceed concurrently or successively, and they differ among cell types at different developmental stages in distinct brain regions. The endocannabinoid system, which involves cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), endogenous cannabinoids and the enzymes that catabolize these compounds, has been shown to contribute to the development of NDDs in several animal models and human studies. In this review, we discuss the functions of the endocannabinoid system in NDDs and converse the therapeutic efficacy of targeting the endocannabinoid system to rescue NDDs. © 2017 International Society for Neurochemistry.

  3. Evolutionary origins of the endocannabinoid system.

    PubMed

    McPartland, John M; Matias, Isabel; Di Marzo, Vincenzo; Glass, Michelle

    2006-03-29

    Endocannabinoid system evolution was estimated by searching for functional orthologs in the genomes of twelve phylogenetically diverse organisms: Homo sapiens, Mus musculus, Takifugu rubripes, Ciona intestinalis, Caenorhabditis elegans, Drosophila melanogaster, Saccharomyces cerevisiae, Arabidopsis thaliana, Plasmodium falciparum, Tetrahymena thermophila, Archaeoglobus fulgidus, and Mycobacterium tuberculosis. Sequences similar to human endocannabinoid exon sequences were derived from filtered BLAST searches, and subjected to phylogenetic testing with ClustalX and tree building programs. Monophyletic clades that agreed with broader phylogenetic evidence (i.e., gene trees displaying topographical congruence with species trees) were considered orthologs. The capacity of orthologs to function as endocannabinoid proteins was predicted with pattern profilers (Pfam, Prosite, TMHMM, and pSORT), and by examining queried sequences for amino acid motifs known to serve critical roles in endocannabinoid protein function (obtained from a database of site-directed mutagenesis studies). This novel transfer of functional information onto gene trees enabled us to better predict the functional origins of the endocannabinoid system. Within this limited number of twelve organisms, the endocannabinoid genes exhibited heterogeneous evolutionary trajectories, with functional orthologs limited to mammals (TRPV1 and GPR55), or vertebrates (CB2 and DAGLbeta), or chordates (MAGL and COX2), or animals (DAGLalpha and CB1-like receptors), or opisthokonta (animals and fungi, NAPE-PLD), or eukaryotes (FAAH). Our methods identified fewer orthologs than did automated annotation systems, such as HomoloGene. Phylogenetic profiles, nonorthologous gene displacement, functional convergence, and coevolution are discussed.

  4. Beyond Cannabis: Plants and the Endocannabinoid System.

    PubMed

    Russo, Ethan B

    2016-07-01

    Plants have been the predominant source of medicines throughout the vast majority of human history, and remain so today outside of industrialized societies. One of the most versatile in terms of its phytochemistry is cannabis, whose investigation has led directly to the discovery of a unique and widespread homeostatic physiological regulator, the endocannabinoid system. While it had been the conventional wisdom until recently that only cannabis harbored active agents affecting the endocannabinoid system, in recent decades the search has widened and identified numerous additional plants whose components stimulate, antagonize, or modulate different aspects of this system. These include common foodstuffs, herbs, spices, and more exotic ingredients: kava, chocolate, black pepper, and many others that are examined in this review. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures.

    PubMed

    Lutz, Beat

    2004-11-01

    Neurons intensively exchange information among each other using both inhibitory and excitatory neurotransmitters. However, if the balance of excitation and inhibition is perturbed, the intensity of excitatory transmission may exceed a certain threshold and epileptic seizures can occur. As the occurrence of epilepsy in the human population is about 1%, the search for therapeutic targets to alleviate seizures is warranted. Extracts of Cannabis sativa have a long history in the treatment of various neurological diseases, including epilepsy. However, cannabinoids have been reported to exert both pro- and anti-convulsive activities. The recent progress in understanding the endogenous cannabinoid system has allowed new insights into these opposing effects of cannabinoids. When excessive neuronal activity occurs, endocannabinoids are generated on demand and activate cannabinoid type 1 (CB1) receptors. Using mice lacking CB1 receptors in principal forebrain neurons in a model of epileptiform seizures, it was shown that CB1 receptors expressed on excitatory glutamatergic neurons mediate the anti-convulsive activity of endocannabinoids. Systemic activation of CB1 receptors by exogenous cannabinoids, however, are anti- or pro-convulsive, depending on the seizure model used. The pro-convulsive activity of exogenous cannabinoids might be explained by the notion that CB1 receptors expressed on inhibitory GABAergic neurons are also activated, leading to a decreased release of GABA, and to a concomitant increase in seizure susceptibility. The concept that the endogenous cannabinoid system is activated on demand suggests that a promising strategy to alleviate seizure frequency is the enhancement of endocannabinoid levels by inhibiting the cellular uptake and the degradation of these endogenous compounds.

  6. The Endocannabinoid System and Plant-Derived Cannabinoids in Diabetes and Diabetic Complications

    PubMed Central

    Horváth, Béla; Mukhopadhyay, Partha; Haskó, György; Pacher, Pál

    2012-01-01

    Oxidative stress and inflammation play critical roles in the development of diabetes and its complications. Recent studies provided compelling evidence that the newly discovered lipid signaling system (ie, the endocannabinoid system) may significantly influence reactive oxygen species production, inflammation, and subsequent tissue injury, in addition to its well-known metabolic effects and functions. The modulation of the activity of this system holds tremendous therapeutic potential in a wide range of diseases, ranging from cancer, pain, neurodegenerative, and cardiovascular diseases to obesity and metabolic syndrome, diabetes, and diabetic complications. This review focuses on the role of the endocannabinoid system in primary diabetes and its effects on various diabetic complications, such as diabetic cardiovascular dysfunction, nephropathy, retinopathy, and neuropathy, particularly highlighting the mechanisms beyond the metabolic consequences of the activation of the endocannabinoid system. The therapeutic potential of targeting the endocannabinoid system and certain plant-derived cannabinoids, such as cannabidiol and Δ9-tetrahydrocannabivarin, which are devoid of psychotropic effects and possess potent anti-inflammatory and/or antioxidant properties, in diabetes and diabetic complications is also discussed. PMID:22155112

  7. Endocannabinoid signaling and synaptic function

    PubMed Central

    Castillo, Pablo E.; Younts, Thomas J.; Chávez, Andrés E.; Hashimotodani, Yuki

    2012-01-01

    Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors. As experimental tools advance, the repertoire of known endocannabinoid-mediated effects at the synapse, and their underlying mechanism, continues to expand. Retrograde signaling is the principal mode by which endocannabinoids mediate short- and long-term forms of plasticity at both excitatory and inhibitory synapses. However, growing evidence suggests that endocannabinoids can also signal in a non-retrograde manner. In addition to mediating synaptic plasticity, the endocannabinoid system is itself subject to plastic changes. Multiple points of interaction with other neuromodulatory and signaling systems have now been identified. Synaptic endocannabinoid signaling is thus mechanistically more complex and diverse than originally thought. In this review, we focus on new advances in endocannabinoid signaling and highlight their role as potent regulators of synaptic function in the mammalian brain. PMID:23040807

  8. Endocannabinoid system: potential novel targets for treatment of schizophrenia.

    PubMed

    Saito, Atsushi; Ballinger, Michael D L; Pletnikov, Mikhail V; Wong, Dean F; Kamiya, Atsushi

    2013-05-01

    Accumulating epidemiological evidences suggest that cannabis use during adolescence is a potential environmental risk for the development of psychosis, including schizophrenia. Consistently, clinical and preclinical studies, using pharmacological approaches and genetically engineered animals to target endocannabinoid signaling, reveal the multiple varieties of endocannabinoid system-mediated human and animal behaviors, including cognition and emotion. Recently, there has been substantial progress in understanding the molecular mechanisms of the endocannabinoid system for synaptic communications in the central nervous system. Furthermore, the impact of endocannabinoid signaling on diverse cellular processes during brain development has emerged. Thus, although schizophrenia has etiological complexities, including genetic heterogeneities and multiple environmental factors, it now becomes crucial to explore molecular pathways of convergence of genetic risk factors and endocannabinoid signaling, which may provide us with clues to find novel targets for therapeutic intervention. In this review, epidemiological, clinical, and pathological evidences on the role of the endocannabinoid system in the pathophysiologies of schizophrenia will be presented. We will also make a brief overview of the recent progress in understanding molecular mechanisms of the endocannabinoid system for brain development and function, with particular focus on cannabinoid receptor type 1 (CB1R)-mediated cascade, the most well-characterized cannabinoid receptor. Lastly, we will discuss the potential of the endocannabinoid system in finding novel therapeutic targets for prevention and treatment of schizophrenia. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. The skeletal endocannabinoid system: clinical and experimental insights.

    PubMed

    Raphael, Bitya; Gabet, Yankel

    2016-05-01

    Recently, there has been a rapidly growing interest in the role of cannabinoids in the regulation of skeletal remodeling and bone mass, addressed in basic, translational and clinical research. Since the first publications in 2005, there are more than 1000 publications addressing the skeletal endocannabinoid system. This review focuses on the roles of the endocannabinoid system in skeletal biology via the cannabinoid receptors CB1, CB2 and others. Endocannabinoids play important roles in bone formation, bone resorption and skeletal growth, and are sometimes age, gender, species and strain dependent. Controversies in the literature and potential therapeutic approaches targeting the endocannabinoid system in skeletal disorders are also discussed.

  10. Alteration of the endocannabinoid system in mouse brain during prion disease.

    PubMed

    Petrosino, S; Ménard, B; Zsürger, N; Di Marzo, V; Chabry, J

    2011-03-17

    Prion diseases are neurodegenerative disorders characterized by deposition of the pathological prion protein (PrPsc) within the brain of affected humans and animals. Microglial cell activation is a common feature of prion diseases; alterations of various neurotransmitter systems and neurotransmission have been also reported. Owing to its ability to modulate both neuroimmune responses and neurotransmission, it was of interest to study the brain endocannabinoid system in a prion-infected mouse model. The production of the endocannabinoid, 2-arachidonoyglycerol (2-AG), was enhanced 10 weeks post-infection, without alteration of the other endocannabinoid, anandamide. The CB2 receptor expression was up-regulated in brains of prion-infected mice as early as 10 weeks and up to 32 weeks post-infection whereas the mRNAs of other cannabinoid receptors (CBRs) remain unchanged. The observed alterations of the endocannabinoid system were specific for prion infection since no significant changes were observed in the brain of prion-resistant mice, that is, mice devoid of the Prnp gene. Our study highlights important alterations of the endocannabinoid system during early stages of the disease long before the clinical signs of the disease. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  11. The Endocannabinoid System Modulating Levels of Consciousness, Emotions and Likely Dream Contents.

    PubMed

    Murillo-Rodriguez, Eric; Pastrana-Trejo, Jose Carlos; Salas-Crisóstomo, Mireille; de-la-Cruz, Miriel

    2017-01-01

    indicate that the sleep-wake cycle is under the influence of endocannabinoids since the blocking of the CB1 cannabinoid receptor or the pharmacological inhibition of FAAH activity promotes wakefulness, whereas the obstruction of AMT function enhances sleep. However, no solid evidence is available regarding the role of the endocannabinoid system in an unquestionable emotional component of the sleep: Dream activity. Since dreaming is a mental activity that occurs during sleep (characterized by emotions, sensory perceptions, and bizarre components) and the endocannabinoid system modulates neurobiological processes involving consciousness, such as learning and memory, attention, pain perception, emotions and sleep, it is acceptable to hypothesize that the endocannabinoid system might be modulating dream activity. In this regard, an accumulative body of evidence in human and animal models has been reported regarding the role of the endocannabinoid system in the control of emotional states and dreams. Moreover, preliminary studies in humans have indicated that treatment with cannabinoids may decrease post-traumatic stress disorder symptoms, including nightmares. Thus, based on a review of the literature available in PubMed, this article hypothesizes a conceptual framework within which the endocannabinoid system might influence the generation of dream experiences. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. Metabolism of endocannabinoids.

    PubMed

    Biernacki, Michał; Skrzydlewska, Elżbieta

    2016-08-11

    Endocannabinoids belong to a group of ester, ether and amide derivatives of fatty acids, which are endogenous ligands of receptors CB1, CB2, TRPV1 and GPR55 that are included in the endocannabinoid system of the animal organism. The best known endocannabinoids are: N-arachidonylethanolamide called anandamide (AEA) and 2-arachidonoylglycerol (2-AG). They occur in all organisms, and their highest level is observed in the brain. In this review the mechanisms of synthesis and degradation of both AEA and 2-AG are shown. Endocannabinoids are synthesized from phospholipids (mainly phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol) located in the cell membrane. As a result of arachidonic acid transfer from phosphatidylcholine to phosphatidylethanolamine, N-arachidonoyl phosphatidylethanolamine is formed, which is hydrolyzed to AEA by phospholipase D, C and A2. However, 2-AG is formed during the hydrolysis of phosphatidylinositol catalyzed mainly by DAGL. The primary role of endocannabinoids is the activation of cannabinoid receptors. Both AEA and 2-AG are primarily agonists of the CB1 receptor and to a lower degree CB2 and TRPV1r eceptors, but 2-AG has stronger affinity for these receptors. Through activation of receptors, endocannabinoids affect cellular metabolism and participate in the metabolic processes by receptor-independent pathways. Endocannabinoids which are not bound to the receptors are degraded. The main enzymes responsible for the hydrolysis of AEA and 2-AG are FAAH and MAGL, respectively. Apart from hydrolytic degradation, endocannabinoids may also be oxidized by cyclooxygenase-2, lipoxygenases, and cytochrome P450. It has been shown that the metabolites of both endocannabinoids also have biological significance.

  13. Endocannabinoid system and drug addiction: new insights from mutant mice approaches.

    PubMed

    Maldonado, Rafael; Robledo, Patricia; Berrendero, Fernando

    2013-08-01

    The involvement of the endocannabinoid system in drug addiction was initially studied by the use of compounds with different affinities for each cannabinoid receptor or for the proteins involved in endocannabinoids inactivation. The generation of genetically modified mice with selective mutations in these endocannabinoid system components has now provided important advances in establishing their specific contribution to drug addiction. These genetic tools have identified the particular interest of CB1 cannabinoid receptor and endogenous anandamide as potential targets for drug addiction treatment. Novel genetic tools will allow determining if the modulation of CB2 cannabinoid receptor activity and 2-arachidonoylglycerol tone can also have an important therapeutic relevance for drug addiction. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Mustard vesicants alter expression of the endocannabinoid system in mouse skin

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wohlman, Irene M.; Composto, Gabriella M.

    Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation. Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARα and FAAH were all constitutively expressed in mouse epidermis andmore » dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARα, a response that persisted throughout the wound healing process. Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical countermeasures against vesicants. - Highlights: • Sulfur mustard and nitrogen mustard are potent skin vesicants. • The endocannabinoid system regulates keratinocyte growth and differentiation. • Vesicants are potent inducers of the endocannabinoid system in mouse skin. • Endocannabinoid proteins upregulated are FAAH, CB1, CB2 and PPARα. • FAAH inhibitors suppress vesicant-induced inflammation in mouse skin.« less

  15. mGluR1/5 activation in the lateral hypothalamus increases food intake via the endocannabinoid system.

    PubMed

    Sánchez-Fuentes, Asai; Marichal-Cancino, Bruno A; Méndez-Díaz, Mónica; Becerril-Meléndez, Alline L; Ruiz-Contreras, Alejandra E; Prospéro-Garcia, Oscar

    2016-09-19

    Mounting evidence has shown that glutamatergic and endocannabinoid systems in the hypothalamus regulate mammalian food intake. Stimulation of hypothalamic mGluR1/5 and CB1 receptors induces hyperphagia suggesting a possible interaction between these systems to control food intake. In addition, synthesis of endocannabinoids has been reported after mGluR1/5 stimulation in the brain. The aim of this study was to examine the potential cannabinergic activity in the food intake induction by lateral hypothalamic stimulation of mGluR1/5. Wistar albino male rats received bilateral infusions in the lateral hypothalamus (LH) of: (i) vehicle; (ii) (RS)-2-Chloro-5-hidroxyphenylglycine (CHPG; mGluR1/5 agonist); (iii) 2-AG (CB1 endogenous agonist); (iv) AM251 (CB1 antagonist); (v) tetrahydrolipstatin (THL, 1.2μg; diacyl-glycerol lipase inhibitor); and (vi) combinations of CHPG + with the other aforementioned drugs. Food intake was evaluated the first two hours after drug administration. CHPG significantly increased food intake; whereas CHPG in combination with a dose of 2-AG (with no effects on food intake) greatly increased food ingestion compared to CHPG alone. The increase induced by CHPG in food intake was prevented with AM251 or THL. These results suggest that activation of mGluR1/5 in the lateral hypothalamus induces an orexigenic effect via activation of the endocannabinoid system. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. Interactions between the endocannabinoid and nicotinic cholinergic systems: preclinical evidence and therapeutic perspectives.

    PubMed

    Scherma, Maria; Muntoni, Anna Lisa; Melis, Miriam; Fattore, Liana; Fadda, Paola; Fratta, Walter; Pistis, Marco

    2016-05-01

    Several lines of evidence suggest that endocannabinoid and nicotinic cholinergic systems are implicated in the regulation of different physiological processes, including reward, and in the neuropathological mechanisms of psychiatric diseases, such as addiction. A crosstalk between these two systems is substantiated by the overlapping distribution of cannabinoid and nicotinic acetylcholine receptors in many brain structures. We will review recent preclinical data showing how the endocannabinoid and nicotinic cholinergic systems interact bidirectionally at the level of the brain reward pathways, and how this interaction plays a key role in modulating nicotine and cannabinoid intake and dependence. Many behavioral and neurochemical effects of nicotine that are related to its addictive potential are reduced by pharmacological blockade or genetic deletion of type-1 cannabinoid receptors, inhibition of endocannabinoid uptake or metabolic degradation, and activation of peroxisome proliferator-activated-receptor-α. On the other hand, cholinergic antagonists at α7 nicotinic acetylcholine receptors as well as endogenous negative allosteric modulators of these receptors are effective in blocking dependence-related effects of cannabinoids. Pharmacological manipulation of the endocannabinoid system and endocannabinoid-like neuromodulators shows promise in the treatment of nicotine dependence and in relapse prevention. Likewise, drugs acting at nicotinic acetylcholine receptors might prove useful in the therapy of cannabinoid dependence. Research by Steven R. Goldberg has significantly contributed to the progress in this research field.

  17. [The role of endocannabinoid system in physiological and pathological processes in the eye].

    PubMed

    Nadolska, Krystyna; Goś, Roman

    2008-01-01

    Plant of Cannabis sativa/ marihuana except for its psychotropic effects possesses a range of pharmacological properties, that has been utilized for medical purposes over a period of millenia. Investigations concerning biochemical mechanism of action of the main and most active pharmacological compound of Cannabis sativa, cannabinoid 9-THC, contributed to the discovery of cannabinoid receptors both in the central nervous system (CNS) and peripheral tissues, that mediated actions of this substance. The discovery made possible identification of a new, endogenous signaling system reffered to as the endocannabinoid system. Besides cannabinoid receptors CB1 and CB2, the system includes it's endogenic ligands (endocannabinoids) and compounds that participate in their biosynthesis and inactivation. Structure and functioning of the endocannabinoid system is conservative in all vertebrates. It's activation with plant, synthetic and endogenous cannabinoids has an influence on multiple physiological and pathological processes within the eye.

  18. Immunomodulatory lipids in plants: plant fatty acid amides and the human endocannabinoid system.

    PubMed

    Gertsch, Jürg

    2008-05-01

    Since the discovery that endogenous lipid mediators show similar cannabimimetic effects as phytocannabinoids from CANNABIS SATIVA, our knowledge about the endocannabinoid system has rapidly expanded. Today, endocannabinoid action is known to be involved in various diseases, including inflammation and pain. As a consequence, the G-protein coupled cannabinoid receptors, endocannabinoid transport, as well as endocannabinoid metabolizing enzymes represent targets to block or enhance cannabinoid receptor-mediated signalling for therapeutic intervention. Based on the finding that certain endocannabinoid-like fatty acid N-alkylamides from purple coneflower ( ECHINACEA spp.) potently activate CB2 cannabinoid receptors we have focused our interest on plant fatty acid amides (FAAs) and their overall cannabinomodulatory effects. Certain FAAs are also able to partially inhibit the action of fatty acid amide hydrolase (FAAH), which controls the breakdown of endocannabinoids. Intriguingly, plants lack CB receptors and do not synthesize endocannabinoids, but express FAAH homologues capable of metabolizing plant endogenous N-acylethanolamines (NAEs). While the site of action of these NAEs in plants is unknown, endogenous NAEs and arachidonic acid glycerols in animals interact with distinct physiological lipid receptors, including cannabinoid receptors. There is increasing evidence that also plant FAAs other than NAEs can pharmacologically modulate the action of these endogenous lipid signals. The interference of plant FAAs with the animal endocannabinoid system could thus be a fortunate evolutionary cross point with yet unexplored therapeutic potential.

  19. The emerging role of the endocannabinoid system in cardiovascular disease

    PubMed Central

    2009-01-01

    Endocannabinoids are endogenous bioactive lipid mediators present both in the brain and various peripheral tissues, which exert their biological effects via interaction with specific G-protein-coupled cannabinoid receptors, the CB1 and CB2. Pathological overactivation of the endocannabinoid system (ECS) in various forms of shock and heart failure may contribute to the underlying pathology and cardiodepressive state by the activation of the cardiovascular CB1 receptors. Furthermore, tonic activation of CB1 receptors by endocannabinoids has also been implicated in the development of various cardiovascular risk factors in obesity/metabolic syndrome and diabetes, such as plasma lipid alterations, abdominal obesity, hepatic steatosis, inflammation, and insulin and leptin resistance. In contrast, activation of CB2 receptors in immune cells exerts various immunomodulatory effects, and the CB2 receptors in endothelial and inflammatory cells appear to limit the endothelial inflammatory response, chemotaxis, and inflammatory cell adhesion and activation in atherosclerosis and reperfusion injury. Here, we will overview the cardiovascular actions of endocannabinoids and the growing body of evidence implicating the dysregulation of the ECS in a variety of cardiovascular diseases. We will also discuss the therapeutic potential of the modulation of the ECS by selective agonists/antagonists in various cardiovascular disorders associated with inflammation and tissue injury, ranging from myocardial infarction and heart failure to atherosclerosis and cardiometabolic disorders. PMID:19357846

  20. Expression and Function of the Endocannabinoid System in the Retina and the Visual Brain.

    PubMed

    Bouchard, Jean-François; Casanova, Christian; Cécyre, Bruno; Redmond, William John

    2016-01-01

    Endocannabinoids are important retrograde modulators of synaptic transmission throughout the nervous system. Cannabinoid receptors are seven transmembrane G-protein coupled receptors favoring Gi/o protein. They are known to play an important role in various processes, including metabolic regulation, craving, pain, anxiety, and immune function. In the last decade, there has been a growing interest for endocannabinoids in the retina and their role in visual processing. The purpose of this review is to characterize the expression and physiological functions of the endocannabinoid system in the visual system, from the retina to the primary visual cortex, with a main interest regarding the retina, which is the best-described area in this system so far. It will show that the endocannabinoid system is widely present in the retina, mostly in the through pathway where it can modulate neurotransmitter release and ion channel activity, although some evidence also indicates possible mechanisms via amacrine, horizontal, and Müller cells. The presence of multiple endocannabinoid ligands, synthesizing and catabolizing enzymes, and receptors highlights various pharmacological targets for novel therapeutic application to retinal diseases.

  1. Endocannabinoid Signaling and the Hypothalamic-Pituitary-Adrenal Axis.

    PubMed

    Hillard, Cecilia J; Beatka, Margaret; Sarvaideo, Jenna

    2016-12-06

    The elucidation of Δ9-tetrahydrocannabinol as the active principal of Cannabis sativa in 1963 initiated a fruitful half-century of scientific discovery, culminating in the identification of the endocannabinoid signaling system, a previously unknown neuromodulatory system. A primary function of the endocannabinoid signaling system is to maintain or recover homeostasis following psychological and physiological threats. We provide a brief introduction to the endocannabinoid signaling system and its role in synaptic plasticity. The majority of the article is devoted to a summary of current knowledge regarding the role of endocannabinoid signaling as both a regulator of endocrine responses to stress and as an effector of glucocorticoid and corticotrophin-releasing hormone signaling in the brain. We summarize data demonstrating that cannabinoid receptor 1 (CB1R) signaling can both inhibit and potentiate the activation of the hypothalamic-pituitary-adrenal axis by stress. We present a hypothesis that the inhibitory arm has high endocannabinoid tone and also serves to enhance recovery to baseline following stress, while the potentiating arm is not tonically active but can be activated by exogenous agonists. We discuss recent findings that corticotropin-releasing hormone in the amygdala enables hypothalamic-pituitary-adrenal axis activation via an increase in the catabolism of the endocannabinoid N-arachidonylethanolamine. We review data supporting the hypotheses that CB1R activation is required for many glucocorticoid effects, particularly feedback inhibition of hypothalamic-pituitary-adrenal axis activation, and that glucocorticoids mobilize the endocannabinoid 2-arachidonoylglycerol. These features of endocannabinoid signaling make it a tantalizing therapeutic target for treatment of stress-related disorders but to date, this promise is largely unrealized. © 2017 American Physiological Society. Compr Physiol 7:1-15, 2017. Copyright © 2017 John Wiley & Sons, Inc.

  2. Endocannabinoids in Liver Disease

    PubMed Central

    Tam, Joseph; Liu, Jie; Mukhopadhyay, Bani; Cinar, Resat; Godlewski, Grzegorz; Kunos, George

    2010-01-01

    Endocannabinoids are lipid mediators of the same cannabinoid (CB) receptors that mediate the effects of marijuana. The endocannabinoid system (ECS) consists of CB receptors, endocannabinoids, and the enzymes involved in their biosynthesis and degradation, and is present both in brain and peripheral tissues, including the liver. The hepatic ECS is activated in various liver diseases, which contributes to the underlying pathologies. In cirrhosis of various etiologies, activation of vascular and cardiac CB1 receptors by macrophage- and platelet-derived endocannabinoids contribute to the vasodilated state and cardiomyopathy, which can be reversed by CB1 blockade. In mouse models of liver fibrosis, activation of CB1 receptors on hepatic stellate cells is fibrogenic, and CB1 blockade slows the progression of fibrosis. Fatty liver induced by high-fat diets or chronic alcohol feeding depend on activation of peripheral, including hepatic CB1 receptors, which also contribute to insulin resistance and dyslipidemias. Although the documented therapeutic potential of CB1 blockade is limited by neuropsychiatric side effects, these may be mitigated by using novel, peripherally restricted CB1 antagonists. PMID:21254182

  3. Endocannabinoids and the Immune System in Health and Disease.

    PubMed

    Cabral, Guy A; Ferreira, Gabriela A; Jamerson, Melissa J

    2015-01-01

    Endocannabinoids are bioactive lipids that have the potential to signal through cannabinoid receptors to modulate the functional activities of a variety of immune cells. Their activation of these seven-transmembranal, G protein-coupled receptors sets in motion a series of signal transductional events that converge at the transcriptional level to regulate cell migration and the production of cytokines and chemokines. There is a large body of data that supports a functional relevance for 2-arachidonoylglycerol (2-AG) as acting through the cannabinoid receptor type 2 (CB2R) to inhibit migratory activities for a diverse array of immune cell types. However, unequivocal data that supports a functional linkage of anandamide (AEA) to a cannabinoid receptor in immune modulation remains to be obtained. Endocannabinoids, as typical bioactive lipids, have a short half-life and appear to act in an autocrine and paracrine fashion. Their immediate effective action on immune function may be at localized sites in the periphery and within the central nervous system. It is speculated that endocannabinoids play an important role in maintaining the overall "fine-tuning" of the immune homeostatic balance within the host.

  4. The Endocannabinoid System and Spermatogenesis

    PubMed Central

    Grimaldi, Paola; Di Giacomo, Daniele; Geremia, Raffaele

    2013-01-01

    Spermatogenesis is a complex process in which male germ cells undergo a mitotic phase followed by meiosis and by a morphogenetic process to form mature spermatozoa. Spermatogenesis is under the control of gonadotropins, steroid hormones and it is modulated by a complex network of autocrine and paracrine factors. These modulators ensure the correct progression of germ cell differentiation to form mature spermatozoa. Recently, it has been pointed out the relevance of endocannabinoids as critical modulators of male reproduction. Endocannabinoids are natural lipids able to bind to cannabinoid receptors and whose levels are regulated by specific biosynthetic and degradative enzymes. Together with their receptors and metabolic enzymes, they form the “endocannabinoid system” (ECS). In male reproductive tracts, they affect Sertoli cell activities, Leydig cell proliferation, germ cell differentiation, sperm motility, capacitation, and acrosome reaction. The ECS interferes with the pituitary-gonadal axis, and an intricate crosstalk between ECS and steroid hormones has been highlighted. This mini-review will focus on the involvement of the ECS in the control of spermatogenesis and on the interaction between ECS and steroid hormones. PMID:24379805

  5. Review article: the endocannabinoid system in liver disease, a potential therapeutic target.

    PubMed

    Basu, P P; Aloysius, M M; Shah, N J; Brown, R S

    2014-04-01

    Endocannabinoids are a family of potent lipid-soluble molecules, acting on the cannabinoid (CB) receptors that mediate the effects of marijuana. The CB receptors, endocannabinoids and the enzymes involved in their synthesis and degradation are located in the brain and peripheral tissues, including the liver. To review the current understanding of the role of the endocannabinoid system in liver disease-associated pathophysiological conditions, and drugs targeting the endocannabinoid system as therapy for liver disease. Original articles and reviews were used to summarise the relevant pre-clinical and clinical research findings relating to this topic. The endocannabinoid system as a whole plays an important role in liver diseases (i.e. non-alcoholic liver disease, alcoholic liver disease, hepatic encephalopathy and autoimmune hepatitis) and related pathophysiological conditions (i.e. altered hepatic haemodynamics, cirrhotic cardiomyopathy, metabolic syndrome and ischaemia/reperfusion disease). Pharmacological targeting of the endocannabinoid system has had success as treatment for patients with liver disease, but adverse events led to withdrawal of marketing approval. However, there is optimism over novel therapeutics targeting the endocannabinoid system currently in the pre-clinical stage of development. The endocannabinoid system plays an important role in the pathophysiology of liver disease and its associated conditions. While some drugs targeting the endocannabinoid system have deleterious neurological adverse events, there is promise for a newer generation of therapies that do not cross the blood-brain barrier. © 2014 John Wiley & Sons Ltd.

  6. The endocannabinoid system and emotional processing: a pharmacological fMRI study with ∆9-tetrahydrocannabinol.

    PubMed

    Bossong, Matthijs G; van Hell, Hendrika H; Jager, Gerry; Kahn, René S; Ramsey, Nick F; Jansma, J Martijn

    2013-12-01

    Various psychiatric disorders such as major depression are associated with abnormalities in emotional processing. Evidence indicating involvement of the endocannabinoid system in emotional processing, and thus potentially in related abnormalities, is increasing. In the present study, we examined the role of the endocannabinoid system in processing of stimuli with a positive and negative emotional content in healthy volunteers. A pharmacological functional magnetic resonance imaging (fMRI) study was conducted with a placebo-controlled, cross-over design, investigating effects of the endocannabinoid agonist ∆9-tetrahydrocannabinol (THC) on brain function related to emotional processing in 11 healthy subjects. Performance and brain activity during matching of stimuli with a negative ('fearful faces') or a positive content ('happy faces') were assessed after placebo and THC administration. After THC administration, performance accuracy was decreased for stimuli with a negative but not for stimuli with a positive emotional content. Our task activated a network of brain regions including amygdala, orbital frontal gyrus, hippocampus, parietal gyrus, prefrontal cortex, and regions in the occipital cortex. THC interacted with emotional content, as activity in this network was reduced for negative content, while activity for positive content was increased. These results indicate that THC administration reduces the negative bias in emotional processing. This adds human evidence to support the hypothesis that the endocannabinoid system is involved in modulation of emotional processing. Our findings also suggest a possible role for the endocannabinoid system in abnormal emotional processing, and may thus be relevant for psychiatric disorders such as major depression. Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.

  7. Targeting the endocannabinoid system to treat anxiety-related disorders.

    PubMed

    Korem, Nachshon; Zer-Aviv, Tomer Mizrachi; Ganon-Elazar, Eti; Abush, Hila; Akirav, Irit

    2016-05-01

    The endocannabinoid system plays an important role in the control of emotions, and its dysregulation has been implicated in several psychiatric disorders. The most common self-reported reason for using cannabis is rooted in its ability to reduce feelings of stress, tension, and anxiety. Nevertheless, there are only few studies in controlled clinical settings that confirm that administration of cannabinoids can benefit patients with a post-traumatic stress disorder (PTSD). There are considerable encouraging preclinical data to suggest that endocannabinoid-targeted therapeutics for anxiety disorders should continue. In this review, we will describe data supporting a role for the endocannabinoid system in preventing and treating anxiety-like behavior in animal models and PTSD patients. Cannabinoids have shown beneficial outcomes in rat and mouse models of anxiety and PTSD, but they also may have untoward effects that discourage their chronic usage, including anxiogenic effects. Hence, clinical and preclinical research on the endocannabinoid system should further study the effects of cannabinoids on anxiety and help determine whether the benefits of using exogenous cannabinoids outweigh the risks. In general, this review suggests that targeting the endocannabinoid system represents an attractive and novel approach to the treatment of anxiety-related disorders and, in particular, PTSD.

  8. The endocannabinoid system and associative learning and memory in zebrafish.

    PubMed

    Ruhl, Tim; Moesbauer, Kirstin; Oellers, Nadine; von der Emde, Gerhard

    2015-09-01

    In zebrafish the medial pallium of the dorsal telencephalon represents an amygdala homolog structure, which is crucially involved in emotional associative learning and memory. Similar to the mammalian amygdala, the medial pallium contains a high density of endocannabinoid receptor CB1. To elucidate the role of the zebrafish endocannabinoid system in associative learning, we tested the influence of acute and chronic administration of receptor agonists (THC, WIN55,212-2) and antagonists (Rimonabant, AM-281) on two different learning paradigms. In an appetitively motivated two-alternative choice paradigm, animals learned to associate a certain color with a food reward. In a second set-up, a fish shuttle-box, animals associated the onset of a light stimulus with the occurrence of a subsequent electric shock (avoidance conditioning). Once fish successfully had learned to solve these behavioral tasks, acute receptor activation or inactivation had no effect on memory retrieval, suggesting that established associative memories were stable and not alterable by the endocannabinoid system. In both learning tasks, chronic treatment with receptor antagonists improved acquisition learning, and additionally facilitated reversal learning during color discrimination. In contrast, chronic CB1 activation prevented aversively motivated acquisition learning, while different effects were found on appetitively motivated acquisition learning. While THC significantly improved behavioral performance, WIN55,212-2 significantly impaired color association. Our findings suggest that the zebrafish endocannabinoid system can modulate associative learning and memory. Stimulation of the CB1 receptor might play a more specific role in acquisition and storage of aversive learning and memory, while CB1 blocking induces general enhancement of cognitive functions. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Role of the endocannabinoid system in the neuroendocrine responses to inflammation.

    PubMed

    De Laurentiis, Andrea; Araujo, Hugo A; Rettori, Valeria

    2014-01-01

    A few years ago the endocannabinoid system has been recognized as a major neuromodulatory system whose main functions are to exert and maintain the body homeostasis. Several different endocannabinoids are synthesized in a broad class of cell types, including those in the brain and the immune system; they bind to cannabinoid G-protein-coupled receptors, having profound effects on a variety of behavioral, neuroendocrine and autonomic functions. The coordinated neural, immune, behavioral and endocrine responses to inflammation are orchestrated to provide an important defense against infections and help homeostasis restoration in the body. These responses are executed and controlled mainly by the hypothalamic-pituitary adrenal axis. Also, the hypothalamic-neurohypophyseal system is essential for survival and plays a role recovering the homeostasis under a variety of stress conditions, including inflammation and infection. Since the endocannabinoid system components are present at sites involved in the hypothalamic-pituitary axis regulation, several studies were performed in order to investigate the endocannabinoid-mediated neurotransmitters and hormones secretion under physiological and pathological conditions. In the present review we focused on the endocannabinoids actions on the neuroendocrine response to inflammation and infection. We provide a detailed overview of the current understanding of the role of the endocannabinoid system in the recovering of homeostasis as well as potential pharmacological therapies based on the manipulation of endocannabinoid system components that could provide novel treatments for a wide range of disorders.

  10. The endocannabinoid system in normal and pathological brain ageing

    PubMed Central

    Bilkei-Gorzo, Andras

    2012-01-01

    The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, pro-ageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brain-derived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing. PMID:23108550

  11. The endocannabinoid system in normal and pathological brain ageing.

    PubMed

    Bilkei-Gorzo, Andras

    2012-12-05

    The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, pro-ageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brain-derived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing.

  12. Alterations in the endocannabinoid system in the rat valproic acid model of autism.

    PubMed

    Kerr, D M; Downey, L; Conboy, M; Finn, D P; Roche, M

    2013-07-15

    The endocannabinoid system plays a crucial role in regulating emotionality and social behaviour, however it is unknown whether this system plays a role in symptoms associated with autism spectrum disorders. The current study evaluated if alterations in the endocannabinoid system accompany behavioural changes in the valproic acid (VPA) rat model of autism. Adolescent rats prenatally exposed to VPA exhibited impaired social investigatory behaviour, hypoalgesia and reduced lococmotor activity on exposure to a novel aversive arena. Levels of the endocananbinoids, anandamide (AEA) and 2-arachidonylglycerol (2-AG) in the hippocampus, frontal cortex or cerebellum were not altered in VPA- versus saline-exposed animals. However, the expression of mRNA for diacylglycerol lipase α, the enzyme primarily responsible for the synthesis of 2-AG, was reduced in the cerebellum of VPA-exposed rats. Furthermore, while the expression of mRNA for the 2-AG-catabolising enzyme monoacylglycerol lipase was reduced, the activity of this enzyme was increased, in the hippocampus of VPA-exposed animals. CB1 or CB2 receptor expression was not altered in any of the regions examined, however VPA-exposed rats exhibited reduced PPARα and GPR55 expression in the frontal cortex and PPARγ and GPR55 expression in the hippocampus, additional receptor targets of the endocannabinoids. Furthermore, tissue levels of the fatty acid amide hydrolase substrates, AEA, oleoylethanolamide and palmitoylethanolamide, were higher in the hippocampus of VPA-exposed rats immediately following social exposure. These data indicate that prenatal VPA exposure is associated with alterations in the brain's endocannabinoid system and support the hypothesis that endocannabinoid dysfunction may underlie behavioural abnormalities observed in autism spectrum disorders. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. Antihyperalgesic Activities of Endocannabinoids in a Mouse Model of Antiretroviral-Induced Neuropathic Pain.

    PubMed

    Munawar, Neha; Oriowo, Mabayoje A; Masocha, Willias

    2017-01-01

    Background: Nucleoside reverse transcriptase inhibitors (NRTIs) are the cornerstone of the antiretroviral therapy for human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS). However, their use is sometimes limited by the development of a painful sensory neuropathy, which does not respond well to drugs. Smoked cannabis has been reported in clinical trials to have efficacy in relieving painful HIV-associated sensory neuropathy. Objectives: The aim of this study was to evaluate whether the expression of endocannabinoid system molecules is altered during NRTI-induced painful neuropathy, and also whether endocannabinoids can attenuate NRTI-induced painful neuropathy. Methods: BALB/c mice were treated with 25 mg/kg of 2',3'-dideoxycytidine (ddC, zalcitabine), a NRTI, to induce thermal hyperalgesia. The expression of endocannabinoid system molecules was evaluated by real time polymerase chain reaction in the brain, spinal cord and paw skin at 6 days post ddC administration, a time point when mice had developed thermal hyperalgesia. The effects of the endocannabinoids, N -arachidonoyl ethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG), the cannabinoid type 1 (CB1) receptor antagonist AM 251, CB2 receptor antagonist AM 630, and G protein-coupled receptor 55 (GPR55) antagonists ML193 and CID 16020046 on ddC-induced thermal hyperalgesia were evaluated using the hot plate test. Results: ddC treatment resulted in thermal hyperalgesia and increased transcripts of the synthesizing enzyme Plcβ1 and decreased Daglβ in the paw skins, but not Napepld , and Daglα compared to vehicle treatment. Transcripts of the inactivating enzymes Faah and Mgll were downregulated in the brain and/or paw skin but not in the spinal cord of ddC-treated mice. Both AEA and 2-AG had antihyperalgesic effects in mice with ddC-induced thermal hyperalgesia, but had no effect in ddC-naïve mice. The antihyperalgesic activity of AEA was antagonized by AM251 and AM630, whereas the

  14. Endocannabinoid system: Role in depression, reward and pain control (Review).

    PubMed

    Huang, Wen-Juan; Chen, Wei-Wei; Zhang, Xia

    2016-10-01

    Depression and pain co-exist in almost 80% of patients and are associated with impaired health-related quality of life, often contributing to high mortality. However, the majority of patients who suffer from the comorbid depression and pain are not responsive to pharmacological treatments that address either pain or depression, making this comorbidity disorder a heavy burden on patients and society. In ancient times, this depression-pain comorbidity was treated using extracts of the Cannabis sativa plant, known now as marijuana and the mode of action of Δ9‑tetrahydrocannabinol, the active cannabinoid ingredient of marijuana, has only recently become known, with the identification of cannabinoid receptor type 1 (CB1) and CB2. Subsequent investigations led to the identification of endocannabinoids, anandamide and 2-arachidonoylglycerol, which exert cannabinomimetic effects through the CB1 and CB2 receptors, which are located on presynaptic membranes in the central nervous system and in peripheral tissues, respectively. These endocannabinoids are produced from membrane lipids and are lipohilic molecules that are synthesized on demand and are eliminated rapidly after their usage by hydrolyzing enzymes. Clinical studies revealed altered endocannabinoid signaling in patients with chronic pain. Considerable evidence suggested the involvement of the endocannabinoid system in eliciting potent effects on neurotransmission, neuroendocrine, and inflammatory processes, which are known to be deranged in depression and chronic pain. Several synthetic cannabinomimetic drugs are being developed to treat pain and depression. However, the precise mode of action of endocannabinoids on different targets in the body and whether their effects on pain and depression follow the same or different pathways, remains to be determined.

  15. The endocannabinoid system as a target for the treatment of cannabis dependence.

    PubMed

    Clapper, Jason R; Mangieri, Regina A; Piomelli, Daniele

    2009-01-01

    The endocannabinoid system modulates neurotransmission at inhibitory and excitatory synapses in brain regions relevant to the regulation of pain, emotion, motivation, and cognition. This signaling system is engaged by the active component of cannabis, Delta9-tetrahydrocannabinol (Delta9-THC), which exerts its pharmacological effects by activation of G protein-coupled type-1 (CB1) and type-2 (CB2) cannabinoid receptors. During frequent cannabis use a series of poorly understood neuroplastic changes occur, which lead to the development of dependence. Abstinence in cannabinoid-dependent individuals elicits withdrawal symptoms that promote relapse into drug use, suggesting that pharmacological strategies aimed at alleviating cannabis withdrawal might prevent relapse and reduce dependence. Cannabinoid replacement therapy and CB1 receptor antagonism are two potential treatments for cannabis dependence that are currently under investigation. However, abuse liability and adverse side-effects may limit the scope of each of these approaches. A potential alternative stems from the recognition that (i) frequent cannabis use may cause an adaptive down-regulation of brain endocannabinoid signaling, and (ii) that genetic traits that favor hyperactivity of the endocannabinoid system in humans may decrease susceptibility to cannabis dependence. These findings suggest in turn that pharmacological agents that elevate brain levels of the endocannabinoid neurotransmitters, anandamide and 2-arachidonoylglycerol (2-AG), might alleviate cannabis withdrawal and dependence. One such agent, the fatty-acid amide hydrolase (FAAH) inhibitor URB597, selectively increases anandamide levels in the brain of rodents and primates. Preclinical studies show that URB597 produces analgesic, anxiolytic-like and antidepressant-like effects in rodents, which are not accompanied by overt signs of abuse liability. In this article, we review evidence suggesting that (i) cannabis influences brain

  16. Endocannabinoid modulation of homeostatic and non-homeostatic feeding circuits.

    PubMed

    Lau, Benjamin K; Cota, Daniela; Cristino, Luigia; Borgland, Stephanie L

    2017-09-15

    The endocannabinoid system has emerged as a key player in the control of eating. Endocannabinoids, including 2-arachidonoylglycerol (2-AG) and anandamide (AEA), modulate neuronal activity via cannabinoid 1 receptors (CB1Rs) in multiple nuclei of the hypothalamus to induce or inhibit food intake depending on nutritional and hormonal status, suggesting that endocannabinoids may act in the hypothalamus to integrate different types of signals informing about the animal's energy needs. In the mesocorticolimbic system, (endo)cannabinoids modulate synaptic transmission to promote dopamine release in response to palatable food. In addition, (endo)cannabinoids act within the nucleus accumbens to increase food's hedonic impact; although this effect depends on activation of CB1Rs at excitatory, but not inhibitory inputs in the nucleus accumbens. While hyperactivation of the endocannabinoid system is typically associated with overeating and obesity, much evidence has emerged in recent years suggesting a more complicated system than first thought - endocannabinoids promote or suppress feeding depending on cell and input type, or modulation by various neuronal or hormonal signals. This review presents our latest knowledge of the endocannabinoid system in non-homeostatic and homeostatic feeding circuits. In particular, we discuss the functional role and cellular mechanism of action by endocannabinoids within the hypothalamus and mesocorticolimbic system, and how these are modulated by neuropeptide signals related to feeding. In light of recent advances and complexity in the field, we review cannabinoid-based therapeutic strategies for the treatment of obesity and how peripheral restriction of CB1R antagonists may provide a different mechanism of weight loss without the central adverse effects. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology". Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. The endocannabinoid system: a general view and latest additions

    PubMed Central

    Petrocellis, Luciano De; Cascio, Maria Grazia; Marzo, Vincenzo Di

    2004-01-01

    After the discovery, in the early 1990s, of specific G-protein-coupled receptors for marijuana's psychoactive principle Δ9-tetrahydrocannabinol, the cannabinoid receptors, and of their endogenous agonists, the endocannabinoids, a decade of investigations has greatly enlarged our understanding of this altogether new signalling system. Yet, while the finding of the endocannabinoids resulted in a new effort to reveal the mechanisms regulating their levels in the brain and peripheral organs under physiological and pathological conditions, more endogenous substances with a similar action, and more molecular targets for the previously discovered endogenous ligands, anandamide and 2-arachidonoylglycerol, or for some of their metabolites, were being proposed. As the scenario becomes subsequently more complicated, and the experimental tasks to be accomplished correspondingly more numerous, we briefly review in this article the latest ‘additions' to the endocannabinoid system together with earlier breakthroughs that have contributed to our present knowledge of the biochemistry and pharmacology of the endocannabinoids. PMID:14744801

  18. The endocannabinoid system in anxiety, fear memory and habituation

    PubMed Central

    Ruehle, S; Rey, A Aparisi; Remmers, F

    2012-01-01

    Evidence for the involvement of the endocannabinoid system (ECS) in anxiety and fear has been accumulated, providing leads for novel therapeutic approaches. In anxiety, a bidirectional influence of the ECS has been reported, whereby anxiolytic and anxiogenic responses have been obtained after both increases and decreases of the endocannabinoid tone. The recently developed genetic tools have revealed different but complementary roles for the cannabinoid type 1 (CB1) receptor on GABAergic and glutamatergic neuronal populations. This dual functionality, together with the plasticity of CB1 receptor expression, particularly on GABAergic neurons, as induced by stressful and rewarding experiences, gives the ECS a unique regulatory capacity for maintaining emotional homeostasis. However, the promiscuity of the endogenous ligands of the CB1 receptor complicates the interpretation of experimental data concerning ECS and anxiety. In fear memory paradigms, the ECS is mostly involved in the two opposing processes of reconsolidation and extinction of the fear memory. Whereas ECS activation deteriorates reconsolidation, proper extinction depends on intact CB1 receptor signalling. Thus, both for anxiety and fear memory processing, endocannabinoid signalling may ensure an appropriate reaction to stressful events. Therefore, the ECS can be considered as a regulatory buffer system for emotional responses. PMID:21768162

  19. Endocannabinoid signaling in neurotoxicity and neuroprotection.

    PubMed

    Pope, C; Mechoulam, R; Parsons, L

    2010-09-01

    The cannabis plant and products produced from it, such as marijuana and hashish, have been used for centuries for their psychoactive properties. The mechanism for how Delta(9)-tetrahydrocannabinol (THC), the active constituent of cannabis, elicits these neurological effects remained elusive until relatively recently, when specific G-protein coupled receptors were discovered that appeared to mediate cellular actions of THC. Shortly after discovery of these specific receptors, endogenous ligands (endocannabinoids) were identified. Since that time, an extensive number of papers have been published on the endocannabinoid signaling system, a widespread neuromodulatory mechanism that influences neurotransmission throughout the nervous system. This paper summarizes presentations given at the 12th International Neurotoxicology Association meeting that described the potential role of endocannabinoids in the expression of neurotoxicity. Dr. Raphael Mechoulam first gave an overview of the discovery of exogenous and endogenous cannabinoids and their potential for neuroprotection in a variety of conditions. Dr. Larry Parsons then described studies suggesting that endocannabinoid signaling may play a selective role in drug reinforcement. Dr. Carey Pope presented information on the role that endocannabinoid signaling may have in the expression of cholinergic toxicity following anticholinesterase exposures. Together, these presentations highlighted the diverse types of neurological insults that may be modulated by endocannabinoids and drugs/toxicants which might influence endocannabinoid signaling pathways. Copyright © 2009 Elsevier Inc. All rights reserved.

  20. ENDOCANNABINOID SIGNALING IN NEUROTOXICITY AND NEUROPROTECTION

    PubMed Central

    Pope, C.; Mechoulam, R.; Parsons, L.

    2010-01-01

    The cannabis plant and products produced from it, such as marijuana and hashish, have been used for centuries for their psychoactive properties. The mechanism for how Δ9 -tetrahydrocannabinol (THC), the active constituent of cannabis, elicits these neurological effects remained elusive until relatively recently, when specific G-protein coupled receptors were discovered that appeared to mediate cellular actions of THC. Shortly after discovery of these specific receptors, endogenous ligands (endocannabinoids) were identified. Since that time, an extensive number of papers have been published on the endocannabinoid signaling system, a widespread neuromodulatory mechanism that influences neurotransmission throughout the nervous system. This paper summarizes presentations given at the 12th International Neurotoxicology Association meeting that described the potential role of endocannabinoids in the expression of neurotoxicity. Dr. Raphael Mechoulam first gave an overview of the discovery of exogenous and endogenous cannabinoids and their potential for neuroprotection in a variety of conditions. Dr. Larry Parsons then described studies suggesting that endocannabinoid signaling may play a selective role in drug reinforcement. Dr. Carey Pope presented information on the role that endocannabinoid signaling may have in the expression of cholinergic toxicity following anticholinesterase exposures. Together, these presentations highlighted the diverse types of neurological insults that may be modulated by endocannabinoids and drugs/toxicants which might influence endocannabinoid signaling pathways. PMID:19969019

  1. Endocannabinoid System: A Multi-Facet Therapeutic Target.

    PubMed

    Kaur, Rimplejeet; Ambwani, Sneha R; Singh, Surjit

    2016-01-01

    Cannabis sativa is also popularly known as marijuana. It has been cultivated and used by man for recreational and medicinal purposes since many centuries. Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries. The research of drugs acting on endocannabinoid system has seen many ups and downs in the recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve "protective role" in many medical conditions. Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson's disease, Huntington's disease, Alzheimer's disease and Tourette's syndrome could possibly be treated by drugs modulating endocannabinoid system. Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008. Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish

  2. Endocannabinoids and neuropathic pain: focus on neuron-glia and endocannabinoid-neurotrophin interactions.

    PubMed

    Luongo, Livio; Maione, Sabatino; Di Marzo, Vincenzo

    2014-02-01

    Although originally described as a signalling system encompassing the cannabinoid CB1 and CB2 receptors, their endogenous agonists (the endocannabinoids), and metabolic enzymes regulating the levels of such agonists, the endocannabinoid system is now viewed as being more complex, and including metabolically related endocannabinoid-like mediators and their molecular targets as well. The function and dysfunction of this complex signalling system in the molecular and cellular mechanisms of pain transduction and control has been widely studied over the last two decades. In this review article, we describe some of the latest advances in our knowledge on the role of the endocannabinoid system, in its most recent and wider conception, in pain pathways, by focusing on: (1) neuron-glia interactions; and (2) emerging data on endocannabinoid cross-talk with neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  3. Antihyperalgesic Activities of Endocannabinoids in a Mouse Model of Antiretroviral-Induced Neuropathic Pain

    PubMed Central

    Munawar, Neha; Oriowo, Mabayoje A.; Masocha, Willias

    2017-01-01

    Background: Nucleoside reverse transcriptase inhibitors (NRTIs) are the cornerstone of the antiretroviral therapy for human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS). However, their use is sometimes limited by the development of a painful sensory neuropathy, which does not respond well to drugs. Smoked cannabis has been reported in clinical trials to have efficacy in relieving painful HIV-associated sensory neuropathy. Objectives: The aim of this study was to evaluate whether the expression of endocannabinoid system molecules is altered during NRTI-induced painful neuropathy, and also whether endocannabinoids can attenuate NRTI-induced painful neuropathy. Methods: BALB/c mice were treated with 25 mg/kg of 2′,3′-dideoxycytidine (ddC, zalcitabine), a NRTI, to induce thermal hyperalgesia. The expression of endocannabinoid system molecules was evaluated by real time polymerase chain reaction in the brain, spinal cord and paw skin at 6 days post ddC administration, a time point when mice had developed thermal hyperalgesia. The effects of the endocannabinoids, N-arachidonoyl ethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG), the cannabinoid type 1 (CB1) receptor antagonist AM 251, CB2 receptor antagonist AM 630, and G protein-coupled receptor 55 (GPR55) antagonists ML193 and CID 16020046 on ddC-induced thermal hyperalgesia were evaluated using the hot plate test. Results: ddC treatment resulted in thermal hyperalgesia and increased transcripts of the synthesizing enzyme Plcβ1 and decreased Daglβ in the paw skins, but not Napepld, and Daglα compared to vehicle treatment. Transcripts of the inactivating enzymes Faah and Mgll were downregulated in the brain and/or paw skin but not in the spinal cord of ddC-treated mice. Both AEA and 2-AG had antihyperalgesic effects in mice with ddC-induced thermal hyperalgesia, but had no effect in ddC-naïve mice. The antihyperalgesic activity of AEA was antagonized by AM251 and AM630, whereas the

  4. Cannabis and endocannabinoid modulators: Therapeutic promises and challenges

    PubMed Central

    Grant, Igor; Cahn, B. Rael

    2008-01-01

    The discovery that botanical cannabinoids such as delta-9 tetrahydrocannabinol exert some of their effect through binding specific cannabinoid receptor sites has led to the discovery of an endocannabinoid signaling system, which in turn has spurred research into the mechanisms of action and addiction potential of cannabis on the one hand, while opening the possibility of developing novel therapeutic agents on the other. This paper reviews current understanding of CB1, CB2, and other possible cannabinoid receptors, their arachidonic acid derived ligands (e.g. anandamide; 2 arachidonoyl glycerol), and their possible physiological roles. CB1 is heavily represented in the central nervous system, but is found in other tissues as well; CB2 tends to be localized to immune cells. Activation of the endocannabinoid system can result in enhanced or dampened activity in various neural circuits depending on their own state of activation. This suggests that one function of the endocannabinoid system may be to maintain steady state. The therapeutic action of botanical cannabis or of synthetic molecules that are agonists, antagonists, or which may otherwise modify endocannabinoid metabolism and activity indicates they may have promise as neuroprotectants, and may be of value in the treatment of certain types of pain, epilepsy, spasticity, eating disorders, inflammation, and possibly blood pressure control. PMID:18806886

  5. Glucocorticoids interact with the hippocampal endocannabinoid system in impairing retrieval of contextual fear memory

    PubMed Central

    Atsak, Piray; Hauer, Daniela; Campolongo, Patrizia; Schelling, Gustav; McGaugh, James L.; Roozendaal, Benno

    2012-01-01

    There is extensive evidence that glucocorticoid hormones impair the retrieval of memory of emotionally arousing experiences. Although it is known that glucocorticoid effects on memory retrieval impairment depend on rapid interactions with arousal-induced noradrenergic activity, the exact mechanism underlying this presumably nongenomically mediated glucocorticoid action remains to be elucidated. Here, we show that the hippocampal endocannabinoid system, a rapidly activated retrograde messenger system, is involved in mediating glucocorticoid effects on retrieval of contextual fear memory. Systemic administration of corticosterone (0.3–3 mg/kg) to male Sprague–Dawley rats 1 h before retention testing impaired the retrieval of contextual fear memory without impairing the retrieval of auditory fear memory or directly affecting the expression of freezing behavior. Importantly, a blockade of hippocampal CB1 receptors with AM251 prevented the impairing effect of corticosterone on retrieval of contextual fear memory, whereas the same impairing dose of corticosterone increased hippocampal levels of the endocannabinoid 2-arachidonoylglycerol. We also found that antagonism of hippocampal β-adrenoceptor activity with local infusions of propranolol blocked the memory retrieval impairment induced by the CB receptor agonist WIN55,212–2. Thus, these findings strongly suggest that the endocannabinoid system plays an intermediary role in regulating rapid glucocorticoid effects on noradrenergic activity in impairing memory retrieval of emotionally arousing experiences. PMID:22331883

  6. Fenitrothion action at the endocannabinoid system leading to spermatotoxicity in Wistar rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ito, Yuki, E-mail: yukey@med.nagoya-cu.ac.jp; Tomizawa, Motohiro; Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo 156-8502

    Organophosphate (OP) compounds as anticholinesterase agents may secondarily act on diverse serine hydrolase targets, revealing unfavorable physiological effects including male reproductive toxicity. The present investigation proposes that fenitrothion (FNT, a major OP compound) acts on the endocannabinoid signaling system in male reproductive organs, thereby leading to spermatotoxicity (sperm deformity, underdevelopment, and reduced motility) in rats. FNT oxon (bioactive metabolite of FNT) preferentially inhibited the fatty acid amide hydrolase (FAAH), an endocannabinoid anandamide (AEA) hydrolase, in the rat cellular membrane preparation from the testis in vitro. Subsequently, male Wistar rats were treated orally with 5 or 10 mg/kg FNT for 9more » weeks and the subchronic exposure unambiguously deteriorated sperm motility and morphology. The activity-based protein profiling analysis with a phosphonofluoridate fluorescent probe revealed that FAAH was selectively inhibited among the FNT-treated cellular membrane proteome in testis. Intriguingly, testicular AEA (endogenous substrate of FAAH) levels were elevated along with the FAAH inhibition caused by the subchronic exposure. More importantly, linear regression analyses for the FNT-elicited spermatotoxicity reveal a good correlation between the testicular FAAH activity and morphological indices or sperm motility. Accordingly, the present study proposes that the FNT-elicited spermatotoxicity appears to be related to inhibition of FAAH leading to overstimulation of the endocannabinoid signaling system, which plays crucial roles in spermatogenesis and sperm motility acquirement. - Highlights: • Subchronic exposure to fenitrothion induces spermatotoxicity in rats. • The fatty acid amide hydrolase is a potential target for the spermatotoxicity. • Overstimulation of the endocannabinoid signal possibly leads to the spermatotoxicity.« less

  7. Involvement of the endocannabinoid system in periodontal healing

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kozono, Sayaka; Matsuyama, Takashi, E-mail: takashi@dent.kagoshima-u.ac.jp; Biwasa, Kamal Krishna

    2010-04-16

    Endocannabinoids including anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are important lipid mediators for immunosuppressive effects and for appropriate homeostasis via their G-protein-coupled cannabinoid (CB) receptors in mammalian organs and tissues, and may be involved in wound healing in some organs. The physiological roles of endocannabinoids in periodontal healing remain unknown. We observed upregulation of the expression of CB1/CB2 receptors localized on fibroblasts and macrophage-like cells in granulation tissue during wound healing in a wound-healing model in rats, as well as an increase in AEA levels in gingival crevicular fluid after periodontal surgery in human patients with periodontitis. In-vitro, the proliferation ofmore » human gingival fibroblasts (HGFs) by AEA was significantly attenuated by AM251 and AM630, which are selective antagonists of CB1 and CB2, respectively. CP55940 (CB1/CB2 agonist) induced phosphorylation of the extracellular-regulated kinases (ERK) 1/2, p38 mitogen-activated protein kinase (p38MAPK), and Akt in HGFs. Wound closure by CP55940 in an in-vitro scratch assay was significantly suppressed by inhibitors of MAP kinase kinase (MEK), p38MAPK, and phosphoinositol 3-kinase (PI3-K). These findings suggest that endocannabinoid system may have an important role in periodontal healing.« less

  8. The Role of the Brain's Endocannabinoid System in Pain and Its Modulation by Stress.

    PubMed

    Corcoran, Louise; Roche, Michelle; Finn, David P

    2015-01-01

    Stress has a complex, bidirectional modulatory influence on pain. Stress may either reduce (stress-induced analgesia) or exacerbate (stress-induced hyperalgesia) pain depending on the nature, duration, and intensity of the stressor. The endogenous cannabinoid (endocannabinoid) system is present throughout the neuroanatomical pathways that mediate and modulate responses to painful stimuli. The specific role of the endocannabinoid system in the brain in pain and the modulation of pain by stress is reviewed herein. We first provide a brief overview of the endocannabinoid system, followed by a review of the evidence that the brain's endocannabinoid system modulates pain. We provide a comprehensive evaluation of the role of the endocannabinoid system supraspinally, and particularly in the rostral ventromedial medulla, periaqueductal gray, amygdala, and prefrontal cortex, in pain, stress-induced analgesia, and stress-induced hyperalgesia. Increased understanding of endocannabinoid-mediated regulation of pain and its modulation by stress will inform the development of novel therapeutic approaches for pain and its comorbidity with stress-related disorders. © 2015 Elsevier Inc. All rights reserved.

  9. The endocannabinoid system as a target for the treatment of neurodegenerative disease.

    PubMed

    Scotter, Emma L; Abood, Mary E; Glass, Michelle

    2010-06-01

    The Cannabis sativa plant has been exploited for medicinal, agricultural and spiritual purposes in diverse cultures over thousands of years. Cannabis has been used recreationally for its psychotropic properties, while effects such as stimulation of appetite, analgesia and anti-emesis have lead to the medicinal application of cannabis. Indeed, reports of medicinal efficacy of cannabis can been traced back as far as 2700 BC, and even at that time reports also suggested a neuroprotective effect of the cultivar. The discovery of the psychoactive component of cannabis resin, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) occurred long before the serendipitous identification of a G-protein coupled receptor at which Delta(9)-THC is active in the brain. The subsequent finding of endogenous cannabinoid compounds, the synthesis of which is directed by neuronal excitability and which in turn served to regulate that excitability, further widened the range of potential drug targets through which the endocannabinoid system can be manipulated. As a result of this, alterations in the endocannabinoid system have been extensively investigated in a range of neurodegenerative disorders. In this review we examine the evidence implicating the endocannabinoid system in the cause, symptomatology or treatment of neurodegenerative disease. We examine data from human patients and compare and contrast this with evidence from animal models of these diseases. On the basis of this evidence we discuss the likely efficacy of endocannabinoid-based therapies in each disease context.

  10. From cannabis to the endocannabinoid system: refocussing attention on potential clinical benefits.

    PubMed

    Youssef, F F; Irving, A J

    2012-06-01

    Cannabis sativa is one of the oldest herbal remedies known to man. Over the past four thousand years, it has been used for the treatment of numerous diseases but due to its psychoactive properties, its current medicinal usage is highly restricted. In this review, we seek to highlight advances made over the last forty years in the understanding of the mechanisms responsible for the effects of cannabis on the human body and how these can potentially be utilized in clinical practice. During this time, the primary active ingredients in cannabis have been isolated, specific cannabinoid receptors have been discovered and at least five endogenous cannabinoid neurotransmitters (endocannabinoids) have been identified. Together, these form the framework of a complex endocannabinoid signalling system that has widespread distribution in the body and plays a role in regulating numerous physiological processes within the body. Cannabinoid ligands are therefore thought to display considerable therapeutic potential and the drive to develop compounds that can be targeted to specific neuronal systems at low enough doses so as to eliminate cognitive side effects remains the 'holy grail' of endocannabinoid research.

  11. Effect of blockage of the endocannabinoid system by CB(1) antagonism on cardiovascular risk.

    PubMed

    Mach, François; Montecucco, Fabrizio; Steffens, Sabine

    2009-01-01

    The endocannabinoid system is a crucial player in the inflammatory processes underlying atherosclerosis. Recently, basic research studies and animal models have strongly supported the role of the endocannabinoid system not only in the regulation of classical cardiovascular risk factors (including lipid profile and glucose homeostasis), but also in the activation of immune cells and inflammatory mediators. Clinical trials investigating treatment with rimonabant (a selective antagonist of the cannabinoid type 1 receptor) have suggested a beneficial effect of this drug in the management of obesity. Further studies are needed to explore a possible use for rimonabant in treating type 2 diabetes and acute and chronic cardiovascular disease. Despite the slight increase in adverse events (mainly psychiatric), which has led to the recent withdrawal of rimonabant from the market, CB(1) receptor antagonism might represent a very promising therapeutic strategy to reduce the cardiovascular risk. In the present review, we focused on the most important experimental investigations into the role of the endocannabinoid system in atherosclerosis and cardiovascular risk.

  12. Endocannabinoids and Mental Disorders.

    PubMed

    Rubino, Tiziana; Zamberletti, Erica; Parolaro, Daniela

    2015-01-01

    Preclinical and clinical data fully support the involvement of the endocannabinoid system in the etiopathogenesis of several mental diseases. In this review we will briefly summarize the most common alterations in the endocannabinoid system, in terms of cannabinoid receptors and endocannabinoid levels, present in mood disorders (anxiety, posttraumatic stress disorder, depression, bipolar disorder, and suicidality) as well as psychosis (schizophrenia) and autism. The arising picture for each pathology is not always straightforward; however, both animal and human studies seem to suggest that pharmacological modulation of this system might represent a novel approach for treatment.

  13. Endocannabinoid Signaling, Glucocorticoid-Mediated Negative Feedback and Regulation of the HPA Axis

    PubMed Central

    Hill, M. N.; Tasker, J. G.

    2012-01-01

    The hypothalamic-pituitary-adrenal (HPA) axis regulates the outflow of glucocorticoid hormones under basal conditions and in response to stress. Within the last decade, a large body of evidence has mounted indicating that the endocannabinoid system is involved in the central regulation of the stress response; however, the specific role endocannabinoid signalling plays in phases of HPA axis regulation, or the neural sites of action mediating this regulation, was not mapped out until recently. This review aims to collapse the current state of knowledge regarding the role of the endocannabinoid system in the regulation of the HPA axis to put together a working model of how and where endocannabinoids act within the brain to regulate outflow of the HPA axis. Specifically, we discuss the role of the endocannabinoid system in the regulation of the HPA axis under basal conditions, activation in response to acute stress and glucocorticoid-mediated negative feedback. Interestingly, there appears to be some anatomical specificity to the role of the endocannabinoid system in each phase of HPA axis regulation, as well as distinct roles of both anandamide and 2-arachidonoylglycerol in these phases. Ultimately, the current level of information indicates that endocannabinoid signalling acts to suppress HPA axis activity through concerted actions within the prefrontal cortex, amygdala and hypothalamus. PMID:22214537

  14. Chemical Probes of Endocannabinoid Metabolism

    PubMed Central

    2013-01-01

    The endocannabinoid signaling system regulates diverse physiologic processes and has attracted considerable attention as a potential pharmaceutical target for treating diseases, such as pain, anxiety/depression, and metabolic disorders. The principal ligands of the endocannabinoid system are the lipid transmitters N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), which activate the two major cannabinoid receptors, CB1 and CB2. Anandamide and 2-AG signaling pathways in the nervous system are terminated by enzymatic hydrolysis mediated primarily by the serine hydrolases fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. In this review, we will discuss the development of FAAH and MAGL inhibitors and their pharmacological application to investigate the function of anandamide and 2-AG signaling pathways in preclinical models of neurobehavioral processes, such as pain, anxiety, and addiction. We will place emphasis on how these studies are beginning to discern the different roles played by anandamide and 2-AG in the nervous system and the resulting implications for advancing endocannabinoid hydrolase inhibitors as next-generation therapeutics. PMID:23512546

  15. The evolution and comparative neurobiology of endocannabinoid signalling

    PubMed Central

    Elphick, Maurice R.

    2012-01-01

    CB1- and CB2-type cannabinoid receptors mediate effects of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide in mammals. In canonical endocannabinoid-mediated synaptic plasticity, 2-AG is generated postsynaptically by diacylglycerol lipase alpha and acts via presynaptic CB1-type cannabinoid receptors to inhibit neurotransmitter release. Electrophysiological studies on lampreys indicate that this retrograde signalling mechanism occurs throughout the vertebrates, whereas system-level studies point to conserved roles for endocannabinoid signalling in neural mechanisms of learning and control of locomotor activity and feeding. CB1/CB2-type receptors originated in a common ancestor of extant chordates, and in the sea squirt Ciona intestinalis a CB1/CB2-type receptor is targeted to axons, indicative of an ancient role for cannabinoid receptors as axonal regulators of neuronal signalling. Although CB1/CB2-type receptors are unique to chordates, enzymes involved in biosynthesis/inactivation of endocannabinoids occur throughout the animal kingdom. Accordingly, non-CB1/CB2-mediated mechanisms of endocannabinoid signalling have been postulated. For example, there is evidence that 2-AG mediates retrograde signalling at synapses in the nervous system of the leech Hirudo medicinalis by activating presynaptic transient receptor potential vanilloid-type ion channels. Thus, postsynaptic synthesis of 2-AG or anandamide may be a phylogenetically widespread phenomenon, and a variety of proteins may have evolved as presynaptic (or postsynaptic) receptors for endocannabinoids. PMID:23108540

  16. Endocannabinoid signaling in reward and addiction

    PubMed Central

    Parsons, Loren H.; Hurd, Yasmin L.

    2015-01-01

    Brain endocannabinoid signaling influences the motivation for natural rewards (such as palatable food, sexual activity and social interaction) and modulates the rewarding effects of addictive drugs. Pathological forms of natural and drug-induced reward are associated with dysregulated endocannabinoid signaling that may derive from pre-existing genetic factors or from prolonged drug exposure. Impaired endocannabinoid signaling contributes to dysregulated synaptic plasticity, increased stress responsivity, negative emotional states, and craving that propel addiction. Understanding the contributions of endocannabinoid disruptions to behavioral and physiological traits provides insight into the endocannabinoid influence on addiction vulnerability. PMID:26373473

  17. Control of synaptic function by endocannabinoid-mediated retrograde signaling.

    PubMed

    Kano, Masanobu

    2014-01-01

    Since the first reports in 2001, great advances have been made towards the understanding of endocannabinoid-mediated synaptic modulation. Electrophysiological studies have revealed that one of the two major endocannabinoids, 2-arachidonoylglycerol (2-AG), is produced from membrane lipids upon postsynaptic Ca(2+) elevation and/or activation of Gq/11-coupled receptors, and released from postsynaptic neurons. The released 2-AG then acts retrogradely onto presynaptic cannabinoid CB1 receptors and induces suppression of neurotransmitter release either transiently or persistently. These forms of 2-AG-mediated retrograde synaptic modulation are functional throughout the brain. The other major endocannabinoid, anandamide, mediates a certain form of endocannabinoid-mediated long-term depression (LTD). Anandamide also functions as an agonist for transient receptor potential vanilloid receptor type 1 (TRPV1) and mediates endocannabinoid-independent and TRPV1-dependent forms of LTD. It has also been demonstrated that the endocannabinoid system itself is plastic, which can be either up- or down-regulated by experimental or environmental conditions. In this review, I will make an overview of the mechanisms underlying endocannabinoid-mediated synaptic modulation.

  18. Control of synaptic function by endocannabinoid-mediated retrograde signaling

    PubMed Central

    KANO, Masanobu

    2014-01-01

    Since the first reports in 2001, great advances have been made towards the understanding of endocannabinoid-mediated synaptic modulation. Electrophysiological studies have revealed that one of the two major endocannabinoids, 2-arachidonoylglycerol (2-AG), is produced from membrane lipids upon postsynaptic Ca2+ elevation and/or activation of Gq/11-coupled receptors, and released from postsynaptic neurons. The released 2-AG then acts retrogradely onto presynaptic cannabinoid CB1 receptors and induces suppression of neurotransmitter release either transiently or persistently. These forms of 2-AG-mediated retrograde synaptic modulation are functional throughout the brain. The other major endocannabinoid, anandamide, mediates a certain form of endocannabinoid-mediated long-term depression (LTD). Anandamide also functions as an agonist for transient receptor potential vanilloid receptor type 1 (TRPV1) and mediates endocannabinoid-independent and TRPV1-dependent forms of LTD. It has also been demonstrated that the endocannabinoid system itself is plastic, which can be either up- or down-regulated by experimental or environmental conditions. In this review, I will make an overview of the mechanisms underlying endocannabinoid-mediated synaptic modulation. PMID:25169670

  19. Endocannabinoid Signaling Regulates Sleep Stability

    PubMed Central

    Pava, Matthew J.; Makriyannis, Alexandros; Lovinger, David M.

    2016-01-01

    The hypnogenic properties of cannabis have been recognized for centuries, but endogenous cannabinoid (endocannabinoid) regulation of vigilance states is poorly characterized. We report findings from a series of experiments in mice measuring sleep with polysomnography after various systemic pharmacological manipulations of the endocannabinoid system. Rapid, unbiased scoring of vigilance states was achieved using an automated algorithm that we devised and validated. Increasing endocannabinoid tone with a selective inhibitor of monoacyglycerol lipase (JZL184) or fatty acid amide hydrolase (AM3506) produced a transient increase in non-rapid eye movement (NREM) sleep due to an augmentation of the length of NREM bouts (NREM stability). Similarly, direct activation of type 1 cannabinoid (CB1) receptors with CP47,497 increased NREM stability, but both CP47,497 and JZL184 had a secondary effect that reduced NREM sleep time and stability. This secondary response to these drugs was similar to the early effect of CB1 blockade with the antagonist/inverse agonist AM281, which fragmented NREM sleep. The magnitude of the effects produced by JZL184 and AM281 were dependent on the time of day this drug was administered. While activation of CB1 resulted in only a slight reduction in gamma power, CB1 blockade had dramatic effects on broadband power in the EEG, particularly at low frequencies. However, CB1 blockade did not significantly reduce the rebound in NREM sleep following total sleep deprivation. These results support the hypothesis that endocannabinoid signaling through CB1 is necessary for NREM stability but it is not necessary for sleep homeostasis. PMID:27031992

  20. Endocannabinoid Signaling Regulates Sleep Stability.

    PubMed

    Pava, Matthew J; Makriyannis, Alexandros; Lovinger, David M

    2016-01-01

    The hypnogenic properties of cannabis have been recognized for centuries, but endogenous cannabinoid (endocannabinoid) regulation of vigilance states is poorly characterized. We report findings from a series of experiments in mice measuring sleep with polysomnography after various systemic pharmacological manipulations of the endocannabinoid system. Rapid, unbiased scoring of vigilance states was achieved using an automated algorithm that we devised and validated. Increasing endocannabinoid tone with a selective inhibitor of monoacyglycerol lipase (JZL184) or fatty acid amide hydrolase (AM3506) produced a transient increase in non-rapid eye movement (NREM) sleep due to an augmentation of the length of NREM bouts (NREM stability). Similarly, direct activation of type 1 cannabinoid (CB1) receptors with CP47,497 increased NREM stability, but both CP47,497 and JZL184 had a secondary effect that reduced NREM sleep time and stability. This secondary response to these drugs was similar to the early effect of CB1 blockade with the antagonist/inverse agonist AM281, which fragmented NREM sleep. The magnitude of the effects produced by JZL184 and AM281 were dependent on the time of day this drug was administered. While activation of CB1 resulted in only a slight reduction in gamma power, CB1 blockade had dramatic effects on broadband power in the EEG, particularly at low frequencies. However, CB1 blockade did not significantly reduce the rebound in NREM sleep following total sleep deprivation. These results support the hypothesis that endocannabinoid signaling through CB1 is necessary for NREM stability but it is not necessary for sleep homeostasis.

  1. The Endocannabinoid System and Anxiety.

    PubMed

    Lisboa, S F; Gomes, F V; Terzian, A L B; Aguiar, D C; Moreira, F A; Resstel, L B M; Guimarães, F S

    2017-01-01

    The medical properties of Cannabis sativa is known for centuries. Since the discovery and characterization of the endogenous cannabinoid system, several studies have evaluated how cannabinoid compounds and, particularly, how the modulation of the endocannabinoid (eCB) system influences a wide range of functions, from metabolic to mental disorders. Cannabinoids and eCB system often exert opposite effects on several functions, such as anxiety. Although the mechanisms are not completely understood, evidence points to different factors influencing those effects. In this chapter, the recent advances in research about the relationship between eCB system and anxiety disorders in humans, as well as in animal models, will be discussed. The recent data addressing modulation of the eCBs in specific brain areas, such as the medial prefrontal cortex, amygdaloid complex, bed nucleus of stria terminalis, hippocampus, and dorsal periaqueductal gray, will be summarized. Finally, data from animal models addressing the mechanisms through which the eCB system modulates anxiety-related behavior dependent on stressful situations, such as the involvement of different receptors, distinct eCBs, modulation of neurotransmitters release, HPA axis and immune system activation, and plastic mechanisms, will also be discussed. © 2017 Elsevier Inc. All rights reserved.

  2. Roles for the endocannabinoid system in ethanol-motivated behavior

    PubMed Central

    Henderson-Redmond, Angela N; Guindon, Josée; Morgan, Daniel J

    2015-01-01

    Alcohol use disorder represents a significant human health problem that leads to substantial loss of human life and financial cost to society. Currently available treatment options do not adequately address this human health problem, and thus, additional therapies are desperately needed. The endocannabinoid system has been shown, using animal models, to modulate ethanol-motivated behavior, and it has also been demonstrated that chronic ethanol exposure can have potentially long-lasting effects on the endocannabinoid system. For example, chronic exposure to ethanol, in either cell culture or preclinical rodent models, causes an increase in endocannabinoid levels that results in down-regulation of the cannabinoid receptor 1 (CB1) and uncoupling of this receptor from downstream G protein signaling pathways. Using positron emission tomography (PET), similar down-regulation of CB1 has been noted in multiple regions of the brain in human alcoholic patients. In rodents, treatment with the CB1 inverse agonist SR141716A (Rimonabant), or genetic deletion of CB1 leads to a reduction in voluntary ethanol drinking, ethanol-stimulated dopamine release in the nucleus accumbens, operant self-administration of ethanol, sensitization to the locomotor effects of ethanol, and reinstatement/relapse of ethanol-motivated behavior. Although the clinical utility of Rimonabant or other antagonists/inverse agonists for CB1 is limited due to negative neuropsychiatric side effects, negative allosteric modulators of CB1 and inhibitors of endocannabinoid catabolism represent therapeutic targets worthy of additional examination. PMID:26123153

  3. Roles for the endocannabinoid system in ethanol-motivated behavior.

    PubMed

    Henderson-Redmond, Angela N; Guindon, Josée; Morgan, Daniel J

    2016-02-04

    Alcohol use disorder represents a significant human health problem that leads to substantial loss of human life and financial cost to society. Currently available treatment options do not adequately address this human health problem, and thus, additional therapies are desperately needed. The endocannabinoid system has been shown, using animal models, to modulate ethanol-motivated behavior, and it has also been demonstrated that chronic ethanol exposure can have potentially long-lasting effects on the endocannabinoid system. For example, chronic exposure to ethanol, in either cell culture or preclinical rodent models, causes an increase in endocannabinoid levels that results in down-regulation of the cannabinoid receptor 1 (CB1) and uncoupling of this receptor from downstream G protein signaling pathways. Using positron emission tomography (PET), similar down-regulation of CB1 has been noted in multiple regions of the brain in human alcoholic patients. In rodents, treatment with the CB1 inverse agonist SR141716A (Rimonabant), or genetic deletion of CB1 leads to a reduction in voluntary ethanol drinking, ethanol-stimulated dopamine release in the nucleus accumbens, operant self-administration of ethanol, sensitization to the locomotor effects of ethanol, and reinstatement/relapse of ethanol-motivated behavior. Although the clinical utility of Rimonabant or other antagonists/inverse agonists for CB1 is limited due to negative neuropsychiatric side effects, negative allosteric modulators of CB1 and inhibitors of endocannabinoid catabolism represent therapeutic targets worthy of additional examination. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. A collaboration investigating endocannabinoid signalling in brain and bone.

    PubMed

    Zimmer, Andreas

    2016-05-01

    Investigations into the cellular and molecular mechanisms underlying the psychoactive effects of cannabis preparations have led to the discovery of the endocannabinoid system. Interest in the central nervous system effects was initially the main focus of the research, but it soon became evident that the endocannabinoid system affects virtually every organ. The research field has therefore experienced a tremendous growth over the last decade and is now truly interdisciplinary. This short review provides a personal account of an interdisciplinary collaboration between Itai Bab from the Hebrew University of Jerusalem and the author. It describes the discovery of the endocannabinoid system in bone and the analysis of its functions. I am summarising the role of CB1 signalling as a modulator of sympathetic inhibition of bone formation. Thus, activation of CB1 receptors on sympathetic nerve terminals in bone, presumably from endocannabinoids released from apposing osteoblasts, reduces the inhibition of bone formation of sympathetic norepinephrine. CB2 receptors on osteoblasts and osteoclasts also modulate the proliferation and functions of these cells. Thus, activation of CB2 stimulates bone formation and represses bone resorption, whereas the genetic disruption of CB2 results in an osteoporosis-like phenotype. This signalling mechanism is clinically relevant, as shown by the association of polymorphisms in the CB2 receptor gene, CNR2, with bone density and osteoporosis. Finally, the review provides a summary of the recently discovered role of endocannabinoid signalling in one elongation. This review will also discuss the benefits of interdisciplinary and international collaborations.

  5. Endocannabinoids: Effectors of glucocorticoid signaling.

    PubMed

    Balsevich, Georgia; Petrie, Gavin N; Hill, Matthew N

    2017-10-01

    For decades, there has been speculation regarding the interaction of cannabinoids with glucocorticoid systems. Given the functional redundancy between many of the physiological effects of glucocorticoids and cannabinoids, it was originally speculated that the biological mechanisms of cannabinoids were mediated by direct interactions with glucocorticoid systems. With the discovery of the endocannabinoid system, additional research demonstrated that it was actually the opposite; glucocorticoids recruit endocannabinoid signaling, and that the engagement of endocannabinoid signaling mediated many of the neurobiological and physiological effects of glucocorticoids. With the development of advances in pharmacology and genetics, significant advances in this area have been made, and it is now clear that functional interactions between these systems are critical for a wide array of physiological processes. The current review acts a comprehensive summary of the contemporary state of knowledge regarding the biological interactions between glucocorticoids and endocannabinoids, and their potential role in health and disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Nicotine-induced neuroprotection against ischemic injury involves activation of endocannabinoid system in rats.

    PubMed

    Chen, Yu; Nie, Huang; Tian, Li; Tong, Li; Yang, Lujia; Lao, Ning; Dong, Hailong; Sang, Hanfei; Xiong, Lize

    2013-02-01

    Nicotine has been reported to exert certain protective effect in the Parkinson's and Alzheimer's diseases. Whether it has a similar action in focal cerebral ischemia was unclear. In the present study, rats received either an injection of (-)-nicotine hydrogen tartrate salt (1.2 mg/kg, i.p.) or the vehicle 2 h before the 120 min middle cerebral artery occlusion. Neurological deficits and histological injury were assessed at 24 h after reperfusion. The content of endocannabinoids and the expression of cannabinoid receptor CB1 in brain tissues were determined at different time points after nicotine administration. Results showed that nicotine administration ameliorated neurological deficits and reduced infarct volume induced by cerebral ischemia in the rats. The neuroprotective effect was partially reversed by CB1 blockage. The content of the endocannabinoids N-arachidonylethanolamine and 2-arachidonoylglycerol, as well as the expression of cannabinoid receptor CB1 were up-regulated in brain tissues after nicotine delivery. These results suggest that endogenous cannabinoid system is involved in the nicotine-induced neuroprotection against transient focal cerebral ischemia.

  7. Circulating Endocannabinoid Concentrations and Sexual Arousal in Women

    PubMed Central

    Klein, Carolin; Hill, Matthew N.; Chang, Sabrina C.H.; Hillard, Cecilia J.; Gorzalka, Boris B.

    2013-01-01

    Introduction Several lines of evidence point to the potential role of the endocannabinoid system in female sexual functioning. These include results from studies describing the subjective effects of exogenous cannabinoids on sexual functioning in humans and the observable effects of exogenous cannabinoids on sexual functioning in other species, as well as results from studies investigating the location of cannabinoid receptors in the brain and periphery, and the effects of cannabinoid receptor activation on neurotransmitters implicated in sexual functioning. While these lines of research suggest a role for the endocannabinoid system in female sexual functioning, no studies investigating the relationship between concentrations of endogenous cannabinoids (i.e., arachidonoylethanolamide [AEA] and 2-arachidonoylglycerol [2-AG]) and sexual functioning have been conducted in any species. Aim To measure circulating endocannabinoid concentrations in relation to subjective and physiological indices of sexual arousal in women (n = 21). Methods Serum endocannabinoid (AEA and 2-AG) concentrations were measured immediately prior to, and immediately following, viewing of neutral (control) and erotic (experimental) film stimuli in a repeated measures design. Physiological sexual arousal was measured via vaginal photoplethysmography. Subjective sexual arousal was measured both continuously and non-continuously. Pearson’s correlations were used to investigate the relationships between endocannabinoid concentrations and sexual arousal. Main Outcome Measures Changes in AEA and 2-AG concentrations from pre- to post-film and in relation to physiological and subjective indices of sexual arousal. Results Results revealed a significant relationship between endocannabinoid concentrations and female sexual arousal, whereby increases in both physiological and subjective indices of sexual arousal were significantly associated with decreases in AEA, and increases in subjective indices of

  8. Peripheral endocannabinoid system dysregulation in first-episode psychosis.

    PubMed

    Bioque, Miquel; García-Bueno, Borja; Macdowell, Karina S; Meseguer, Ana; Saiz, Pilar A; Parellada, Mara; Gonzalez-Pinto, Ana; Rodriguez-Jimenez, Roberto; Lobo, Antonio; Leza, Juan C; Bernardo, Miguel

    2013-12-01

    Several hypotheses involving alterations of the immune system have been proposed among etiological explanations for psychotic disorders. The endocannabinoid system (ECS) has a homeostatic role as an endogenous neuroprotective and anti-inflammatory system. Alterations of this system have been associated with psychosis. Cannabis use is a robust risk factor for these disorders that could alter the ECS signalling. In this study, 95 patients with a first episode of psychosis (FEP) and 90 healthy controls were recruited. Protein expression of cannabinoid receptor 2 (CB2), the protein levels of the main endocannabinoid synthesizing enzymes N-acyl phosphatidylethanolamine phospholipase (NAPE) and diacylglycerol lipase (DAGL), and of degradation enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) were determined by western blot analysis in peripheral blood mononuclear cells (PBMCs). Patients with a FEP showed a decreased expression of CB2 and of both endocannabinoids synthesizing enzymes (NAPE and DAGL) in comparison to healthy controls. After controlling for age, gender, body mass index, and cannabis use, NAPE and DAGL expression remained significantly decreased, whereas FAAH and MAGL expression were increased. On the other hand, FEP subjects with history of severe cannabis use showed a larger ECS dysregulation compared with healthy controls. These results indicate an ECS dysregulation in PBMC of FEP patients. The alteration of the ECS presented at the initial phases of psychosis could be contributing to the pathophysiology of the disease and constitutes a possible biomarker of psychotic disorders and an interesting pharmacological target to take into account for therapeutic purposes.

  9. FABP-1 gene ablation impacts brain endocannabinoid system in male mice.

    PubMed

    Martin, Gregory G; Chung, Sarah; Landrock, Danilo; Landrock, Kerstin K; Huang, Huan; Dangott, Lawrence J; Peng, Xiaoxue; Kaczocha, Martin; Seeger, Drew R; Murphy, Eric J; Golovko, Mikhail Y; Kier, Ann B; Schroeder, Friedhelm

    2016-08-01

    Liver fatty acid-binding protein (FABP1, L-FABP) has high affinity for and enhances uptake of arachidonic acid (ARA, C20:4, n-6) which, when esterified to phospholipids, is the requisite precursor for synthesis of endocannabinoids (EC) such as arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG). The brain derives most of its ARA from plasma, taking up ARA and transporting it intracellularly via cytosolic fatty acid-binding proteins (FABPs 3,5, and 7) localized within the brain. In contrast, the much more prevalent cytosolic FABP1 is not detectable in the brain but is instead highly expressed in the liver. Therefore, the possibility that FABP1 outside the central nervous system may regulate brain AEA and 2-AG was examined in wild-type (WT) and FABP1 null (LKO) male mice. LKO increased brain levels of AA-containing EC (AEA, 2-AG), correlating with increased free and total ARA in brain and serum. LKO also increased brain levels of non-ARA that contain potentiating endocannabinoids (EC*) such as oleoyl ethanolamide (OEA), PEA, 2-OG, and 2-PG. Concomitantly, LKO decreased serum total ARA-containing EC, but not non-ARA endocannabinoids. LKO did not elicit these changes in the brain EC and EC* as a result of compensatory up-regulation of brain protein levels of enzymes in EC synthesis (NAPEPLD, DAGLα) or cytosolic EC chaperone proteins (FABPs 3, 5, 7, SCP-2, HSP70), or cannabinoid receptors (CB1, TRVP1). These data show for the first time that the non-CNS fatty acid-binding protein FABP1 markedly affected brain levels of both ARA-containing endocannabinoids (AEA, 2-AG) as well as their non-ARA potentiating endocannabinoids. Fatty acid-binding protein-1 (FABP-1) is not detectable in brain but instead is highly expressed in liver. The possibility that FABP1 outside the central nervous system may regulate brain endocannabinoids arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG) was examined in wild-type (WT) and FABP-1 null (LKO) male mice. LKO

  10. Crosstalk between liver antioxidant and the endocannabinoid systems after chronic administration of the FAAH inhibitor, URB597, to hypertensive rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Biernacki, Michał; Łuczaj, Wojciech; Gęgotek, Agni

    Hypertension is accompanied by perturbations to the endocannabinoid and antioxidant systems. Thus, potential pharmacological treatments for hypertension should be examined as modulators of these two metabolic systems. The aim of this study was to evaluate the effects of chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl)phenyl]N-cyclohexylcarbamate (URB597) on the endocannabinoid system and on the redox balance in the livers of DOCA-salt hypertensive rats. Hypertension caused an increase in the levels of endocannabinoids [anandamide (AEA), 2-arachidonoyl-glycerol (2-AG) and N-arachidonoyl-dopamine (NADA)] and CB{sub 1} receptor and the activities of FAAH and monoacylglycerol lipase (MAGL). These effects were accompanied bymore » an increase in the level of reactive oxygen species (ROS), a decrease in antioxidant activity/level, enhanced expression of transcription factor Nrf2 and changes to Nrf2 activators and inhibitors. Moreover, significant increases in lipid, DNA and protein oxidative modifications, which led to enhanced levels of proapoptotic caspases, were also observed. URB597 administration to the hypertensive rats resulted in additional increases in the levels of AEA, NADA and the CB{sub 1} receptor, as well as decreases in vitamin E and C levels, glutathione peroxidase and glutathione reductase activities and Nrf2 expression. Thus, after URB597 administration, oxidative modifications of cellular components were increased, while the inflammatory response was reduced. This study revealed that chronic treatment of hypertensive rats with URB597 disrupts the endocannabinoid system, which causes an imbalance in redox status. This imbalance increases the levels of electrophilic lipid peroxidation products, which later participate in metabolic disturbances in liver homeostasis. - Highlights: • Chronic administration of URB597 to hypertensive rats reduces liver inflammation. • URB597 enhances the redox imbalance

  11. Increased Contextual Fear Conditioning in iNOS Knockout Mice: Additional Evidence for the Involvement of Nitric Oxide in Stress-Related Disorders and Contribution of the Endocannabinoid System

    PubMed Central

    Gomes, Felipe V.; Silva, Andréia L.; Uliana, Daniela L.; Camargo, Laura H. A.; Guimarães, Francisco S.; Cunha, Fernando Q.; Joca, Sâmia R. L.; Resstel, Leonardo B. M.

    2015-01-01

    Background: Inducible or neuronal nitric oxide synthase gene deletion increases or decreases anxiety-like behavior in mice, respectively. Since nitric oxide and endocannabinoids interact to modulate defensive behavior, the former effect could involve a compensatory increase in basal brain nitric oxide synthase activity and/or changes in the endocannabinoid system. Thus, we investigated the expression and extinction of contextual fear conditioning of inducible nitric oxide knockout mice and possible involvement of endocannabinoids in these responses. Methods: We evaluated the effects of a preferential neuronal nitric oxide synthase inhibitor, 7-nitroindazol, nitric oxide synthase activity, and mRNA changes of nitrergic and endocannabinoid systems components in the medial prefrontal cortex and hippocampus of wild-type and knockout mice. The effects of URB597, an inhibitor of the fatty acid amide hydrolase enzyme, which metabolizes the endocannabinoid anandamide, WIN55,212-2, a nonselective cannabinoid agonist, and AM281, a selective CB1 antagonist, on contextual fear conditioning were also evaluated. Results: Contextual fear conditioning expression was similar in wild-type and knockout mice, but the latter presented extinction deficits and increased basal nitric oxide synthase activity in the medial prefrontal cortex. 7-Nitroindazol decreased fear expression and facilitated extinction in wild-type and knockout mice. URB597 decreased fear expression in wild-type and facilitated extinction in knockout mice, whereas WIN55,212-2 and AM281 increased it in wild-type mice. Nonconditioned knockout mice showed changes in the mRNA expression of nitrergic and endocannabinoid system components in the medial prefrontal cortex and hippocampus that were modified by fear conditioning. Conclusion: These data reinforce the involvement of the nitric oxide and endocannabinoids (anandamide) in stress-related disorders and point to a deregulation of the endocannabinoid system in

  12. Increased Contextual Fear Conditioning in iNOS Knockout Mice: Additional Evidence for the Involvement of Nitric Oxide in Stress-Related Disorders and Contribution of the Endocannabinoid System.

    PubMed

    Lisboa, Sabrina F; Gomes, Felipe V; Silva, Andréia L; Uliana, Daniela L; Camargo, Laura H A; Guimarães, Francisco S; Cunha, Fernando Q; Joca, Sâmia R L; Resstel, Leonardo B M

    2015-01-24

    Inducible or neuronal nitric oxide synthase gene deletion increases or decreases anxiety-like behavior in mice, respectively. Since nitric oxide and endocannabinoids interact to modulate defensive behavior, the former effect could involve a compensatory increase in basal brain nitric oxide synthase activity and/or changes in the endocannabinoid system. Thus, we investigated the expression and extinction of contextual fear conditioning of inducible nitric oxide knockout mice and possible involvement of endocannabinoids in these responses. We evaluated the effects of a preferential neuronal nitric oxide synthase inhibitor, 7-nitroindazol, nitric oxide synthase activity, and mRNA changes of nitrergic and endocannabinoid systems components in the medial prefrontal cortex and hippocampus of wild-type and knockout mice. The effects of URB597, an inhibitor of the fatty acid amide hydrolase enzyme, which metabolizes the endocannabinoid anandamide, WIN55,212-2, a nonselective cannabinoid agonist, and AM281, a selective CB1 antagonist, on contextual fear conditioning were also evaluated. Contextual fear conditioning expression was similar in wild-type and knockout mice, but the latter presented extinction deficits and increased basal nitric oxide synthase activity in the medial prefrontal cortex. 7-Nitroindazol decreased fear expression and facilitated extinction in wild-type and knockout mice. URB597 decreased fear expression in wild-type and facilitated extinction in knockout mice, whereas WIN55,212-2 and AM281 increased it in wild-type mice. Nonconditioned knockout mice showed changes in the mRNA expression of nitrergic and endocannabinoid system components in the medial prefrontal cortex and hippocampus that were modified by fear conditioning. These data reinforce the involvement of the nitric oxide and endocannabinoids (anandamide) in stress-related disorders and point to a deregulation of the endocannabinoid system in situations where nitric oxide signaling is

  13. Enhanced endocannabinoid tone as a potential target of pharmacotherapy.

    PubMed

    Toczek, Marek; Malinowska, Barbara

    2018-07-01

    The endocannabinoid system is up-regulated in numerous pathophysiological states such as inflammatory, neurodegenerative, gastrointestinal, metabolic and cardiovascular diseases, pain, and cancer. It has been suggested that this phenomenon primarily serves an autoprotective role in inhibiting disease progression and/or diminishing signs and symptoms. Accordingly, enhancement of endogenous endocannabinoid tone by inhibition of endocannabinoid degradation represents a promising therapeutic approach for the treatment of many diseases. Importantly, this allows for the avoidance of unwanted psychotropic side effects that accompany exogenously administered cannabinoids. The effects of endocannabinoid metabolic pathway modulation are complex, as endocannabinoids can exert their actions directly or via numerous metabolites. The two main strategies for blocking endocannabinoid degradation are inhibition of endocannabinoid-degrading enzymes and inhibition of endocannabinoid cellular uptake. To date, the most investigated compounds are inhibitors of fatty acid amide hydrolase (FAAH), an enzyme that degrades the endocannabinoid anandamide. However, application of FAAH inhibitors (and consequently other endocannabinoid degradation inhibitors) in medicine became questionable due to a lack of therapeutic efficacy in clinical trials and serious adverse effects evoked by one specific compound. In this paper, we discuss multiple pathways of endocannabinoid metabolism, changes in endocannabinoid levels across numerous human diseases and corresponding experimental models, pharmacological strategies for enhancing endocannabinoid tone and potential therapeutic applications including multi-target drugs with additional targets outside of the endocannabinoid system (cyclooxygenase-2, cholinesterase, TRPV1, and PGF 2α -EA receptors), and currently used medicines or medicinal herbs that additionally enhance endocannabinoid levels. Ultimately, further clinical and preclinical studies are

  14. Hemopressin Peptides as Modulators of the Endocannabinoid System and their Potential Applications as Therapeutic Tools.

    PubMed

    Macedonio, Giorgia; Stefanucci, Azzurra; Maccallini, Cristina; Mirzaie, Sako; Novellino, Ettore; Mollica, Adriano

    2016-01-01

    The endocannabinoid system (ECS) is activated when natural arachidonic acid derivatives (endogenous cannabinoids or endocannabinoids) bind as lipophilic messengers to cannabinoid receptors CB1 and CB2. The ECS comprises many hydrolytic enzymes responsible for the endocannabinoids cleavage. These hydrolases, such as fatty acid amide hydrolase (FAAH) and monoacylglyceride lipase (MAGL), are possible therapeutic targets for the development of new drugs as indirect cannabinoid agonists. Recently, a new family of endocannabinoid modulators was discovered; the lead structure of this family is the nonapeptide hemopressin produced from enzymatic cleavage of the α-chain of hemoglobin and acting as negative allosteric modulator of CB1. Hemopressin shows several physiological effects, e.g., antinociception, hypophagy, and hypotension. However, it is still a matter of debate whether this peptide, isolated from the brain of rats, is a real neuromodulator of the ECS. Recent evidence indicates that hemopressin could be a by-product formed by chemical degradation of a longer peptide RVD-hemopressin during the extraction from the brain homolysate. Indeed, RVD-hemopressin is more active than hemopressin in certain biological tests and may bind to the same subsite as Rimonabant, which is an inverse agonist of CB1 and a μ-opioid receptor antagonist. These findings have stimulated several studies to verify this hypothesis and to evaluate possible therapeutic applications of hemopressin, its peptidic derivatives, and synthetic analogues, opening new perspectives to the development of novel cannabinoid drugs.

  15. Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility.

    PubMed

    du Plessis, Stefan S; Agarwal, Ashok; Syriac, Arun

    2015-11-01

    Marijuana has the highest consumption rate among all of the illicit drugs used in the USA, and its popularity as both a recreational and medicinal drug is increasing especially among men of reproductive age. Male factor infertility is on the increase, and the exposure to the cannabinoid compounds released by marijuana could be a contributing cause. The endocannabinoid system (ECS) is deeply involved in the complex regulation of male reproduction through the endogenous release of endocannabinoids and binding to cannabinoid receptors. Disturbing the delicate balance of the ECS due to marijuana use can negatively impact reproductive potential. Various in vivo and in vitro studies have reported on the empirical role that marijuana plays in disrupting the hypothalamus-pituitary-gonadal axis, spermatogenesis, and sperm function such as motility, capacitation, and the acrosome reaction. In this review, we highlight the latest evidence regarding the effect of marijuana use on male fertility and also provide a detailed insight into the ECS and its significance in the male reproductive system.

  16. The therapeutic potential of targeting the peripheral endocannabinoid/CB1 receptor system.

    PubMed

    Tam, Joseph; Hinden, Liad; Drori, Adi; Udi, Shiran; Azar, Shahar; Baraghithy, Saja

    2018-03-01

    Endocannabinoids (eCBs) are internal lipid mediators recognized by the cannabinoid-1 and -2 receptors (CB 1 R and CB 2 R, respectively), which also mediate the different physiological effects of marijuana. The endocannabinoid system, consisting of eCBs, their receptors, and the enzymes involved in their biosynthesis and degradation, is present in a vast number of peripheral organs. In this review we describe the role of the eCB/CB 1 R system in modulating the metabolism in several peripheral organs. We assess how eCBs, via activating the CB 1 R, contribute to obesity and regulate food intake. In addition, we describe their roles in modulating liver and kidney functions, as well as bone remodeling and mass. Special importance is given to emphasizing the efficacy of the recently developed peripherally restricted CB 1 R antagonists, which were pre-clinically tested in the management of energy homeostasis, and in ameliorating both obesity- and diabetes-induced metabolic complications. Copyright © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  17. Regulation of GPR119 receptor activity with endocannabinoid-like lipids.

    PubMed

    Syed, Samreen K; Bui, Hai Hoang; Beavers, Lisa S; Farb, Thomas B; Ficorilli, James; Chesterfield, Amy K; Kuo, Ming-Shang; Bokvist, Krister; Barrett, David G; Efanov, Alexander M

    2012-12-15

    The GPR119 receptor plays an important role in the secretion of incretin hormones in response to nutrient consumption. We have studied the ability of an array of naturally occurring endocannabinoid-like lipids to activate GPR119 and have identified several lipid receptor agonists. The most potent receptor agonists identified were three N-acylethanolamines: oleoylethanolamine (OEA), palmitoleoylethanolamine, and linoleylethanolamine (LEA), all of which displayed similar potency in activating GPR119. Another lipid, 2-oleoylglycerol (2-OG), also activated GPR119 receptor but with significantly lower potency. Endogenous levels of endocannabinoid-like lipids were measured in intestine in fasted and refed mice. Of the lipid GPR119 agonists studied, the intestinal levels of only OEA, LEA, and 2-OG increased significantly upon refeeding. Intestinal levels of OEA and LEA in the fasted mice were low. In the fed state, OEA levels only moderately increased, whereas LEA levels rose drastically. 2-OG was the most abundant of the three GPR119 agonists in intestine, and its levels were radically elevated in fed mice. Our data suggest that, in lean mice, 2-OG and LEA may serve as physiologically relevant endogenous GPR119 agonists that mediate receptor activation upon nutrient uptake.

  18. Lipidomic Analysis of Endocannabinoid Signaling: Targeted Metabolite Identification and Quantification

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Keereetaweep, Jantana; Chapman, Kent D.

    The endocannabinoidsN-arachidonoylethanolamide (or anandamide, AEA) and 2-arachidonoylglycerol (2-AG) belong to the larger groups ofN-acylethanolamines (NAEs) and monoacylglycerol (MAG) lipid classes, respectively. They are biologically active lipid molecules that activate G-protein-coupled cannabinoid receptors found in various organisms. After AEA and 2-AG were discovered in the 1990s, they have been extensively documented to have a broad range of physiological functions. Along with AEA, several NAEs, for example,N-palmitoylethanolamine (PEA),N-stearoylethanolamine (SEA), andN-oleoylethanolamine (OEA) are also present in tissues, usually at much larger concentrations than AEA. Any perturbation that involves the endocannabinoid pathway may subsequently alter basal level or metabolism of these lipid mediators. Further,more » the altered levels of these molecules often reflect pathological conditions associated with tissue damage. Robust and sensitive methodologies to analyze these lipid mediators are essential to understanding how they act as endocannabinoids. Lastly, the recent advances in mass spectrometry allow researchers to develop lipidomics approaches and several methodologies have been proposed to quantify endocannabinoids in various biological systems.« less

  19. Lipidomic Analysis of Endocannabinoid Signaling: Targeted Metabolite Identification and Quantification

    DOE PAGES

    Keereetaweep, Jantana; Chapman, Kent D.

    2016-01-01

    The endocannabinoidsN-arachidonoylethanolamide (or anandamide, AEA) and 2-arachidonoylglycerol (2-AG) belong to the larger groups ofN-acylethanolamines (NAEs) and monoacylglycerol (MAG) lipid classes, respectively. They are biologically active lipid molecules that activate G-protein-coupled cannabinoid receptors found in various organisms. After AEA and 2-AG were discovered in the 1990s, they have been extensively documented to have a broad range of physiological functions. Along with AEA, several NAEs, for example,N-palmitoylethanolamine (PEA),N-stearoylethanolamine (SEA), andN-oleoylethanolamine (OEA) are also present in tissues, usually at much larger concentrations than AEA. Any perturbation that involves the endocannabinoid pathway may subsequently alter basal level or metabolism of these lipid mediators. Further,more » the altered levels of these molecules often reflect pathological conditions associated with tissue damage. Robust and sensitive methodologies to analyze these lipid mediators are essential to understanding how they act as endocannabinoids. Lastly, the recent advances in mass spectrometry allow researchers to develop lipidomics approaches and several methodologies have been proposed to quantify endocannabinoids in various biological systems.« less

  20. Lipidomic Analysis of Endocannabinoid Signaling: Targeted Metabolite Identification and Quantification

    PubMed Central

    Keereetaweep, Jantana; Chapman, Kent D.

    2016-01-01

    The endocannabinoids N-arachidonoylethanolamide (or anandamide, AEA) and 2-arachidonoylglycerol (2-AG) belong to the larger groups of N-acylethanolamines (NAEs) and monoacylglycerol (MAG) lipid classes, respectively. They are biologically active lipid molecules that activate G-protein-coupled cannabinoid receptors found in various organisms. After AEA and 2-AG were discovered in the 1990s, they have been extensively documented to have a broad range of physiological functions. Along with AEA, several NAEs, for example, N-palmitoylethanolamine (PEA), N-stearoylethanolamine (SEA), and N-oleoylethanolamine (OEA) are also present in tissues, usually at much larger concentrations than AEA. Any perturbation that involves the endocannabinoid pathway may subsequently alter basal level or metabolism of these lipid mediators. Further, the altered levels of these molecules often reflect pathological conditions associated with tissue damage. Robust and sensitive methodologies to analyze these lipid mediators are essential to understanding how they act as endocannabinoids. The recent advances in mass spectrometry allow researchers to develop lipidomics approaches and several methodologies have been proposed to quantify endocannabinoids in various biological systems. PMID:26839710

  1. The endocannabinoid system and appetite: relevance for food reward.

    PubMed

    Jager, Gerry; Witkamp, Renger F

    2014-06-01

    Mounting evidence substantiates the central role of the endocannabinoid system (ECS) in the modulation of both homeostatic and hedonic elements of appetite and food intake. Conversely, feeding status and dietary patterns directly influence activity of the ECS. Following a general introduction on the functioning of the ECS, the present review specifically addresses its role in the modulation of hedonic eating. Humans possess strong motivational systems triggered by rewarding aspects of food. Food reward is comprised of two components: one appetitive (orienting towards food); the other consummatory (hedonic evaluation), also referred to as 'wanting' and 'liking', respectively. Endocannabinoid tone seems to influence both the motivation to feed and the hedonic value of foods, probably by modifying palatability. Human physiology underlying hedonic eating is still not fully understood. A better understanding of the role of the ECS in the rewarding value of specific foods or diets could offer new possibilities to optimise the balance between energy and nutrient intake for different target groups. These groups include the obese and overweight, and potentially individuals suffering from malnutrition. Examples for the latter group are patients with disease-related anorexia, as well as the growing population of frail elderly suffering from persistent loss of food enjoyment and appetite resulting in malnutrition and involuntary weight loss. It has become clear that the psychobiology of food hedonics is extremely complex and the clinical failure of CB1 inverse agonists including rimonabant (Accomplia®) has shown that 'quick wins' in this field are unlikely.

  2. Developmental regulation of fear learning and anxiety behavior by endocannabinoids

    PubMed Central

    Lee, Tiffany T.-Y.; Hill, Matthew N.; Lee, Francis S.

    2015-01-01

    The developing brain undergoes substantial maturation into adulthood and the development of specific neural structures occurs on differing timelines. Transient imbalances between developmental trajectories of corticolimbic structures, which are known to contribute to regulation over fear learning and anxiety, can leave an individual susceptible to mental illness, particularly anxiety disorders. There is a substantial body of literature indicating that the endocannabinoid system critically regulates stress responsivity and emotional behavior throughout the life span, making this system a novel therapeutic target for stress- and anxiety-related disorders. During early life and adolescence, corticolimbic endocannabinoid signaling changes dynamically and coincides with different sensitive periods of fear learning, suggesting that endocannabinoid signaling underlies age-specific fear learning responses. Moreover, perturbations to these normative fluctuations in corticolimbic endocannabinoid signaling, such as stress or cannabinoid exposure, could serve as a neural substrate contributing to alterations to the normative developmental trajectory of neural structures governing emotional behavior and fear learning. In this review, we first introduce the components of the endocannabinoid system and discuss clinical and rodent models demonstrating endocannabinoid regulation of fear learning and anxiety in adulthood. Next, we highlight distinct fear learning and regulation profiles throughout development and discuss the ontogeny of the endocannabinoid system in the central nervous system, and models of pharmacological augmentation of endocannabinoid signaling during development in the context of fear learning and anxiety. PMID:26419643

  3. A critical role for prefrontocortical endocannabinoid signaling in the regulation of stress and emotional behavior.

    PubMed

    McLaughlin, Ryan J; Hill, Matthew N; Gorzalka, Boris B

    2014-05-01

    The prefrontal cortex (PFC) provides executive control of the brain in humans and rodents, coordinating cognitive, emotional, and behavioral responses to threatening stimuli and subsequent feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis. The endocannabinoid system has emerged as a fundamental regulator of HPA axis feedback inhibition and an important modulator of emotional behavior. However, the precise role of endocannabinoid signaling within the PFC with respect to stress coping and emotionality has only recently been investigated. This review discusses the current state of knowledge regarding the localization and function of the endocannabinoid system in the PFC, its sensitivity to stress and its role in modulating the neuroendocrine and behavioral responses to aversive stimuli. We propose a model whereby steady-state endocannabinoid signaling in the medial PFC indirectly regulates the outflow of pyramidal neurons by fine-tuning GABAergic inhibition. Local activation of this population of CB1 receptors increases the downstream targets of medial PFC activation, which include inhibitory interneurons in the basolateral amygdala, inhibitory relay neurons in the bed nucleus of the stria terminalis and monoamine cell bodies such as the dorsal raphe nucleus. This ultimately produces beneficial effects on emotionality (active coping responses to stress and reduced anxiety) and assists in constraining activation of the HPA axis. Under conditions of chronic stress, or in individuals suffering from mood disorders, this system may be uniquely recruited to help maintain appropriate function in the face of adversity, while breakdown of the endocannabinoid system in the medial PFC may be, in and of itself, sufficient to produce neuropsychiatric illness. Thus, we suggest that endocannabinoid signaling in the medial PFC may represent an attractive target for the treatment of stress-related disorders. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Endocannabinoid mechanism in amphetamine-type stimulant use disorders: A short review.

    PubMed

    Su, Hang; Zhao, Min

    2017-12-01

    Recent evidence shows that the endocannabinoid system is involved in amphetamine-type stimulants (ATS) use disorders. To elucidate the role of the endocannabinoid system in ATS addiction, we reviewed results of studies using cannabinoid receptor agonists, antagonists as well as knockout model. The endocannabinoid system seems to play a role in reinstatement and relapse of ATS addiction and ATS-induced psychiatric symptoms. The molecular mechanisms of this system remains unclear, the association with dopamine system in nucleus accumbens is most likely involved. However, the function of the endocannabinoid system in anxiety and anti-anxiety effects induced by ATS is more complicated. These findings suggest that the endocannabinoid system may play an important role in the mechanism of ATS addiction and provide new idea for treating ATS addiction. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. FABP-1 GENE ABLATION IMPACTS BRAIN ENDOCANNABINOID SYSTEM IN MALE MICE

    PubMed Central

    Martin, Gregory G.; Chung, Sarah; Landrock, Danilo; Landrock, Kerstin K.; Huang, Huan; Dangott, Lawrence J.; Peng, Xiaoxue; Kaczocha, Martin; Seeger, Drew R.; Murphy, Eric J.; Golovko, Mikhail Y.; Kier, Ann B.; Schroeder, Friedhelm

    2016-01-01

    Liver fatty acid binding protein (FABP1, L-FABP) has high affinity for and enhances uptake of arachidonic acid (ARA, C20:4, n-6) which, when esterified to phospholipids, is the requisite precursor for synthesis of endocannabinoids (EC) such as arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG). The brain derives most of its ARA from plasma, taking up ARA and transporting it intracellularly via cytosolic fatty acid binding proteins (FABPs 3,5, and 7) localized within the brain. In contrast, the much more prevalent cytosolic FABP1 is not detectable in the brain but is instead highly expressed in the liver. Therefore, the possibility that FABP1 outside the central nervous system may regulate brain AEA and 2-AG was examined in wild-type (WT) and FABP1 null (LKO) male mice. LKO increased brain levels of AA-containing EC (AEA, 2-AG), correlating with increased free and total ARA in brain and serum. LKO also increased brain levels of non-ARA that contain potentiating endocannabinoids (EC*) such as OEA, PEA, 2-OG, and 2-PG. Concomitantly, LKO decreased serum total ARA-containing EC, but not non-ARA endocannabinoids. LKO did not elicit these changes in the brain EC and EC* due to compensatory upregulation of brain protein levels of enzymes in EC synthesis (NAPEPLD, DAGLα) or cytosolic EC chaperone proteins (FABPs 3, 5, 7, SCP-2, HSP70), or cannabinoid receptors (CB1, TRVP1). These data show for the first time that the non-CNS fatty acid binding protein FABP1 markedly affected brain levels of both ARA-containing endocannabinoids (AEA, 2-AG) as well as their non-ARA potentiating endocannabinoids. PMID:27167970

  6. Endocannabinoids in the Retina: From Marijuana to Neuroprotection

    PubMed Central

    Yazulla, Stephen

    2008-01-01

    The active component of the marijuana plant Cannabis sativa, Δ9-tetrahydrocannabinol (THC), produces numerous beneficial effects, including analgesia, appetite stimulation and nausea reduction, in addition to its psychotropic effects. THC mimics the action of endogenous fatty acid derivatives, referred to as endocannabinoids. The effects of THC and the endocannabinoids are mediated largely by metabotropic receptors that are distributed throughout the nervous and peripheral organ systems. There is great interest in endocannabinoids for their role in neuroplasticity as well as for therapeutic use in numerous conditions, including pain, stroke, cancer, obesity, osteoporosis, fertility, neurodegenerative diseases, multiple sclerosis, glaucoma and inflammatory diseases, among others. However, there has been relatively far less research on this topic in the eye and retina compared with the brain and other organ systems. The purpose of this review is to introduce the “cannabinergic” field to the retinal community. All of the fundamental work on cannabinoids has been performed in non-retinal preparations, necessitating extensive dependence on this literature for background. Happily, the retinal cannabinoid system has much in common with other regions of the central nervous system. For example, there is general agreement that cannabinoids suppress dopamine release and presynaptically reduce transmitter release from cones and bipolar cells. How these effects relate to light and dark adaptation, receptive field formation, temporal properties of ganglion cells or visual perception are unknown. The presence of multiple endocannabinoids, degradative enzymes with their bioactive metabolites, and receptors provides a broad spectrum of opportunities for basic research and to identify targets for therapeutic application to retinal diseases. PMID:18725316

  7. Endocannabinoids in the retina: from marijuana to neuroprotection.

    PubMed

    Yazulla, Stephen

    2008-09-01

    The active component of the marijuana plant Cannabis sativa, Delta9-tetrahydrocannabinol (THC), produces numerous beneficial effects, including analgesia, appetite stimulation and nausea reduction, in addition to its psychotropic effects. THC mimics the action of endogenous fatty acid derivatives, referred to as endocannabinoids. The effects of THC and the endocannabinoids are mediated largely by metabotropic receptors that are distributed throughout the nervous and peripheral organ systems. There is great interest in endocannabinoids for their role in neuroplasticity as well as for therapeutic use in numerous conditions, including pain, stroke, cancer, obesity, osteoporosis, fertility, neurodegenerative diseases, multiple sclerosis, glaucoma and inflammatory diseases, among others. However, there has been relatively far less research on this topic in the eye and retina compared with the brain and other organ systems. The purpose of this review is to introduce the "cannabinergic" field to the retinal community. All of the fundamental works on cannabinoids have been performed in non-retinal preparations, necessitating extensive dependence on this literature for background. Happily, the retinal cannabinoid system has much in common with other regions of the central nervous system. For example, there is general agreement that cannabinoids suppress dopamine release and presynaptically reduce transmitter release from cones and bipolar cells. How these effects relate to light and dark adaptations, receptive field formation, temporal properties of ganglion cells or visual perception are unknown. The presence of multiple endocannabinoids, degradative enzymes with their bioactive metabolites, and receptors provides a broad spectrum of opportunities for basic research and to identify targets for therapeutic application to retinal diseases.

  8. ENDOCANNABINOID INFLUENCE IN DRUG REINFORCEMENT, DEPENDENCE AND ADDICTION-RELATED BEHAVIORS

    PubMed Central

    Serrano, Antonia; Parsons, Loren H.

    2011-01-01

    The endogenous cannabinoid system is an important regulatory system involved in physiological homeostasis. Endocannabinoid signaling is known to modulate neural development, immune function, metabolism, synaptic plasticity and emotional state. Accumulating evidence also implicates brain endocannabinoid signaling in the etiology of drug addiction which is characterized by compulsive drug seeking, loss of control in limiting drug intake, emergence of a negative emotional state in the absence of drug use and a persistent vulnerability toward relapse to drug use during protracted abstinence. In this review we discuss the effects of drug intake on brain endocannabinoid signaling, evidence implicating the endocannabinoid system in the motivation for drug consumption, and drug-induced alterations in endocannabinoid function that may contribute to various aspects of addiction including dysregulated synaptic plasticity, increased stress responsivity, negative affective states, drug craving and relapse to drug taking. Current knowledge of genetic variants in endocannabinoid signaling associated with addiction is also discussed. PMID:21798285

  9. State-dependent, bidirectional modulation of neural network activity by endocannabinoids.

    PubMed

    Piet, Richard; Garenne, André; Farrugia, Fanny; Le Masson, Gwendal; Marsicano, Giovanni; Chavis, Pascale; Manzoni, Olivier J

    2011-11-16

    The endocannabinoid (eCB) system and the cannabinoid CB1 receptor (CB1R) play key roles in the modulation of brain functions. Although actions of eCBs and CB1Rs are well described at the synaptic level, little is known of their modulation of neural activity at the network level. Using microelectrode arrays, we have examined the role of CB1R activation in the modulation of the electrical activity of rat and mice cortical neural networks in vitro. We find that exogenous activation of CB1Rs expressed on glutamatergic neurons decreases the spontaneous activity of cortical neural networks. Moreover, we observe that the net effect of the CB1R antagonist AM251 inversely correlates with the initial level of activity in the network: blocking CB1Rs increases network activity when basal network activity is low, whereas it depresses spontaneous activity when its initial level is high. Our results reveal a complex role of CB1Rs in shaping spontaneous network activity, and suggest that the outcome of endogenous neuromodulation on network function might be state dependent.

  10. Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity.

    PubMed

    Argueta, Donovan A; DiPatrizio, Nicholas V

    2017-03-15

    The endocannabinoid system in the brain and periphery plays a major role in controlling food intake and energy balance. We reported that tasting dietary fats was met with increased levels of the endocannabinoids, 2-arachidonoyl-sn-glycerol (2-AG) and anandamide, in the rat upper small intestine, and pharmacological inhibition of this local signaling event dose-dependently blocked sham feeding of fats. We now investigated the contribution of peripheral endocannabinoid signaling in hyperphagia associated with chronic consumption of a western-style diet in mice ([WD] i.e., high fat and sucrose). Feeding patterns were assessed in male C57BL/6Tac mice maintained for 60days on WD or a standard rodent chow (SD), and the role for peripheral endocannabinoid signaling at CB 1 Rs in controlling food intake was investigated via pharmacological interventions. In addition, levels of the endocannabinoids, 2-AG and anandamide, in the upper small intestine and circulation of mice were analyzed via liquid chromatography coupled to tandem mass spectrometry to evaluate diet-related changes in endocannabinoid signaling and the potential impact on food intake. Mice fed WD for 60days exhibited large increases in body weight, daily caloric intake, average meal size, and rate of feeding when compared to control mice fed SD. Inhibiting peripheral CB 1 Rs with the peripherally-restricted neutral cannabinoid CB 1 receptor antagonist, AM6545 (10mg/kg), significantly reduced intake of WD during a 6h test, but failed to modify intake of SD in mice. AM6545 normalized intake of WD, average meal size, and rate of feeding to levels found in SD control mice. These results suggest that endogenous activity at peripheral CB 1 Rs in WD mice is critical for driving hyperphagia. In support of this hypothesis, levels of 2-AG and anandamide in both, jejunum mucosa and plasma, of ad-libitum fed WD mice increased when compared to SC mice. Furthermore, expression of genes for primary components of the

  11. Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity

    PubMed Central

    Argueta, Donovan A.; DiPatrizio, Nicholas V.

    2017-01-01

    The endocannabinoid system in the brain and periphery plays a major role in controlling food intake and energy balance. We reported that tasting dietary fats was met with increased levels of the endocannabinoids, 2-arachidonoyl-sn-glycerol (2-AG) and anandamide, in the rat upper small intestine, and pharmacological inhibition of this local signaling event dose-dependently blocked sham feeding of fats. We now investigated the contribution of peripheral endocannabinoid signaling in hyperphagia associated with chronic consumption of a western-style diet in mice ([WD] i.e., high fat and sucrose). Feeding patterns were assessed in male C57BL/6Tac mice maintained for 60 days on WD or a standard rodent chow (SD), and the role for peripheral endocannabinoid signaling at CB1Rs in controlling food intake was investigated via pharmacological interventions. In addition, levels of the endocannabinoids, 2-AG and anandamide, in the upper small intestine and circulation of mice were analyzed via liquid chromatography coupled to tandem mass spectrometry to evaluate diet-related changes in endocannabinoid signaling and the potential impact on food intake. Mice fed WD for 60 days exhibited large increases in body weight, daily caloric intake, average meal size, and rate of feeding when compared to control mice fed SD. Inhibiting peripheral CB1Rs with the peripherally-restricted neutral cannabinoid CB1 receptor antagonist, AM6545 (10mg/kg), significantly reduced intake of WD during a 6 h test, but failed to modify intake of SD in mice. AM6545 normalized intake of WD, average meal size, and rate of feeding to levels found in SD control mice. These results suggest that endogenous activity at peripheral CB1Rs in WD mice is critical for driving hyperphagia. In support of this hypothesis, levels of 2-AG and anandamide in both, jejunum mucosa and plasma, of ad-libitum fed WD mice increased when compared to SC mice. Furthermore, expression of genes for primary components of the

  12. The Endocannabinoid System in the Retina: From Physiology to Practical and Therapeutic Applications.

    PubMed

    Schwitzer, Thomas; Schwan, Raymund; Angioi-Duprez, Karine; Giersch, Anne; Laprevote, Vincent

    2016-01-01

    Cannabis is one of the most prevalent drugs used in industrialized countries. The main effects of Cannabis are mediated by two major exogenous cannabinoids: ∆9-tetrahydroxycannabinol and cannabidiol. They act on specific endocannabinoid receptors, especially types 1 and 2. Mammals are endowed with a functional cannabinoid system including cannabinoid receptors, ligands, and enzymes. This endocannabinoid signaling pathway is involved in both physiological and pathophysiological conditions with a main role in the biology of the central nervous system. As the retina is a part of the central nervous system due to its embryonic origin, we aim at providing the relevance of studying the endocannabinoid system in the retina. Here, we review the distribution of the cannabinoid receptors, ligands, and enzymes in the retina and focus on the role of the cannabinoid system in retinal neurobiology. This review describes the presence of the cannabinoid system in critical stages of retinal processing and its broad involvement in retinal neurotransmission, neuroplasticity, and neuroprotection. Accordingly, we support the use of synthetic cannabinoids as new neuroprotective drugs to prevent and treat retinal diseases. Finally, we argue for the relevance of functional retinal measures in cannabis users to evaluate the impact of cannabis use on human retinal processing.

  13. The Endocannabinoid System in the Retina: From Physiology to Practical and Therapeutic Applications

    PubMed Central

    Schwitzer, Thomas; Schwan, Raymund; Angioi-Duprez, Karine; Giersch, Anne; Laprevote, Vincent

    2016-01-01

    Cannabis is one of the most prevalent drugs used in industrialized countries. The main effects of Cannabis are mediated by two major exogenous cannabinoids: ∆9-tetrahydroxycannabinol and cannabidiol. They act on specific endocannabinoid receptors, especially types 1 and 2. Mammals are endowed with a functional cannabinoid system including cannabinoid receptors, ligands, and enzymes. This endocannabinoid signaling pathway is involved in both physiological and pathophysiological conditions with a main role in the biology of the central nervous system. As the retina is a part of the central nervous system due to its embryonic origin, we aim at providing the relevance of studying the endocannabinoid system in the retina. Here, we review the distribution of the cannabinoid receptors, ligands, and enzymes in the retina and focus on the role of the cannabinoid system in retinal neurobiology. This review describes the presence of the cannabinoid system in critical stages of retinal processing and its broad involvement in retinal neurotransmission, neuroplasticity, and neuroprotection. Accordingly, we support the use of synthetic cannabinoids as new neuroprotective drugs to prevent and treat retinal diseases. Finally, we argue for the relevance of functional retinal measures in cannabis users to evaluate the impact of cannabis use on human retinal processing. PMID:26881099

  14. Western Blotting of the Endocannabinoid System.

    PubMed

    Wager-Miller, Jim; Mackie, Ken

    2016-01-01

    Measuring expression levels of G protein-coupled receptors (GPCRs) is an important step for understanding the distribution, function, and regulation of these receptors. A common approach for detecting proteins from complex biological systems is Western blotting. In this chapter, we describe a general approach to Western blotting protein components of the endocannabinoid system using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and nitrocellulose membranes, with a focus on detecting type 1 cannabinoid (CB1) receptors. When this technique is carefully used, specifically with validation of the primary antibodies, it can provide quantitative information on protein expression levels. Additional information can also be inferred from Western blotting such as potential posttranslational modifications that can be further evaluated by specific analytical techniques.

  15. Emerging Role of (Endo)Cannabinoids in Migraine.

    PubMed

    Leimuranta, Pinja; Khiroug, Leonard; Giniatullin, Rashid

    2018-01-01

    In this mini-review, we summarize recent discoveries and present new hypotheses on the role of cannabinoids in controlling trigeminal nociceptive system underlying migraine pain. Individual sections of this review cover key aspects of this topic, such as: (i) the current knowledge on the endocannabinoid system (ECS) with emphasis on expression of its components in migraine related structures; (ii) distinguishing peripheral from central site of action of cannabinoids, (iii) proposed mechanisms of migraine pain and control of nociceptive traffic by cannabinoids at the level of meninges and in brainstem, (iv) therapeutic targeting in migraine of monoacylglycerol lipase and fatty acid amide hydrolase, enzymes which control the level of endocannabinoids; (v) dual (possibly opposing) actions of cannabinoids via anti-nociceptive CB1 and CB2 and pro-nociceptive TRPV1 receptors. We explore the cannabinoid-mediated mechanisms in the frame of the Clinical Endocannabinoid Deficiency (CECD) hypothesis, which implies reduced tone of endocannabinoids in migraine patients. We further discuss the control of cortical excitability by cannabinoids via inhibition of cortical spreading depression (CSD) underlying the migraine aura. Finally, we present our view on perspectives of Cannabis-derived (extracted or synthetized marijuana components) or novel endocannabinoid therapeutics in migraine treatment.

  16. Regulation of brain reward by the endocannabinoid system: a critical review of behavioral studies in animals.

    PubMed

    Vlachou, S; Panagis, G

    2014-01-01

    The endocannabinoid system has been implicated in the regulation of a variety of physiological processes, including a crucial involvement in brain reward systems and the regulation of motivational processes. Behavioral studies have shown that cannabinoid reward may involve the same brain circuits and similar brain mechanisms with other drugs of abuse, such as nicotine, cocaine, alcohol and heroin, as well as natural rewards, such as food, water and sucrose, although the conditions under which cannabinoids exert their rewarding effects may be more limited. The purpose of the present review is to briefly describe and evaluate the behavioral and pharmacological research concerning the major components of the endocannabinoid system and reward processes. Special emphasis is placed on data received from four procedures used to test the effects of the endocannabinoid system on brain reward in animals; namely, the intracranial self-stimulation paradigm, the self-administration procedure, the conditioned place preference procedure and the drug-discrimination procedure. The effects of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor agonists, antagonists and endocannabinoid modulators in these procedures are examined. Further, the involvement of CB1 and CB2 receptors, as well the fatty acid amid hydrolase (FAAH) enzyme in reward processes is investigated through presentation of respective genetic ablation studies in mice. We suggest that the endocannabinoid system plays a major role in modulating motivation and reward processes. Further research will provide us with a better understanding of these processes and, thus, could lead to the development of potential therapeutic compounds for the treatment of reward-related disorders.

  17. Endocannabinoids control vesicle release mode at midbrain periaqueductal grey inhibitory synapses.

    PubMed

    Aubrey, Karin R; Drew, Geoffrey M; Jeong, Hyo-Jin; Lau, Benjamin K; Vaughan, Christopher W

    2017-01-01

    The midbrain periaqueductal grey (PAG) forms part of an endogenous analgesic system which is tightly regulated by the neurotransmitter GABA. The role of endocannabinoids in regulating GABAergic control of this system was examined in rat PAG slices. Under basal conditions GABAergic neurotransmission onto PAG output neurons was multivesicular. Activation of the endocannabinoid system reduced GABAergic inhibition by reducing the probability of release and by shifting release to a univesicular mode. Blockade of endocannabinoid system unmasked a tonic control over the probability and mode of GABA release. These findings provides a mechanistic foundation for the control of the PAG analgesic system by disinhibition. The midbrain periaqueductal grey (PAG) has a crucial role in coordinating endogenous analgesic responses to physiological and psychological stressors. Endocannabinoids are thought to mediate a form of stress-induced analgesia within the PAG by relieving GABAergic inhibition of output neurons, a process known as disinhibition. This disinhibition is thought to be achieved by a presynaptic reduction in GABA release probability. We examined whether other mechanisms have a role in endocannabinoid modulation of GABAergic synaptic transmission within the rat PAG. The group I mGluR agonist DHPG ((R,S)-3,5-dihydroxyphenylglycine) inhibited evoked IPSCs and increased their paired pulse ratio in normal external Ca 2+ , and when release probability was reduced by lowering Ca 2+ . However, the effect of DHPG on the coefficient of variation and kinetics of evoked IPSCs differed between normal and low Ca 2+ . Lowering external Ca 2+ had a similar effect on evoked IPSCs to that observed for DHPG in normal external Ca 2+ . The low affinity GABA A receptor antagonist TPMPA ((1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid) inhibited evoked IPSCs to a greater extent in low than in normal Ca 2+ . Together these findings indicate that the normal mode of GABA release is

  18. The Therapeutic Aspects of the Endocannabinoid System (ECS) for Cancer and their Development: From Nature to Laboratory.

    PubMed

    Khan, Mohammed I; Sobocińska, Anna A; Czarnecka, Anna M; Król, Magdalena; Botta, Bruno; Szczylik, Cezary

    2016-01-01

    The endocannabinoid system (ECS) is a group of neuromodulatory lipids and their receptors, which are widely distributed in mammalian tissues. ECS regulates various cardiovascular, nervous, and immune system functions inside cells. In recent years, there has been a growing body of evidence for the use of synthetic and natural cannabinoids as potential anticancer agents. For instance, the CB1 and CB2 receptors are assumed to play an important role inside the endocannabinoid system. These receptors are abundantly expressed in the brain and fatty tissue of the human body. Despite recent developments in molecular biology, there is still a lack of knowledge about the distribution of CB1 and CB2 receptors in the human kidney and their role in kidney cancer. To address this gap, we explore and demonstrate the role of the endocannabinoid system in renal cell carcinoma (RCC). In this brief overview, we elucidate the therapeutic aspects of the endocannabinoid system for various cancers and explain how this system can be used for treating kidney cancer. Overall, this review provides new insights into cannabinoids' mechanisms of action in both in vivo and in vitro models, and focuses on recent discoveries in the field.

  19. Presence and regulation of the endocannabinoid system in human dendritic cells.

    PubMed

    Matias, Isabel; Pochard, Pierre; Orlando, Pierangelo; Salzet, Michel; Pestel, Joel; Di Marzo, Vincenzo

    2002-08-01

    Cannabinoid receptors and their endogenous ligands, the endocannabinoids, have been detected in several blood immune cells, including monocytes/macrophages, basophils and lymphocytes. However, their presence in dendritic cells, which play a key role in the initiation and development of the immune response, has never been investigated. Here we have analyzed human dendritic cells for the presence of the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), the cannabinoid CB1 and CB2 receptors, and one of the enzymes mostly responsible for endocannabinoid hydrolysis, the fatty acid amide hydrolase (FAAH). By using a very sensitive liquid chromatography-atmospheric pressure chemical ionization-mass spectrometric (LC-APCI-MS) method, lipids extracted from immature dendritic cells were shown to contain 2-AG, anandamide and the anti-inflammatory anandamide congener, N-palmitoylethanolamine (PalEtn) (2.1 +/- 1.0, 0.14 +/- 0.02 and 8.2 +/- 3.9 pmol x 10(-7) cells, respectively). The amounts of 2-AG, but not anandamide or PalEtn, were significantly increased following cell maturation induced by bacterial lipopolysaccharide (LPS) or the allergen Der p 1 (2.8- and 1.9-fold, respectively). By using both RT-PCR and Western immunoblotting, dendritic cells were also found to express measurable amounts of CB1 and CB2 receptors and of FAAH. Cell maturation did not consistently modify the expression of these proteins, although in some cell preparations a decrease of the levels of both CB1 and CB2 mRNA transcripts was observed after LPS stimulation. These findings demonstrate for the first time that the endogenous cannabinoid system is present in human dendritic cells and can be regulated by cell activation.

  20. The role of the endocannabinoid system in the brain-gut axis

    PubMed Central

    Sharkey, Keith A.; Wiley, John W.

    2016-01-01

    The actions of cannabis are mediated by receptors that are part of an endogenous cannabinoid system. The endocannabinoid system (ECS) consists of the naturally occurring ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the cannabinoid receptors CB1 and CB2. The ECS is a widely distributed transmitter system that controls gut functions peripherally and centrally. It is an important physiologic regulator of gastrointestinal motility. Polymorphisms in the gene encoding CB1 (CNR1) have been associated with some forms of irritable bowel syndrome. The ECS is involved in the control of nausea and vomiting and visceral sensation. The homeostatic role of the ECS also extends to the control of intestinal inflammation. We review the mechanisms by which the ECS links stress and visceral pain. CB1 in sensory ganglia controls visceral sensation, and transcription of CNR1 is modified through epigenetic processes under conditions of chronic stress. These processes might link stress with abdominal pain. The ECS is also involved centrally in the manifestation of stress, and endocannabinoid signaling reduces the activity of hypothalamic–pituitary–adrenal pathways via actions in specific brain regions—notably the prefrontal cortex, amygdala, and hypothalamus. Agents that modulate the ECS are in early stages of development for treatment of gastrointestinal diseases. Increasing our understanding of the ECS will greatly advance our knowledge of interactions between the brain and gut and could lead to new treatments for gastrointestinal disorders. PMID:27133395

  1. Increasing Endocannabinoid Levels in the Ventral Pallidum Restore Aberrant Dopamine Neuron Activity in the Subchronic PCP Rodent Model of Schizophrenia

    PubMed Central

    Chen, Li; Lodge, Daniel J

    2015-01-01

    Background: Schizophrenia is a debilitating disorder that affects 1% of the US population. While the exogenous administration of cannabinoids such as tetrahydrocannabinol is reported to exacerbate psychosis in schizophrenia patients, augmenting the levels of endogenous cannabinoids has gained attention as a possible alternative therapy to schizophrenia due to clinical and preclinical observations. Thus, patients with schizophrenia demonstrate an inverse relationship between psychotic symptoms and levels of the endocannabinoid anandamide. In addition, increasing endocannabinoid levels (by blockade of enzymatic degradation) has been reported to attenuate social withdrawal in a preclinical model of schizophrenia. Here we examine the effects of increasing endogenous cannabinoids on dopamine neuron activity in the sub-chronic phencyclidine (PCP) model. Aberrant dopamine system function is thought to underlie the positive symptoms of schizophrenia. Methods: Using in vivo extracellular recordings in chloral hydrate–anesthetized rats, we now demonstrate an increase in dopamine neuron population activity in PCP-treated rats. Results: Interestingly, endocannabinoid upregulation, induced by URB-597, was able to normalize this aberrant dopamine neuron activity. Furthermore, we provide evidence that the ventral pallidum is the site where URB-597 acts to restore ventral tegmental area activity. Conclusions: Taken together, we provide preclinical evidence that augmenting endogenous cannabinoids may be an effective therapy for schizophrenia, acting in part to restore ventral pallidal activity. PMID:25539511

  2. Endocannabinoids Acting at Cannabinoid-1 Receptors Regulate Cardiovascular Function in Hypertension

    PubMed Central

    Bátkai, Sándor; Pacher, Pál; Osei-Hyiaman, Douglas; Radaeva, Svetlana; Liu, Jie; Harvey-White, Judith; Offertáler, László; Mackie, Ken; Audrey Rudd, M.; Bukoski, Richard D.; Kunos, George

    2009-01-01

    Background Endocannabinoids are novel lipid mediators with hypotensive and cardiodepressor activity. Here, we examined the possible role of the endocannabinergic system in cardiovascular regulation in hypertension. Methods and Results In spontaneously hypertensive rats (SHR), cannabinoid-1 receptor (CB1) antagonists increase blood pressure and left ventricular contractile performance. Conversely, preventing the degradation of the endocannabinoid anandamide by an inhibitor of fatty acid amidohydrolase reduces blood pressure, cardiac contractility, and vascular resistance to levels in normotensive rats, and these effects are prevented by CB1 antagonists. Similar changes are observed in 2 additional models of hypertension, whereas in normotensive control rats, the same parameters remain unaffected by any of these treatments. CB1 agonists lower blood pressure much more in SHR than in normotensive Wistar-Kyoto rats, and the expression of CB1 is increased in heart and aortic endothelium of SHR compared with Wistar-Kyoto rats. Conclusions We conclude that endocannabinoids tonically suppress cardiac contractility in hypertension and that enhancing the CB1-mediated cardiodepressor and vasodilator effects of endogenous anandamide by blocking its hydrolysis can normalize blood pressure. Targeting the endocannabinoid system offers novel therapeutic strategies in the treatment of hypertension. PMID:15451779

  3. Interplay Between n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair.

    PubMed

    Dyall, Simon C

    2017-11-01

    The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), long-chain polyunsaturated fatty acids (LCPUFAs) of the n-6 and n-3 series, respectively. Both are essential for optimal brain development and function. Dietary enrichment with DHA and other long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA), has shown beneficial effects on learning and memory, neuroinflammatory processes, and synaptic plasticity and neurogenesis. ARA, DHA and EPA are precursors to a diverse repertoire of bioactive lipid mediators, including endocannabinoids. The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most widely studied endocannabinoids and are both derived from phospholipid-bound ARA. The endocannabinoid system also has well-established roles in neuroinflammation, synaptic plasticity and neurogenesis, suggesting an overlap in the neuroprotective effects observed with these different classes of lipids. Indeed, growing evidence suggests a complex interplay between n-3 and n-6 LCPUFA and the endocannabinoid system. For example, long-term DHA and EPA supplementation reduces AEA and 2-AG levels, with reciprocal increases in levels of the analogous endocannabinoid-like DHA and EPA-derived molecules. This review summarises current evidence of this interplay and discusses the therapeutic potential for brain protection and repair.

  4. Using the endocannabinoid system as a neuroprotective strategy in perinatal hypoxic-ischemic brain injury

    PubMed Central

    Lara-Celador, I.; Goñi-de-Cerio, F.; Alvarez, Antonia; Hilario, Enrique

    2013-01-01

    One of the most important causes of brain injury in the neonatal period is a perinatal hypoxic-ischemic event. This devastating condition can lead to long-term neurological deficits or even death. After hypoxic-ischemic brain injury, a variety of specific cellular mechanisms are set in motion, triggering cell damage and finally producing cell death. Effective therapeutic treatments against this phenomenon are still unavailable because of complex molecular mechanisms underlying hypoxic-ischemic brain injury. After a thorough understanding of the mechanism underlying neural plasticity following hypoxic-ischemic brain injury, various neuroprotective therapies have been developed for alleviating brain injury and improving long-term outcomes. Among them, the endocannabinoid system emerges as a natural system of neuroprotection. The endocannabinoid system modulates a wide range of physiological processes in mammals and has demonstrated neuroprotective effects in different paradigms of acute brain injury, acting as a natural neuroprotectant. The aim of this review is to study the use of different therapies to induce long-term therapeutic effects after hypoxic-ischemic brain injury, and analyze the important role of the endocannabinoid system as a new neuroprotective strategy against perinatal hypoxic-ischemic brain injury. PMID:25206720

  5. Mechanism of platelet activation induced by endocannabinoids in blood and plasma.

    PubMed

    Brantl, S Annette; Khandoga, Anna L; Siess, Wolfgang

    2014-01-01

    Platelets play a central role in atherosclerosis and atherothrombosis, and circulating endocannabinoids might modulate platelet function. Previous studies concerning effects of anandamide (N-arachidonylethanolamide) and 2-arachidonoylglycerol (2-AG) on platelets, mainly performed on isolated cells, provided conflicting results. We therefore investigated the action of three main endocannabinoids [anandamide, 2-AG and virodhamine (arachidonoylethanolamine)] on human platelets in blood and platelet-rich plasma (PRP). 2-AG and virodhamine induced platelet aggregation in blood, and shape change, aggregation and adenosine triphosphate (ATP) secretion in PRP. The EC50 of 2-AG and virodhamine for platelet aggregation in blood was 97 and 160 µM, respectively. Lower concentrations of 2-AG (20 µM) and virodhamine (50 µM) synergistically induced aggregation with other platelet stimuli. Platelet activation induced by 2-AG and virodhamine resembled arachidonic acid (AA)-induced aggregation: shape change, the first platelet response, ATP secretion and aggregation induced by 2-AG and virodhamine were all blocked by acetylsalicylic acid (ASA) or the specific thromboxane A2 (TXA2) antagonist daltroban. In addition, platelet activation induced by 2-AG and virodhamine in blood and PRP were inhibited by JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL). In contrast to 2-AG and virodhamine, anandamide, a substrate of fatty acid amidohydrolase, was inactive. Synthetic cannabinoid receptor subtype 1 (CB1) and 2 (CB2) agonists lacked stimulatory as well as inhibitory platelet activity. We conclude that 2-AG and virodhamine stimulate platelets in blood and PRP by a MAGL-triggered mechanism leading to free AA and its metabolism by platelet cyclooxygenase-1/thromboxane synthase to TXA2. CB1, CB2 or non-CB1/CB2 receptors are not involved. Our results imply that ASA and MAGL inhibitors will protect platelets from activation by high endocannabinoid levels, and that

  6. Endocannabinoid hydrolases in avian HD11 macrophages identified by chemoproteomics: inactivation by small molecule inhibitors and pathogen-induced downregulation of their activity.

    USDA-ARS?s Scientific Manuscript database

    The endocannabinoids (eCBs) are endogenous arachidonoyl-containing lipid mediators with important roles in host defense. Macrophages are first-line defenders of the innate immune system and biosynthesize large amounts of eCBs when activated. The cellular levels of eCBs are controlled by the activiti...

  7. Endocannabinoid regulation of β-cell functions: implications for glycaemic control and diabetes.

    PubMed

    Jourdan, T; Godlewski, G; Kunos, G

    2016-06-01

    Visceral obesity is a major risk factor for the development of insulin resistance which can progress to overt type 2 diabetes (T2D) with loss of β-cell function and, ultimately, loss of β-cells. Insulin secretion by β-cells of the pancreatic islets is tightly coupled to blood glucose concentration and modulated by a large number of blood-borne or locally released mediators, including endocannabinoids. Obesity and its complications, including T2D, are associated with increased activity of the endocannabinoid/CB1 receptor (CB1 R) system, as indicated by the therapeutic effects of CB1 R antagonists. Similar beneficial effects of CB1 R antagonists with limited brain penetrance indicate the important role of CB1 R in peripheral tissues, including the endocrine pancreas. Pancreatic β-cells express all of the components of the endocannabinoid system, and endocannabinoids modulate their function via both autocrine and paracrine mechanisms, which influence basal and glucose-induced insulin secretion and also affect β-cell proliferation and survival. The present brief review will survey available information on the modulation of these processes by endocannabinoids and their receptors, with an attempt to assess the contribution of such effects to glycaemic control in T2D and insulin resistance. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

  8. The Role of the Endocannabinoid System in the Brain-Gut Axis.

    PubMed

    Sharkey, Keith A; Wiley, John W

    2016-08-01

    The actions of cannabis are mediated by receptors that are part of an endogenous cannabinoid system. The endocannabinoid system (ECS) consists of the naturally occurring ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the cannabinoid (CB) receptors CB1 and CB2. The ECS is a widely distributed transmitter system that controls gut functions peripherally and centrally. It is an important physiologic regulator of gastrointestinal motility. Polymorphisms in the gene encoding CB1 (CNR1) have been associated with some forms of irritable bowel syndrome. The ECS is involved in the control of nausea and vomiting and visceral sensation. The homeostatic role of the ECS also extends to the control of intestinal inflammation. We review the mechanisms by which the ECS links stress and visceral pain. CB1 in sensory ganglia controls visceral sensation, and transcription of CNR1 is modified through epigenetic processes under conditions of chronic stress. These processes might link stress with abdominal pain. The ECS is also involved centrally in the manifestation of stress, and endocannabinoid signaling reduces the activity of hypothalamic-pituitary-adrenal pathways via actions in specific brain regions, notably the prefrontal cortex, amygdala, and hypothalamus. Agents that modulate the ECS are in early stages of development for treatment of gastrointestinal diseases. Increasing our understanding of the ECS will greatly advance our knowledge of interactions between the brain and gut and could lead to new treatments for gastrointestinal disorders. Copyright © 2016. Published by Elsevier Inc.

  9. Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

    PubMed Central

    Malenczyk, Katarzyna; Keimpema, Erik; Piscitelli, Fabiana; Calvigioni, Daniela; Björklund, Peyman; Mackie, Kenneth; Di Marzo, Vincenzo; Hökfelt, Tomas G. M.; Dobrzyn, Agnieszka; Harkany, Tibor

    2015-01-01

    Endocannabinoids are implicated in the control of glucose utilization and energy homeostasis by orchestrating pancreatic hormone release. Moreover, in some cell niches, endocannabinoids regulate cell proliferation, fate determination, and migration. Nevertheless, endocannabinoid contributions to the development of the endocrine pancreas remain unknown. Here, we show that α cells produce the endocannabinoid 2-arachidonoylglycerol (2-AG) in mouse fetuses and human pancreatic islets, which primes the recruitment of β cells by CB1 cannabinoid receptor (CB1R) engagement. Using subtractive pharmacology, we extend these findings to anandamide, a promiscuous endocannabinoid/endovanilloid ligand, which impacts both the determination of islet size by cell proliferation and α/β cell sorting by differential activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) and CB1Rs. Accordingly, genetic disruption of TRPV1 channels increases islet size whereas CB1R knockout augments cellular heterogeneity and favors insulin over glucagon release. Dietary enrichment in ω-3 fatty acids during pregnancy and lactation in mice, which permanently reduces endocannabinoid levels in the offspring, phenocopies CB1R−/− islet microstructure and improves coordinated hormone secretion. Overall, our data mechanistically link endocannabinoids to cell proliferation and sorting during pancreatic islet formation, as well as to life-long programming of hormonal determinants of glucose homeostasis. PMID:26494286

  10. Non-psychotropic analgesic drugs from the endocannabinoid system: "magic bullet" or "multiple-target" strategies?

    PubMed

    Starowicz, Katarzyna; Di Marzo, Vincenzo

    2013-09-15

    The exploitation of preparations of Cannabis sativa to combat pain seems to date back to time immemorial, although their psychotropic effects, which are at the bases of their recreational use and limit their therapeutic use, are at least as ancient. Indeed, it has always been different to tease apart the unwanted central effects from the therapeutic benefits of Δ⁹-tetrahydrocannabinol (THC), the main psychotropic component of cannabis. The discovery of the cannabinoid receptors and of their endogenous ligands, the endocannabinoids, which, unlike THC, play a pro-homeostatic function in a tissue- and time-selective manner, offered the opportunity to develop new analgesics from synthetic inhibitors of endocannabinoid inactivation. The advantages of this approach over direct activation of cannabinoid receptors as a therapeutic strategy against neuropathic and inflammatory pain are discussed here along with its potential complications. These latter have been such that clinical success has been achieved so far more rapidly with naturally occurring THC or endocannabinoid structural analogues acting at a plethora of cannabinoid-related and -unrelated molecular targets, than with selective inhibitors of endocannabinoid enzymatic hydrolysis, thus leading to revisit the potential usefulness of "multi-target" versus "magic bullet" compounds as new analgesics. © 2013 Elsevier B.V. All rights reserved.

  11. The endocannabinoid system: a new pharmacological target for obesity treatment?

    PubMed

    Hu, Jia; Zhu, Chao; Huang, Mao

    2009-06-01

    Being a great threaten for human health, obesity has become a pandemic chronic disease. There have been several therapeutic treatments for this social health issue, including diet and exercise therapy, medication and surgery, among which the diet is still the most common way. However, none of these therapeutic measures available is ideal, making it necessary to find an effective medical treatment. The endocannabinoid system, which is well known for its contributions in certain mental processes such as relaxation, amelioration of pain and anxiety, and sedation initiation, has been recently reported to play an essential role in regulating appetite and metabolism to maintain energy balance, leading to the belief that endocannabinoid system is closely related to obesity. This new discovery deepens our understanding of obesity, and provides us with a new direction for clinical obesity treatment. Rimonabant is an antagonist for CB1, and has entered the market in some countries. However, although effective as an anti-obesity drug, rimonabant also causes obviously adverse side-effects, thus is being doubted and denied for medical usage.

  12. THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the subchronic PCP model of schizophrenia.

    PubMed

    Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J

    2016-02-01

    Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the cerebrospinal fluid levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid-enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared with THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach. © The Author(s) 2015.

  13. Differences in chloride gradients allow for three distinct types of synaptic modulation by endocannabinoids.

    PubMed

    Wang, Yanqing; Burrell, Brian D

    2016-08-01

    Endocannabinoids can elicit persistent depression of excitatory and inhibitory synapses, reducing or enhancing (disinhibiting) neural circuit output, respectively. In this study, we examined whether differences in Cl(-) gradients can regulate which synapses undergo endocannabinoid-mediated synaptic depression vs. disinhibition using the well-characterized central nervous system (CNS) of the medicinal leech, Hirudo verbana Exogenous application of endocannabinoids or capsaicin elicits potentiation of pressure (P) cell synapses and depression of both polymodal (Npoly) and mechanical (Nmech) nociceptive synapses. In P synapses, blocking Cl(-) export prevented endocannabinoid-mediated potentiation, consistent with a disinhibition process that has been indicated by previous experiments. In Nmech neurons, which are depolarized by GABA due to an elevated Cl(-) equilibrium potentials (ECl), endocannabinoid-mediated depression was prevented by blocking Cl(-) import, indicating that this decrease in synaptic signaling was due to depression of excitatory GABAergic input (disexcitation). Npoly neurons are also depolarized by GABA, but endocannabinoids elicit depression in these synapses directly and were only weakly affected by disruption of Cl(-) import. Consequently, the primary role of elevated ECl may be to protect Npoly synapses from disinhibition. All forms of endocannabinoid-mediated plasticity required activation of transient potential receptor vanilloid (TRPV) channels. Endocannabinoid/TRPV-dependent synaptic plasticity could also be elicited by distinct patterns of afferent stimulation with low-frequency stimulation (LFS) eliciting endocannabinoid-mediated depression of Npoly synapses and high-frequency stimulus (HFS) eliciting endocannabinoid-mediated potentiation of P synapses and depression of Nmech synapses. These findings demonstrate a critical role of differences in Cl(-) gradients between neurons in determining the sign, potentiation vs. depression, of

  14. Differences in chloride gradients allow for three distinct types of synaptic modulation by endocannabinoids

    PubMed Central

    Wang, Yanqing

    2016-01-01

    Endocannabinoids can elicit persistent depression of excitatory and inhibitory synapses, reducing or enhancing (disinhibiting) neural circuit output, respectively. In this study, we examined whether differences in Cl− gradients can regulate which synapses undergo endocannabinoid-mediated synaptic depression vs. disinhibition using the well-characterized central nervous system (CNS) of the medicinal leech, Hirudo verbana. Exogenous application of endocannabinoids or capsaicin elicits potentiation of pressure (P) cell synapses and depression of both polymodal (Npoly) and mechanical (Nmech) nociceptive synapses. In P synapses, blocking Cl− export prevented endocannabinoid-mediated potentiation, consistent with a disinhibition process that has been indicated by previous experiments. In Nmech neurons, which are depolarized by GABA due to an elevated Cl− equilibrium potentials (ECl), endocannabinoid-mediated depression was prevented by blocking Cl− import, indicating that this decrease in synaptic signaling was due to depression of excitatory GABAergic input (disexcitation). Npoly neurons are also depolarized by GABA, but endocannabinoids elicit depression in these synapses directly and were only weakly affected by disruption of Cl− import. Consequently, the primary role of elevated ECl may be to protect Npoly synapses from disinhibition. All forms of endocannabinoid-mediated plasticity required activation of transient potential receptor vanilloid (TRPV) channels. Endocannabinoid/TRPV-dependent synaptic plasticity could also be elicited by distinct patterns of afferent stimulation with low-frequency stimulation (LFS) eliciting endocannabinoid-mediated depression of Npoly synapses and high-frequency stimulus (HFS) eliciting endocannabinoid-mediated potentiation of P synapses and depression of Nmech synapses. These findings demonstrate a critical role of differences in Cl− gradients between neurons in determining the sign, potentiation vs. depression, of

  15. Endocannabinoids Measurement in Human Saliva as Potential Biomarker of Obesity

    PubMed Central

    Tabarin, Antoine; Clark, Samantha; Leste-Lasserre, Thierry; Marsicano, Giovanni; Piazza, Pier Vincenzo; Cota, Daniela

    2012-01-01

    Background The discovery of the endocannabinoid system and of its role in the regulation of energy balance has significantly advanced our understanding of the physiopathological mechanisms leading to obesity and type 2 diabetes. New knowledge on the role of this system in humans has been acquired by measuring blood endocannabinoids. Here we explored endocannabinoids and related N-acylethanolamines in saliva and verified their changes in relation to body weight status and in response to a meal or to body weight loss. Methodology/Principal Findings Fasting plasma and salivary endocannabinoids and N-acylethanolamines were measured through liquid mass spectrometry in 12 normal weight and 12 obese, insulin-resistant subjects. Salivary endocannabinoids and N-acylethanolamines were evaluated in the same cohort before and after the consumption of a meal. Changes in salivary endocannabinoids and N-acylethanolamines after body weight loss were investigated in a second group of 12 obese subjects following a 12-weeks lifestyle intervention program. The levels of mRNAs coding for enzymes regulating the metabolism of endocannabinoids, N-acylethanolamines and of cannabinoid type 1 (CB1) receptor, alongside endocannabinoids and N-acylethanolamines content, were assessed in human salivary glands. The endocannabinoids 2-arachidonoylglycerol (2-AG), N-arachidonoylethanolamide (anandamide, AEA), and the N-acylethanolamines (oleoylethanolamide, OEA and palmitoylethanolamide, PEA) were quantifiable in saliva and their levels were significantly higher in obese than in normal weight subjects. Fasting salivary AEA and OEA directly correlated with BMI, waist circumference and fasting insulin. Salivary endocannabinoids and N-acylethanolamines did not change in response to a meal. CB1 receptors, ligands and enzymes were expressed in the salivary glands. Finally, a body weight loss of 5.3% obtained after a 12-weeks lifestyle program significantly decreased salivary AEA levels. Conclusions

  16. Truffles contain endocannabinoid metabolic enzymes and anandamide.

    PubMed

    Pacioni, Giovanni; Rapino, Cinzia; Zarivi, Osvaldo; Falconi, Anastasia; Leonardi, Marco; Battista, Natalia; Colafarina, Sabrina; Sergi, Manuel; Bonfigli, Antonella; Miranda, Michele; Barsacchi, Daniela; Maccarrone, Mauro

    2015-02-01

    Truffles are the fruiting body of fungi, members of the Ascomycota phylum endowed with major gastronomic and commercial value. The development and maturation of their reproductive structure are dependent on melanin synthesis. Since anandamide, a prominent member of the endocannabinoid system (ECS), is responsible for melanin synthesis in normal human epidermal melanocytes, we thought that ECS might be present also in truffles. Here, we show the expression, at the transcriptional and translational levels, of most ECS components in the black truffle Tuber melanosporum Vittad. at maturation stage VI. Indeed, by means of molecular biology and immunochemical techniques, we found that truffles contain the major metabolic enzymes of the ECS, while they do not express the most relevant endocannabinoid-binding receptors. In addition, we measured anandamide content in truffles, at different maturation stages (from III to VI), through liquid chromatography-mass spectrometric analysis, whereas the other relevant endocannabinoid 2-arachidonoylglycerol was below the detection limit. Overall, our unprecedented results suggest that anandamide and ECS metabolic enzymes have evolved earlier than endocannabinoid-binding receptors, and that anandamide might be an ancient attractant to truffle eaters, that are well-equipped with endocannabinoid-binding receptors. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Endocannabinoids in cerebrovascular regulation

    PubMed Central

    Ruisanchez, Éva; Leszl-Ishiguro, Miriam; Sándor, Péter; Pacher, Pál

    2016-01-01

    The cerebral blood flow is tightly regulated by myogenic, endothelial, metabolic, and neural mechanisms under physiological conditions, and a large body of recent evidence indicates that inflammatory pathways have a major influence on the cerebral blood perfusion in certain central nervous system disorders, like hemorrhagic and ischemic stroke, traumatic brain injury, and vascular dementia. All major cell types involved in cerebrovascular control pathways (i.e., smooth muscle, endothelium, neurons, astrocytes, pericytes, microglia, and leukocytes) are capable of synthesizing endocannabinoids and/or express some or several of their target proteins [i.e., the cannabinoid 1 and 2 (CB1 and CB2) receptors and the transient receptor potential vanilloid type 1 ion channel]. Therefore, the endocannabinoid system may importantly modulate the regulation of cerebral circulation under physiological and pathophysiological conditions in a very complex manner. Experimental data accumulated since the late 1990s indicate that the direct effect of cannabinoids on cerebral vessels is vasodilation mediated, at least in part, by CB1 receptors. Cannabinoid-induced cerebrovascular relaxation involves both a direct inhibition of smooth muscle contractility and a release of vasodilator mediator(s) from the endothelium. However, under stress conditions (e.g., in conscious restrained animals or during hypoxia and hypercapnia), cannabinoid receptor activation was shown to induce a reduction of the cerebral blood flow, probably via inhibition of the electrical and/or metabolic activity of neurons. Finally, in certain cerebrovascular pathologies (e.g., subarachnoid hemorrhage, as well as traumatic and ischemic brain injury), activation of CB2 (and probably yet unidentified non-CB1/non-CB2) receptors appear to improve the blood perfusion of the brain via attenuating vascular inflammation. PMID:26825517

  18. Endocannabinoids in cerebrovascular regulation.

    PubMed

    Benyó, Zoltán; Ruisanchez, Éva; Leszl-Ishiguro, Miriam; Sándor, Péter; Pacher, Pál

    2016-04-01

    The cerebral blood flow is tightly regulated by myogenic, endothelial, metabolic, and neural mechanisms under physiological conditions, and a large body of recent evidence indicates that inflammatory pathways have a major influence on the cerebral blood perfusion in certain central nervous system disorders, like hemorrhagic and ischemic stroke, traumatic brain injury, and vascular dementia. All major cell types involved in cerebrovascular control pathways (i.e., smooth muscle, endothelium, neurons, astrocytes, pericytes, microglia, and leukocytes) are capable of synthesizing endocannabinoids and/or express some or several of their target proteins [i.e., the cannabinoid 1 and 2 (CB1 and CB2) receptors and the transient receptor potential vanilloid type 1 ion channel]. Therefore, the endocannabinoid system may importantly modulate the regulation of cerebral circulation under physiological and pathophysiological conditions in a very complex manner. Experimental data accumulated since the late 1990s indicate that the direct effect of cannabinoids on cerebral vessels is vasodilation mediated, at least in part, by CB1 receptors. Cannabinoid-induced cerebrovascular relaxation involves both a direct inhibition of smooth muscle contractility and a release of vasodilator mediator(s) from the endothelium. However, under stress conditions (e.g., in conscious restrained animals or during hypoxia and hypercapnia), cannabinoid receptor activation was shown to induce a reduction of the cerebral blood flow, probably via inhibition of the electrical and/or metabolic activity of neurons. Finally, in certain cerebrovascular pathologies (e.g., subarachnoid hemorrhage, as well as traumatic and ischemic brain injury), activation of CB2 (and probably yet unidentified non-CB1/non-CB2) receptors appear to improve the blood perfusion of the brain via attenuating vascular inflammation.

  19. Endocannabinoids and striatal function: implications for addiction-related behaviours

    PubMed Central

    Moreira, Fabricio A.; Jupp, Bianca; Belin, David

    2015-01-01

    Since the identification and cloning of the major cannabinoid receptor expressed in the brain almost 25 years ago research has highlighted the potential of drugs that target the endocannabinoid system for treating addiction. The endocannabinoids, anandamide and 2-arachidonoyl glycerol, are lipid-derived metabolites found in abundance in the basal ganglia and other brain areas innervated by the mesocorticolimbic dopamine systems. Cannabinoid CB1 receptor antagonists/inverse agonists reduce reinstatement of responding for cocaine, alcohol and opiates in rodents. However, compounds acting on the endocannabinoid system may have broader application in treating drug addiction by ameliorating associated traits and symptoms such as impulsivity and anxiety that perpetuate drug use and interfere with rehabilitation. As a trait, impulsivity is known to predispose to addiction and facilitate the emergence of addiction to stimulant drugs. In contrast, anxiety and elevated stress responses accompany extended drug use and may underlie the persistence of drug intake in dependent individuals. In this article we integrate and discuss recent findings in rodents showing selective pharmacological modulation of impulsivity and anxiety by cannabinoid agents. We highlight the potential of selective inhibitors of endocannabinoid metabolism, directed at fatty acid amide hydrolase and monoacylglycerol lipase, to reduce anxiety and stress responses, and discuss novel mechanisms underlying the modulation of the endocannabinoid system, including the attenuation of impulsivity, anxiety, and drug reward by selective CB2 receptor agonists. PMID:25369747

  20. High Times for Painful Blues: The Endocannabinoid System in Pain-Depression Comorbidity

    PubMed Central

    Fitzgibbon, Marie; Finn, David P.

    2016-01-01

    Depression and pain are two of the most debilitating disorders worldwide and have an estimated cooccurrence of up to 80%. Comorbidity of these disorders is more difficult to treat, associated with significant disability and impaired health-related quality of life than either condition alone, resulting in enormous social and economic cost. Several neural substrates have been identified as potential mediators in the association between depression and pain, including neuroanatomical reorganization, monoamine and neurotrophin depletion, dysregulation of the hypothalamo-pituitary-adrenal axis, and neuroinflammation. However, the past decade has seen mounting evidence supporting a role for the endogenous cannabinoid (endocannabinoid) system in affective and nociceptive processing, and thus, alterations in this system may play a key role in reciprocal interactions between depression and pain. This review will provide an overview of the preclinical evidence supporting an interaction between depression and pain and the evidence supporting a role for the endocannabinoid system in this interaction. PMID:26342110

  1. Lifelong imbalanced LA/ALA intake impairs emotional and cognitive behavior via changes in brain endocannabinoid system

    PubMed Central

    Zamberletti, Erica; Piscitelli, Fabiana; De Castro, Valentina; Murru, Elisabetta; Gabaglio, Marina; Colucci, Paola; Fanali, Chiara; Prini, Pamela; Bisogno, Tiziana; Maccarrone, Mauro; Campolongo, Patrizia; Banni, Sebastiano; Rubino, Tiziana; Parolaro, Daniela

    2017-01-01

    Imbalanced dietary n-3 and n-6 PUFA content has been associated with a number of neurological conditions. Endocannabinoids are n-6 PUFA derivatives, whose brain concentrations are sensitive to modifications of fatty acid composition of the diet and play a central role in the regulation of mood and cognition. As such, the endocannabinoid system appears to be an ideal candidate for mediating the effects of dietary fatty acids on mood and cognition. Lifelong administration of isocaloric α-linolenic acid (ALA)-deficient and -enriched diets induced short-term memory deficits, whereas only dietary ALA enrichment altered emotional reactivity in adult male rats compared with animals fed a standard diet that was balanced in ALA/linoleic acid (LA) ratio. In the prefrontal cortex, both diets reduced 2-AG levels and increased MAG lipase expression, whereas only the enriched diet reduced AEA levels, simultaneously increasing FAAH expression. In the hippocampus, an ALA-enriched diet decreased AEA content and NAPE-PLD expression, and reduced 2-AG content while increasing MAG lipase expression. These findings highlight the importance of a diet balanced in fatty acid content for normal brain functions and to support a link between dietary ALA, the brain endocannabinoid system, and behavior, which indicates that dietary ALA intake is a sufficient condition for altering the endocannabinoid system in brain regions modulating mood and cognition. PMID:27903595

  2. Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury

    DTIC Science & Technology

    2013-11-01

    COVERED 4 October 201 - 3 October 201 4. TITLE AND SUBTITLE Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury 5a. CONTRACT...injury, blood brain barrier, neuroinflammation, neurological dysfunction, endocannabinoids Table of Contents Introduction...promote neuroinflammation and potentially lead to neurodegeneration. We have previously demonstrated that treatments to the endocannabinoid system 2

  3. Dietary docosahexaenoic acid supplementation alters select physiological endocannabinoid-system metabolites in brain and plasma

    PubMed Central

    Wood, JodiAnne T.; Williams, John S.; Pandarinathan, Lakshmipathi; Janero, David R.; Lammi-Keefe, Carol J.; Makriyannis, Alexandros

    2010-01-01

    The endocannabinoid metabolome consists of a growing, (patho)physiologically important family of fatty-acid derived signaling lipids. Diet is a major source of fatty acid substrate for mammalian endocannabinoid biosynthesis. The principal long-chain PUFA found in mammalian brain, docosahexaenoic acid (DHA), supports neurological function, retinal development, and overall health. The extent to which dietary DHA supplementation influences endocannabinoid-related metabolites in brain, within the context of the circulating endocannabinoid profile, is currently unknown. We report the first lipidomic analysis of acute 2-week DHA dietary supplementation effects on the physiological state of 15 fatty-acid, N-acylethanolamine, and glycerol-ester endocannabinoid metabolome constituents in murine plasma and brain. The DHA-rich diet markedly elevated DHA, eicosapentaenoic acid, 2-eicosapentanoylglycerol (EPG), and docosahexanoylethanolamine in both compartments. Dietary DHA enhancement generally affected the synthesis of the N-acyl-ethanolamine and glycerol-ester metabolites to favor the docosahexaenoic and eicosapentaenoic vs. arachidonoyl and oleoyl homologs in both brain and plasma. The greater overall responsiveness of the endocannabinoid metabolome in plasma versus brain may reflect a more circumscribed homeostatic response range of brain lipids to dietary DHA supplementation. The ability of short-term DHA enhancement to modulate select constituents of the physiological brain and plasma endocannabinoid metabolomes carries metabolic and therapeutic implications. PMID:20071693

  4. Dietary docosahexaenoic acid supplementation alters select physiological endocannabinoid-system metabolites in brain and plasma.

    PubMed

    Wood, Jodianne T; Williams, John S; Pandarinathan, Lakshmipathi; Janero, David R; Lammi-Keefe, Carol J; Makriyannis, Alexandros

    2010-06-01

    The endocannabinoid metabolome consists of a growing, (patho)physiologically important family of fatty-acid derived signaling lipids. Diet is a major source of fatty acid substrate for mammalian endocannabinoid biosynthesis. The principal long-chain PUFA found in mammalian brain, docosahexaenoic acid (DHA), supports neurological function, retinal development, and overall health. The extent to which dietary DHA supplementation influences endocannabinoid-related metabolites in brain, within the context of the circulating endocannabinoid profile, is currently unknown. We report the first lipidomic analysis of acute 2-week DHA dietary supplementation effects on the physiological state of 15 fatty-acid, N-acylethanolamine, and glycerol-ester endocannabinoid metabolome constituents in murine plasma and brain. The DHA-rich diet markedly elevated DHA, eicosapentaenoic acid, 2-eicosapentanoylglycerol (EPG), and docosahexanoylethanolamine in both compartments. Dietary DHA enhancement generally affected the synthesis of the N-acyl-ethanolamine and glycerol-ester metabolites to favor the docosahexaenoic and eicosapentaenoic vs. arachidonoyl and oleoyl homologs in both brain and plasma. The greater overall responsiveness of the endocannabinoid metabolome in plasma versus brain may reflect a more circumscribed homeostatic response range of brain lipids to dietary DHA supplementation. The ability of short-term DHA enhancement to modulate select constituents of the physiological brain and plasma endocannabinoid metabolomes carries metabolic and therapeutic implications.

  5. Endocannabinoid system dysfunction in mood and related disorders.

    PubMed

    Ashton, C H; Moore, P B

    2011-10-01

    The endocannabinoid (EC) system is widely distributed throughout the brain and modulates many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids. This article examines the therapeutic potential of cannabinoids in psychiatric disorders. An overview is presented of the literature focussed on the functions of the EC system, its dysfunction in mood disorders and the therapeutic potential of exogenous cannabinoids. We propose (hypothesize) that the EC system, which is homoeostatic in cortical excitation and inhibition, is dysfunctional in mood and related disorders. Anandamide, tetrahydrocannabinol (THC) and cannabidiol (CBD) variously combine antidepressant, antipsychotic, anxiolytic, analgesic, anticonvulsant actions, suggesting a therapeutic potential in mood and related disorders. Currently, cannabinoids find a role in pain control. Post mortem and other studies report EC system abnormalities in depression, schizophrenia and suicide. Abnormalities in the cannabinoid-1 receptor (CNR1) gene that codes for cannabinoid-1 (CB1) receptors are reported in psychiatric disorders. However, efficacy trials of cannabinoids in psychiatric disorders are limited but offer some encouragement. Research is needed to elucidate the role of the EC system in psychiatric disorders and for clinical trials with THC, CBD and synthetic cannabinoids to assess their therapeutic potential. © 2011 John Wiley & Sons A/S.

  6. Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury

    DTIC Science & Technology

    2012-11-01

    DATES COVERED 4 October 2011- 3 October 2012 4. TITLE AND SUBTITLE Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury 5a...interventions aimed at modulation of the endocannabinoid (EC) system targeting degradation of 20arachidonoyl glycerlol (2- AG) and N-arachidonoyl...percussion, traumatic brain injury, blood brain barrier, neuroinflammination, neurological dysfunction, endocannabinoids . 16. SECURITY CLASSIFICATION

  7. THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the sub-chronic PCP model of schizophrenia

    PubMed Central

    Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J

    2017-01-01

    Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the CSF levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared to THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach. PMID:26510449

  8. Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Vilela, Luciano R.; Gobira, Pedro H.; Viana, Thercia G.

    Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. Themore » molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB{sub 1} receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB{sub 1} receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. - Highlights: • Cocaine toxicity is characterized by seizures and hippocampal cell death. • The endocannabinoid anandamide acts as a brain protective mechanism. • Inhibition of anandamide

  9. Driving the need to feed: Insight into the collaborative interaction between ghrelin and endocannabinoid systems in modulating brain reward systems.

    PubMed

    Edwards, Alexander; Abizaid, Alfonso

    2016-07-01

    Independent stimulation of either the ghrelin or endocannabinoid system promotes food intake and increases adiposity. Given the similar distribution of their receptors in feeding associated brain regions and organs involved in metabolism, it is not surprising that evidence of their interaction and its importance in modulating energy balance has emerged. This review documents the relationship between ghrelin and endocannabinoid systems within the periphery and hypothalamus (HYP) before presenting evidence suggesting that these two systems likewise work collaboratively within the ventral tegmental area (VTA) to modulate non-homeostatic feeding. Mechanisms, consistent with current evidence and local infrastructure within the VTA, will be proposed. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Modulation of sweet taste sensitivities by endogenous leptin and endocannabinoids in mice

    PubMed Central

    Niki, Mayu; Jyotaki, Masafumi; Yoshida, Ryusuke; Yasumatsu, Keiko; Shigemura, Noriatsu; DiPatrizio, Nicholas V; Piomelli, Daniele; Ninomiya, Yuzo

    2015-01-01

    Leptin is an anorexigenic mediator that reduces food intake by acting on hypothalamic receptor Ob-Rb. In contrast, endocannabinoids are orexigenic mediators that act via cannabinoid CB1 receptors in hypothalamus, limbic forebrain, and brainstem. In the peripheral taste system, leptin administration selectively inhibits behavioural, taste nerve and taste cell responses to sweet compounds. Opposing the action of leptin, endocannabinoids enhance sweet taste responses. However, potential roles of endogenous leptin and endocannabinoids in sweet taste remain unclear. Here, we used pharmacological antagonists (Ob-Rb: L39A/D40A/F41A (LA), CB1: AM251) and examined the effects of their blocking activation of endogenous leptin and endocannabinoid signalling on taste responses in lean control, leptin receptor deficient db/db, and diet-induced obese (DIO) mice. Lean mice exhibited significant increases in chorda tympani (CT) nerve responses to sweet compounds after LA administration, while they showed no significant changes in CT responses after AM251. In contrast, db/db mice showed clear suppression of CT responses to sweet compounds after AM251, increased endocannabinoid (2-arachidonoyl-sn-glycerol (2-AG)) levels in the taste organ, and enhanced expression of a biosynthesizing enzyme (diacylglycerol lipase α (DAGLα)) of 2-AG in taste cells. In DIO mice, the LA effect was gradually decreased and the AM251 effect was increased during the course of obesity. Taken together, our results suggest that circulating leptin, but not local endocannabinoids, may be a dominant modulator for sweet taste in lean mice; however, endocannabinoids may become more effective modulators of sweet taste under conditions of deficient leptin signalling, possibly due to increased production of endocannabinoids in taste tissue. Key points Potential roles of endogenous leptin and endocannabinoids in sweet taste were examined by using pharmacological antagonists and mouse models including leptin receptor

  11. Lifelong imbalanced LA/ALA intake impairs emotional and cognitive behavior via changes in brain endocannabinoid system.

    PubMed

    Zamberletti, Erica; Piscitelli, Fabiana; De Castro, Valentina; Murru, Elisabetta; Gabaglio, Marina; Colucci, Paola; Fanali, Chiara; Prini, Pamela; Bisogno, Tiziana; Maccarrone, Mauro; Campolongo, Patrizia; Banni, Sebastiano; Rubino, Tiziana; Parolaro, Daniela

    2017-02-01

    Imbalanced dietary n-3 and n-6 PUFA content has been associated with a number of neurological conditions. Endocannabinoids are n-6 PUFA derivatives, whose brain concentrations are sensitive to modifications of fatty acid composition of the diet and play a central role in the regulation of mood and cognition. As such, the endocannabinoid system appears to be an ideal candidate for mediating the effects of dietary fatty acids on mood and cognition. Lifelong administration of isocaloric α-linolenic acid (ALA)-deficient and -enriched diets induced short-term memory deficits, whereas only dietary ALA enrichment altered emotional reactivity in adult male rats compared with animals fed a standard diet that was balanced in ALA/linoleic acid (LA) ratio. In the prefrontal cortex, both diets reduced 2-AG levels and increased MAG lipase expression, whereas only the enriched diet reduced AEA levels, simultaneously increasing FAAH expression. In the hippocampus, an ALA-enriched diet decreased AEA content and NAPE-PLD expression, and reduced 2-AG content while increasing MAG lipase expression. These findings highlight the importance of a diet balanced in fatty acid content for normal brain functions and to support a link between dietary ALA, the brain endocannabinoid system, and behavior, which indicates that dietary ALA intake is a sufficient condition for altering the endocannabinoid system in brain regions modulating mood and cognition. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  12. Oleamide: a member of the endocannabinoid family?

    PubMed Central

    Fowler, Christopher J

    2003-01-01

    The fatty acid amide class of compounds, which include the endocannabinoid anandamide and the sleep-inducing compound oleamide, have been shown in vitro to have a multiplicity of actions upon different neurochemical systems. In the present issue of this journal, Leggett et al present data indicating that oleamide functionally activates CB1 cannabinoid receptors in vitro. The significance of their finding is discussed in this commentary. PMID:14691053

  13. Endocannabinoids as endometrial inflammatory markers in lactating Holstein cows.

    PubMed

    Bonsale, R; Seyed Sharifi, R; Dirandeh, E; Hedayat, N; Mojtahedin, A; Ghorbanalinia, M; Abolghasemi, A

    2018-06-01

    The objective of this study was to consider endocannabinoid system as inflammatory markers in bovine endometrium to better understand the role of this system in regulating many of the functions that are related to inflammatory condition. At day 26 post-partum, fourteen cows were divided into two groups depending on the inflammatory condition: 1- subclinical endometritis (n = 7, with purulent or mucopurulent uterine discharge detectable in the vagina) and 2- healthy (n = 7, No (muco)) purulent discharge. Blood samples were collected at 26 and 30 days relative to calving to determine plasma tumour necrosis factor (TNF) and lipopolysaccharide-binding protein (LBP) concentrations; moreover, uterine biopsy was carried out on day 26 post-partum to measure mRNA abundance of TNF, interleukin-1B (IL1B), interleukin-6 (IL-6), C-X-C motif chemokine ligand 8 (CXCL8), endocannabinoid receptor (CNR2), N-acyl phosphatidylethanolamine phospholipase D (NAPEPLD), fatty acid amide hydrolase (FAAH), N-acylethanolamine acid amidase (NAAA) and monoglyceride lipase (MGLL) by real-time PCR. Results showed mean plasma concentrations of TNF and LBP were lower in healthy cows compared to subclinical endometritis cows (p < .05). Relative mRNA expression for NAAA and FAAH was decreased (p < .05), and relative mRNA expression for CNR2 and NAPEPLD increased in cows with subclinical endometritis compared to healthy cows. In conclusion, relative mRNA expression of TNF, IL1B and CXCL8 and plasma concentration of LBP increased during inflammatory condition along with decreased endocannabinoids hydrolyzing enzyme (NAAA and FAAH), increased enzymes that synthesize endocannabinoids (NAPEPLD) and relative gene expression of the endocannabinoid receptor; together, these contribute to increased endocannabinoids levels during inflammation. Overall, we provide evidence that endocannabinoid system is altered in endometrium tissue during inflammation through increased mRNA expression of CNR2 and

  14. Endocannabinoid system acts as a regulator of immune homeostasis in the gut.

    PubMed

    Acharya, Nandini; Penukonda, Sasi; Shcheglova, Tatiana; Hagymasi, Adam T; Basu, Sreyashi; Srivastava, Pramod K

    2017-05-09

    Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipid. Anandamide (AEA) is an endogenous intestinal cannabinoid that controls appetite and energy balance by engagement of the enteric nervous system through cannabinoid receptors. Here, we uncover a role for AEA and its receptor, cannabinoid receptor 2 (CB2), in the regulation of immune tolerance in the gut and the pancreas. This work demonstrates a major immunological role for an endocannabinoid. The pungent molecule capsaicin (CP) has a similar effect as AEA; however, CP acts by engagement of the vanilloid receptor TRPV1, causing local production of AEA, which acts through CB2. We show that the engagement of the cannabinoid/vanilloid receptors augments the number and immune suppressive function of the regulatory CX3CR1 hi macrophages (Mϕ), which express the highest levels of such receptors among the gut immune cells. Additionally, TRPV1 -/- or CB2 -/- mice have fewer CX3CR1 hi Mϕ in the gut. Treatment of mice with CP also leads to differentiation of a regulatory subset of CD4 + cells, the Tr1 cells, in an IL-27-dependent manner in vitro and in vivo. In a functional demonstration, tolerance elicited by engagement of TRPV1 can be transferred to naïve nonobese diabetic (NOD) mice [model of type 1 diabetes (T1D)] by transfer of CD4 + T cells. Further, oral administration of AEA to NOD mice provides protection from T1D. Our study unveils a role for the endocannabinoid system in maintaining immune homeostasis in the gut/pancreas and reveals a conversation between the nervous and immune systems using distinct receptors.

  15. Endocannabinoid Signaling in Motivation, Reward, and Addiction: Influences on Mesocorticolimbic Dopamine Function.

    PubMed

    Sagheddu, Claudia; Muntoni, Anna Lisa; Pistis, Marco; Melis, Miriam

    2015-01-01

    Evidence suggests that the endocannabinoid system has been conserved in the animal kingdom for 500 million years, and this system influences many critical behavioral processes including associative learning, reward signaling, goal-directed behavior, motor skill learning, and action-habit transformation. Additionally, the neurotransmitter dopamine has long been recognized to play a critical role in the processing of natural rewards, as well as of motivation that regulates approach and avoidance behavior. This motivational role of dopamine neurons is also based upon the evidence provided by several studies investigating disorders of dopamine pathways such as drug addiction and Parkinson's disease. From an evolutionary point of view, individuals engage in behaviors aimed at maximizing and minimizing positive and aversive consequences, respectively. Accordingly, those with the greatest fitness have a better potential to survival. Hence, deviations from fitness can be viewed as a part of the evolutionary process by means of natural selection. Given the long evolutionary history of both the endocannabinoid and dopaminergic systems, it is plausible that they must serve as fundamental and basic modulators of physiological functions and needs. Notably, endocannabinoids regulate dopamine neuronal activity and its influence on behavioral output. The goal of this chapter is to examine the endocannabinoid influence on dopamine signaling specifically related to (i) those behavioral processes that allow us to successfully adapt to ever-changing environments (i.e., reward signaling and motivational processes) and (ii) derangements from behavioral flexibility that underpin drug addiction. © 2015 Elsevier Inc. All rights reserved.

  16. Potential of Endocannabinoids to Control Bladder Pain.

    PubMed

    Bjorling, Dale E; Wang, Zun-Yi

    2018-01-01

    Bladder-related pain is one of the most common forms of visceral pain, and visceral pain is among the most common complaints for which patients seek physician consultation. Despite extensive studies of visceral innervation and treatment of visceral pain, opioids remain a mainstay for management of bladder pain. Side effects associated with opioid therapy can profoundly diminish quality of life, and improved options for treatment of bladder pain remain a high priority. Endocannabinoids, primarily anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are endogenously-produced fatty acid ethanolamides with that induce analgesia. Animal experiments have demonstrated that inhibition of enzymes that degrade AEA or 2-AG have the potential to prevent development of visceral and somatic pain. Although experimental results in animal models have been promising, clinical application of this approach has proven difficult. In addition to fatty acid amide hydrolase (FAAH; degrades AEA) and monacylglycerol lipase (MAGL; degrades 2-AG), cyclooxygenase (COX) acts to metabolize endocannabinoids. Another potential limitation of this strategy is that AEA activates pro-nociceptive transient receptor potential vanilloid 1 (TRPV1) channels. Dual inhibitors of FAAH and TRPV1 or FAAH and COX have been synthesized and are currently undergoing preclinical testing for efficacy in providing analgesia. Local inhibition of FAAH or MAGL within the bladder may be viable options to reduce pain associated with cystitis with fewer systemic side effects, but this has not been explored. Further investigation is required before manipulation of the endocannabinoid system can be proven as an efficacious alternative for management of bladder pain.

  17. Role of Endocannabinoids and Cannabinoid-1 Receptors in Cerebrocortical Blood Flow Regulation

    PubMed Central

    Horváth, Béla; Benkő, Rita; Lacza, Zsombor; Járai, Zoltán; Sándor, Péter; Di Marzo, Vincenzo; Pacher, Pál; Benyó, Zoltán

    2013-01-01

    Background Endocannabinoids are among the most intensively studied lipid mediators of cardiovascular functions. In the present study the effects of decreased and increased activity of the endocannabinoid system (achieved by cannabinoid-1 (CB1) receptor blockade and inhibition of cannabinoid reuptake, respectively) on the systemic and cerebral circulation were analyzed under steady-state physiological conditions and during hypoxia and hypercapnia (H/H). Methodology/Principal Findings In anesthetized spontaneously ventilating rats the CB1-receptor antagonist/inverse agonist AM-251 (10 mg/kg, i.v.) failed to influence blood pressure (BP), cerebrocortical blood flow (CoBF, measured by laser-Doppler flowmetry) or arterial blood gas levels. In contrast, the putative cannabinoid reuptake inhibitor AM-404 (10 mg/kg, i.v.) induced triphasic responses, some of which could be blocked by AM-251. Hypertension during phase I was resistant to AM-251, whereas the concomitant CoBF-increase was attenuated. In contrast, hypotension during phase III was sensitive to AM-251, whereas the concomitant CoBF-decrease was not. Therefore, CoBF autoregulation appeared to shift towards higher BP levels after CB1-blockade. During phase II H/H developed due to respiratory depression, which could be inhibited by AM-251. Interestingly, however, the concomitant rise in CoBF remained unchanged after AM-251, indicating that CB1-blockade potentially enhanced the reactivity of the CoBF to H/H. In accordance with this hypothesis, AM-251 induced a significant enhancement of the CoBF responses during controlled stepwise H/H. Conclusion/Significance Under resting physiological conditions CB1-receptor mediated mechanisms appear to have limited influence on systemic or cerebral circulation. Enhancement of endocannabinoid levels, however, induces transient CB1-independent hypertension and sustained CB1-mediated hypotension. Furthermore, enhanced endocannabinoid activity results in respiratory depression in a

  18. Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3.

    PubMed

    Rodríguez-Cueto, Carmen; Hernández-Gálvez, Mariluz; Hillard, Cecilia J; Maciel, Patricia; García-García, Luis; Valdeolivas, Sara; Pozo, Miguel A; Ramos, José A; Gómez-Ruiz, María; Fernández-Ruiz, Javier

    2016-12-17

    Spinocerebellar ataxia type-3 (SCA-3) is a rare disease but it is the most frequent type within the autosomal dominant inherited ataxias. The disease lacks an effective treatment to alleviate major symptoms and to modify disease progression. Our recent findings that endocannabinoid receptors and enzymes are significantly altered in the post-mortem cerebellum of patients affected by autosomal-dominant hereditary ataxias suggest that targeting the endocannabinoid signaling system may be a promising therapeutic option. Our goal was to investigate the status of the endocannabinoid signaling system in a transgenic mouse model of SCA-3, in the two CNS structures most affected in this disease - cerebellum and brainstem. These animals exhibited progressive motor incoordination, imbalance, abnormal gait, muscle weakness, and dystonia, in parallel to reduced in vivo brain glucose metabolism, deterioration of specific neuron subsets located in the dentate nucleus and pontine nuclei, small changes in microglial morphology, and reduction in glial glutamate transporters. Concerning the endocannabinoid signaling, our data indicated no changes in CB 2 receptors. By contrast, CB 1 receptors increased in the Purkinje cell layer, in particular in terminals of basket cells, but they were reduced in the dentate nucleus. We also measured the levels of endocannabinoid lipids and found reductions in anandamide and oleoylethanolamide in the brainstem. These changes correlated with an increase in the FAAH enzyme in the brainstem, which also occurred in some cerebellar areas, whereas other endocannabinoid-related enzymes were not altered. Collectively, our results in SCA-3 mutant mice confirm a possible dysregulation in the endocannabinoid system in the most important brain structures affected in this type of ataxia, suggesting that a pharmacological manipulation addressed to correct these changes could be a promising option in SCA-3. Copyright © 2016 IBRO. Published by Elsevier Ltd. All

  19. Genetic variation in the endocannabinoid system and response to Cognitive Behavior Therapy for child anxiety disorders.

    PubMed

    Lester, Kathryn J; Coleman, Jonathan R I; Roberts, Susanna; Keers, Robert; Breen, Gerome; Bögels, Susan; Creswell, Cathy; Hudson, Jennifer L; McKinnon, Anna; Nauta, Maaike; Rapee, Ronald M; Schneider, Silvia; Silverman, Wendy K; Thastum, Mikael; Waite, Polly; Wergeland, Gro Janne H; Eley, Thalia C

    2017-03-01

    Extinction learning is an important mechanism in the successful psychological treatment of anxiety. Individual differences in response and relapse following Cognitive Behavior Therapy may in part be explained by variability in the ease with which fears are extinguished or the vulnerability of these fears to re-emerge. Given the role of the endocannabinoid system in fear extinction, this study investigates whether genetic variation in the endocannabinoid system explains individual differences in response to CBT. Children (N = 1,309) with a primary anxiety disorder diagnosis were recruited. We investigated the relationship between variation in the CNR1, CNR2, and FAAH genes and change in primary anxiety disorder severity between pre- and post-treatment and during the follow-up period in the full sample and a subset with fear-based anxiety disorder diagnoses. Change in symptom severity during active treatment was nominally associated (P < 0.05) with two SNPs. During the follow-up period, five SNPs were nominally associated with a poorer treatment response (rs806365 [CNR1]; rs2501431 [CNR2]; rs2070956 [CNR2]; rs7769940 [CNR1]; rs2209172 [FAAH]) and one with a more favorable response (rs6928813 [CNR1]). Within the fear-based subset, the effect of rs806365 survived multiple testing corrections (P < 0.0016). We found very limited evidence for an association between variants in endocannabinoid system genes and treatment response once multiple testing corrections were applied. Larger, more homogenous cohorts are needed to allow the identification of variants of small but statistically significant effect and to estimate effect sizes for these variants with greater precision in order to determine their potential clinical utility. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by

  20. Genetic variation in the endocannabinoid system and response to Cognitive Behavior Therapy for child anxiety disorders

    PubMed Central

    Coleman, Jonathan R. I.; Roberts, Susanna; Keers, Robert; Breen, Gerome; Bögels, Susan; Creswell, Cathy; Hudson, Jennifer L.; McKinnon, Anna; Nauta, Maaike; Rapee, Ronald M.; Schneider, Silvia; Silverman, Wendy K.; Thastum, Mikael; Waite, Polly; Wergeland, Gro Janne H.; Eley, Thalia C.

    2016-01-01

    Extinction learning is an important mechanism in the successful psychological treatment of anxiety. Individual differences in response and relapse following Cognitive Behavior Therapy may in part be explained by variability in the ease with which fears are extinguished or the vulnerability of these fears to re‐emerge. Given the role of the endocannabinoid system in fear extinction, this study investigates whether genetic variation in the endocannabinoid system explains individual differences in response to CBT. Children (N = 1,309) with a primary anxiety disorder diagnosis were recruited. We investigated the relationship between variation in the CNR1, CNR2, and FAAH genes and change in primary anxiety disorder severity between pre‐ and post‐treatment and during the follow‐up period in the full sample and a subset with fear‐based anxiety disorder diagnoses. Change in symptom severity during active treatment was nominally associated (P < 0.05) with two SNPs. During the follow‐up period, five SNPs were nominally associated with a poorer treatment response (rs806365 [CNR1]; rs2501431 [CNR2]; rs2070956 [CNR2]; rs7769940 [CNR1]; rs2209172 [FAAH]) and one with a more favorable response (rs6928813 [CNR1]). Within the fear‐based subset, the effect of rs806365 survived multiple testing corrections (P < 0.0016). We found very limited evidence for an association between variants in endocannabinoid system genes and treatment response once multiple testing corrections were applied. Larger, more homogenous cohorts are needed to allow the identification of variants of small but statistically significant effect and to estimate effect sizes for these variants with greater precision in order to determine their potential clinical utility. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. PMID:27346075

  1. Neuromodulatory effects of the dorsal hippocampal endocannabinoid system in dextromethorphan/morphine-induced amnesia.

    PubMed

    Ghasemzadeh, Zahra; Rezayof, Ameneh

    2017-01-05

    Dextromethorphan which is an active ingredient in many cough medicines has been previously shown to potentiate amnesic effect of morphine in rats. However, the effect of dextromethorphan, that is also a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, in combination with morphine on hippocampus-based long term memory has not been well characterized. The aim of the present study was to assess the possible role of endocannabinoid system of the dorsal hippocampus in dextromethorphan /morphine-induced amnesia. Our results showed that intraperitoneal (i.p.) injection of morphine (5mg/kg) or dextromethorphan (5-15mg/kg) before testing the passive avoidance learning induced amnesia. Combination of ineffective doses of dextromethorphan (7.5mg/kg, i.p.) and morphine (2mg/kg, i.p.) also produced amnesia, suggesting the enhancing effects of the drugs. To assess the effect of the activation or inhibition of the dorsal hippocampal cannabinoid CB 1 receptors on this amnesia, ACPA or AM251 as selective receptor agonists or antagonists were respectively injected into the CA1 regions before systemic injection of dextromethorphan and morphine. Interestingly, intra-CA1 microinjection of ACPA (0.5-1ng/rat) improved the amnesic effect of dextromethorphan /morphine combination. The microinjection of AM251 into the CA1 region enhanced the response of the combination of dextromethorphan /morphine in inducing amnesia. Moreover, Intra-CA1 microinjection of AM251 inhibited the improving effect of ACPA on dextromethorphan /morphine-induced amnesia. It is important to note that intra-CA1 microinjection of the same doses of the agonist or antagonist by itself had no effects on memory formation. Thus, it can be concluded that the dorsal hippocampal endocannabinoid system, via CB 1 receptor-dependent mechanism, may be involved in morphine/dextromethorphan -induced amnesia. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Cocaine-induced endocannabinoid release modulates behavioral and neurochemical sensitization in mice.

    PubMed

    Mereu, Maddalena; Tronci, Valeria; Chun, Lauren E; Thomas, Alexandra M; Green, Jennifer L; Katz, Jonathan L; Tanda, Gianluigi

    2015-01-01

    The endocannabinoid system has been implicated in the development of synaptic plasticity induced by several drugs abused by humans, including cocaine. However, there remains some debate about the involvement of cannabinoid receptors/ligands in cocaine-induced plasticity and corresponding behavioral actions. Here, we show that a single cocaine injection in Swiss-Webster mice produces behavioral and neurochemical alterations that are under the control of the endocannabinoid system. This plasticity may be the initial basis for changes in brain processes leading from recreational use of cocaine to its abuse and ultimately to dependence. Locomotor activity was monitored with photobeam cell detectors, and accumbens shell/core microdialysate dopamine levels were monitored by high-performance liquid chromatography with electrochemical detection. Development of single-trial cocaine-induced behavioral sensitization, measured as increased distance traveled in sensitized mice compared to control mice, was paralleled by a larger stimulation of extracellular dopamine levels in the core but not the shell of the nucleus accumbens. Both the behavioral and neurochemical effects were reversed by CB1 receptor blockade produced by rimonabant pre-treatments. Further, both behavioral and neurochemical cocaine sensitization were facilitated by pharmacological blockade of endocannabinoid metabolism, achieved by inhibiting the fatty acid amide hydrolase enzyme. In conclusion, our results suggest that a single unconditioned exposure to cocaine produces sensitization through neuronal alterations that require regionally specific release of endocannabinoids. Further, the present results suggest that endocannabinoids play a primary role from the earliest stage of cocaine use, mediating the inception of long-term brain-adaptive responses, shaping central pathways and likely increasing vulnerability to stimulant abuse disorders. Published 2013. This article is a U.S. Government work and is in the

  3. Role of the endocannabinoid system in brain functions relevant for schizophrenia: an overview of human challenge studies with cannabis or ∆9-tetrahydrocannabinol (THC).

    PubMed

    Bossong, Matthijs G; Jansma, J Martijn; Bhattacharyya, Sagnik; Ramsey, Nick F

    2014-07-03

    Accumulating evidence suggests involvement of the endocannabinoid system in the pathophysiology of schizophrenia, which signifies a potential application for this system in the treatment of this disorder. However, before new research can focus on potential treatments that work by manipulating the endocannabinoid system, it needs to be elucidated how this system is involved in symptoms of schizophrenia. Here we review human studies that investigated acute effects of cannabis or ∆9-tetrahydrocannabinol (THC) on brain functions that are implicated in schizophrenia. Results suggest that the impact of THC administration depends on the difficulty of the task performed. Impaired performance of cognitive paradigms is reported on more challenging tasks, which is associated with both activity deficits in temporal and prefrontal areas and a failure to deactivate regions of the default mode network. Comparable reductions in prefrontal activity and impairments in deactivation of the default mode network are seen in patients during performance of cognitive paradigms. Normal performance levels after THC administration demonstrated for less demanding tasks are shown to be related to either increased neural effort in task-specific regions ('neurophysiological inefficiency'), or recruitment of alternative brain areas, which suggests a change in strategy to meet cognitive demands. Particularly a pattern of performance and brain activity corresponding with an inefficient working memory system is consistently demonstrated in patients. These similarities in brain function between intoxicated healthy volunteers and schizophrenia patients provide an argument for a role of the endocannabinoid system in symptoms of schizophrenia, and further emphasize this system as a potential novel target for treatment of these symptoms. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Cannabinoids and endocannabinoids in metabolic disorders with focus on diabetes.

    PubMed

    Di Marzo, Vincenzo; Piscitelli, Fabiana; Mechoulam, Raphael

    2011-01-01

    The cannabinoid receptors for Δ(9)-THC, and particularly, the CB(1) receptor, as well as its endogenous ligands, the endocannabinoids anandamide and 2-arachidonoylglycerol, are deeply involved in all aspects of the control of energy balance in mammals. While initially it was believed that this endocannabinoid signaling system would only facilitate energy intake, we now know that perhaps even more important functions of endocannabinoids and CB(1) receptors in this context are to enhance energy storage into the adipose tissue and reduce energy expenditure by influencing both lipid and glucose metabolism. Although normally well controlled by hormones and neuropeptides, both central and peripheral aspects of endocannabinoid regulation of energy balance can become dysregulated and contribute to obesity, dyslipidemia, and type 2 diabetes, thus raising the possibility that CB(1) antagonists might be used for the treatment of these metabolic disorders. On the other hand, evidence is emerging that some nonpsychotropic plant cannabinoids, such as cannabidiol, can be employed to retard β-cell damage in type 1 diabetes. These novel aspects of endocannabinoid research are reviewed in this chapter, with emphasis on the biological effects of plant cannabinoids and endocannabinoid receptor antagonists in diabetes.

  5. Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis.

    PubMed

    Murillo-Rodríguez, Eric; Machado, Sergio; Rocha, Nuno Barbosa; Budde, Henning; Yuan, Ti-Fei; Arias-Carrión, Oscar

    2016-12-17

    The endocannabinoid system comprises receptors (CB 1 and CB 2 cannabinoid receptors), enzymes (Fatty Acid Amide Hydrolase [FAAH], which synthesizes the endocannabinoid anandamide), as well as the anandamide membrane transporter (AMT). Importantly, previous experiments have demonstrated that the endocannabinoid system modulates multiple neurobiological functions, including sleep. For instance, SR141716A (the CB 1 cannabinoid receptor antagonist) as well as URB597 (the FAAH inhibitor) increase waking in rats whereas VDM-11 (the blocker of the AMT) enhances sleep in rodents. However, no further evidence is available regarding the neurobiological role of the endocannabinoid system in the homeostatic control of sleep. Therefore, the aim of the current experiment was to test if SR141716A, URB597 or VDM-11 would modulate the sleep rebound after sleep deprivation. Thus, these compounds were systemically injected (5, 10, 20mg/kg; ip; separately each one) into rats after prolonged waking. We found that SR141716A and URB597 blocked in dose-dependent fashion the sleep rebound whereas animals treated with VDM-11 displayed sleep rebound during the recovery period. Complementary, injection after sleep deprivation of either SR141716A or URB597 enhanced dose-dependently the extracellular levels of dopamine (DA), norepinephrine (NE), epinephrine (EP), serotonin (5-HT), as well as adenosine (AD) while VDM-11 caused a decline in contents of these molecules. These findings suggest that SR141716A or URB597 behave as a potent stimulants since they suppressed the sleep recovery period after prolonged waking. It can be concluded that elements of the endocannabinoid system, such as the CB 1 cannabinoid receptor, FAAH and AMT, modulate the sleep homeostasis after prolonged waking. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  6. Reduced levels of the endocannabinoid arachidonylethanolamide (AEA) in hair in patients with borderline personality disorder - a pilot study.

    PubMed

    Wingenfeld, Katja; Dettenborn, Lucia; Kirschbaum, Clemens; Gao, Wei; Otte, Christian; Roepke, Stefan

    2018-03-16

    Endocannabinoids are involved in depressive and anxious symptoms and might play a role in stress-associated psychiatric disorders. While alterations in the endogenous cannabinoid system have been repeatedly found in patients with posttraumatic stress disorder (PTSD), this system has been mostly neglected in borderline personality disorder (BPD). However, there is first evidence for elevated serum levels of the endocannabinoids arachidonylethanolamide (AEA) and 2-arachidonyl-sn-glycerol (2-AG) in BPD patients compared to healthy controls and PTSD patients. In this study, hair endocannabinoids were analyzed, reflecting long-term endocannabinoid concentrations. We assessed AEA concentrations as well as 2-AG and the 2-AG main isomer 1-AG (1-AG/2-AG) in hair in women with BPD (n = 15) and age- and education-matched healthy women (n = 16). We found significantly reduced log AEA in BPD patients compared to healthy women (p = .03) but no differences in log 1-AG/2-AG concentrations. In addition, there was no association between 1-AG/2-AG and hair cortisol, but we found a non-significant correlation between hair concentrations of AEA and cortisol (p = .06). Our data indicate altered long-term release of endogenous cannabinoids in women with BPD depending on type of endocannabinoid. AEA has been suggested to modulate the basal activity of the endocannabinoid system and seems to attenuate depressive and anxious symptoms. Thus, chronically reduced AEA might contribute to psychiatric symptoms in BPD.

  7. Social isolation and chronic handling alter endocannabinoid signaling and behavioral reactivity to context in adult rats

    PubMed Central

    Sciolino, Natale R.; Bortolato, Marco; Eisenstein, Sarah A.; Fu, Jin; Oveisi, Fariba; Hohmann, Andrea G.; Piomelli, Daniele

    2010-01-01

    Social deprivation in early life disrupts emotionality and attentional processes in humans. Rearing rats in isolation reproduces some of these abnormalities, which are attenuated by daily handling. However, the neurochemical mechanisms underlying these responses remain poorly understood. We hypothesized that post-weaning social isolation alters the endocannabinoid system, a neuromodulatory system that controls emotional responding. We characterized behavioral consequences of social isolation and evaluated whether handling would reverse social isolation-induced alterations in behavioral reactivity to context and the endocannabinoid system. At weaning, pups were single or group housed and concomitantly handled or not handled daily until adulthood. Rats were tested in emotionality- and attentional-sensitive behavioral assays (open field, elevated plus maze, startle and prepulse inhibition). Cannabinoid receptor densities and endocannabinoid levels were quantified in a separate group of rats. Social isolation negatively altered behavioral responding. Socially-isolated rats that were handled showed less deficits in the open field, elevated plus maze, and prepulse inhibition tests. Social isolation produced site-specific alterations (supraoptic nucleus, ventrolateral thalamus, rostral striatum) in cannabinoid receptor densities compared to group rearing. Handling altered the endocannabinoid system in neural circuitry controlling emotional expression. Handling altered endocannabinoid content (prefrontal and piriform cortices, nucleus accumbens) and cannabinoid receptor densities (lateral globus pallidus, cingulate and piriform cortices, hippocampus) in a region-specific manner. Some effects of social isolation on the endocannabinoid system were moderated by handling. Isolates were unresponsive to handling-induced increases in cannabinoid receptor densities (caudal striatum, anterior thalamus), but were sensitive to handling-induced increases in endocannabinoid content

  8. Anxiety, Stress, and Fear Response in Mice With Reduced Endocannabinoid Levels.

    PubMed

    Jenniches, Imke; Ternes, Svenja; Albayram, Onder; Otte, David M; Bach, Karsten; Bindila, Laura; Michel, Kerstin; Lutz, Beat; Bilkei-Gorzo, Andras; Zimmer, Andreas

    2016-05-15

    Disruption of the endocannabinoid system through pharmacological or genetic invalidation of cannabinoid CB1 receptors has been linked to depression in humans and depression-like behaviors in mice. The two main endogenous cannabinoids, anandamide and 2-arachidonoyl glycerol (2-AG), are produced on demand from phospholipids. The pathways and enzymes involved in endocannabinoid biosynthesis thus play a major role in regulating the activity of this system. This study investigates the role of the main 2-AG producing enzyme diacylglycerol lipase α (DAGL-α). We generated and used knockout mice lacking DAGL-α (Dagla(-/-)) to assess the behavioral consequences of reduced endocannabinoid levels in the brain. We performed different behavior tests to determine anxiety- and depression-related behavioral changes in Dagla(-/-) mice. We also analyzed expression of genes related to the endocannabinoid system via real-time polymerase chain reaction and used the mitotic marker 5-bromo-2'-deoxyuridine to analyze adult neurogenesis. Dagla(-/-) animals show an 80% reduction of brain 2-AG levels but also a reduction in cortical and amygdalar anandamide. The behavioral changes induced by Dagla deletion include a reduced exploration of the central area of the open field, a maternal neglect behavior, a fear extinction deficit, increased behavioral despair, increased anxiety-related behaviors in the light/dark box, and reduced hippocampal neurogenesis. Some of these behavioral changes resemble those observed in animals lacking the CB1 receptor. Our findings demonstrate that the deletion of Dagla adversely affects the emotional state of animals and results in enhanced anxiety, stress, and fear responses. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  9. Abnormalities in neuroendocrine stress response in psychosis: the role of endocannabinoids.

    PubMed

    Appiah-Kusi, E; Leyden, E; Parmar, S; Mondelli, V; McGuire, P; Bhattacharyya, S

    2016-01-01

    The aim of this article is to summarize current evidence regarding alterations in the neuroendocrine stress response system and endocannabinoid system and their relationship in psychotic disorders such as schizophrenia. Exposure to stress is linked to the development of a number of psychiatric disorders including psychosis. However, the precise role of stress in the development of psychosis and the possible mechanisms that might underlie this are not well understood. Recently the cannabinoid hypothesis of schizophrenia has emerged as a potential line of enquiry. Endocannabinoid levels are increased in patients with psychosis compared with healthy volunteers; furthermore, they increase in response to stress, which suggests another potential mechanism for how stress might be a causal factor in the development of psychosis. However, research regarding the links between stress and the endocannabinoid system is in its infancy. Evidence summarized here points to an alteration in the baseline tone and reactivity of the hypothalamic-pituitary-adrenal (HPA) axis as well as in various components of the endocannabinoid system in patients with psychosis. Moreover, the precise nature of the inter-relationship between these two systems is unclear in man, especially their biological relevance in the context of psychosis. Future studies need to simultaneously investigate HPA axis and endocannabinoid alterations both at baseline and following experimental perturbation in healthy individuals and those with psychosis to understand how they interact with each other in health and disease and obtain mechanistic insight as to their relevance to the pathophysiology of schizophrenia.

  10. Prior stimulation of the endocannabinoid system prevents methamphetamine-induced dopaminergic neurotoxicity in the striatum through activation of CB2 receptors.

    PubMed

    Nader, Joëlle; Rapino, Cinzia; Gennequin, Benjamin; Chavant, Francois; Francheteau, Maureen; Makriyannis, Alexandros; Duranti, Andrea; Maccarrone, Mauro; Solinas, Marcello; Thiriet, Nathalie

    2014-12-01

    Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in the striatum similar to what is found in some neurodegenerative diseases. Conversely, the endocannabinoid system (ECS) has been suggested to be neuroprotective in the brain, and new pharmacological tools have been developed to increase their endogenous tone. In this study, we evaluated whether ECS stimulation could reduce the neurotoxicity of high doses of methamphetamine on the dopamine system. We found that methamphetamine alters the levels of the major endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participates in the brain responses to methamphetamine. Δ(9)-tetrahydrocannabinol (THC), a cannabis-derived agonist of both CB1 and CB2 cannabinoid receptors, or inhibitors of the main enzymes responsible for the degradation of AEA and 2-AG (URB597 and JZL184, respectively), blunted the decrease in striatal protein levels of tyrosine hydroxylase induced by methamphetamine. In addition, antagonists of CB2, but not of CB1, blocked the preventive effects of URB597 and JZL184, suggesting that only the former receptor subtype is engaged in neuroprotection exerted by ECS stimulation. Finally, we found that methamphetamine increases striatal levels of the cytokine tumor necrosis factor alpha, an effect that was blocked by ECS stimulation. Altogether, our results indicate that stimulation of ECS prior to the administration of an overdose of methamphetamine considerably reduces the neurotoxicity of the drug through CB2 receptor activation and highlight a protective function for the ECS against the toxicity induced by drugs and other external insults to the brain. This article is part of the Special Issue entitled 'CNS Stimulants'. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Prior stimulation of the endocannabinoid system prevents methamphetamine-induced dopaminergic neurotoxicity in the striatum through activation of CB2 receptors

    PubMed Central

    Nader, Joëlle; Rapino, Cinzia; Gennequin, Benjamin; Chavant, Francois; Francheteau, Maureen; Makriyannis, Alexandros; Duranti, Andrea; Maccarrone, Mauro; Solinas, Marcello; Thiriet, Nathalie

    2016-01-01

    Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in the striatum similar to what is found in some neurodegenerative diseases. Conversely, the endocannabinoid system (ECS) has been suggested to be neuroprotective in the brain, and new pharmacological tools have been developed to increase their endogenous tone. In this study, we evaluated whether ECS stimulation could reduce the neurotoxicity of high doses of methamphetamine on the dopamine system. We found that methamphetamine alters the levels of the major endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participates in the brain responses to methamphetamine. Δ9-tetrahydrocannabinol (THC), a cannabis-derived agonist of both CB1 and CB2 cannabinoid receptors, or inhibitors of the main enzymes responsible for the degradation of AEA and 2-AG (URB597 and JZL184, respectively), blunted the decrease in striatal protein levels of tyrosine hydroxylase induced by methamphetamine. In addition, antagonists of CB2, but not of CB1, blocked the preventive effects of URB597 and JZL184, suggesting that only the former receptor subtype is engaged in neuroprotection exerted by ECS stimulation. Finally, we found that methamphetamine increases striatal levels of the cytokine tumor necrosis factor alpha, an effect that was blocked by ECS stimulation. Altogether, our results indicate that stimulation of ECS prior to the administration of an overdose of meth-amphetamine considerably reduces the neurotoxicity of the drug through CB2 receptor activation and highlight a protective function for the ECS against the toxicity induced by drugs and other external insults to the brain. This article is part of the Special Issue entitled ‘CNS Stimulants’. PMID:24709540

  12. Early phytocannabinoid chemistry to endocannabinoids and beyond.

    PubMed

    Mechoulam, Raphael; Hanuš, Lumír O; Pertwee, Roger; Howlett, Allyn C

    2014-11-01

    Isolation and structure elucidation of most of the major cannabinoid constituents--including Δ(9)-tetrahydrocannabinol (Δ(9)-THC), which is the principal psychoactive molecule in Cannabis sativa--was achieved in the 1960s and 1970s. It was followed by the identification of two cannabinoid receptors in the 1980s and the early 1990s and by the identification of the endocannabinoids shortly thereafter. There have since been considerable advances in our understanding of the endocannabinoid system and its function in the brain, which reveal potential therapeutic targets for a wide range of brain disorders.

  13. Sleep restriction alters plasma endocannabinoids concentrations before but not after exercise in humans.

    PubMed

    Cedernaes, Jonathan; Fanelli, Flaminia; Fazzini, Alessia; Pagotto, Uberto; Broman, Jan-Erik; Vogel, Heike; Dickson, Suzanne L; Schiöth, Helgi B; Benedict, Christian

    2016-12-01

    Following binding to cannabinoid receptors, endocannabinoids regulate a variety of central nervous system processes including appetite and mood. Recent evidence suggests that the systemic release of these lipid metabolites can be altered by acute exercise and that their levels also vary across the 24-h sleep-wake cycle. The present study utilized a within-subject design (involving 16 normal-weight men) to determine whether daytime circulating endocannabinoid concentrations differ following three nights of partial sleep deprivation (4.25-h sleep opportunity, 2:45-7a.m. each night) vs. normal sleep (8.5-h sleep opportunity, 10:30p.m.-7a.m. each night), before and after an acute bout of ergometer cycling in the morning. In addition, subjective hunger and stress were measured. Pre-exercise plasma concentrations of 2-arachidonoylglycerol (2AG) were 80% higher 1.5h after awakening (vs. normal sleep, p<0.05) when participants were sleep-deprived. This coincided with increased hunger ratings (+25% vs. normal sleep, p<0.05). Moreover, plasma 2AG was elevated 15min post-exercise (+44%, p<0.05). Sleep duration did not however modulate this exercise-induced rise. Finally, subjective stress was generally lower on the day after three nights of short sleep vs. normal sleep, especially after exercise (p<0.05). Given that activation of the endocannabinoid system has been previously shown to acutely increase appetite and mood, our results could suggest that behavioral effects of acute sleep loss, such as increased hunger and transiently improved psychological state, may partially result from activation of this signaling pathway. In contrast, more pronounced exercise-induced elevations of endocannabinoids appear to be less affected by short sleep duration. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  14. Marijuana, the Endocannabinoid System and the Female Reproductive System

    PubMed Central

    Brents, Lisa K.

    2016-01-01

    Marijuana use among women is highly prevalent, but the societal conversation on marijuana rarely focuses on how marijuana affects female reproduction and endocrinology. This article reviews the current scientific literature regarding marijuana use and hypothalamic-pituitary-ovarian (HPO) axis regulation, ovarian hormone production, the menstrual cycle, and fertility. Evidence suggests that marijuana can reduce female fertility by disrupting hypothalamic release of gonadotropin releasing hormone (GnRH), leading to reduced estrogen and progesterone production and anovulatory menstrual cycles. Tolerance to these effects has been shown in rhesus monkeys, but the effects of chronic marijuana use on human female reproduction are largely unknown. Marijuana-induced analgesia, drug reinforcement properties, tolerance, and dependence are influenced by ovarian hormones, with estrogen generally increasing and progesterone decreasing sensitivity to marijuana. Carefully controlled regulation of the Endocannabinoid System (ECS) is required for successful reproduction, and the exogenous cannabinoids in marijuana may disrupt the delicate balance of the ECS in the female reproductive system. PMID:27354844

  15. Marijuana, the Endocannabinoid System and the Female Reproductive System.

    PubMed

    Brents, Lisa K

    2016-06-01

    Marijuana use among women is highly prevalent, but the societal conversation on marijuana rarely focuses on how marijuana affects female reproduction and endocrinology. This article reviews the current scientific literature regarding marijuana use and hypothalamic-pituitary-ovarian (HPO) axis regulation, ovarian hormone production, the menstrual cycle, and fertility. Evidence suggests that marijuana can reduce female fertility by disrupting hypothalamic release of gonadotropin releasing hormone (GnRH), leading to reduced estrogen and progesterone production and anovulatory menstrual cycles. Tolerance to these effects has been shown in rhesus monkeys, but the effects of chronic marijuana use on human female reproduction are largely unknown. Marijuana-induced analgesia, drug reinforcement properties, tolerance, and dependence are influenced by ovarian hormones, with estrogen generally increasing and progesterone decreasing sensitivity to marijuana. Carefully controlled regulation of the Endocannabinoid System (ECS) is required for successful reproduction, and the exogenous cannabinoids in marijuana may disrupt the delicate balance of the ECS in the female reproductive system.

  16. Fatty acid binding protein-1 (FABP1) and the human FABP1 T94A Variant: Roles in the Endocannabinoid System and Dyslipidemias

    PubMed Central

    Schroeder, Friedhelm; McIntosh, Avery L.; Martin, Gregory G.; Huang, Huan; Landrock, Danilo; Chung, Sarah; Landrock, Kerstin K.; Dangott, Lawrence J.; Li, Shengrong; Kaczocha, Martin; Murphy, Eric J.; Atshaves, Barbara P.; Kier, Ann B.

    2017-01-01

    The first discovered member of the mammalian FABP family, liver fatty acid binding protein (FABP1, L-FABP), occurs at high cytosolic concentration in liver, intestine and in the case of humans also in kidney. While the rat FABP1 is well studied, the extent these findings translate to human FABP1 is not clear—especially in view of recent studies showing that endocannabinoids and cannabinoids represent novel rat FABP1 ligands and FABP1 gene ablation impacts the hepatic endocannabinoid system, known to be involved in non-alcoholic fatty liver (NAFLD) development. Although not detectable in brain, FABP1 ablation nevertheless also impacts brain endocannabinoids. Despite overall tertiary structure similarity, human FABP1 differs significantly from rat FABP1 in secondary structure, much larger ligand binding cavity, and affinities/specificities for some ligands. Moreover, while both mouse and human FABP1 mediate ligand induction of peroxisome proliferator activated receptor-α, (PPARα), they differ markedly in pattern of genes induced. This is critically important because a highly prevalent human SNP (26–38% minor allele frequency and 8.3±1.9% homozygous) results in a FABP1 T94A substitution that further accentuates these species differences. The human FABP1 T94A variant is associated with altered body mass index (BMI), clinical dyslipidemias (elevated plasma triglycerides and LDL cholesterol), atherothrombotic cerebral infarction, and non-alcoholic fatty liver disease (NAFLD). Resolving human FABP1 and the T94A variant’s impact on the endocannabinoid and cannabinoid system is an exciting challenge due to the importance of this system on hepatic lipid accumulation as well as behavior, pain, inflammation, and satiety. PMID:27117865

  17. Fatty Acid Binding Protein-1 (FABP1) and the Human FABP1 T94A Variant: Roles in the Endocannabinoid System and Dyslipidemias.

    PubMed

    Schroeder, Friedhelm; McIntosh, Avery L; Martin, Gregory G; Huang, Huan; Landrock, Danilo; Chung, Sarah; Landrock, Kerstin K; Dangott, Lawrence J; Li, Shengrong; Kaczocha, Martin; Murphy, Eric J; Atshaves, Barbara P; Kier, Ann B

    2016-06-01

    The first discovered member of the mammalian FABP family, liver fatty acid binding protein (FABP1, L-FABP), occurs at high cytosolic concentration in liver, intestine, and in the case of humans also in kidney. While the rat FABP1 is well studied, the extent these findings translate to human FABP1 is not clear-especially in view of recent studies showing that endocannabinoids and cannabinoids represent novel rat FABP1 ligands and FABP1 gene ablation impacts the hepatic endocannabinoid system, known to be involved in non-alcoholic fatty liver (NAFLD) development. Although not detectable in brain, FABP1 ablation nevertheless also impacts brain endocannabinoids. Despite overall tertiary structure similarity, human FABP1 differs significantly from rat FABP1 in secondary structure, much larger ligand binding cavity, and affinities/specificities for some ligands. Moreover, while both mouse and human FABP1 mediate ligand induction of peroxisome proliferator activated receptor-α (PPARα), they differ markedly in pattern of genes induced. This is critically important because a highly prevalent human single nucleotide polymorphism (SNP) (26-38 % minor allele frequency and 8.3 ± 1.9 % homozygous) results in a FABP1 T94A substitution that further accentuates these species differences. The human FABP1 T94A variant is associated with altered body mass index (BMI), clinical dyslipidemias (elevated plasma triglycerides and LDL cholesterol), atherothrombotic cerebral infarction, and non-alcoholic fatty liver disease (NAFLD). Resolving human FABP1 and the T94A variant's impact on the endocannabinoid and cannabinoid system is an exciting challenge due to the importance of this system in hepatic lipid accumulation as well as behavior, pain, inflammation, and satiety.

  18. Stress Response Recruits the Hippocampal Endocannabinoid System for the Modulation of Fear Memory

    ERIC Educational Resources Information Center

    Alvares, Lucas de Oliveira; Engelke, Douglas Senna; Diehl, Felipe; Scheffer-Teixeira, Robson; Haubrich, Josue; Cassini, Lindsey de Freitas; Molina, Victor Alejandro; Quillfeldt, Jorge Alberto

    2010-01-01

    The modulation of memory processes is one of the several functions of the endocannabinoid system (ECS) in the brain, with CB1 receptors highly expressed in areas such as the dorsal hippocampus. Experimental evidence suggested an important role of the ECS in aversively motivated memories. Similarly, glucocorticoids released in response to stress…

  19. Endocannabinoid Signaling in Autism.

    PubMed

    Chakrabarti, Bhismadev; Persico, Antonio; Battista, Natalia; Maccarrone, Mauro

    2015-10-01

    Autism spectrum disorder (ASD) is a complex behavioral condition with onset during early childhood and a lifelong course in the vast majority of cases. To date, no behavioral, genetic, brain imaging, or electrophysiological test can specifically validate a clinical diagnosis of ASD. However, these medical procedures are often implemented in order to screen for syndromic forms of the disorder (i.e., autism comorbid with known medical conditions). In the last 25 years a good deal of information has been accumulated on the main components of the "endocannabinoid (eCB) system", a rather complex ensemble of lipid signals ("endocannabinoids"), their target receptors, purported transporters, and metabolic enzymes. It has been clearly documented that eCB signaling plays a key role in many human health and disease conditions of the central nervous system, thus opening the avenue to the therapeutic exploitation of eCB-oriented drugs for the treatment of psychiatric, neurodegenerative, and neuroinflammatory disorders. Here we present a modern view of the eCB system, and alterations of its main components in human patients and animal models relevant to ASD. This review will thus provide a critical perspective necessary to explore the potential exploitation of distinct elements of eCB system as targets of innovative therapeutics against ASD.

  20. Endocannabinoid antagonism: blocking the excess in the treatment of high-risk abdominal obesity.

    PubMed

    Duffy, Danielle; Rader, Daniel

    2007-02-01

    Abdominal obesity is a prevalent, worldwide problem linked to cardiometabolic comorbidities and an increased risk of coronary heart disease. First-line therapy to reduce such risk revolves around diet and exercise; however, such changes are often difficult to implement and unsuccessful. Understanding the underlying pathophysiology of underlying metabolic derangements could provide new targets for pharmacologic therapy. One system that has gained recent attention is the endocannabinoid system. The endocannabinoid system has a significant role in central appetite control and peripheral lipogenesis and is up-regulated in diet-induced obesity. Rimonabant is a selective cannabinoid-1 receptor antagonist and is the first compound of its type to test the hypothesis that down-regulating an overactive endocannabinoid system could have therapeutic benefit not only for weight loss but also for the atherogenic dyslipidemia and insulin resistance that cluster with abdominal obesity in particular. Animal models have been critical for elucidating the role of the endocannabinoid system in obesity and in demonstrating that antagonism with rimonabant can induce loss of visceral fat and improve insulin sensitivity. Early human trials with rimonabant have confirmed significant reductions in weight, as well as favorable changes in atherogenic dyslipidemia, insulin resistance, and markers of inflammation. Interestingly, some of these beneficial metabolic effects are partially weight-loss-independent, confirming the importance of peripheral endocannabinoid system effects in addition to central effects.

  1. Endocannabinoids selectively enhance sweet taste.

    PubMed

    Yoshida, Ryusuke; Ohkuri, Tadahiro; Jyotaki, Masafumi; Yasuo, Toshiaki; Horio, Nao; Yasumatsu, Keiko; Sanematsu, Keisuke; Shigemura, Noriatsu; Yamamoto, Tsuneyuki; Margolskee, Robert F; Ninomiya, Yuzo

    2010-01-12

    Endocannabinoids such as anandamide [N-arachidonoylethanolamine (AEA)] and 2-arachidonoyl glycerol (2-AG) are known orexigenic mediators that act via CB(1) receptors in hypothalamus and limbic forebrain to induce appetite and stimulate food intake. Circulating endocannabinoid levels inversely correlate with plasma levels of leptin, an anorexigenic mediator that reduces food intake by acting on hypothalamic receptors. Recently, taste has been found to be a peripheral target of leptin. Leptin selectively suppresses sweet taste responses in wild-type mice but not in leptin receptor-deficient db/db mice. Here, we show that endocannabinoids oppose the action of leptin to act as enhancers of sweet taste. We found that administration of AEA or 2-AG increases gustatory nerve responses to sweeteners in a concentration-dependent manner without affecting responses to salty, sour, bitter, and umami compounds. The cannabinoids increase behavioral responses to sweet-bitter mixtures and electrophysiological responses of taste receptor cells to sweet compounds. Mice genetically lacking CB(1) receptors show no enhancement by endocannnabinoids of sweet taste responses at cellular, nerve, or behavioral levels. In addition, the effects of endocannabinoids on sweet taste responses of taste cells are diminished by AM251, a CB(1) receptor antagonist, but not by AM630, a CB(2) receptor antagonist. Immunohistochemistry shows that CB(1) receptors are expressed in type II taste cells that also express the T1r3 sweet taste receptor component. Taken together, these observations suggest that the taste organ is a peripheral target of endocannabinoids. Reciprocal regulation of peripheral sweet taste reception by endocannabinoids and leptin may contribute to their opposing actions on food intake and play an important role in regulating energy homeostasis.

  2. Effect of endocannabinoid signalling on cell fate: life, death, differentiation and proliferation of brain cells.

    PubMed

    Garcia-Arencibia, Moises; Molina-Holgado, Eduardo; Molina-Holgado, Francisco

    2018-05-24

    Cell fate events are regulated by different endogenous developmental factors such as the cell micro-environment, external or remote signals and epigenetic factors. Among the many regulatory factors, endocannabinoid-associated signalling pathways are known to conduct several of these events in the developing nervous system and in the adult brain. Interestingly, endocannabinoids exert modulatory actions in both physiological and pathological conditions. Endocannabinoid signalling can promote cell survival by acting on non-transformed brain cells (neurons, astrocytes or oligodendrocytes) and can have either a protumoural or antitumoural effect on transformed cells. Moreover, endocannabinoids are able to attenuate the detrimental effects on neurogenesis and neuroinflammation associated with ageing. Thus, the endocannabinoid system emerges as an important regulator of cell fate, controlling cell survival/cell death decisions depending on the cell type and its environment. © 2018 The British Pharmacological Society.

  3. Modulation of 3,4-methylenedioxymethamphetamine effects by endocannabinoid system.

    PubMed

    Valverde, Olga; Rodríguez-Árias, Marta

    2013-01-01

    The amphetamine derivative 3, 4 Methylenedioxymethanphetamine (MDMA) is a powerful central nervous system stimulant that displays numerous pharmacological effects, including neurotoxicity. MDMA, or ecstasy, acts by inducing the release of different neurotransmitters depending on the animal species and, in particular, it produces the release of serotonin and dopamine. MDMA induces rewarding and reinforcing effects in rodents, primates and humans, and is currently consumed as an illicit psychostimulant among young people. One of the most reported side effects is the hyperthermic effect and the neurotoxicity on central serotonergic and dopaminergic neurons, depending on the species of animal. It seems that MDMA may also produce neurotoxic effects in humans. To date, the most consistent findings associated to MDMA consumption in humans relate to cognitive deficits in heavy users. MDMA when consumed as an illicit psychostimulant is commonly co-used with other abusers, being frequently associated with cannabinoids. The interaction between MDMA and cannabis effects is complex. Cannabis derivatives act on endocannabinoid system. Thus, at cellular levels, cannabinoids acting through CB1 cannabinoid receptors display opposite effects to those induced by MDMA, and they have been reported to develop neuroprotective actions, including the blockage of MDMA induced neurotoxicity, in laboratory animals. However, cannabis use is a recognized risk factor in the presentation and development of neuropsychiatric disorders, and also contributes to the development of psychological problems and cognitive failures observed in MDMA users. This paper represents a brief overview of the pharmacological interaction between MDMA and cannabis derivatives acting in the endocannabinoid system. We have evaluated recent findings in the literature of the most representative pharmacological effects displayed by both types of drugs. We analyze both, the synergic and opposite effects produced by these

  4. Re-visiting the Endocannabinoid System and Its Therapeutic Potential in Obesity and Associated Diseases.

    PubMed

    Richey, Joyce M; Woolcott, Orison

    2017-09-14

    The purpose of the review was to revisit the possibility of the endocannabinoid system being a therapeutic target for the treatment of obesity by focusing on the peripheral roles in regulating appetite and energy metabolism. Previous studies with the global cannabinoid receptor blocker rimonabant, which has both central and peripheral properties, showed that this drug has beneficial effects on cardiometabolic function but severe adverse psychiatric side effects. Consequently, focus has shifted to peripherally restricted cannabinoid 1 (CB1) receptor blockers as possible therapeutic agents that mitigate or eliminate the untoward effects in the central nervous system. Targeting the endocannabinoid system using novel peripheral CB1 receptor blockers with negligible penetrance across the blood-brain barrier may prove to be effective therapy for obesity and its co-morbidities. Perhaps the future of blockers targeting CB1 receptors will be tissue-specific neutral antagonists (e.g., skeletal muscle specific to treat peripheral insulin resistance, adipocyte-specific to treat fat excess, liver-specific to treat fatty liver and hepatic insulin resistance).

  5. Endocannabinoids and stress.

    PubMed

    Riebe, Caitlin J; Wotjak, Carsten T

    2011-07-01

    Endogenous cannabinoids play an important role in the physiology and behavioral expression of stress responses. Activation of the hypothalamic-pituitary-adrenal (HPA) axis, including the release of glucocorticoids, is the fundamental hormonal response to stress. Endocannabinoid (eCB) signaling serves to maintain HPA-axis homeostasis, by buffering basal activity as well as by mediating glucocorticoid fast feedback mechanisms. Following chronic stressor exposure, eCBs are also involved in physiological and behavioral habituation processes. Behavioral consequences of stress include fear and stress-induced anxiety as well as memory formation in the context of stress, involving contextual fear conditioning and inhibitory avoidance learning. Chronic stress can also lead to depression-like symptoms. Prominent in these behavioral stress responses is the interaction between eCBs and the HPA-axis. Future directions may differentiate among eCB signaling within various brain structures/neuronal subpopulations as well as between the distinct roles of the endogenous cannabinoid ligands. Investigation into the role of the eCB system in allostatic states and recovery processes may give insight into possible therapeutic manipulations of the system in treating chronic stress-related conditions in humans.

  6. Neuroprotective Properties of Endocannabinoids N-Arachidonoyl Dopamine and N-Docosahexaenoyl Dopamine Examined in Neuronal Precursors Derived from Human Pluripotent Stem Cells.

    PubMed

    Novosadova, E V; Arsenyeva, E L; Manuilova, E S; Khaspekov, L G; Bobrov, M Yu; Bezuglov, V V; Illarioshkin, S N; Grivennikov, I A

    2017-11-01

    Neuroprotective properties of endocannabinoids N-arachidonoyl dopamine (NADA) and N-docosahexaenoyl dopamine (DHDA) were examined in neuronal precursor cells differentiated from human induced pluripotent stem cells and subjected to oxidative stress. Both compounds exerted neuroprotective activity, which was enhanced by elevating the concentration of the endocannabinoids within the 0.1-10 µM range. However, both agents at 10 µM concentration showed a marked toxic effect resulting in death of ~30% of the cells. Finally, antagonists of cannabinoid receptors as well as the receptor of the TRPV1 endovanilloid system did not hamper the neuroprotective effects of these endocannabinoids.

  7. Endocannabinoid signalling: has it got rhythm?

    PubMed Central

    Vaughn, Linda K; Denning, Gerene; Stuhr, Kara L; de Wit, Harriet; Hill, Matthew N; Hillard, Cecilia J

    2010-01-01

    Endogenous cannabinoid signalling is widespread throughout the body, and considerable evidence supports its modulatory role in many fundamental physiological processes. The daily and seasonal cycles of the relationship of the earth and sun profoundly affect the terrestrial environment. Terrestrial species have adapted to these cycles in many ways, most well studied are circadian rhythms and hibernation. The purpose of this review was to examine literature support for three hypotheses: (i) endocannabinoid signalling exhibits brain region-specific circadian rhythms; (ii) endocannabinoid signalling modulates the rhythm of circadian processes in mammals; and (iii) changes in endocannabinoid signalling contribute to the state of hibernation. The results of two novel studies are presented. First, we report the results of a study of healthy humans demonstrating that plasma concentrations of the endocannabinoid, N-arachidonylethanolamine (anandamide), exhibit a circadian rhythm. Concentrations of anandamide are threefold higher at wakening than immediately before sleep, a relationship that is dysregulated by sleep deprivation. Second, we investigated differences in endocannabinoids and congeners in plasma from Marmota monax obtained in the summer and during the torpor state of hibernation. We report that 2-arachidonoylglycerol is below detection in M. monax plasma and that concentrations of anandamide are not different. However, plasma concentrations of the anorexigenic lipid oleoylethanolamide were significantly lower in hibernation, while the concentrations of palmitoylethanolamide and 2-oleoylglycerol were significantly greater in hibernation. We conclude that available data support a bidirectional relationship between endocannabinoid signalling and circadian processes, and investigation of the contribution of endocannabinoid signalling to the dramatic physiological changes that occur during hibernation is warranted. This article is part of a themed issue on

  8. Quantification of endocannabinoids in postmortem brain of schizophrenic subjects.

    PubMed

    Muguruza, Carolina; Lehtonen, Marko; Aaltonen, Niina; Morentin, Benito; Meana, J Javier; Callado, Luis F

    2013-08-01

    Numerous studies have implicated the endocannabinoid system in the pathophysiology of schizophrenia. Endocannabinoids have been measured in blood and cerebrospinal fluid in schizophrenic patients but, to the date, there are no published reports dealing with measurements of endocannabinoid levels in schizophrenics' brain tissue. In the present study, postmortem brain samples from 19 subjects diagnosed with schizophrenia (DSM-IV) and 19 matched controls were studied. In specific brain regions, levels of four endocannabinoids (2-arachidonoylglycerol (2-AG), arachidonoylethanolamine (anandamide, AEA), dihomo-γ-linolenoylethanolamine (LEA), and docosahexaenoylethanolamine (DHEA)) and two cannabimimetic compounds (palmitoyl-ethanolamine (PEA) and oleoyl-ethanolamine (OEA)) were measured using quantitative liquid chromatography with triple quadrupole mass spectrometric detection. Suffering from schizophrenia significantly affects the brain levels of 2-AG (p<0.001), AEA (p<0.0001), DHEA (p<0.0001), LEA (p<0.01) and PEA (p<0.05). In schizophrenic subjects, the three studied brain regions (cerebellum: 130±18%; p=0.16; hippocampus: 168±28%, p<0.01; prefrontal cortex: 237±45%, p<0.05) showed higher 2-AG levels when compared to matched controls. Conversely, AEA levels were lower in all brain regions of schizophrenic subjects (cerebellum: 66±7%, p<0.01; hippocampus: 66±7%, p<0.01; prefrontal cortex: 75±10%, p=0.07). Statistically significant lower levels of DHEA were also found in cerebellum (60±6%, p<0.001) and hippocampus (68±7%, p<0.05) of schizophrenic subjects. PEA (71±6%, p<0.05) and LEA (72±6%, p<0.05) levels were also found to be lower in cerebellum. No significant differences were found in OEA levels. Our results evidence specific alterations in the levels of some endocannabinoids in different brain regions of schizophrenic subjects. Furthermore, these data evidence the involvement of the endocannabinoid system in the pathophysiology of schizophrenia

  9. Potential control of multiple sclerosis by cannabis and the endocannabinoid system.

    PubMed

    Pryce, Gareth; Baker, David

    2012-08-01

    For many years, multiple sclerosis (MS) patients have been self-medicating with illegal street cannabis to alleviate symptoms associated with MS. Data from animal models of MS and clinical studies have supported the anecdotal data that cannabis can improve symptoms such as limb spasticity, which are commonly associated with progressive MS, by the modulation of excessive neuronal signalling. This has lead to cannabis-based medicines being approved for the treatment of pain and spasticity in MS for the first time. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have activity, not only in symptom relief but also potentially in neuroprotective strategies which may slow disease progression and thus delay the onset of symptoms such as spasticity. This review appraises the current knowledge of cannabinoid biology particularly as it pertains to MS and outlines potential future therapeutic strategies for the treatment of disease progression in MS.

  10. Cocaine-Induced Behavioral Sensitization Is Associated With Changes in the Expression of Endocannabinoid and Glutamatergic Signaling Systems in the Mouse Prefrontal Cortex

    PubMed Central

    Blanco, Eduardo; Pavón, Francisco J.; Palomino, Ana; Luque-Rojas, María Jesús; Serrano, Antonia; Rivera, Patricia; Bilbao, Ainhoa; Alen, Francisco; Vida, Margarita; Suárez, Juan

    2015-01-01

    Background: Endocannabinoids modulate the glutamatergic excitatory transmission by acting as retrograde messengers. A growing body of studies has reported that both signaling systems in the mesocorticolimbic neural circuitry are involved in the neurobiological mechanisms underlying drug addiction. Methods: We investigated whether the expression of both endocannabinoid and glutamatergic systems in the prefrontal cortex (PFC) were altered by an acute and/or repeated cocaine administration schedule that resulted in behavioral sensitization. We measured the protein and mRNA expression of the main endocannabinoid metabolic enzymes and the cannabinoid receptor type 1 (CB1). We also analyzed the mRNA expression of relevant components of the glutamate-signaling system, including glutamate-synthesizing enzymes, metabotropic receptors, and ionotropic receptors. Results: Although acute cocaine (10mg/kg) produced no significant changes in the endocannabinoid-related proteins, repeated cocaine administration (20mg/kg daily) induced a pronounced increase in the CB1 receptor expression. In addition, acute cocaine administration (10mg/kg) in cocaine-sensitized mice (referred to as cocaine priming) induced a selective increase in the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). These protein changes were accompanied by an overall decrease in the ratios of endocannabinoid synthesis/degradation, especially the N-acyl phosphatidylethanolamine phospholipase D/FAAH and diacylglycerol lipase alpha/MAGL ratios. Regarding mRNA expression, while acute cocaine administration produced a decrease in CB1 receptors and N-acyl phosphatidylethanolamine phospholipase D, repeated cocaine treatment enhanced CB1 receptor expression. Cocaine-sensitized mice that were administered priming injections of cocaine mainly displayed an increased FAAH expression. These endocannabinoid changes were associated with modifications in glutamatergic

  11. Masturbation to Orgasm Stimulates the Release of the Endocannabinoid 2-Arachidonoylglycerol in Humans.

    PubMed

    Fuss, Johannes; Bindila, Laura; Wiedemann, Klaus; Auer, Matthias K; Briken, Peer; Biedermann, Sarah V

    2017-11-01

    Endocannabinoids are critical for rewarding behaviors such as eating, physical exercise, and social interaction. The role of endocannabinoids in mammalian sexual behavior has been suggested because of the influence of cannabinoid receptor agonists and antagonists on rodent sexual activity. However, the involvement of endocannabinoids in human sexual behavior has not been studied. To investigate plasma endocannabinoid levels before and after masturbation in healthy male and female volunteers. Plasma levels of the endocannabinoids 2-arachidonoylglycerol (2-AG), anandamide, the endocannabinoid-like lipids oleoyl ethanolamide and palmitoyl ethanolamide, arachidonic acid, and cortisol before and after masturbation to orgasm. In study 1, endocannabinoid and cortisol levels were measured before and after masturbation to orgasm. In study 2, masturbation to orgasm was compared with a control condition using a single-blinded, randomized, 2-session crossover design. In study 1, masturbation to orgasm significantly increased plasma levels of the endocannabinoid 2-AG, whereas anandamide, oleoyl ethanolamide, palmitoyl ethanolamide, arachidonic acid, and cortisol levels were not altered. In study 2, only masturbation to orgasm, not the control condition, led to a significant increase in 2-AG levels. Interestingly, we also found a significant increase of oleoyl ethanolamide after masturbation to orgasm in study 2. Endocannabinoids might play an important role in the sexual response cycle, leading to possible implications for the understanding and treatment of sexual dysfunctions. We found an increase of 2-AG through masturbation to orgasm in 2 studies including a single-blinded randomized design. The exact role of endocannabinoid release as part of the sexual response cycle and the biological significance of the finding should be studied further. Cannabis and other drug use and the attainment of orgasm were self-reported in the present study. Our data indicate that the

  12. Alterations in endocannabinoid tone following chemotherapy-induced peripheral neuropathy: effects of endocannabinoid deactivation inhibitors targeting fatty-acid amide hydrolase and monoacylglycerol lipase in comparison to reference analgesics following cisplatin treatment.

    PubMed

    Guindon, Josée; Lai, Yvonne; Takacs, Sara M; Bradshaw, Heather B; Hohmann, Andrea G

    2013-01-01

    Cisplatin, a platinum-derived chemotherapeutic agent, produces mechanical and coldallodynia reminiscent of chemotherapy-induced neuropathy in humans. The endocannabinoid system represents a novel target for analgesic drug development. The endocannabinoid signaling system consists of endocannabinoids (e.g. anandamide (AEA) and 2-arachidonoylglycerol (2-AG)), cannabinoid receptors (e.g. CB(1) and CB(2)) and the enzymes controlling endocannabinoid synthesis and degradation. AEA is hydrolyzed by fatty-acid amide hydrolase (FAAH) whereas 2-AG is hydrolyzed primarily by monoacylglycerol lipase (MGL). We compared effects of brain permeant (URB597) and impermeant (URB937) inhibitors of FAAH with an irreversible inhibitor of MGL (JZL184) on cisplatin-evoked behavioral hypersensitivities. Endocannabinoid modulators were compared with agents used clinically to treat neuropathy (i.e. the opioid analgesic morphine, the anticonvulsant gabapentin and the tricyclic antidepressant amitriptyline). Cisplatin produced robust mechanical and cold allodynia but did not alter responsiveness to heat. After neuropathy was fully established, groups received acute intraperitoneal (i.p.) injections of vehicle, amitriptyline (30 mg/kg), gabapentin (100 mg/kg), morphine (6 mg/kg), URB597 (0.1 or 1 mg/kg), URB937 (0.1 or 1 mg/kg) or JZL184 (1, 3 or 8 mg/kg). Pharmacological specificity was assessed by coadministering each endocannabinoid modulator with either a CB(1) (AM251 3 mg/kg), CB(2) (AM630 3 mg/kg), TRPV1 (AMG9810 3 mg/kg) or TRPA1 (HC030031 8 mg/kg) antagonist. Effects of cisplatin on endocannabinoid levels and transcription of receptors (CB(1), CB(2), TRPV1, TRPA1) and enzymes (FAAH, MGL) linked to the endocannabinoid system were also assessed. URB597, URB937, JZL184 and morphine reversed cisplatin-evoked mechanical and cold allodynia to pre-cisplatin levels. By contrast, gabapentin only partially reversed the observed allodynia while amitriptyline, administered acutely, was ineffective

  13. Endocannabinoids Stimulate Human Melanogenesis via Type-1 Cannabinoid Receptor*

    PubMed Central

    Pucci, Mariangela; Pasquariello, Nicoletta; Battista, Natalia; Di Tommaso, Monia; Rapino, Cinzia; Fezza, Filomena; Zuccolo, Michela; Jourdain, Roland; Finazzi Agrò, Alessandro; Breton, Lionel; Maccarrone, Mauro

    2012-01-01

    We show that a fully functional endocannabinoid system is present in primary human melanocytes (normal human epidermal melanocyte cells), including anandamide (AEA), 2-arachidonoylglycerol, the respective target receptors (CB1, CB2, and TRPV1), and their metabolic enzymes. We also show that at higher concentrations AEA induces normal human epidermal melanocyte apoptosis (∼3-fold over controls at 5 μm) through a TRPV1-mediated pathway that increases DNA fragmentation and p53 expression. However, at lower concentrations, AEA and other CB1-binding endocannabinoids dose-dependently stimulate melanin synthesis and enhance tyrosinase gene expression and activity (∼3- and ∼2-fold over controls at 1 μm). This CB1-dependent activity was fully abolished by the selective CB1 antagonist SR141716 or by RNA interference of the receptor. CB1 signaling engaged p38 and p42/44 mitogen-activated protein kinases, which in turn activated the cyclic AMP response element-binding protein and the microphthalmia-associated transcription factor. Silencing of tyrosinase or microphthalmia-associated transcription factor further demonstrated the involvement of these proteins in AEA-induced melanogenesis. In addition, CB1 activation did not engage the key regulator of skin pigmentation, cyclic AMP, showing a major difference compared with the regulation of melanogenesis by α-melanocyte-stimulating hormone through melanocortin 1 receptor. PMID:22431736

  14. Endocannabinoids as physiological regulators of colonic propulsion in mice.

    PubMed

    Pinto, Luisa; Izzo, Angelo A; Cascio, Maria Grazia; Bisogno, Tiziana; Hospodar-Scott, Karen; Brown, David R; Mascolo, Nicola; Di Marzo, Vincenzo; Capasso, Francesco

    2002-07-01

    Activation of enteric cannabinoid CB1 receptors inhibits motility in the small intestine; however, it is not known whether endogenous cannabinoids (anandamide and 2-arachidonylglycerol) play a physiologic role in regulating intestinal motility. In the present study, we investigated the possible involvement of endocannabinoids in regulating intestinal propulsion in the mouse colon in vivo. Intestinal motility was studied measuring the expulsion of a glass bead inserted into the distal colon; endocannabinoid levels were measured by isotope-dilution gas chromatography-mass spectrometry; anandamide amidohydrolase activity was measured by specific enzyme assays. CB1 receptors were localized by immunohistochemistry. Anandamide, WIN 55,212-2, cannabinol (nonselective cannabinoid agonists), and ACEA (a selective CB1 agonist) inhibited colonic propulsion; this effect was counteracted by SR141716A, a CB1 receptor antagonist. Administered alone, SR141716A increased motility, whereas the inhibitor of anandamide cellular reuptake, VDM11, decreased motility. High amounts of 2-arachidonylglycerol and particularly anandamide were found in the colon, together with a high activity of anandamide amidohydrolase. CB1 receptor immunoreactivity was colocalized to a subpopulation of choline acetyltransferase-immunoreactive neurons and fiber bundles in the myenteric plexus. We conclude that endocannabinoids acting on myenteric CB1 receptors tonically inhibit colonic propulsion in mice.

  15. Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system.

    PubMed

    McPartland, John M; Guy, Geoffrey W; Di Marzo, Vincenzo

    2014-01-01

    The "classic" endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the "eCB deficiency syndrome" as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system--ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation. We searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and 36 human studies. Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as "complementary and alternative medicine" also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances--alcohol, tobacco, coffee, cannabis) also modulate the eCB system. Few clinical trials have assessed interventions that upregulate the eCB system. Many preclinical studies point to other potential approaches; human trials are needed to explore these promising interventions.

  16. The Endocannabinoid System, Aggression, and the Violence of Synthetic Cannabinoid Use, Borderline Personality Disorder, Antisocial Personality Disorder, and Other Psychiatric Disorders.

    PubMed

    Kolla, Nathan J; Mishra, Achal

    2018-01-01

    Endogenous and exogenous cannabinoids bind to central cannabinoid receptors to control a multitude of behavioral functions, including aggression. The first main objective of this review is to dissect components of the endocannabinoid system, including cannabinoid 1 and cannabinoid 2 receptors; the endogenous cannabinoids anandamide and 2-arachidonoylglycerol; and the indirect cannabinoid modulators fatty acid amide hydrolase and monoacylglycerol lipase; that have shown abnormalities in basic research studies investigating mechanisms of aggression. While most human research has concluded that the active ingredient of marijuana, Δ9-tetrahydrocannabinol, tends to dampen rather than provoke aggression in acute doses, recent evidence supports a relationship between the ingestion of synthetic cannabinoids and emergence of violent or aggressive behavior. Thus, another objective is to evaluate the emerging clinical data. This paper also discusses the relationship between prenatal and perinatal exposure to cannabis as well as use of cannabis in adolescence on aggressive outcomes. A final objective of the paper is to discuss endocannabinoid abnormalities in psychotic and affective disorders, as well as clinically aggressive populations, such as borderline personality disorder and antisocial personality disorder. With regard to the former condition, decreased anandamide metabolites have been reported in the cerebrospinal fluid, while some preliminary evidence suggests that fatty acid amide hydrolase genetic polymorphisms are linked to antisocial personality disorder and impulsive-antisocial psychopathic traits. To summarize, this paper will draw upon basic and clinical research to explain how the endocannabinoid system may contribute to the genesis of aggressive behavior.

  17. An endocannabinoid hypothesis of drug reward and drug addiction.

    PubMed

    Onaivi, Emmanuel S

    2008-10-01

    Pharmacologic treatment of drug and alcohol dependency has largely been disappointing, and new therapeutic targets and hypotheses are needed. There is accumulating evidence indicating a central role for the previously unknown but ubiquitous endocannabinoid physiological control system (EPCS) in the regulation of the rewarding effects of abused substances. Thus an endocannabinoid hypothesis of drug reward is postulated. Endocannabinoids mediate retrograde signaling in neuronal tissues and are involved in the regulation of synaptic transmission to suppress neurotransmitter release by the presynaptic cannabinoid receptors (CB-Rs). This powerful modulatory action on synaptic transmission has significant functional implications and interactions with the effects of abused substances. Our data, along with those from other investigators, provide strong new evidence for a role for EPCS modulation in the effects of drugs of abuse, and specifically for involvement of cannabinoid receptors in the neural basis of addiction. Cannabinoids and endocannabinoids appear to be involved in adding to the rewarding effects of addictive substances, including, nicotine, opiates, alcohol, cocaine, and BDZs. The results suggest that the EPCS may be an important natural regulatory mechanism for drug reward and a target for the treatment of addictive disorders.

  18. Obesity, the Endocannabinoid System, and Bias Arising from Pharmaceutical Sponsorship

    PubMed Central

    McPartland, John M.

    2009-01-01

    Background Previous research has shown that academic physicians conflicted by funding from the pharmaceutical industry have corrupted evidence based medicine and helped enlarge the market for drugs. Physicians made pharmaceutical-friendly statements, engaged in disease mongering, and signed biased review articles ghost-authored by corporate employees. This paper tested the hypothesis that bias affects review articles regarding rimonabant, an anti-obesity drug that blocks the central cannabinoid receptor. Methods/Principal Findings A MEDLINE search was performed for rimonabant review articles, limited to articles authored by USA physicians who served as consultants for the company that manufactures rimonabant. Extracted articles were examined for industry-friendly bias, identified by three methods: analysis with a validated instrument for monitoring bias in continuing medical education (CME); analysis for bias defined as statements that ran contrary to external evidence; and a tally of misrepresentations about the endocannabinoid system. Eight review articles were identified, but only three disclosed authors' financial conflicts of interest, despite easily accessible information to the contrary. The Takhar CME bias instrument demonstrated statistically significant bias in all the review articles. Biased statements that were nearly identical reappeared in the articles, including disease mongering, exaggerating rimonabant's efficacy and safety, lack of criticisms regarding rimonabant clinical trials, and speculations about surrogate markers stated as facts. Distinctive and identical misrepresentations regarding the endocannabinoid system also reappeared in articles by different authors. Conclusions The findings are characteristic of bias that arises from financial conflicts of interest, and suggestive of ghostwriting by a common author. Resolutions for this scenario are proposed. PMID:19333392

  19. Role of PUFAs, the precursors of endocannabinoids, in human obesity and type 2 diabetes.

    PubMed

    Dain, Alejandro; Repossi, Gaston; Das, Undurti N; Eynard, Aldo Renato

    2010-06-01

    Polyunsaturated fatty acids (PUFAs) serve as precursors of the endocannabinoids (ECs) that are bioactive lipids molecules. Recent studies revealed that ECs participate in several physiological and pathological processes including obesity and type 2 diabetes mellitus. Here we review the experimental and clinical aspects of the role of endocannabinoids in obesity and type 2 diabetes mellitus and the modification of the endocannabinoids by exogenously administered PUFAs. Based on these evidences, we propose that the endocannabinoid system (ECS) can be modulated by exogenous manipulation of PUFAs that could help in the prevention and management of human diseases such as obesity, metabolic syndrome and type 2 diabetes mellitus.

  20. Role of the endocannabinoid system in the emotional manifestations of osteoarthritis pain.

    PubMed

    La Porta, Carmen; Bura, S Andreea; Llorente-Onaindia, Jone; Pastor, Antoni; Navarrete, Francisco; García-Gutiérrez, María Salud; De la Torre, Rafael; Manzanares, Jorge; Monfort, Jordi; Maldonado, Rafael

    2015-10-01

    In this study, we investigated the role of the endocannabinoid system (ECS) in the emotional and cognitive alterations associated with osteoarthritis pain. The monosodium iodoacetate model was used to evaluate the affective and cognitive manifestations of osteoarthritis pain in type 1 (CB1R) and type 2 (CB2R) cannabinoid receptor knockout and wild-type mice and the ability of CB1R (ACEA) and CB2R (JWH133) selective agonists to improve these manifestations during a 3-week time period. The levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured in plasma and brain areas involved in the control of these manifestations. Patients with knee osteoarthritis and healthy controls were recruited to evaluate pain, affective, and cognitive symptoms, as well as plasma endocannabinoid levels and cannabinoid receptor gene expression in peripheral blood lymphocytes. The affective manifestations of osteoarthritis were enhanced in CB1R knockout mice and absent in CB2R knockouts. Interestingly, both ACEA and JWH133 ameliorated the nociceptive and affective alterations, whereas ACEA also improved the associated memory impairment. An increase of 2-AG levels in prefrontal cortex and plasma was observed in this mouse model of osteoarthritis. In agreement, an increase of 2-AG plasmatic levels and an upregulation of CB1R and CB2R gene expression in peripheral blood lymphocytes were observed in patients with osteoarthritis compared with healthy subjects. Changes found in these biomarkers of the ECS correlated with pain, affective, and cognitive symptoms in these patients. The ECS plays a crucial role in osteoarthritis and represents an interesting pharmacological target and biomarker of this disease.

  1. Role of the endocannabinoid system in the emotional manifestations of osteoarthritis pain

    PubMed Central

    La Porta, Carmen; Bura, S. Andreea; Llorente-Onaindia, Jone; Pastor, Antoni; Navarrete, Francisco; García-Gutiérrez, María Salud; De la Torre, Rafael; Manzanares, Jorge; Monfort, Jordi; Maldonado, Rafael

    2015-01-01

    Abstract In this study, we investigated the role of the endocannabinoid system (ECS) in the emotional and cognitive alterations associated with osteoarthritis pain. The monosodium iodoacetate model was used to evaluate the affective and cognitive manifestations of osteoarthritis pain in type 1 (CB1R) and type 2 (CB2R) cannabinoid receptor knockout and wild-type mice and the ability of CB1R (ACEA) and CB2R (JWH133) selective agonists to improve these manifestations during a 3-week time period. The levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured in plasma and brain areas involved in the control of these manifestations. Patients with knee osteoarthritis and healthy controls were recruited to evaluate pain, affective, and cognitive symptoms, as well as plasma endocannabinoid levels and cannabinoid receptor gene expression in peripheral blood lymphocytes. The affective manifestations of osteoarthritis were enhanced in CB1R knockout mice and absent in CB2R knockouts. Interestingly, both ACEA and JWH133 ameliorated the nociceptive and affective alterations, whereas ACEA also improved the associated memory impairment. An increase of 2-AG levels in prefrontal cortex and plasma was observed in this mouse model of osteoarthritis. In agreement, an increase of 2-AG plasmatic levels and an upregulation of CB1R and CB2R gene expression in peripheral blood lymphocytes were observed in patients with osteoarthritis compared with healthy subjects. Changes found in these biomarkers of the ECS correlated with pain, affective, and cognitive symptoms in these patients. The ECS plays a crucial role in osteoarthritis and represents an interesting pharmacological target and biomarker of this disease. PMID:26067584

  2. Involvement of the endocannabinoid system in reward processing in the human brain.

    PubMed

    van Hell, Hendrika H; Jager, Gerry; Bossong, Matthijs G; Brouwer, Annelies; Jansma, J Martijn; Zuurman, Lineke; van Gerven, Joop; Kahn, René S; Ramsey, Nick F

    2012-02-01

    Disturbed reward processing in humans has been associated with a number of disorders, such as depression, addiction, and attention-deficit hyperactivity disorder. The endocannabinoid (eCB) system has been implicated in reward processing in animals, but in humans, the relation between eCB functioning and reward is less clear. The current study uses functional magnetic resonance imaging (fMRI) to investigate the role of the eCB system in reward processing in humans by examining the effect of the eCB agonist Δ(9)-tetrahydrocannabinol (THC) on reward-related brain activity. Eleven healthy males participated in a randomized placebo-controlled pharmacological fMRI study with administration of THC to challenge the eCB system. We compared anticipatory and feedback-related brain activity after placebo and THC, using a monetary incentive delay task. In this task, subjects are notified before each trial whether a correct response is rewarded ("reward trial") or not ("neutral trial"). Subjects showed faster reaction times during reward trials compared to neutral trials, and this effect was not altered by THC. THC induced a widespread attenuation of the brain response to feedback in reward trials but not in neutral trials. Anticipatory brain activity was not affected. These results suggest a role for the eCB system in the appreciation of rewards. The involvement of the eCB system in feedback processing may be relevant for disorders in which appreciation of natural rewards may be affected such as addiction.

  3. Possible inhibitory role of endogenous 2-arachidonoylglycerol as an endocannabinoid in (±)-epibatidine-induced activation of central adrenomedullary outflow in the rat.

    PubMed

    Shimizu, Takahiro; Tanaka, Kenjiro; Shimizu, Shogo; Higashi, Youichirou; Yawata, Toshio; Nakamura, Kumiko; Taniuchi, Keisuke; Ueba, Tetsuya; Yuri, Kazunari; Saito, Motoaki

    2015-08-01

    We previously reported that intracerebroventricularly (i.c.v.) administered (±)-epibatidine (1, 5 or 10 nmol/animal), a nicotinic acetylcholine receptor agonist, dose-dependently induced secretion of noradrenaline and adrenaline (catecholamines) from the rat adrenal medulla by brain diacylglycerol lipase- (DGL), monoacylglycerol lipase- (MGL) and cyclooxygenase-mediated mechanisms. Diacylglycerol is hydrolyzed by DGL into 2-arachidonoylglycerol (2-AG), which is further hydrolyzed by MGL to arachidonic acid (AA), a cyclooxygenase substrate. These findings suggest that brain 2-AG-derived AA is involved in the (±)-epibatidine-induced response. This AA precursor 2-AG is also a major brain endocannabinoid, which inhibits synaptic transmission through presynaptic cannabinoid CB1 receptors. Released 2-AG into the synaptic cleft is rapidly inactivated by cellular uptake. Here, we examined a role of brain 2-AG as an endocannabinoid in the (±)-epibatidine-induced activation of central adrenomedullary outflow using anesthetized male Wistar rats. In central presence of AM251 (CB1 antagonist) (90 and 180 nmol/animal, i.c.v.), (±)-epibatidine elevated plasma catecholamines even at an ineffective dose (1 nmol/animal, i.c.v.). Central pretreatment with ACEA (CB1 agonist) (0.7 and 1.4 μmol/animal, i.c.v.), 2-AG ether (stable 2-AG analog for MGL) (0.5 and 1.0 μmol/animal, i.c.v.) or AM404 (endocannabinoid uptake inhibitor) (80 and 250 nmol/animal, i.c.v.) significantly reduced an effective dose of (±)-epibatidine- (5 nmol/animal, i.c.v.) induced elevation of plasma catecholamines, and AM251 (90 and 180 nmol/animal, i.c.v.) centrally abolished the reduction induced by 2-AG ether (1.0 μmol/animal, i.c.v.) or AM404 (250 nmol/animal, i.c.v.). Immunohistochemical studies demonstrated that (±)-epibatidine (10 nmol/animal, i.c.v.) activated DGLα-positive spinally projecting neurons in the hypothalamic paraventricular nucleus, a control center of central adrenomedullary system

  4. Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake.

    PubMed

    Chicca, Andrea; Nicolussi, Simon; Bartholomäus, Ruben; Blunder, Martina; Aparisi Rey, Alejandro; Petrucci, Vanessa; Reynoso-Moreno, Ines Del Carmen; Viveros-Paredes, Juan Manuel; Dalghi Gens, Marianela; Lutz, Beat; Schiöth, Helgi B; Soeberdt, Michael; Abels, Christoph; Charles, Roch-Philippe; Altmann, Karl-Heinz; Gertsch, Jürg

    2017-06-20

    The extracellular effects of the endocannabinoids anandamide and 2-arachidonoyl glycerol are terminated by enzymatic hydrolysis after crossing cellular membranes by facilitated diffusion. The lack of potent and selective inhibitors for endocannabinoid transport has prevented the molecular characterization of this process, thus hindering its biochemical investigation and pharmacological exploitation. Here, we report the design, chemical synthesis, and biological profiling of natural product-derived N -substituted 2,4-dodecadienamides as a selective endocannabinoid uptake inhibitor. The highly potent (IC 50 = 10 nM) inhibitor N -(3,4-dimethoxyphenyl)ethyl amide (WOBE437) exerted pronounced cannabinoid receptor-dependent anxiolytic, antiinflammatory, and analgesic effects in mice by increasing endocannabinoid levels. A tailored WOBE437-derived diazirine-containing photoaffinity probe (RX-055) irreversibly blocked membrane transport of both endocannabinoids, providing mechanistic insights into this complex process. Moreover, RX-055 exerted site-specific anxiolytic effects on in situ photoactivation in the brain. This study describes suitable inhibitors to target endocannabinoid membrane trafficking and uncovers an alternative endocannabinoid pharmacology.

  5. Multiple Functions of Endocannabinoid Signaling in the Brain

    PubMed Central

    Katona, István; Freund, Tamás F.

    2014-01-01

    Despite being regarded as a hippie science for decades, cannabinoid research has finally found its well-deserved position in mainstream neuroscience. A series of groundbreaking discoveries revealed that endocannabinoid molecules are as widespread and important as conventional neurotransmitters like glutamate or GABA, yet act in profoundly unconventional ways. We aim to illustrate how uncovering the molecular, anatomical and physiological characteristics of endocannabinoid signaling revealed new mechanistic insights into several fundamental phenomena in synaptic physiology. First, we summarize unexpected advances in the molecular complexity of biogenesis and inactivation of the two endocannabinoids, anandamide and 2-arachidonoylglycerol. Then we show how these new metabolic routes are integrated into well-known intracellular signaling pathways. These endocannabinoid-producing signalosomes operate in phasic and tonic modes thereby differentially governing homeostatic, short-term and long-term synaptic plasticity throughout the brain. Finally, we discuss how cell type- and synapse-specific refinement of endocannabinoid signaling may explain the characteristic behavioral effects of cannabinoids. PMID:22524785

  6. Perinatal asphyxia results in altered expression of the hippocampal acylethanolamide/endocannabinoid signaling system associated to memory impairments in postweaned rats.

    PubMed

    Blanco, Eduardo; Galeano, Pablo; Holubiec, Mariana I; Romero, Juan I; Logica, Tamara; Rivera, Patricia; Pavón, Francisco J; Suarez, Juan; Capani, Francisco; Rodríguez de Fonseca, Fernando

    2015-01-01

    Perinatal asphyxia (PA) is an obstetric complication that strongly affects the CNS. The endocannabinoid system (ECS) is a lipid transmitter system involved in several physiological processes including synaptic plasticity, neurogenesis, memory, and mood. Endocannabinoids, and other acylethanolamides (AEs) without endocannabinoid activity, have recently received growing attention due to their potential neuroprotective functions in neurological disorders, including cerebral ischemia. In the present study, we aimed to analyze the changes produced by PA in the major metabolic enzymes and receptors of the ECS/AEs in the hippocampus using a rodent model of PA. To induce PA, we removed uterine horns from ready-to-deliver rats and immersed them into a water bath during 19 min. Animals delivered spontaneously or by cesarean section were employed as controls. At 1 month of age, cognitive functions were assessed and immunohistochemical procedures were carried out to determine the expression of NeuN and glial fibrillary acidic protein, enzymes responsible for synthesis (DAGLα and NAPE-PLD) and degradation (FAAH) of ECS/AEs and their receptors (CB1 and PPARα) in the hippocampus. Postweaned asphyctic rats showed impaired recognition and spatial reference memory that were accompanied by hippocampal astrogliosis and changes in the expression of enzymes and receptors. The most remarkable findings in asphyctic rats were a decrease in the expression of NAPE-PLD and PPARα in both hippocampal areas CA1 and CA3. In addition, postweaned cesarean delivery rats showed an increase in the immunolabeling for FAAH in the hippocampal CA3 area. Since, NAPE-PLD and PPARα are proteins that participate in the biochemical process of AEs, specially the neuroprotective oleoylethanolamide, these results suggest that PA dysregulates this system. These data encourage conducting future studies using AEs as potential neuroprotective compounds in animal models of PA.

  7. Perinatal asphyxia results in altered expression of the hippocampal acylethanolamide/endocannabinoid signaling system associated to memory impairments in postweaned rats

    PubMed Central

    Blanco, Eduardo; Galeano, Pablo; Holubiec, Mariana I.; Romero, Juan I.; Logica, Tamara; Rivera, Patricia; Pavón, Francisco J.; Suarez, Juan; Capani, Francisco; Rodríguez de Fonseca, Fernando

    2015-01-01

    Perinatal asphyxia (PA) is an obstetric complication that strongly affects the CNS. The endocannabinoid system (ECS) is a lipid transmitter system involved in several physiological processes including synaptic plasticity, neurogenesis, memory, and mood. Endocannabinoids, and other acylethanolamides (AEs) without endocannabinoid activity, have recently received growing attention due to their potential neuroprotective functions in neurological disorders, including cerebral ischemia. In the present study, we aimed to analyze the changes produced by PA in the major metabolic enzymes and receptors of the ECS/AEs in the hippocampus using a rodent model of PA. To induce PA, we removed uterine horns from ready-to-deliver rats and immersed them into a water bath during 19 min. Animals delivered spontaneously or by cesarean section were employed as controls. At 1 month of age, cognitive functions were assessed and immunohistochemical procedures were carried out to determine the expression of NeuN and glial fibrillary acidic protein, enzymes responsible for synthesis (DAGLα and NAPE-PLD) and degradation (FAAH) of ECS/AEs and their receptors (CB1 and PPARα) in the hippocampus. Postweaned asphyctic rats showed impaired recognition and spatial reference memory that were accompanied by hippocampal astrogliosis and changes in the expression of enzymes and receptors. The most remarkable findings in asphyctic rats were a decrease in the expression of NAPE-PLD and PPARα in both hippocampal areas CA1 and CA3. In addition, postweaned cesarean delivery rats showed an increase in the immunolabeling for FAAH in the hippocampal CA3 area. Since, NAPE-PLD and PPARα are proteins that participate in the biochemical process of AEs, specially the neuroprotective oleoylethanolamide, these results suggest that PA dysregulates this system. These data encourage conducting future studies using AEs as potential neuroprotective compounds in animal models of PA. PMID:26578900

  8. Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways.

    PubMed

    Dyall, S C; Mandhair, H K; Fincham, R E A; Kerr, D M; Roche, M; Molina-Holgado, F

    2016-08-01

    Emerging evidence suggests a complex interplay between the endocannabinoid system, omega-3 fatty acids and the immune system in the promotion of brain self-repair. However, it is unknown if all omega-3 fatty acids elicit similar effects on adult neurogenesis and if such effects are mediated or regulated by interactions with the endocannabinoid system. This study investigated the effects of DHA and EPA on neural stem cell (NSC) fate and the role of the endocannabinoid signalling pathways in these effects. EPA, but not DHA, significantly increased proliferation of NSCs compared to controls, an effect associated with enhanced levels of the endocannabinoid 2-arachidonylglycerol (2-AG) and p-p38 MAPK, effects attenuated by pre-treatment with CB1 (AM251) or CB2 (AM630) receptor antagonists. Furthermore, in NSCs derived from IL-1β deficient mice, EPA significantly decreased proliferation and p-p38 MAPK levels compared to controls, suggesting a key role for IL-1β signalling in the effects observed. Although DHA similarly increased 2-AG levels in wild-type NSCs, there was no concomitant increase in proliferation or p-p38 MAPK activity. In addition, in NSCs from IL-1β deficient mice, DHA significantly increased proliferation without effects on p-P38 MAPK, suggesting effects of DHA are mediated via alternative signalling pathways. These results provide crucial new insights into the divergent effects of EPA and DHA in regulating NSC proliferation and the pathways involved, and highlight the therapeutic potential of their interplay with endocannabinoid signalling in brain repair. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents

    PubMed Central

    Wiley, Jenny L.; Walentiny, D. Matthew; Wright, M. Jerry; Beardsley, Patrick M.; Burston, James J.; Poklis, Justin L.; Lichtman, Aron H.; Vann, Robert E.

    2014-01-01

    The mechanism through which marijuana produces its psychoactive effects is Δ9- tetrahydrocannabinol (THC)-induced activation of cannabinoid CB1 receptors. These receptors are normally activated by endogenous lipids, including anandamide and 2-arachidonoyl glycerol (2-AG). A logical “first step” in determination of the role of these endocannabinoids in THC’s psychoactive effects is to investigate the degree to which pharmacologically induced increases in anandamide and/or 2-AG concentrations through exogenous administration and/or systemic administration of inhibitors of their metabolism, fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), respectively, share THC’s discriminative stimulus effects. To this end, adult male mice and rats were trained to discriminate THC (5.6 and 3 mg/kg, respectively). In Experiment 1, exogenous administration of anandamide or 2-AG did not substitute for THC in mice nor was substitution enhanced by co-administration of the FAAH or MAGL inhibitors, URB597 and N-arachidonyl maleimide (NAM), respectively. Significant decreases in responding may have prevented assessment of adequate endocannabinoid doses. In mice trained at higher baseline response rates (Experiment 2), the FAAH inhibitor PF3845 (10 mg/kg) enhanced anandamide substitution for THC without producing effects of its own. The MAGL inhibitor JZL184 increased brain levels of 2-AG in vitro and in vivo, increased THC-like responding without co-administration of 2-AG. In rats, neither URB597 nor JZL184 engendered significant THC-appropriate responding, but co-administration of these two enzyme inhibitors approached full substitution. The present results highlight the complex interplay between anandamide and 2-AG and suggest that endogenous increases of both endocannabinoids are most effective in elicitation of THC-like discriminative stimulus effects. PMID:24858366

  10. Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans.

    PubMed

    Smith, Douglas R; Stanley, Christine M; Foss, Theodore; Boles, Richard G; McKernan, Kevin

    2017-01-01

    Rare genetic variants in the core endocannabinoid system genes CNR1, CNR2, DAGLA, MGLL and FAAH were identified in molecular testing data from 6,032 patients with a broad spectrum of neurological disorders. The variants were evaluated for association with phenotypes similar to those observed in the orthologous gene knockouts in mice. Heterozygous rare coding variants in CNR1, which encodes the type 1 cannabinoid receptor (CB1), were found to be significantly associated with pain sensitivity (especially migraine), sleep and memory disorders-alone or in combination with anxiety-compared to a set of controls without such CNR1 variants. Similarly, heterozygous rare variants in DAGLA, which encodes diacylglycerol lipase alpha, were found to be significantly associated with seizures and neurodevelopmental disorders, including autism and abnormalities of brain morphology, compared to controls. Rare variants in MGLL, FAAH and CNR2 were not associated with any neurological phenotypes in the patients tested. Diacylglycerol lipase alpha synthesizes the endocannabinoid 2-AG in the brain, which interacts with CB1 receptors. The phenotypes associated with rare CNR1 variants are reminiscent of those implicated in the theory of clinical endocannabinoid deficiency syndrome. The severe phenotypes associated with rare DAGLA variants underscore the critical role of rapid 2-AG synthesis and the endocannabinoid system in regulating neurological function and development. Mapping of the variants to the 3D structure of the type 1 cannabinoid receptor, or primary structure of diacylglycerol lipase alpha, reveals clustering of variants in certain structural regions and is consistent with impacts to function.

  11. Novel natural and synthetic ligands of the endocannabinoid system.

    PubMed

    Hanus, Lumír O; Mechoulam, Raphael

    2010-01-01

    In this review we describe recent advances in the chemistry of novel CB(1)/CB(2) agonists, CB(1) antagonists, selective CB(2) agonists, fatty acid amide hydrolase inibitors, monoglyceride (MGL) and diglyceride (DAGL) inhibitors and cannabinoid-type agonists and antagonists of non CB(1)/CB(2) receptors. In view of recent interest in the activities of fatty acid amides of amino acids (N-acyl amino acids) a list of this type of compounds was compiled and is presented as a Table. We conclude that further synthetic work based on both the plant cannabinoids and on the endocannabinoids may lead to novel therapeutics and that the identification and the elucidation of the biological profile of the myriad of endogenous N-acyl amino acids and related compounds may enhance the already wide spectrum of lipidomics.

  12. The endocannabinoid system in guarding against fear, anxiety and stress.

    PubMed

    Lutz, Beat; Marsicano, Giovanni; Maldonado, Rafael; Hillard, Cecilia J

    2015-12-01

    The endocannabinoid (eCB) system has emerged as a central integrator linking the perception of external and internal stimuli to distinct neurophysiological and behavioural outcomes (such as fear reaction, anxiety and stress-coping), thus allowing an organism to adapt to its changing environment. eCB signalling seems to determine the value of fear-evoking stimuli and to tune appropriate behavioural responses, which are essential for the organism's long-term viability, homeostasis and stress resilience; and dysregulation of eCB signalling can lead to psychiatric disorders. An understanding of the underlying neural cell populations and cellular processes enables the development of therapeutic strategies to mitigate behavioural maladaptation.

  13. The endocannabinoid system in guarding against fear, anxiety and stress

    PubMed Central

    Lutz, Beat; Marsicano, Giovanni; Maldonado, Rafael; Hillard, Cecilia J.

    2018-01-01

    The endocannabinoid (eCB) system has emerged as a central integrator linking the perception of external and internal stimuli to distinct neurophysiological and behavioural outcomes (such as fear reaction, anxiety and stress-coping), thus allowing an organism to adapt to its changing environment. eCB signalling seems to determine the value of fear-evoking stimuli and to tune appropriate behavioural responses, which are essential for the organism’s long-term viability, homeostasis and stress resilience; and dysregulation of eCB signalling can lead to psychiatric disorders. An understanding of the underlying neural cell populations and cellular processes enables the development of therapeutic strategies to mitigate behavioural maladaptation. PMID:26585799

  14. Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System

    PubMed Central

    McPartland, John M.; Guy, Geoffrey W.; Di Marzo, Vincenzo

    2014-01-01

    Background The “classic” endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the “eCB deficiency syndrome” as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system—ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation. Methodology/Principal Findings We searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and 36 human studies. Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as “complementary and alternative medicine” also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances—alcohol, tobacco, coffee, cannabis) also modulate the eCB system. Conclusions/Significance Few clinical trials have assessed interventions that upregulate the eCB system. Many preclinical studies point to other potential approaches; human trials are needed to explore these promising interventions. PMID:24622769

  15. The interplay between inflammatory cytokines and the endocannabinoid system in the regulation of synaptic transmission.

    PubMed

    Rossi, Silvia; Motta, Caterina; Musella, Alessandra; Centonze, Diego

    2015-09-01

    Excessive glutamate-mediated synaptic transmission and secondary excitotoxicity have been proposed as key determinants of neurodegeneration in many neurological diseases. Soluble mediators of inflammation have recently gained attention owing to their ability to enhance glutamate transmission and affect synaptic sensitivity to neurotransmitters. In the complex crosstalk between soluble immunoactive molecules and synapses, the endocannabinoid system (ECS) plays a central role, exerting an indirect neuroprotective action by inhibiting cytokine-dependent synaptic alterations, and a direct neuroprotective effect by limiting glutamate transmission and excitotoxic damage. On the other hand, the endocannabinoid (eCB)-mediated control of synaptic transmission is altered by proinflammatory cytokines with consequent effects in central nervous system (CNS) disorders. In this review, we summarize the interactions, at the pre- and postsynaptic level, between major inflammatory cytokines and the ECS. In addition, the behavioral and clinical consequences of the modulation of synaptic transmission during neuroinflammation are discussed. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. The cannabinoid transporter inhibitor OMDM-2 reduces social interaction: Further evidence for transporter-mediated endocannabinoid release.

    PubMed

    Seillier, Alexandre; Giuffrida, Andrea

    2018-03-01

    Experimental evidence suggests that the transport of endocannabinoids might work bi-directionally. Accordingly, it is possible that pharmacological blockade of the latter affects not only the re-uptake, but also the release of endocannabinoids, thus preventing them from stimulating CB 1 receptors. We used biochemical, pharmacological, and behavioral approaches to investigate the effects of the transporter inhibitor OMDM-2 on social interaction, a behavioral assay that requires activation of CB 1 receptors. The underlying mechanisms of OMDM-2 were compared with those of the Fatty Acid Amide Hydrolase (FAAH) inhibitor URB597. Systemic administration of OMDM-2 reduced social interaction, but in contrast to URB597-induced social deficit, this effect was not reversed by the TRPV1 antagonist capsazepine. The CB 1 antagonist AM251, which did not affect URB597-induced social withdrawal, exacerbated OMDM-2 effect. In addition, the potent CB 1 agonist CP55,940 reversed OMDM-2-, but not URB597-, induced social withdrawal. Blockade of CB 1 receptor by AM251 reduced social interaction and the cholecystokinin CCK2 antagonist LY225910 reversed this effect. Similarly, OMDM-2-induced social withdrawal was reversed by LY225910, whereas URB597 effect was not. Elevation of endocannabinoid levels by URB597 or JZL184, an inhibitor of 2-AG degradation, failed to reverse OMDM-2-induced social withdrawal, and did not show additive effects on cannabinoid measurements when co-administered with OMDM-2. Taken together, these findings indicate that OMDM-2 impaired social interaction in a manner that is consistent with reduced activation of presynaptic CB 1 receptors. As cannabinoid reuptake inhibitors may impair endocannabinoid release, caution should be taken when using these drugs to enhance endocannabinoid tone in vivo. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Endocannabinoid and Mood Responses to Exercise in Adults with Varying Activity Levels.

    PubMed

    Brellenthin, Angelique G; Crombie, Kevin M; Hillard, Cecilia J; Koltyn, Kelli F

    2017-08-01

    Acute aerobic exercise improves mood and activates the endocannabinoid (eCB) system in physically active individuals; however, both mood and eCB responses to exercise may vary based on habitual levels of physical activity. This study aimed to examine eCB and mood responses to prescribed and preferred exercises among individuals with low, moderate, and high levels of physical activity. Thirty-six healthy adults (21 ± 4 yr) were recruited from low (≤60 min moderate-vigorous physical activity [MVPA] per week), moderate (150-299 min MVPA per week), and high (≥300 MVPA per week) physical activity groups. Participants performed both prescribed (approximately 70%-75% max) and preferred (i.e., self-selected) aerobic exercise on separate days. Mood states and eCB concentrations were assessed before and after exercise conditions. Both preferred and prescribed exercise resulted in significant increases (P < 0.01) in circulating eCB (N-arachidonoylethanolamine [AEA] and 2-arachidonoylglycerol); however, increases in AEA (P < 0.05) were larger in the prescribed condition. Likewise, both preferred and prescribed exercise elicited positive mood improvements compared with preexercise values, but changes in state anxiety, total mood disturbance, and confusion were greater in the preferred condition (P < 0.05). Changes in 2-arachidonoylglycerol concentrations were found to negatively correlate with changes in depression, tension, and total mood disturbance in the preferred condition (P < 0.05), and changes in AEA were positively associated with changes in vigor in the prescribed condition (P < 0.05). There were no significant group differences for mood or eCB outcomes. These results indicate that eCB and mood responses to exercise do not differ significantly between samples with varying physical activity levels. This study also demonstrates that in addition to prescribed exercise, preferred exercise activates the eCB system, and this activation may contribute to positive mood

  18. Crystallographic study of FABP5 as an intracellular endocannabinoid transporter

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sanson, Benoît; Wang, Tao; Sun, Jing

    2014-02-01

    FABP5 was recently found to intracellularly transport endocannabinoid signaling lipids. The structures of FABP5 complexed with two endocannabinoids and an inhibitor were solved. Human FABP5 was found to dimerize via a domain-swapping mechanism. This work will help in the development of inhibitors to raise endocannabinoid levels. In addition to binding intracellular fatty acids, fatty-acid-binding proteins (FABPs) have recently been reported to also transport the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), arachidonic acid derivatives that function as neurotransmitters and mediate a diverse set of physiological and psychological processes. To understand how the endocannabinoids bind to FABPs, the crystal structures of FABP5more » in complex with AEA, 2-AG and the inhibitor BMS-309403 were determined. These ligands are shown to interact primarily with the substrate-binding pocket via hydrophobic interactions as well as a common hydrogen bond to the Tyr131 residue. This work advances our understanding of FABP5–endocannabinoid interactions and may be useful for future efforts in the development of small-molecule inhibitors to raise endocannabinoid levels.« less

  19. Endocannabinoids in amygdala and nucleus accumbens mediate social play reward in adolescent rats.

    PubMed

    Trezza, Viviana; Damsteegt, Ruth; Manduca, Antonia; Petrosino, Stefania; Van Kerkhof, Linda W M; Pasterkamp, R Jeroen; Zhou, Yeping; Campolongo, Patrizia; Cuomo, Vincenzo; Di Marzo, Vincenzo; Vanderschuren, Louk J M J

    2012-10-24

    The brain endocannabinoid system plays a crucial role in emotional processes. We have previously identified an important role for endocannabinoids in social play behavior, a highly rewarding form of social interaction in adolescent rats. Here, we tested the hypothesis that endocannabinoid modulation of social play behavior occurs in brain regions implicated in emotion and motivation. Social play increased levels of the endocannabinoid anandamide in the amygdala and nucleus accumbens (NAc), but not in prefrontal cortex or hippocampus of 4- to 5-week-old male Wistar rats. Furthermore, social play increased phosphorylation of CB1 cannabinoid receptors in the amygdala. Systemic administration of the anandamide hydrolysis inhibitor URB597 increased social play behavior, and augmented the associated elevation in anandamide levels in the amygdala, but not the NAc. Infusion of URB597 into the basolateral amygdala (BLA) increased social play behavior, and blockade of BLA CB1 cannabinoid receptors with the antagonist/inverse agonist SR141716A prevented the play-enhancing effects of systemic administration of URB597. Infusion of URB597 into the NAc also increased social play, but blockade of NAc CB1 cannabinoid receptors did not antagonize the play-enhancing effects of systemic URB597 treatment. Last, SR141716A did not affect social play after infusion into the core and shell subregions of the NAc, while it reduced social play when infused into the BLA. These data show that increased anandamide signaling in the amygdala and NAc augments social play, and identify the BLA as a prominent site of action for endocannabinoids to modulate the rewarding properties of social interactions in adolescent rats.

  20. Endocannabinoids in amygdala and nucleus accumbens mediate social play reward in adolescent rats

    PubMed Central

    Trezza, Viviana; Damsteegt, Ruth; Manduca, Antonia; Petrosino, Stefania; Van Kerkhof, Linda W.M.; Pasterkamp, R. Jeroen; Zhou, Yeping; Campolongo, Patrizia; Cuomo, Vincenzo; Di Marzo, Vincenzo; Vanderschuren, Louk J.M.J.

    2012-01-01

    The brain endocannabinoid system plays a crucial role in emotional processes. We have previously identified an important role for endocannabinoids in social play behavior, a highly rewarding form of social interaction in adolescent rats. Here, we tested the hypothesis that endocannabinoid modulation of social play behavior occurs in brain regions implicated in emotion and motivation. Social play increased levels of the endocannabinoid anandamide in the amygdala and nucleus accumbens (NAc), but not in prefrontal cortex or hippocampus of 4–5 week old male Wistar rats. Furthermore, social play increased phosphorylation of CB1 cannabinoid receptors in the amygdala. Systemic administration of the anandamide hydrolysis inhibitor URB597 increased social play behavior, and augmented the associated elevation in anandamide levels in the amygdala, but not the NAc. Infusion of URB597 into the basolateral amygdala (BLA) increased social play behavior, and blockade of BLA CB1 cannabinoid receptors with the antagonist/inverse agonist SR141716A prevented the play-enhancing effects of systemic administration of URB597. Infusion of URB597 into the NAc also increased social play, but blockade of NAc CB1 cannabinoid receptors did not antagonize the play-enhancing effects of systemic URB597 treatment. Last, SR141716A did not affect social play after infusion into the core and shell subregions of the NAc, while it reduced social play when infused into the BLA. These data show that increased anandamide signalling in the amygdala and NAc augments social play, and identify the BLA as a prominent site of action for endocannabinoids to modulate the rewarding properties of social interactions in adolescent rats. PMID:23100412

  1. Phytocannabinoids and endocannabinoids.

    PubMed

    Fisar, Zdenek

    2009-01-01

    Progress in understanding the molecular mechanisms of cannabis action was made after discovery of cannabinoid receptors in the brain and the finding of endogenous metabolites with affinity to them. Activation of cannabinoid receptors on synaptic terminals results in regulation of ion channels, neurotransmitter release and synaptic plasticity. Neuromodulation of synapses by the cannabinoids is proving to have a wide range of functional effects, making them potential targets as medical preparations in a variety of illnesses, including some mental disorders and neurodegenerative illnesses. Cannabis contains a large amount of substances with affinity for the cannabinoid receptors. The endocannabinoids are a family of lipid neurotransmitters that engage the same membrane receptors targeted by tetrahydrocannabinol and that mediate retrograde signal from postsynaptic neurons to presynaptic ones. Discovery of endogenous cannabinoids and studies of the physiological functions of the cannabinoid system in the brain and body are producing a number of important findings about the role of membrane lipids and fatty acids in nerve signal transduction. Plant, endogenous and synthetic cannabinoids are using in these studies. The role of lipid membranes in the cannabinoid system follows from the fact that the source and supply of endogenous cannabinoids are derived from arachidonic acid, an important membrane constituent. The study of structure-activity relationships of molecules which influence the cannabinoid system in the brain and body is crucial in search of medical preparations with the therapeutic effects of the phytocannabinoids without the negative effects on cognitive function attributed to cannabis.

  2. Characterization of endocannabinoids and related acylethanolamides in the synovial fluid of dogs with osteoarthritis: a pilot study.

    PubMed

    Valastro, Carmela; Campanile, Debora; Marinaro, Mariarosaria; Franchini, Delia; Piscitelli, Fabiana; Verde, Roberta; Di Marzo, Vincenzo; Di Bello, Antonio

    2017-11-06

    Cannabis-based drugs have been shown to be effective in inflammatory diseases. A number of endocannabinoids including N- arachidonoylethanolamide (anandamide, AEA) and 2-arachidonyl glycerol (2-AG) with activity at the cannabinoid receptors (CBR) CBR1 and CBR2, have been identified. Other structurally related endogenous fatty acid compounds such as oleoylethanolamide (OEA) and palmitoyl ethanolamide (PEA) have been identified in biological tissues. These compounds do not bind to CBR but might be involved in facilitating the actions of directly acting endocannabinoids and thus are commonly termed "entourage" compounds due to their ability to modulate the endocannabinoid system. The aim of this study was to evaluate the presence of endocannabinoids and entourage compounds in the synovial fluid of dogs with osteoarthritis subjected to arthrotomy of the knee joint. Cytokines and cytology were studied as well. AEA, 2-AG, OEA and PEA were all present in the synovial fluid of arthritic knees and in the contralateral joints; in addition, a significant increase of OEA and 2AG levels were noted in SF from OA knees when compared to the contralateral joints. The identification and quantification of endocannabinoids and entourage compounds levels in synovial fluids from dogs with OA of the knee is reported for the first time. Our data are instrumental for future studies involving a greater number of dogs. Cannabinoids represent an emerging and innovative pharmacological tool for the treatment of OA and further studies are warranted to evaluate the effectiveness of cannabinoids in veterinary medicine.

  3. Cocaine-induced behavioral sensitization decreases the expression of endocannabinoid signaling-related proteins in the mouse hippocampus.

    PubMed

    Blanco, Eduardo; Galeano, Pablo; Palomino, Ana; Pavón, Francisco J; Rivera, Patricia; Serrano, Antonia; Alen, Francisco; Rubio, Leticia; Vargas, Antonio; Castilla-Ortega, Estela; Decara, Juan; Bilbao, Ainhoa; de Fonseca, Fernando Rodríguez; Suárez, Juan

    2016-03-01

    In the reward mesocorticolimbic circuits, the glutamatergic and endocannabinoid systems are implicated in neurobiological mechanisms underlying cocaine addiction. However, the involvement of both systems in the hippocampus, a critical region to process relational information relevant for encoding drug-associated memories, in cocaine-related behaviors remains unknown. In the present work, we studied whether the hippocampal gene/protein expression of relevant glutamate signaling components, including glutamate-synthesizing enzymes and metabotropic and ionotropic receptors, and the hippocampal gene/protein expression of cannabinoid type 1 (CB1) receptor and endocannabinoid metabolic enzymes were altered following acute and/or repeated cocaine administration resulting in conditioned locomotion and locomotor sensitization. Results showed that acute cocaine administration induced an overall down-regulation of glutamate-related gene expression and, specifically, a low phosphorylation level of GluA1. In contrast, locomotor sensitization to cocaine produced an up-regulation of several glutamate receptor-related genes and, specifically, an increased protein expression of the GluN1 receptor subunit. Regarding the endocannabinoid system, acute and repeated cocaine administration were associated with an increased gene/protein expression of CB1 receptors and a decreased gene/protein expression of the endocannabinoid-synthesis enzymes N-acyl phosphatidylethanolamine D (NAPE-PLD) and diacylglycerol lipase alpha (DAGLα). These changes resulted in an overall decrease in endocannabinoid synthesis/degradation ratios, especially NAPE-PLD/fatty acid amide hydrolase and DAGLα/monoacylglycerol lipase, suggesting a reduced endocannabinoid production associated with a compensatory up-regulation of CB1 receptor. Overall, these findings suggest that repeated cocaine administration resulting in locomotor sensitization induces a down-regulation of the endocannabinoid signaling that could

  4. The endocannabinoid system and its therapeutic exploitation in multiple sclerosis: Clues for other neuroinflammatory diseases.

    PubMed

    Chiurchiù, Valerio; van der Stelt, Mario; Centonze, Diego; Maccarrone, Mauro

    2018-01-01

    Multiple sclerosis is the most common inflammatory demyelinating disease of the central nervous system, caused by an autoimmune response against myelin that eventually leads to progressive neurodegeneration and disability. Although the knowledge on its underlying neurobiological mechanisms has considerably improved, there is a still unmet need for new treatment options, especially for the progressive forms of the disease. Both preclinical and clinical data suggest that cannabinoids, derived from the Cannabis sativa plant, may be used to control symptoms such as spasticity and chronic pain, whereas only preclinical data indicate that these compounds and their endogenous counterparts, i.e. the endocannabinoids, may also exert neuroprotective effects and slow down disease progression. Here, we review the preclinical and clinical studies that could explain the therapeutic action of cannabinoid-based medicines, as well as the medical potential of modulating endocannabinoid signaling in multiple sclerosis, with a link to other neuroinflammatory disorders that share common hallmarks and pathogenetic features. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  5. Disruption of social cognition in the sub-chronic PCP rat model of schizophrenia: Possible involvement of the endocannabinoid system.

    PubMed

    Seillier, Alexandre; Giuffrida, Andrea

    2016-02-01

    Previous studies have shown that social withdrawal in the phencyclidine (PCP) rat model of schizophrenia results from deficient endocannabinoid-induced activation of CB1 receptors. To understand the underlying cognitive mechanisms of the social deficit in PCP-treated rats, we examined the impact of pharmacological manipulation of the endocannabinoid system on sociability (i.e. social approach) and social novelty preference (which relies on social recognition). Control rats showed a clear preference for a "social" cage (i.e. unfamiliar stimulus rat placed under a wire mesh cage) versus an "empty" cage, and spent more time exploring a "novel" cage (i.e. new stimulus rat) versus a "familiar" cage. In contrast, rats receiving PCP (5 mg/kg, b.i.d. for 7 days, followed by a 7 day-washout period) showed intact sociability, but lacked social novelty preference. This PCP-induced deficit was due to increased activity at CB1 receptors as it was reversed by systemic administration of the CB1 antagonist AM251 (1 mg/kg). In agreement with this hypothesis, the cannabinoid agonist CP55,940 (0.003-0.03 mg/kg) dose-dependently suppressed social novelty preference in control animals without affecting sociability. Taken together, these data suggest that PCP-treated rats have a deficit in social cognition, possibly induced by increased stimulation of CB1 receptors. This deficit, however, is distinct from the social withdrawal previously observed in these animals, as the latter is due to deficient, rather than increased, CB1 stimulation. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  6. Glial Control of Endocannabinoid Heterosynaptic Modulation in Hypothalamic Magnocellular Neuroendocrine Cells

    PubMed Central

    Popescu, Ion R.

    2013-01-01

    Cannabinoid receptors are functionally operant at both glutamate and GABA synapses on hypothalamic magnocellular neuroendocrine cells; however, retrograde endocannabinoid actions are evoked at only glutamate synapses. We tested whether the functional targeting of evoked retrograde endocannabinoid actions to glutamate, and not GABA, synapses on magnocellular neurons is the result of the spatial restriction of extracellular endocannabinoids by astrocytes. Whole-cell GABA synaptic currents were recorded in magnocellular neurons in rat hypothalamic slices following manipulations to reduce glial buffering of extracellular signals. Depolarization- and glucocorticoid-evoked retrograde endocannabinoid suppression of synaptic GABA release was not detected under normal conditions, but occurred in both oxytocin and vasopressin neurons under conditions of attenuated glial coverage and depressed glial metabolic function, suggesting an emergent endocannabinoid modulation of GABA synapses with the loss of astrocyte function. Tonic endocannabinoid suppression of GABA release was insensitive to glial manipulation. Blocking cannabinoid transport mimicked, and increasing the extracellular viscosity reversed, the effect of suppressed glial buffering on the endocannabinoid modulation of GABA release. Evoked, but not tonic, endocannabinoid modulation of GABA synapses was mediated by 2-arachidonoylglycerol. Therefore, depolarization- and glucocorticoid-evoked 2-arachidonoylglycerol release from magnocellular neurons is spatially restricted to glutamate synapses by astrocytes, but spills over onto GABA synapses under conditions of reduced astrocyte buffering; tonic endocannabinoid modulation of GABA release, in contrast, is likely mediated by anandamide and is insensitive to astrocytic buffering. Astrocytes, therefore, provide dynamic control of stimulus-evoked 2-arachidonoylglycerol, but not tonic anandamide, regulation of GABA synaptic inputs to magnocellular neuroendocrine cells under

  7. Neurobiological Interactions Between Stress and the Endocannabinoid System.

    PubMed

    Morena, Maria; Patel, Sachin; Bains, Jaideep S; Hill, Matthew N

    2016-01-01

    Stress affects a constellation of physiological systems in the body and evokes a rapid shift in many neurobehavioral processes. A growing body of work indicates that the endocannabinoid (eCB) system is an integral regulator of the stress response. In the current review, we discuss the evidence to date that demonstrates stress-induced regulation of eCB signaling and the consequential role changes in eCB signaling have with respect to many of the effects of stress. Across a wide array of stress paradigms, studies have generally shown that stress evokes bidirectional changes in the two eCB molecules, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with stress exposure reducing AEA levels and increasing 2-AG levels. Additionally, in almost every brain region examined, exposure to chronic stress reliably causes a downregulation or loss of cannabinoid type 1 (CB1) receptors. With respect to the functional role of changes in eCB signaling during stress, studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and increases in anxiety behavior, while the increased 2-AG signaling contributes to termination and adaptation of the HPA axis, as well as potentially contributing to changes in pain perception, memory and synaptic plasticity. More so, translational studies have shown that eCB signaling in humans regulates many of the same domains and appears to be a critical component of stress regulation, and impairments in this system may be involved in the vulnerability to stress-related psychiatric conditions, such as depression and posttraumatic stress disorder. Collectively, these data create a compelling argument that eCB signaling is an important regulatory system in the brain that largely functions to buffer against many of the effects of stress and that dynamic changes in this system contribute to different aspects of the stress response.

  8. Neurobiological Interactions Between Stress and the Endocannabinoid System

    PubMed Central

    Morena, Maria; Patel, Sachin; Bains, Jaideep S; Hill, Matthew N

    2016-01-01

    Stress affects a constellation of physiological systems in the body and evokes a rapid shift in many neurobehavioral processes. A growing body of work indicates that the endocannabinoid (eCB) system is an integral regulator of the stress response. In the current review, we discuss the evidence to date that demonstrates stress-induced regulation of eCB signaling and the consequential role changes in eCB signaling have with respect to many of the effects of stress. Across a wide array of stress paradigms, studies have generally shown that stress evokes bidirectional changes in the two eCB molecules, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with stress exposure reducing AEA levels and increasing 2-AG levels. Additionally, in almost every brain region examined, exposure to chronic stress reliably causes a downregulation or loss of cannabinoid type 1 (CB1) receptors. With respect to the functional role of changes in eCB signaling during stress, studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic–pituitary–adrenal (HPA) axis and increases in anxiety behavior, while the increased 2-AG signaling contributes to termination and adaptation of the HPA axis, as well as potentially contributing to changes in pain perception, memory and synaptic plasticity. More so, translational studies have shown that eCB signaling in humans regulates many of the same domains and appears to be a critical component of stress regulation, and impairments in this system may be involved in the vulnerability to stress-related psychiatric conditions, such as depression and posttraumatic stress disorder. Collectively, these data create a compelling argument that eCB signaling is an important regulatory system in the brain that largely functions to buffer against many of the effects of stress and that dynamic changes in this system contribute to different aspects of the stress

  9. Ischemia/Reperfusion Model Impairs Endocannabinoid Signaling and Na+/K+ ATPase Expression and Activity in Kidney Proximal Tubule Cells.

    PubMed

    Sampaio, Luzia S; Iannotti, Fabio A; Veneziani, Luciana; Borelli-Tôrres, Rosa T; De Maio, Fabrizia; Piscitelli, Fabiana; Reis, Ricardo A M; Di Marzo, Vincenzo; Einicker-Lamas, Marcelo

    2018-06-08

    LLC-PK1 cells, an immortalized epithelial cell line derived from pig renal proximal tubules, express all the major players of the endocannabinoid system (ECS) such as CB1, CB2 and TRPV1 receptor, as well as the main enzymes involved in the biosynthesis and degradation of the major endocannabinoids named 2-arachidonoylglycerol, 2-AG and anandamide, AEA. Here we investigated whether the damages caused by ischemic insult either in vitro using LLC-PK1 cells exposed to antimycin A (an inductor of ATP-depletion) or in vivo using Wistar rats in a classic renal ischemia and reperfusion (IR) protocol, lead to changes in AEA and 2-AG levels, as well as altered expression of genes from the main enzymes involved in the regulation of the ECS. Our data show that the mRNA levels of CB1 receptor gene were downregulated, while the transcript levels of monoacylglycerol lipase (MAGL), the main 2-AG degradative enzyme, are upregulated in LLC-PK1 cells after IR model. Accordingly, IR was accompanied by a significant reduction in the levels of 2-AG and AEA, as well as of the two endocannabinoid related molecules, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) in LLC-PK1 cells. In kidney cortex homogenates, the AEA levels were selectively significantly decreased. In addition, we found that both the in vitro and in vivo model of IR caused a reduction in the expression and activity of the Na + /K + ATPase. These changes were reversed by the CB1/CB2 agonist WIN55,212, in a CB1-receptor dependent manner on LLC-PK1 IR model. In conclusion, the ECS and Na + /K + ATPase are down-regulated following IR model in LLC-PK1 cells and rat kidney. We suggest that CB1 agonists might represent a potential strategy to reverse the consequences of IR injury in kidney tissues. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Endocannabinoids in Multiple Sclerosis and Amyotrophic Lateral Sclerosis.

    PubMed

    Pryce, Gareth; Baker, David

    2015-01-01

    There are numerous reports that people with multiple sclerosis (MS) have for many years been self-medicating with illegal street cannabis or more recently medicinal cannabis to alleviate the symptoms associated with MS and also amyotrophic lateral sclerosis (ALS). These anecdotal reports have been confirmed by data from animal models and more recently clinical trials on the ability of cannabinoids to alleviate limb spasticity, a common feature of progressive MS (and also ALS) and neurodegeneration. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have efficacy, not only in symptom relief but also as neuroprotective agents which may slow disease progression and thus delay the onset of symptoms. This review discusses what we now know about the endocannabinoid system as it relates to MS and ALS and also the therapeutic potential of cannabinoid therapeutics as disease-modifying or symptom control agents, as well as future therapeutic strategies including the potential for slowing disease progression in MS and ALS.

  11. Cannabinoid CB1 Discrimination: Effects of Endocannabinoids and Catabolic Enzyme Inhibitors.

    PubMed

    Leonard, Michael Z; Alapafuja, Shakiru O; Ji, Lipin; Shukla, Vidyanand G; Liu, Yingpeng; Nikas, Spyros P; Makriyannis, Alexandros; Bergman, Jack; Kangas, Brian D

    2017-12-01

    An improved understanding of the endocannabinoid system has provided new avenues of drug discovery and development toward the management of pain and other behavioral maladies. Exogenous cannabinoid type 1 (CB 1 ) receptor agonists such as Δ 9 -tetrahydrocannabinol are increasingly used for their medicinal actions; however, their utility is constrained by concern regarding abuse-related subjective effects. This has led to growing interest in the clinical benefit of indirectly enhancing the activity of the highly labile endocannabinoids N -arachidonoylethanolamine [AEA (or anandamide)] and/or 2-arachidonoylglycerol (2-AG) via catabolic enzyme inhibition. The present studies were conducted to determine whether such actions can lead to CB 1 agonist-like subjective effects, as reflected in CB 1 -related discriminative stimulus effects in laboratory subjects. Squirrel monkeys ( n = 8) that discriminated the CB 1 full agonist AM4054 (0.01 mg/kg) from vehicle were used to study, first, the inhibitors of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MGL) alone or in combination [FAAH (URB597, AM4303); MGL (AM4301); FAAH/MGL (JZL195, AM4302)] and, second, the ability of the endocannabinoids AEA and 2-AG to produce CB 1 agonist-like effects when administered alone or after enzyme inhibition. Results indicate that CB 1 -related discriminative stimulus effects were produced by combined, but not selective, inhibition of FAAH and MGL, and that these effects were nonsurmountably antagonized by low doses of rimonabant. Additionally, FAAH or MGL inhibition revealed CB 1 -like subjective effects produced by AEA but not by 2-AG. Taken together, the present data suggest that therapeutic effects of combined, but not selective, enhancement of AEA or 2-AG activity via enzyme inhibition may be accompanied by CB 1 receptor-mediated subjective effects. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  12. Troubleshooting in LC-MS/MS method for determining endocannabinoid and endocannabinoid-like molecules in rat brain structures applied to assessing the brain endocannabinoid/endovanilloid system significance.

    PubMed

    Bystrowska, Beata; Smaga, Irena; Tyszka-Czochara, Małgorzata; Filip, Małgorzata

    2014-05-01

    In recent years, a potential participation of endocannabinoids (eCBs) and related endocannabinoid-like molecules, including N-acylethanolamines (NAEs), in the physiological and pathophysiological processes has been highlighted, whereas measurement of their levels still remains difficult. The aim of this study was to develop a bioanalytical method that would enable researchers to simultaneously determine quantitatively eCBs (anandamide - AEA and 2-arachidonoylglycerol - 2-AG) and NAEs (oleoylethanolamide or oleoylethanolamine - OEA, palmitoylethanolamide or palmitoylethanolamine - PEA and linoleoylethanolamide or linoleoylethanolamine - LEA) in the rat brain. The analytical problems with analysis and possible solutions have been also shown. The methodology for quantifying eCBs/NAEs by means of a sensitive and selective liquid chromatography tandem mass spectrometry (LC-MS/MS) with electrospray positive ionization and multiple reaction monitoring (MRM) mode was developed and validated. Analytical problems with analyzed compounds were estimated. Reasonably high precision and accuracy of the method were demonstrated in the validation process. The method is linear up to 200 ng/g for AEA, OEA, PEA and LEA and up to 100 μg/g for 2-AG, while the quantification limit reaches 0.2 ng/g and 0.8 μg/g, respectively. Simplicity and rapidity of the assay allows analyzing many samples on a routine basis. This article presents the new procedure applied to the analysis of brain tissues.

  13. “Redundancy” of Endocannabinoid Inactivation: New Challenges and Opportunities for Pain Control

    PubMed Central

    2012-01-01

    Redundancy of metabolic pathways and molecular targets is a typical feature of all lipid mediators, and endocannabinoids, which were originally defined as endogenous agonists at cannabinoid CB1 and CB2 receptors, are no exception. In particular, the two most studied endocannabinoids, anandamide and 2-arachidonoylglycerol, are inactivated through alternative biochemical routes, including hydrolysis and oxidation, and more than one enzyme might be used even for the same type of inactivating reaction. These enzymes also recognize as substrates other concurrent lipid mediators, whereas, in turn, endocannabinoids might interact with noncannabinoid receptors with subcellular distribution and ultimate biological actions either similar to or completely different from those of cannabinoid receptors. Even splicing variants of endocannabinoid hydrolyzing enzymes, such as FAAH-1, might play distinct roles in endocannabinoid inactivation. Finally, the products of endocannabinoid catabolism may have their own targets, with biological roles different from those of cannabinoid receptors. These peculiarities of endocannabinoid signaling have complicated the use of inhibitors of its inactivation mechanisms as a safer and more efficacious alternative to the direct targeting of cannabinoid receptors for the treatment of several pathological conditions, including pain. However, new strategies, including the rediscovery of “dirty drugs”, and the use of certain natural products (including non-THC cannabis constituents), are emerging that might allow us to make a virtue of necessity and exploit endocannabinoid redundancy to develop new analgesics. PMID:22860203

  14. Acute Stress Suppresses Synaptic Inhibition and Increases Anxiety via Endocannabinoid Release in the Basolateral Amygdala

    PubMed Central

    Itoga, Christy A.; Fisher, Marc O.; Solomonow, Jonathan; Roltsch, Emily A.; Gilpin, Nicholas W.

    2016-01-01

    Stress and glucocorticoids stimulate the rapid mobilization of endocannabinoids in the basolateral amygdala (BLA). Cannabinoid receptors in the BLA contribute to anxiogenesis and fear-memory formation. We tested for rapid glucocorticoid-induced endocannabinoid regulation of synaptic inhibition in the rat BLA. Glucocorticoid application to amygdala slices elicited a rapid, nonreversible suppression of spontaneous, but not evoked, GABAergic synaptic currents in BLA principal neurons; the effect was also seen with a membrane-impermeant glucocorticoid, but not with intracellular glucocorticoid application, implicating a membrane-associated glucocorticoid receptor. The glucocorticoid suppression of GABA currents was not blocked by antagonists of nuclear corticosteroid receptors, or by inhibitors of gene transcription or protein synthesis, but was blocked by inhibiting postsynaptic G-protein activity, suggesting a postsynaptic nongenomic steroid signaling mechanism that stimulates the release of a retrograde messenger. The rapid glucocorticoid-induced suppression of inhibition was prevented by blocking CB1 receptors and 2-arachidonoylglycerol (2-AG) synthesis, and it was mimicked and occluded by CB1 receptor agonists, indicating it was mediated by the retrograde release of the endocannabinoid 2-AG. The rapid glucocorticoid effect in BLA neurons in vitro was occluded by prior in vivo acute stress-induced, or prior in vitro glucocorticoid-induced, release of endocannabinoid. Acute stress also caused an increase in anxiety-like behavior that was attenuated by blocking CB1 receptor activation and inhibiting 2-AG synthesis in the BLA. Together, these findings suggest that acute stress causes a long-lasting suppression of synaptic inhibition in BLA neurons via a membrane glucocorticoid receptor-induced release of 2-AG at GABA synapses, which contributes to stress-induced anxiogenesis. SIGNIFICANCE STATEMENT We provide a cellular mechanism in the basolateral amygdala (BLA) for

  15. Fabp1 gene ablation inhibits high-fat diet-induced increase in brain endocannabinoids.

    PubMed

    Martin, Gregory G; Landrock, Danilo; Chung, Sarah; Dangott, Lawrence J; Seeger, Drew R; Murphy, Eric J; Golovko, Mikhail Y; Kier, Ann B; Schroeder, Friedhelm

    2017-01-01

    The endocannabinoid system shifts energy balance toward storage and fat accumulation, especially in the context of diet-induced obesity. Relatively little is known about factors outside the central nervous system that may mediate the effect of high-fat diet (HFD) on brain endocannabinoid levels. One candidate is the liver fatty acid binding protein (FABP1), a cytosolic protein highly prevalent in liver, but not detected in brain, which facilitates hepatic clearance of fatty acids. The impact of Fabp1 gene ablation (LKO) on the effect of high-fat diet (HFD) on brain and plasma endocannabinoid levels was examined and data expressed for each parameter as the ratio of high-fat diet/control diet. In male wild-type mice, HFD markedly increased brain N-acylethanolamides, but not 2-monoacylglycerols. LKO blocked these effects of HFD in male mice. In female wild-type mice, HFD slightly decreased or did not alter these endocannabinoids as compared with male wild type. LKO did not block the HFD effects in female mice. The HFD-induced increase in brain arachidonic acid-derived arachidonoylethanolamide in males correlated with increased brain-free and total arachidonic acid. The ability of LKO to block the HFD-induced increase in brain arachidonoylethanolamide correlated with reduced ability of HFD to increase brain-free and total arachidonic acid in males. In females, brain-free and total arachidonic acid levels were much less affected by either HFD or LKO in the context of HFD. These data showed that LKO markedly diminished the impact of HFD on brain endocannabinoid levels, especially in male mice. © 2016 International Society for Neurochemistry.

  16. Methods of the pharmacological imaging of the cannabinoid system (PhICS) study: towards understanding the role of the brain endocannabinoid system in human cognition.

    PubMed

    van Hell, Hendrika H; Bossong, Matthijs G; Jager, Gerry; Kahn, René S; Ramsey, Nick F

    2011-03-01

    Various lines of (pre)clinical research indicate that cannabinoid agents carry the potential for therapeutic application to reduce symptoms in several psychiatric disorders. However, direct testing of the involvement of cannabinoid brain systems in psychiatric syndromes is essential for further development. In the Pharmacological Imaging of the Cannabinoid System (PhICS) study, the involvement of the endocannabinoid system in cognitive brain function is assessed by comparing acute effects of the cannabinoid agonist Δ9-tetrahydrocannabinol (THC) on brain function between healthy controls and groups of psychiatric patients showing cognitive dysfunction. This article describes the objectives and methods of the PhICS study and presents preliminary results of the administration procedure on subjective and neurophysiological parameters. Core elements in the methodology of PhICS are the administration method (THC is administered by inhalation using a vaporizing device) and a comprehensive use of pharmacological magnetic resonance imaging (phMRI) combining several types of MRI scans including functional MRI (fMRI), Arterial Spin Labeling (ASL) to measure brain perfusion, and resting-state fMRI. Additional methods like neuropsychological testing further specify the exact role of the endocannabinoid system in regulating cognition. Preliminary results presented in this paper indicate robust behavioral and subjective effects of THC. In addition, fMRI paradigms demonstrate activation of expected networks of brain regions in the cognitive domains of interest. The presented administration and assessment protocol provides a basis for further research on the involvement of the endocannabionoid systems in behavior and in psychopathology, which in turn may lead to development of therapeutic opportunities of cannabinoid ligands. Copyright © 2011 John Wiley & Sons, Ltd.

  17. Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons

    PubMed Central

    Cristino, Luigia; Busetto, Giuseppe; Imperatore, Roberta; Ferrandino, Ida; Palomba, Letizia; Silvestri, Cristoforo; Petrosino, Stefania; Orlando, Pierangelo; Bentivoglio, Marina; Mackie, Kenneth; Di Marzo, Vincenzo

    2013-01-01

    Acute or chronic alterations in energy status alter the balance between excitatory and inhibitory synaptic transmission and associated synaptic plasticity to allow for the adaptation of energy metabolism to new homeostatic requirements. The impact of such changes on endocannabinoid and cannabinoid receptor type 1 (CB1)-mediated modulation of synaptic transmission and strength is not known, despite the fact that this signaling system is an important target for the development of new drugs against obesity. We investigated whether CB1-expressing excitatory vs. inhibitory inputs to orexin-A–containing neurons in the lateral hypothalamus are altered in obesity and how this modifies endocannabinoid control of these neurons. In lean mice, these inputs are mostly excitatory. By confocal and ultrastructural microscopic analyses, we observed that in leptin-knockout (ob/ob) obese mice, and in mice with diet-induced obesity, orexinergic neurons receive predominantly inhibitory CB1-expressing inputs and overexpress the biosynthetic enzyme for the endocannabinoid 2-arachidonoylglycerol, which retrogradely inhibits synaptic transmission at CB1-expressing axon terminals. Patch-clamp recordings also showed increased CB1-sensitive inhibitory innervation of orexinergic neurons in ob/ob mice. These alterations are reversed by leptin administration, partly through activation of the mammalian target of rapamycin pathway in neuropeptide-Y-ergic neurons of the arcuate nucleus, and are accompanied by CB1-mediated enhancement of orexinergic innervation of target brain areas. We propose that enhanced inhibitory control of orexin-A neurons, and their CB1-mediated disinhibition, are a consequence of leptin signaling impairment in the arcuate nucleus. We also provide initial evidence of the participation of this phenomenon in hyperphagia and hormonal dysregulation in obesity. PMID:23630288

  18. A moderate diet restriction during pregnancy alters the levels of endocannabinoids and endocannabinoid-related lipids in the hypothalamus, hippocampus and olfactory bulb of rat offspring in a sex-specific manner

    PubMed Central

    Ramírez-López, María Teresa; Vázquez, Mariam; Lomazzo, Ermelinda; Hofmann, Clementine; Blanco, Rosario Noemi; Alén, Francisco; Antón, María; Decara, Juan; Arco, Rocío; Orio, Laura; Suárez, Juan; Lutz, Beat; Gómez de Heras, Raquel; Bindila, Laura

    2017-01-01

    Undernutrition during pregnancy has been associated to increased vulnerability to develop metabolic and behavior alterations later in life. The endocannabinoid system might play an important role in these processes. Therefore, we investigated the effects of a moderate maternal calorie-restricted diet on the levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG), arachidonic acid (AA) and the N-acylethanolamines (NAEs) anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) in the brain of newborn rat offspring. We focused on brain structures involved in metabolism, feeding behavior, as well as emotional and cognitive responses. Female Wistar rats were assigned during the entire pregnancy to either control diet (C) or restriction diet (R), consisting of a 20% calorie-restricted diet. Weight gain and caloric intake of rat dams were monitored and birth outcomes were assessed. 2-AG, AA and NAE levels were measured in hypothalamus, hippocampus and olfactory bulb of the offspring. R dams displayed lower gain weight from the middle pregnancy and consumed less calories during the entire pregnancy. Offspring from R dams were underweight at birth, but litter size was unaffected. In hypothalamus, R male offspring displayed decreased levels of AA and OEA, with no change in the levels of the endocannabinoids 2-AG and AEA. R female exhibited decreased 2-AG and PEA levels. The opposite was found in the hippocampus, where R male displayed increased 2-AG and AA levels, and R female exhibited elevated levels of AEA, AA and PEA. In the olfactory bulb, only R female presented decreased levels of AEA, AA and PEA. Therefore, a moderate diet restriction during the entire pregnancy alters differentially the endocannabinoids and/or endocannabinoid-related lipids in hypothalamus and hippocampus of the underweight offspring, similarly in both sexes, whereas sex-specific alterations occur in the olfactory bulb. Consequently, endocannabinoid and endocannabinoid

  19. A moderate diet restriction during pregnancy alters the levels of endocannabinoids and endocannabinoid-related lipids in the hypothalamus, hippocampus and olfactory bulb of rat offspring in a sex-specific manner.

    PubMed

    Ramírez-López, María Teresa; Vázquez, Mariam; Lomazzo, Ermelinda; Hofmann, Clementine; Blanco, Rosario Noemi; Alén, Francisco; Antón, María; Decara, Juan; Arco, Rocío; Orio, Laura; Suárez, Juan; Lutz, Beat; Gómez de Heras, Raquel; Bindila, Laura; Rodríguez de Fonseca, Fernando

    2017-01-01

    Undernutrition during pregnancy has been associated to increased vulnerability to develop metabolic and behavior alterations later in life. The endocannabinoid system might play an important role in these processes. Therefore, we investigated the effects of a moderate maternal calorie-restricted diet on the levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG), arachidonic acid (AA) and the N-acylethanolamines (NAEs) anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) in the brain of newborn rat offspring. We focused on brain structures involved in metabolism, feeding behavior, as well as emotional and cognitive responses. Female Wistar rats were assigned during the entire pregnancy to either control diet (C) or restriction diet (R), consisting of a 20% calorie-restricted diet. Weight gain and caloric intake of rat dams were monitored and birth outcomes were assessed. 2-AG, AA and NAE levels were measured in hypothalamus, hippocampus and olfactory bulb of the offspring. R dams displayed lower gain weight from the middle pregnancy and consumed less calories during the entire pregnancy. Offspring from R dams were underweight at birth, but litter size was unaffected. In hypothalamus, R male offspring displayed decreased levels of AA and OEA, with no change in the levels of the endocannabinoids 2-AG and AEA. R female exhibited decreased 2-AG and PEA levels. The opposite was found in the hippocampus, where R male displayed increased 2-AG and AA levels, and R female exhibited elevated levels of AEA, AA and PEA. In the olfactory bulb, only R female presented decreased levels of AEA, AA and PEA. Therefore, a moderate diet restriction during the entire pregnancy alters differentially the endocannabinoids and/or endocannabinoid-related lipids in hypothalamus and hippocampus of the underweight offspring, similarly in both sexes, whereas sex-specific alterations occur in the olfactory bulb. Consequently, endocannabinoid and endocannabinoid

  20. Control of excessive neural circuit excitability and prevention of epileptic seizures by endocannabinoid signaling.

    PubMed

    Sugaya, Yuki; Kano, Masanobu

    2018-05-08

    Progress in research on endocannabinoid signaling has greatly advanced our understanding of how it controls neural circuit excitability in health and disease. In general, endocannabinoid signaling at excitatory synapses suppresses seizures by inhibiting glutamate release. In contrast, endocannabinoid signaling promotes seizures by inhibiting GABA release at inhibitory synapses. The physiological distribution of endocannabinoid signaling molecules becomes disrupted with the development of epileptic focus in patients with mesial temporal lobe epilepsy and in animal models of experimentally induced epilepsy. Augmentation of endocannabinoid signaling can promote the development of epileptic focus at initial stages. However, at later stages, increased endocannabinoid signaling delays it and suppresses spontaneous seizures. Thus, the regulation of endocannabinoid signaling at specific synapses that cause hyperexcitability during particular stages of disease development may be effective for treating epilepsy and epileptogenesis.

  1. Activation of Both CB1 and CB2 Endocannabinoid Receptors Is Critical for Masculinization of the Developing Medial Amygdala and Juvenile Social Play Behavior

    PubMed Central

    Falvo, David J; Whitaker, Allison R

    2017-01-01

    Abstract Juvenile social play behavior is a shared trait across a wide variety of mammalian species. When play is characterized by the frequency or duration of physical contact, males usually display more play relative to females. The endocannabinoid system contributes to the development of the sex difference in social play behavior in rats. Treating newborn pups with a nonspecific endocannabinoid agonist, WIN55,212-2, masculinizes subsequent juvenile rough-and-tumble play behavior by females. Here we use specific drugs to target signaling through either the CB1 or CB2 endocannabinoid receptor (CB1R or CB2R) to determine which modulates the development of sex differences in play. Our data reveal that signaling through both CB1R and CB2R must be altered neonatally to modify development of neural circuitry regulating sex differences in play. Neonatal co-agonism of CB1R and CB2R masculinized play by females, whereas co-antagonism of these receptors feminized rates of male play. Because of a known role for the medial amygdala in the sexual differentiation of play, we reconstructed Golgi-impregnated neurons in the juvenile medial amygdala and used factor analysis to identify morphological parameters that were sexually differentiated and responsive to dual agonism of CB1R and CB2R during the early postnatal period. Our results suggest that sex differences in the medial amygdala are modulated by the endocannabinoid system during early development. Sex differences in play behavior are loosely correlated with differences in neuronal morphology. PMID:28144625

  2. Activation of Both CB1 and CB2 Endocannabinoid Receptors Is Critical for Masculinization of the Developing Medial Amygdala and Juvenile Social Play Behavior.

    PubMed

    Argue, Kathryn J; VanRyzin, Jonathan W; Falvo, David J; Whitaker, Allison R; Yu, Stacey J; McCarthy, Margaret M

    2017-01-01

    Juvenile social play behavior is a shared trait across a wide variety of mammalian species. When play is characterized by the frequency or duration of physical contact, males usually display more play relative to females. The endocannabinoid system contributes to the development of the sex difference in social play behavior in rats. Treating newborn pups with a nonspecific endocannabinoid agonist, WIN55,212-2, masculinizes subsequent juvenile rough-and-tumble play behavior by females. Here we use specific drugs to target signaling through either the CB1 or CB2 endocannabinoid receptor (CB1R or CB2R) to determine which modulates the development of sex differences in play. Our data reveal that signaling through both CB1R and CB2R must be altered neonatally to modify development of neural circuitry regulating sex differences in play. Neonatal co-agonism of CB1R and CB2R masculinized play by females, whereas co-antagonism of these receptors feminized rates of male play. Because of a known role for the medial amygdala in the sexual differentiation of play, we reconstructed Golgi-impregnated neurons in the juvenile medial amygdala and used factor analysis to identify morphological parameters that were sexually differentiated and responsive to dual agonism of CB1R and CB2R during the early postnatal period. Our results suggest that sex differences in the medial amygdala are modulated by the endocannabinoid system during early development. Sex differences in play behavior are loosely correlated with differences in neuronal morphology.

  3. Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury

    DTIC Science & Technology

    2014-11-01

    Award Number: W81XWH-11-2-0011 TITLE: Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury PRINCIPAL INVESTIGATOR...Oct 2014 4. TITLE AND SUBTITLE Endocannabinoids as a Target for the Treatment of Traumatic Brain Injury 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH...fluid percussion, traumatic brain injury, blood brain barrier, neuroinflammation, neurological dysfunction, endocannabinoids , microglia and 16

  4. Crystallographic study of FABP5 as an intracellular endocannabinoid transporter

    PubMed Central

    Sanson, Benoît; Wang, Tao; Sun, Jing; Wang, Liqun; Kaczocha, Martin; Ojima, Iwao; Deutsch, Dale; Li, Huilin

    2014-01-01

    In addition to binding intracellular fatty acids, fatty-acid-binding proteins (FABPs) have recently been reported to also transport the endocannabinoids anandamide (AEA) and 2-­arachidonoylglycerol (2-AG), arachidonic acid derivatives that function as neurotransmitters and mediate a diverse set of physiological and psychological processes. To understand how the endocannabinoids bind to FABPs, the crystal structures of FABP5 in complex with AEA, 2-AG and the inhibitor BMS-309403 were determined. These ligands are shown to interact primarily with the substrate-binding pocket via hydrophobic interactions as well as a common hydrogen bond to the Tyr131 residue. This work advances our understanding of FABP5–endocannabinoid interactions and may be useful for future efforts in the development of small-molecule inhibitors to raise endocannabinoid levels. PMID:24531463

  5. A role for endocannabinoids in viral-induced dyskinetic and convulsive phenomena.

    PubMed

    Solbrig, Marylou V; Adrian, Russell; Baratta, Janie; Piomelli, Daniele; Giuffrida, Andrea

    2005-08-01

    Dyskinesias and seizures are both medically refractory disorders for which cannabinoid-based treatments have shown early promise as primary or adjunctive therapy. Using the Borna disease (BD) virus rat, an animal model of viral encephalopathy with spontaneous hyperkinetic movements and seizure susceptibility, we identified a key role for endocannabinoids in the maintenance of a balanced tone of activity in extrapyramidal and limbic circuits. BD rats showed significant elevations of the endocannabinoid anandamide in subthalamic nucleus, a relay nucleus compromised in hyperkinetic disorders. While direct and indirect cannabinoid agonists had limited motor effects in BD rats, abrupt reductions of endocannabinoid tone by the CB1 antagonist SR141716A (0.3 mg/kg, i.p.) caused seizures characterized by myoclonic jerks time-locked to periodic spike/sharp wave discharges on hippocampal electroencephalography. The general opiate antagonist naloxone (NLX) (1 mg/kg, s.c.), another pharmacologic treatment with potential efficacy in dyskinesias or L-DOPA motor complications, produced similar seizures. No changes in anandamide levels in hippocampus and amygdala were found in convulsing NLX-treated BD rats. In contrast, NLX significantly increased anandamide levels in the same areas of normal uninfected animals, possibly protecting against seizures. Pretreatment with the anandamide transport blocker AM404 (20 mg/kg, i.p.) prevented NLX-induced seizures. These findings are consistent with an anticonvulsant role for endocannabinoids, counteracting aberrant firing produced by convulsive agents, and with a functional or reciprocal relation between opioid and cannabinoid tone with respect to limbic convulsive phenomena.

  6. Glucocorticoids shift arachidonic acid metabolism toward endocannabinoid synthesis: a non-genomic anti-inflammatory switch

    PubMed Central

    Malcher-Lopes, Renato; Franco, Alier; Tasker, Jeffrey G.

    2008-01-01

    Glucocorticoids are capable of exerting both genomic and non-genomic actions in target cells of multiple tissues, including the brain, which trigger an array of electrophysiological, metabolic, secretory and inflammatory regulatory responses. Here, we have attempted to show how glucocorticoids may generate a rapid anti-inflammatory response by promoting arachidonic acid-derived endocannabinoid biosynthesis. According to our hypothesized model, non-genomic action of glucocorticoids results in the global shift of membrane lipid metabolism, subverting metabolic pathways toward the synthesis of the anti-inflammatory endocannabinoids, anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), and away from arachidonic acid production. Post-transcriptional inhibition of cyclooxygenase-2 (COX2) synthesis by glucocorticoids assists this mechanism by suppressing the synthesis of pro-inflammatory prostaglandins as well as endocannabinoid-derived prostanoids. In the central nervous system (CNS) this may represent a major neuroprotective system, which may cross-talk with leptin signaling in the hypothalamus allowing for the coordination between energy homeostasis and the inflammatory response. PMID:18295199

  7. Adipose tissue endocannabinoid system gene expression: depot differences and effects of diet and exercise

    PubMed Central

    2011-01-01

    Background Alterations of endocannabinoid system in adipose tissue play an important role in lipid regulation and metabolic dysfunction associated with obesity. The purpose of this study was to determine whether gene expression levels of cannabinoid type 1 receptor (CB1) and fatty acid amide hydrolase (FAAH) are different in subcutaneous abdominal and gluteal adipose tissue, and whether hypocaloric diet and aerobic exercise influence subcutaneous adipose tissue CB1 and FAAH gene expression in obese women. Methods Thirty overweight or obese, middle-aged women (BMI = 34.3 ± 0.8 kg/m2, age = 59 ± 1 years) underwent one of three 20-week weight loss interventions: caloric restriction only (CR, N = 9), caloric restriction plus moderate-intensity aerobic exercise (CRM, 45-50% HRR, N = 13), or caloric restriction plus vigorous-intensity aerobic exercise (CRV, 70-75% HRR, N = 8). Subcutaneous abdominal and gluteal adipose tissue samples were collected before and after the interventions to measure CB1 and FAAH gene expression. Results At baseline, FAAH gene expression was higher in abdominal, compared to gluteal adipose tissue (2.08 ± 0.11 vs. 1.78 ± 0.10, expressed as target gene/β-actin mRNA ratio × 10-3, P < 0.05). Compared to pre-intervention, CR did not change abdominal, but decreased gluteal CB1 (Δ = -0.82 ± 0.25, P < 0.05) and FAAH (Δ = -0.49 ± 0.14, P < 0.05) gene expression. CRM or CRV alone did not change adipose tissue CB1 and FAAH gene expression. However, combined CRM and CRV (CRM+CRV) decreased abdominal adipose tissue FAAH gene expression (Δ = -0.37 ± 0.18, P < 0.05). The changes in gluteal CB1 and abdominal FAAH gene expression levels in the CR alone and the CRM+CRV group were different (P < 0.05) or tended to be different (P = 0.10). Conclusions There are depot differences in subcutaneous adipose tissue endocannabinoid system gene expression in obese individuals. Aerobic exercise training may preferentially modulate abdominal adipose tissue

  8. A shifted repertoire of endocannabinoid genes in the zebrafish (Danio rerio).

    PubMed

    McPartland, J M; Glass, Michelle; Matias, Isabel; Norris, Ryan W; Kilpatrick, C William

    2007-05-01

    The zebrafish has served as a model organism for developmental biology. Sequencing its genome has expanded zebrafish research into physiology and drug-development testing. Several cannabinoid pharmaceuticals are in development, but expression of endocannabinoid receptors and enzymes remains unknown in this species. We conducted a bioinformatics analysis of the zebrafish genome using 17 human endocannabinoid genes as a reference set. Putative zebrafish orthologs were identified in filtered BLAST searches as reciprocal best hits. Orthology was confirmed by three in silico methods: phylogenetic testing, synteny analysis, and functional mapping. Zebrafish expressed orthologs of cannabinoid receptor 1, transient receptor potential channel vanilloid receptor 4, GPR55 receptor, fatty acid amide hydrolase 1, monoacylglycerol lipase, NAPE-selective phospholipase D, abhydrolase domain-containing protein 4, and diacylglycerol lipase alpha and beta; and paired paralogs of cannabinoid receptor 2, fatty acid amide hydrolase 2, peroxisome proliferator-activated receptor alpha, prostaglandin-endoperoxide synthase 2, and transient receptor potential cation channel subtype A1. Functional mapping suggested the orthologs of transient receptor potential vanilloid receptor 1 and peroxisome proliferator-activated receptor gamma lack specific amino acids critical for cannabinoid ligand binding. No orthologs of N-acylethanolamine acid amidase or protein tyrosine phosphatase, non-receptor type 22 were identified. In conclusion, the zebrafish genome expresses a shifted repertoire of endocannabinoid genes. In vitro analyses are warranted before using zebrafish for cannabinoid development testing.

  9. Inhibition of endocannabinoid metabolism by the metabolites of ibuprofen and flurbiprofen.

    PubMed

    Karlsson, Jessica; Fowler, Christopher J

    2014-01-01

    In addition to their effects upon prostaglandin synthesis, the non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen inhibit the metabolism of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) by cyclooxygenase-2 (COX-2) and fatty acid amide hydrolase (FAAH), respectively. Here, we investigated whether these effects upon endocannabinoid metabolism are shared by the main metabolites of ibuprofen and flurbiprofen. COX activities were measured via changes in oxygen consumption due to oxygenation of arachidonic acid (for COX-1) and arachidonic acid and 2-AG (for COX-2). FAAH activity was quantified by measuring hydrolysis of tritium labelled AEA in rat brain homogenates. The ability of ibuprofen and flurbiprofen to inhibit COX-2-catalysed oxygenation of 2-AG at lower concentrations than the oxygenation of arachidonic acid was seen with 4'-hydroxyflurbiprofen and possibly also 3'-hydroxyibuprofen, albeit at lower potencies than the parent compounds. All ibuprofen and flurbiprofen metabolites retained the ability to inhibit FAAH in a pH-dependent manner, although the potency was lower than seen with the parent compounds. It is concluded that the primary metabolites of ibuprofen and flurbiprofen retain some of the properties of the parent compound with respect to inhibition of endocannabinoid metabolism. However, these effects are unlikely to contribute to the actions of the parent compounds in vivo.

  10. Inhibition of Endocannabinoid Metabolism by the Metabolites of Ibuprofen and Flurbiprofen

    PubMed Central

    Karlsson, Jessica; Fowler, Christopher J.

    2014-01-01

    Background In addition to their effects upon prostaglandin synthesis, the non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen inhibit the metabolism of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) by cyclooxygenase-2 (COX-2) and fatty acid amide hydrolase (FAAH), respectively. Here, we investigated whether these effects upon endocannabinoid metabolism are shared by the main metabolites of ibuprofen and flurbiprofen. Methodology/Principal Findings COX activities were measured via changes in oxygen consumption due to oxygenation of arachidonic acid (for COX-1) and arachidonic acid and 2-AG (for COX-2). FAAH activity was quantified by measuring hydrolysis of tritium labelled AEA in rat brain homogenates. The ability of ibuprofen and flurbiprofen to inhibit COX-2-catalysed oxygenation of 2-AG at lower concentrations than the oxygenation of arachidonic acid was seen with 4′-hydroxyflurbiprofen and possibly also 3′-hydroxyibuprofen, albeit at lower potencies than the parent compounds. All ibuprofen and flurbiprofen metabolites retained the ability to inhibit FAAH in a pH-dependent manner, although the potency was lower than seen with the parent compounds. Conclusions/Significance It is concluded that the primary metabolites of ibuprofen and flurbiprofen retain some of the properties of the parent compound with respect to inhibition of endocannabinoid metabolism. However, these effects are unlikely to contribute to the actions of the parent compounds in vivo. PMID:25061885

  11. Orexin-A and Endocannabinoid Activation of the Descending Antinociceptive Pathway Underlies Altered Pain Perception in Leptin Signaling Deficiency.

    PubMed

    Cristino, Luigia; Luongo, Livio; Imperatore, Roberta; Boccella, Serena; Becker, Thorsten; Morello, Giovanna; Piscitelli, Fabiana; Busetto, Giuseppe; Maione, Sabatino; Di Marzo, Vincenzo

    2016-01-01

    Pain perception can become altered in individuals with eating disorders and obesity for reasons that have not been fully elucidated. We show that leptin deficiency in ob/ob mice, or leptin insensitivity in the arcuate nucleus of the hypothalamus in mice with high-fat diet (HFD)-induced obesity, are accompanied by elevated orexin-A (OX-A) levels and orexin receptor-1 (OX1-R)-dependent elevation of the levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), in the ventrolateral periaqueductal gray (vlPAG). In ob/ob mice, these alterations result in the following: (i) increased excitability of OX1-R-expressing vlPAG output neurons and subsequent increased OFF and decreased ON cell activity in the rostral ventromedial medulla, as assessed by patch clamp and in vivo electrophysiology; and (ii) analgesia, in both healthy and neuropathic mice. In HFD mice, instead, analgesia is only unmasked following leptin receptor antagonism. We propose that OX-A/endocannabinoid cross talk in the descending antinociceptive pathway might partly underlie increased pain thresholds in conditions associated with impaired leptin signaling.

  12. Rhythmic control of endocannabinoids in the rat pineal gland.

    PubMed

    Koch, Marco; Ferreirós, Nerea; Geisslinger, Gerd; Dehghani, Faramarz; Korf, Horst-Werner

    2015-01-01

    Endocannabinoids modulate neuroendocrine networks by directly targeting cannabinoid receptors. The time-hormone melatonin synchronizes these networks with external light condition and guarantees time-sensitive and ecologically well-adapted behaviors. Here, the endocannabinoid arachidonoyl ethanolamide (AEA) showed rhythmic changes in rat pineal glands with higher levels during the light-period and reduced amounts at the onset of darkness. Norepinephrine, the essential stimulus for nocturnal melatonin biosynthesis, acutely down-regulated AEA and other endocannabinoids in cultured pineal glands. These temporal dynamics suggest that AEA exerts time-dependent autocrine and/or paracrine functions within the pineal. Moreover, endocananbinoids may be released from the pineal into the CSF or blood stream.

  13. Endocannabinoid dysregulation in cognitive and stress-related brain regions in the Nrg1 mouse model of schizophrenia.

    PubMed

    Clarke, David J; Stuart, Jordyn; McGregor, Iain S; Arnold, Jonathon C

    2017-01-04

    The endocannabinoid system is dysregulated in schizophrenia. Mice with heterozygous deletion of neuregulin 1 (Nrg1 HET mice) provide a well-characterised animal model of schizophrenia, and display enhanced sensitivity to stress and cannabinoids during adolescence. However, no study has yet determined whether these mice have altered brain endocannabinoid concentrations. Nrg1 application to hippocampal slices decreased 2-arachidonoylglycerol (2-AG) signalling and disrupted long-term depression, a form of synaptic plasticity critical to spatial learning. Therefore we specifically aimed to examine whether Nrg1 HET mice exhibit increased 2-AG concentrations and disruption of spatial learning. As chronic stress influences brain endocannabinoids, we also sought to examine whether Nrg1 deficiency moderates adolescent stress-induced alterations in brain endocannabinoids. Adolescent Nrg1 HET and wild-type (WT) mice were submitted to chronic restraint stress and brain endocannabinoid concentrations were analysed. A separate cohort of WT and Nrg1 HET mice was also assessed for spatial learning performance in the Morris Water Maze. Partial genetic deletion of Nrg1 increased anandamide concentrations in the amygdala and decreased 2-AG concentrations in the hypothalamus. Further, Nrg1 HET mice exhibited increased 2-AG concentrations in the hippocampus and impaired spatial learning performance. Chronic adolescent stress increased anandamide concentrations in the amygdala, however, Nrg1 disruption did not influence this stress-induced change. These results demonstrate for the first time in vivo interplay between Nrg1 and endocannabinoids in the brain. Our results demonstrate that aberrant Nrg1 and endocannabinoid signalling may cooperate in the hippocampus to impair cognition, and that Nrg1 deficiency alters endocannabinoid signalling in brain stress circuitry. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Glucose metabolism: focus on gut microbiota, the endocannabinoid system and beyond.

    PubMed

    Cani, P D; Geurts, L; Matamoros, S; Plovier, H; Duparc, T

    2014-09-01

    The gut microbiota is now considered as a key factor in the regulation of numerous metabolic pathways. Growing evidence suggests that cross-talk between gut bacteria and host is achieved through specific metabolites (such as short-chain fatty acids) and molecular patterns of microbial membranes (lipopolysaccharides) that activate host cell receptors (such as toll-like receptors and G-protein-coupled receptors). The endocannabinoid (eCB) system is an important target in the context of obesity, type 2 diabetes (T2D) and inflammation. It has been demonstrated that eCB system activity is involved in the control of glucose and energy metabolism, and can be tuned up or down by specific gut microbes (for example, Akkermansia muciniphila). Numerous studies have also shown that the composition of the gut microbiota differs between obese and/or T2D individuals and those who are lean and non-diabetic. Although some shared taxa are often cited, there is still no clear consensus on the precise microbial composition that triggers metabolic disorders, and causality between specific microbes and the development of such diseases is yet to be proven in humans. Nevertheless, gastric bypass is most likely the most efficient procedure for reducing body weight and treating T2D. Interestingly, several reports have shown that the gut microbiota is profoundly affected by the procedure. It has been suggested that the consistent postoperative increase in certain bacterial groups such as Proteobacteria, Bacteroidetes and Verrucomicrobia (A. muciniphila) may explain its beneficial impact in gnotobiotic mice. Taken together, these data suggest that specific gut microbes modulate important host biological systems that contribute to the control of energy homoeostasis, glucose metabolism and inflammation in obesity and T2D. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  15. Important role of endocannabinoid signaling in the development of functional vision and locomotion in zebrafish.

    PubMed

    Martella, Andrea; Sepe, Rosa M; Silvestri, Cristoforo; Zang, Jingjing; Fasano, Giulia; Carnevali, Oliana; De Girolamo, Paolo; Neuhauss, Stephan C F; Sordino, Paolo; Di Marzo, Vincenzo

    2016-12-01

    The developmental role of the endocannabinoid system still remains to be fully understood. Here, we report the presence of a complete endocannabinoid system during zebrafish development and show that the genes that code for enzymes that catalyze the anabolism and catabolism (mgll and dagla) of the endocannabinoid, 2-AG (2-arachidonoylglycerol), as well as 2-AG main receptor in the brain, cannabinoid receptor type 1, are coexpressed in defined regions of axonal growth. By using morpholino-induced transient knockdown of the zebrafish Daglα homolog and its pharmacologic rescue, we suggest that synthesis of 2-AG is implicated in the control of axon formation in the midbrain-hindbrain region and that animals that lack Daglα display abnormal physiological behaviors in tests that measure stereotyped movement and motion perception. Our results suggest that the well-established role for 2-AG in axonal outgrowth has implications for the control of vision and movement in zebrafish and, thus, is likely common to all vertebrates.-Martella, A., Sepe, R. M., Silvestri, C., Zang, J., Fasano, G., Carnevali, O., De Girolamo, P., Neuhauss, S. C. F., Sordino, P., Di Marzo, V. Important role of endocannabinoid signaling in the development of functional vision and locomotion in zebrafish. © FASEB.

  16. Comparative Effects of Parathion and Chlorpyrifos on Endocannabinoid and Endocannabinoid-Like Lipid Metabolites in Rat Striatum

    PubMed Central

    Liu, Jing; Parsons, Loren; Pope, Carey

    2015-01-01

    Parathion and chlorpyrifos are organophosphorus insecticides (OPs) that elicit acute toxicity by inhibiting acetylcholinesterase (AChE). The endocannabinoids (eCBs, N-arachidonoylethanolamine, AEA; 2-arachidonoylglycerol, 2AG) are endogenous neuromodulators that regulate presynaptic neurotransmitter release in neurons throughout the central and peripheral nervous systems. While substantial information is known about the eCBs, less is known about a number of endocannabinoid-like metabolites (eCBLs, e.g., N-palmitoylethanolamine, PEA; N-oleoylethanolamine, OEA). We report the comparative effects of parathion and chlorpyrifos on AChE and enzymes responsible for inactivation of the eCBs, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and changes in the eCBs AEA and 2AG and eCBLs PEA and OEA, in rat striatum. Adult, male rats were treated with vehicle (peanut oil, 2 ml/kg, sc), parathion (27 mg/kg) or chlorpyrifos (280 mg/kg) 6-7 days after surgical implantation of microdialysis cannulae into the right striatum, followed by microdialysis two or four days later. Additional rats were similarly treated and sacrificed for evaluation of tissue levels of eCBs and eCBLs. Dialysates and tissue extracts were analyzed by LC-MS/MS. AChE and FAAH were extensively inhibited at both time-points (85-96%), while MAGL activity was significantly but lesser affected (37-62% inhibition) by parathion and chlorpyrifos. Signs of toxicity were noted only in parathion-treated rats. In general, chlorpyrifos increased eCB levels while parathion had no or lesser effects. Early changes in extracellular AEA, 2AG and PEA levels were significantly different between parathion and chlorpyrifos exposures. Differential changes in extracellular and/or tissue levels of eCBs and eCBLs could potentially influence a number of signaling pathways and contribute to selective neurological changes following acute OP intoxications. PMID:26215119

  17. Comparative effects of parathion and chlorpyrifos on endocannabinoid and endocannabinoid-like lipid metabolites in rat striatum.

    PubMed

    Liu, Jing; Parsons, Loren; Pope, Carey

    2015-09-01

    Parathion and chlorpyrifos are organophosphorus insecticides (OPs) that elicit acute toxicity by inhibiting acetylcholinesterase (AChE). The endocannabinoids (eCBs, N-arachidonoylethanolamine, AEA; 2-arachidonoylglycerol, 2AG) are endogenous neuromodulators that regulate presynaptic neurotransmitter release in neurons throughout the central and peripheral nervous systems. While substantial information is known about the eCBs, less is known about a number of endocannabinoid-like metabolites (eCBLs, e.g., N-palmitoylethanolamine, PEA; N-oleoylethanolamine, OEA). We report the comparative effects of parathion and chlorpyrifos on AChE and enzymes responsible for inactivation of the eCBs, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and changes in the eCBs AEA and 2AG and eCBLs PEA and OEA, in rat striatum. Adult, male rats were treated with vehicle (peanut oil, 2 ml/kg, sc), parathion (27 mg/kg) or chlorpyrifos (280 mg/kg) 6-7 days after surgical implantation of microdialysis cannulae into the right striatum, followed by microdialysis two or four days later. Additional rats were similarly treated and sacrificed for evaluation of tissue levels of eCBs and eCBLs. Dialysates and tissue extracts were analyzed by LC-MS/MS. AChE and FAAH were extensively inhibited at both time-points (85-96%), while MAGL activity was significantly but lesser affected (37-62% inhibition) by parathion and chlorpyrifos. Signs of toxicity were noted only in parathion-treated rats. In general, chlorpyrifos increased eCB levels while parathion had no or lesser effects. Early changes in extracellular AEA, 2AG and PEA levels were significantly different between parathion and chlorpyrifos exposures. Differential changes in extracellular and/or tissue levels of eCBs and eCBLs could potentially influence a number of signaling pathways and contribute to selective neurological changes following acute OP intoxications. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Sleep Restriction Enhances the Daily Rhythm of Circulating Levels of Endocannabinoid 2-Arachidonoylglycerol

    PubMed Central

    Hanlon, Erin C.; Tasali, Esra; Leproult, Rachel; Stuhr, Kara L.; Doncheck, Elizabeth; de Wit, Harriet; Hillard, Cecilia J.; Van Cauter, Eve

    2016-01-01

    Study Objectives: Increasing evidence from laboratory and epidemiologic studies indicates that insufficient sleep may be a risk factor for obesity. Sleep curtailment results in stimulation of hunger and food intake that exceeds the energy cost of extended wakefulness, suggesting the involvement of reward mechanisms. The current study tested the hypothesis that sleep restriction is associated with activation of the endocannabinoid (eCB) system, a key component of hedonic pathways involved in modulating appetite and food intake. Methods: In a randomized crossover study comparing 4 nights of normal (8.5 h) versus restricted sleep (4.5 h) in healthy young adults, we examined the 24-h profiles of circulating concentrations of the endocannabinoid 2-arachidonoylglycerol (2-AG) and its structural analog 2-oleoylglycerol (2-OG). We concomitantly assessed hunger, appetite, and food intake under controlled conditions. Results: A robust daily variation of 2-AG concentrations with a nadir around the middle of the sleep/overnight fast, followed by a continuous increase culminating in the early afternoon, was evident under both sleep conditions but sleep restriction resulted in an amplification of this rhythm with delayed and extended maximum values. Concentrations of 2-OG followed a similar pattern, but with a lesser amplitude. When sleep deprived, participants reported increases in hunger and appetite concomitant with the afternoon elevation of 2-AG concentrations, and were less able to inhibit intake of palatable snacks. Conclusions: Our findings suggest that activation of the eCB system may be involved in excessive food intake in a state of sleep debt and contribute to the increased risk of obesity associated with insufficient sleep. Commentary: A commentary on this article appears in this issue on page 495. Citation: Hanlon EC, Tasali E, Leproult R, Stuhr KL, Doncheck E, de Wit H, Hillard CJ, Van Cauter E. Sleep restriction enhances the daily rhythm of circulating levels of

  19. The emerging role of the endocannabinoid system in the pathogenesis and treatment of kidney diseases.

    PubMed

    Tam, Joseph

    2016-05-01

    Endocannabinoids (eCBs) are endogenous lipid ligands that bind to cannabinoid receptors that also mediate the effects of marijuana. The eCB system is comprised of eCBs, anandamide, and 2-arachidonoyl glycerol, their cannabinoid-1 and cannabinoid-2 receptors (CB1 and CB2, respectively), and the enzymes involved in their biosynthesis and degradation. It is present in both the central nervous system and peripheral organs including the kidney. The current review focuses on the role of the eCB system in normal kidney function and various diseases, such as diabetes and obesity, that directly contributes to the development of renal pathologies. Normally, activation of the CB1 receptor regulates renal vascular hemodynamics and stimulates the transport of ions and proteins in different nephron compartments. In various mouse and rat models of obesity and type 1 and 2 diabetes mellitus, eCBs generated in various renal cells activate CB1 receptors and contribute to the development of oxidative stress, inflammation, and renal fibrosis. These effects can be chronically ameliorated by CB1 receptor blockers. In contrast, activation of the renal CB2 receptors reduces the deleterious effects of these chronic diseases. Because the therapeutic potential of globally acting CB1 receptor antagonists in these conditions is limited due to their neuropsychiatric adverse effects, the recent development of peripherally restricted CB1 receptor antagonists may represent a novel pharmacological approach in treating renal diseases.

  20. Processing cardiovascular information in the vlPAG during electroacupuncture in rats: roles of endocannabinoids and GABA

    PubMed Central

    Tjen-A-Looi, Stephanie C.; Li, Peng; Longhurst, John C.

    2009-01-01

    A long-loop pathway, involving the hypothalamic arcuate nucleus (ARC), ventrolateral periaqueductal gray (vlPAG), and the rostral ventrolateral medulla (rVLM), is essential in electroacupuncture (EA) attenuation of sympathoexcitatory cardiovascular reflex responses. The ARC provides excitatory input to the vlPAG, which, in turn, inhibits neuronal activity in the rVLM. Although previous studies have shown that endocannabinoid CB1 receptor activation modulates γ-aminobutyric acid (GABA)-ergic and glutamatergic neurotransmission in the dorsolateral PAG in stress-induced analgesia, an important role for endocannabinoids in the vlPAG has not yet been observed. We recently have shown (Fu LW, Longhurst JC. J Appl Physiol; doi:10.1152/japplphysiol.91648.2008) that EA reduces the local vlPAG concentration of GABA, but not glutamate, as measured with high-performance liquid chromatography from extracellular samples collected by microdialysis. We, therefore, hypothesized that, during EA, endocannabinoids, acting through CB1 receptors, presynaptically inhibit GABA release to disinhibit the vlPAG and ultimately modulate excitatory reflex blood pressure responses. Rats were anesthetized, ventilated, and instrumented to measure heart rate and blood pressure. Gastric distention-induced blood pressure responses of 18 ± 5 mmHg were reduced to 6 ± 1 mmHg by 30 min of low-current, low-frequency EA applied bilaterally at pericardial P 5–6 acupoints overlying the median nerves. Like EA, microinjection of the fatty acid amide hydrolase inhibitor URB597 (0.1 nmol, 50 nl) into the vlPAG to increase endocannabinoids locally reduced the gastric distention cardiovascular reflex response from 21 ± 5 to 3 ± 4 mmHg. This inhibition was reversed by pretreatment with the GABAA antagonist gabazine (27 mM, 50 nl), suggesting that endocannabinoids exert their action through a GABAergic receptor mechanism in the vlPAG. The EA-related inhibition from 18 ± 3 to 8 ± 2 mmHg was reversed to 14

  1. Endocannabinoids in brain plasticity: Cortical maturation, HPA axis function and behavior.

    PubMed

    Dow-Edwards, Diana; Silva, Lindsay

    2017-01-01

    Marijuana use during adolescence has reached virtually every strata of society. The general population has the perception that marijuana use is safe for mature people and therefore is also safe for developing adolescents. However, both clinical and preclinical research shows that marijuana use, particularly prior to age 16, could have long-term effects on cognition, anxiety and stress-related behaviors, mood disorders and substance abuse. These effects derive from the role of the endocannabinoid system, the endogenous cannabinoid system, in the development of cortex, amygdala, hippocampus and hypothalamus during adolescence. Endocannabinoids are necessary for normal neuronal excitation and inhibition through actions at glutamate and GABA terminals. Synaptic pruning at excitatory synapses and sparing of inhibitory synapses likely results in changes in the balance of excitation/inhibition in individual neurons and within networks; processes which are necessary for normal cortical development. The interaction between prefrontal cortex (PFC), amygdala and hippocampus is responsible for emotional memory, anxiety-related behaviors and drug abuse and all utilize the endogenous cannabinoid system to maintain homeostasis. Also, endocannabinoids are required for fast and slow feedback in the normal stress response, processes which mature during adolescence. Therefore, exogenous cannabinoids, such as marijuana, have the potential to alter the course of development of each of these major systems (limbic, hypothalamic-pituitary-adrenal (HPA) axis and neocortex) if used during the critical period of brain development, adolescence. This article is part of a Special Issue entitled SI: Adolescent plasticity. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Mechanisms of TNFalpha-induced cardiac dysfunction in cholestatic bile duct-ligated mice: interaction between TNFalpha and endocannabinoids.

    PubMed

    Yang, Ying-Ying; Liu, Hongqun; Nam, Soon Woo; Kunos, George; Lee, Samuel S

    2010-08-01

    Chronic liver disease is associated with endotoxemia, oxidative stress, increased endocannabinoids and decreased cardiac responsiveness. Endocannabinoids activate the tumor necrosis factor-alpha (TNFalpha)-nuclear factor kappaB (NFkappaB) pathway. However, how they interact with each other remains obscure. We therefore aimed to clarify the relationship between the TNFalpha-NFkappaB pathway and endocannabinoids in the pathogenesis of cardiodepression of cholestatic bile duct ligated (BDL) mice. BDL mice with TNFalpha knockout (TNFalpha-/-) and infusion of anti-TNFalpha antibody were used. Cardiac mRNA and protein expression of NFkappaBp65, c-Jun-N-terminal kinases (JNK), p38 mitogen-activated protein kinase (p38MAPK), extracelullar-signal- regulated kinase (ERK), inducible nitric oxide synthase (iNOS), Copper/Zinc and Magnesium-superoxide dismutase (Cu/ Zn- and Mn-SOD), cardiac anandamide, 2-arachidonoylglycerol (2-AG), nitric oxide (NOx) and glutathione, and plasma TNFalpha were measured. The effects of TNFalpha, cannabinoid receptor (CB1) antagonist AM251 and the endocannabinoid reuptake inhibitor UCM707, on the contractility of isolated cardiomyocytes, were assessed. In BDL mice, cardiac mRNA and protein expression of NFkappaBp65, p38MAPK, iNOS, NOx, anandamide, and plasma TNFa were increased, whereas glutathione, Cu/Zn-SOD, and Mn-SOD were decreased. Cardiac contractility was blunted in BDL mice. Anti-TNFa treatment in BDL mice decreased cardiac anandamide and NOx, reduced expression of NFkappaBp65, p38MAPK, and iNOS, enhanced expression of Cu/Zn-SOD and Mn-SOD, increased reductive glutathione and restored cardiomyocyte contractility. TNFa-depressed contractility was worsened by UCM707, whereas AM251 improved contractility. Increased TNFalpha, acting via NFkappaB-iNOS and p38MAPK signaling pathways, plays an important role in the pathogenesis of cardiodepression in BDL mice. TNFalpha also suppressed contractility by increasing oxidative stress and

  3. Endocannabinoid signalling and the deteriorating brain

    PubMed Central

    Di Marzo, Vincenzo; Stella, Nephi; Zimmer, Andreas

    2015-01-01

    Ageing is characterized by the progressive impairment of physiological functions and increased risk of developing debilitating disorders, including chronic inflammation and neurodegenerative diseases. These disorders have common molecular mechanisms that can be targeted therapeutically. In the wake of the approval of the first cannabinoid-based drug for the symptomatic treatment of multiple sclerosis, we examine how endocannabinoid (eCB) signalling controls — and is affected by — normal ageing and neuroinflammatory and neurodegenerative disorders. We propose a conceptual framework linking eCB signalling to the control of the cellular and molecular hallmarks of these processes, and categorize the key components of endocannabinoid signalling that may serve as targets for novel therapeutics. PMID:25524120

  4. Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

    PubMed

    Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

    2010-01-01

    For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists.

  5. Polypharmacological profile of 1,2-dihydro-2-oxo-pyridine-3-carboxamides in the endocannabinoid system.

    PubMed

    Chicca, Andrea; Arena, Chiara; Bertini, Simone; Gado, Francesca; Ciaglia, Elena; Abate, Mario; Digiacomo, Maria; Lapillo, Margherita; Poli, Giulio; Bifulco, Maurizio; Macchia, Marco; Tuccinardi, Tiziano; Gertsch, Jürg; Manera, Clementina

    2018-05-14

    The endocannabinoid system (ECS) represents one of the major neuromodulatory systems involved in different physiological and pathological processes. Multi-target compounds exert their activities by acting via multiple mechanisms of action and represent a promising pharmacological modulation of the ECS. In this work we report 4-substituted and 4,5-disubstituted 1,2-dihydro-2-oxo-pyridine-3-carboxamide derivatives with a broad spectrum of affinity and functional activity towards both cannabinoid receptors and additional effects on the main components of the ECS. In particular compound B3 showed high affinity for CB1R (K i  = 23.1 nM, partial agonist) and CB2R (K i  = 6.9 nM, inverse agonist) and also significant inhibitory activity (IC 50  = 70 nM) on FAAH with moderate inhibition of ABHD12 (IC 50  = 2.5 μΜ). Compounds B4, B5 and B6 that act as full agonists at CB1R and as partial agonists (B5 and B6) or antagonist (B4) at CB2R, exhibited an additional multi-target property by inhibiting anandamide uptake with sub-micromolar IC 50 values (0.28-0.62 μΜ). The best derivatives showed cytotoxic activity on U937 lymphoblastoid cells. Finally, molecular docking analysis carried out on the three-dimensional structures of CB1R and CB2R and of FAAH allowed to rationalize the structure-activity relationships of this series of compounds. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  6. Endocannabinoids and related lipids in blood plasma following touch massage: a randomised, crossover study.

    PubMed

    Lindgren, Lenita; Gouveia-Figueira, Sandra; Nording, Malin L; Fowler, Christopher J

    2015-09-29

    The endocannabinoid system is involved in the regulation of stress and anxiety. In a recent study, it was reported that short-term changes in mood produced by a pleasant ambience were correlated with changes in the levels of plasma endocannabinoids and related N-acylethanolamines (Schrieks et al. PLoS One 10: e0126421, 2015). In the present study, we investigated whether stress reduction by touch massage (TM) affects blood plasma levels of endocannabinoids and related N-acylethanolamines. A randomized two-session crossover design for 20 healthy participants was utilised, with one condition that consisted of TM and a rest condition as control. TM increased the perceived pleasantness rating of the participants, and both TM and rest reduced the basal anxiety level as assessed by the State scale of the STAI-Y inventory. However, there were no significant effects of either time (pre- vs. post-treatment measures) as main effect or the interaction time x treatment for the plasma levels of the endocannabinoids anandamide and 2-arachidonoylglycerol or for eight other related lipids. Four lipids showed acceptable relative reliabilities, and for two of these (linoleoyl ethanolamide and palmitoleoyl ethanolamide) a significant correlation was seen between the TM-related change in levels, calculated as (post-TM value minus pre-TM value) - (post-rest value minus pre-rest value), and the corresponding TM-related change in perceived pleasantness. It is concluded that in the participants studied here, there are no overt effects of TM upon plasma endocannabinoid levels. Possible associations of related N-acylethanolamines with the perceived pleasantness should be investigated further.

  7. Seeing through the smoke: Human and animal studies of cannabis use and endocannabinoid signalling in corticolimbic networks.

    PubMed

    Silveira, Mason M; Arnold, Jonathon C; Laviolette, Steven R; Hillard, Cecilia J; Celorrio, Marta; Aymerich, María S; Adams, Wendy K

    2017-05-01

    Public opinion surrounding the recreational use and therapeutic potential of cannabis is shifting. This review describes new work examining the behavioural and neural effects of cannabis and the endocannabinoid system, highlighting key regions within corticolimbic brain circuits. First, we consider the role of human genetic factors and cannabis strain chemotypic differences in contributing to interindividual variation in the response to cannabinoids, such as THC, and review studies demonstrating that THC-induced impairments in decision-making processes are mediated by actions at prefrontal CB 1 receptors. We further describe evidence that signalling through prefrontal or ventral hippocampal CB 1 receptors modulates mesolimbic dopamine activity, aberrations of which may contribute to emotional processing deficits in schizophrenia. Lastly, we review studies suggesting that endocannabinoid tone in the amygdala is a critical regulator of anxiety, and report new data showing that FAAH activity is integral to this response. Together, these findings underscore the importance of cannabinoid signalling in the regulation of cognitive and affective behaviours, and encourage further research given their social, political, and therapeutic implications. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Seeing through the smoke: human and animal studies of cannabis use and endocannabinoid signalling in corticolimbic networks

    PubMed Central

    Silveira, Mason M.; Arnold, Jonathon C.; Laviolette, Steven R.; Hillard, Cecilia J.; Celorrio, Marta; Aymerich, María S.; Adams, Wendy K.

    2016-01-01

    Public opinion surrounding the recreational use and therapeutic potential of cannabis is shifting. This review describes new work examining the behavioural and neural effects of cannabis and the endocannabinoid system, highlighting key regions within corticolimbic brain circuits. First, we consider the role of human genetic factors and cannabis strain chemotypic differences in contributing to interindividual variation in the response to cannabinoids, such as THC, and review studies demonstrating that THC-induced impairments in decision-making processes are mediated by actions at prefrontal CB1 receptors. We further describe evidence that signalling through prefrontal or ventral hippocampal CB1 receptors modulates mesolimbic dopamine activity, aberrations of which may contribute to emotional processing deficits in schizophrenia. Lastly, we review studies suggesting that endocannabinoid tone in the amygdala is a critical regulator of anxiety, and report new data showing that FAAH activity is integral to this response. Together, these findings underscore the importance of cannabinoid signalling in the regulation of cognitive and affective behaviours, and encourage further research given their social, political, and therapeutic implications. PMID:27639448

  9. Endocannabinoids as mediators in the heart: a potential target for therapy of remodelling after myocardial infarction?

    PubMed Central

    Hiley, C Robin; Ford, William R

    2003-01-01

    Endocannabinoid production by platelets and macrophages is increased in circulatory shock. This may be protective of the cardiovascular system as blockade of CB1 cannabinoid receptors exacerbates endothelial dysfunction in haemorrhagic and endotoxin shock and reduces survival. Now evidence suggests that blockade of CB1 receptors starting 24 h after myocardial infarction in rats has a deleterious effect on cardiac performance, while use of a nonselective cannabinoid receptor agonist prevents hypotension and reduces endothelial dysfunction, although left ventricular end diastolic pressure is elevated. Cannabinoids and endocannabinoid systems may therefore present useful targets for therapy following myocardial infarction. PMID:12711614

  10. Sustained Endocannabinoid Signaling Compromises Decidual Function and Promotes Inflammation-induced Preterm Birth.

    PubMed

    Sun, Xiaofei; Deng, Wenbo; Li, Yingju; Tang, Shuang; Leishman, Emma; Bradshaw, Heather B; Dey, Sudhansu K

    2016-04-08

    Recent studies provide evidence that premature maternal decidual senescence resulting from heightened mTORC1 signaling is a cause of preterm birth (PTB). We show here that mice devoid of fatty acid amide hydrolase (FAAH) with elevated levels ofN-arachidonyl ethanolamide (anandamide), a major endocannabinoid lipid mediator, were more susceptible to PTB upon lipopolysaccharide (LPS) challenge. Anandamide is degraded by FAAH and primarily works by activating two G-protein-coupled receptors CB1 and CB2, encoded by Cnr1 and Cnr2, respectively. We found thatFaah(-/-)decidual cells progressively underwent premature senescence as marked by increased senescence-associated β-galactosidase (SA-β-Gal) staining and γH2AX-positive decidual cells. Interestingly, increased endocannabinoid signaling activated MAPK p38, but not p42/44 or mTORC1 signaling, inFaah(-/-)deciduae, and inhibition of p38 halted premature decidual senescence. We further showed that treatment of a long-acting anandamide in wild-type mice at midgestation triggered premature decidual senescence utilizing CB1, since administration of a CB1 antagonist greatly reduced the rate of PTB inFaah(-/-)females exposed to LPS. These results provide evidence that endocannabinoid signaling is critical in regulating decidual senescence and parturition timing. This study identifies a previously unidentified pathway in decidual senescence, which is independent of mTORC1 signaling. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. p21-activated kinase 1 restricts tonic endocannabinoid signaling in the hippocampus

    PubMed Central

    Xia, Shuting; Zhou, Zikai; Leung, Celeste; Zhu, Yuehua; Pan, Xingxiu; Qi, Junxia; Morena, Maria; Hill, Matthew N; Xie, Wei; Jia, Zhengping

    2016-01-01

    PAK1 inhibitors are known to markedly improve social and cognitive function in several animal models of brain disorders, including autism, but the underlying mechanisms remain elusive. We show here that disruption of PAK1 in mice suppresses inhibitory neurotransmission through an increase in tonic, but not phasic, secretion of endocannabinoids (eCB). Consistently, we found elevated levels of anandamide (AEA), but not 2-arachidonoylglycerol (2-AG) following PAK1 disruption. This increased tonic AEA signaling is mediated by reduced cyclooxygenase-2 (COX-2), and COX-2 inhibitors recapitulate the effect of PAK1 deletion on GABAergic transmission in a CB1 receptor-dependent manner. These results establish a novel signaling process whereby PAK1 upregulates COX-2, reduces AEA and restricts tonic eCB-mediated processes. Because PAK1 and eCB are both critically involved in many other organ systems in addition to the brain, our findings may provide a unified mechanism by which PAK1 regulates these systems and their dysfunctions including cancers, inflammations and allergies. DOI: http://dx.doi.org/10.7554/eLife.14653.001 PMID:27296803

  12. Endocannabinoids as positive or negative factors in hematopoietic cell migration and differentiation.

    PubMed

    Patinkin, Deborah; Milman, Garry; Breuer, Aviva; Fride, Ester; Mechoulam, Raphael

    2008-10-24

    The ethanolamides of arachidonic, myristic and linoleic acids reduce bone marrow cell migration, while the 2-glyceryl esters of these acids enhance migration. Thus the 2 major endocannabinoids, anandamide (arachidonoyl ethanolamide) and 2-AG (2-arachidonoyl glycerol), whose structural difference lies in the nature of the end-group alone, work in opposite directions. The endocannabinoid arachidonoyl serine, a vasodilator, also reduces migration. The effect of 2-AG is mediated, in part at least, through the cannabinoid receptors, while the effect of anandamide, as well as the rest of the compounds assayed, are not mediated through them. Almost all cannabinoids tested, including anandamide and 2-AG, lead to approximate doubling of CFU-GEMM (colony-forming unit: granulocyte, erythrocyte, macrophage, megakaryocyte) colonies. The effect of anandamide is considerably more potent than that of 2-AG. A surprising dose-response increase of erythroid cells is noted in cultures with the ester cannabinoids (in the absence of the cytokine erythropoietin), while a considerable dose-response augmentation of megakaryocytes is noted in cultures with the ethanolamide cannabinoids (in the presence of erythropoietin). This is suggestive of some cross-talk between two different regulatory systems, one governed by glycoprotein ligands and the other by endocannabinoids.

  13. The endocannabinoid system in the rat dorsolateral periaqueductal grey mediates fear-conditioned analgesia and controls fear expression in the presence of nociceptive tone

    PubMed Central

    Olango, WM; Roche, M; Ford, GK; Harhen, B; Finn, DP

    2012-01-01

    BACKGROUND AND PURPOSE Endocannabinoids in the midbrain periaqueductal grey (PAG) modulate nociception and unconditioned stress-induced analgesia; however, their role in fear-conditioned analgesia (FCA) has not been examined. The present study examined the role of the endocannabinoid system in the dorsolateral (dl) PAG in formalin-evoked nociceptive behaviour, conditioned fear and FCA in rats. EXPERIMENTAL APPROACH Rats received intra-dlPAG administration of the CB1 receptor antagonist/inverse agonist rimonabant, or vehicle, before re-exposure to a context paired 24 h previously with foot shock. Formalin-evoked nociceptive behaviour and fear-related behaviours (freezing and 22 kHz ultrasonic vocalization) were assessed. In a separate cohort, levels of endocannabinoids [2-arachidonoyl glycerol (2-AG) and N-arachidonoyl ethanolamide (anandamide; AEA)] and the related N-acylethanolamines (NAEs) [N-palmitoyl ethanolamide (PEA) and N-oleoyl ethanolamide (OEA)] were measured in dlPAG tissue following re-exposure to conditioned context in the presence or absence of formalin-evoked nociceptive tone. KEY RESULTS Re-exposure of rats to the context previously associated with foot shock resulted in FCA. Intra-dlPAG administration of rimonabant significantly attenuated FCA and fear-related behaviours expressed in the presence of nociceptive tone. Conditioned fear without formalin-evoked nociceptive tone was associated with increased levels of 2-AG, AEA, PEA and OEA in the dlPAG. FCA was specifically associated with an increase in AEA levels in the dlPAG. CONCLUSIONS AND IMPLICATIONS Conditioned fear to context mobilises endocannabinoids and NAEs in the dlPAG. These data support a role for endocannabinoids in the dlPAG in mediating the potent suppression of pain responding which occurs during exposure to conditioned aversive contexts. LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit

  14. Translational Evidence for a Role of Endocannabinoids in the Etiology and Treatment of Posttraumatic Stress Disorder

    PubMed Central

    Neumeister, Alexander; Seidel, Jordan; Ragen, Benjamin J.; Pietrzak, Robert H.

    2014-01-01

    Introduction Posttraumatic stress disorder (PTSD) is a prevalent, chronic, and disabling anxiety disorder that may develop following exposure to a traumatic event. Despite the public health significance of PTSD, relatively little is known about the etiology or pathophysiology of this disorder, and pharmacotherapy development to date has been largely opportunistic instead of mechanism-based. Recently, an accumulating body of evidence has implicated the endocannabinoid system in the etiology of PTSD, and targets within this system are believed to be suitable for treatment development. Methods Herein, we describe evidence from translational studies arguing for the relevance of the endocannabinoid system in the etiology of PTSD. We also show mechanisms relevant for treatment development. Results There is convincing evidence from multiple studies for reduced endocannabinoid availability in PTSD. Brain imaging studies show molecular adaptations with elevated cannabinoid type 1 (CB1) receptor availability in PTSD which is linked to abnormal threat processing and anxious arousal symptoms. Conclusion Of particular relevance is evidence showing reduced levels of the endocannabinoid anandamide and compensatory increase of CB1 receptor availability in PTSD, and an association between increased CB1 receptor availability in the amygdala and abnormal threat processing, as well as increased severity of hyperarousal, but not dysphoric symptomatology, in trauma survivors. Given that hyperarousal symptoms are the key drivers of more disabling aspects of PTSD such as emotional numbing or suicidality, novel, mechanism-based pharmacotherapies that target this particular symptom cluster in patients with PTSD may have utility in mitigating the chronicity and morbidity of the disorder. PMID:25456347

  15. Translational evidence for a role of endocannabinoids in the etiology and treatment of posttraumatic stress disorder.

    PubMed

    Neumeister, Alexander; Seidel, Jordan; Ragen, Benjamin J; Pietrzak, Robert H

    2015-01-01

    Posttraumatic stress disorder (PTSD) is a prevalent, chronic, and disabling anxiety disorder that may develop following exposure to a traumatic event. Despite the public health significance of PTSD, relatively little is known about the etiology or pathophysiology of this disorder, and pharmacotherapy development to date has been largely opportunistic instead of mechanism-based. Recently, an accumulating body of evidence has implicated the endocannabinoid system in the etiology of PTSD, and targets within this system are believed to be suitable for treatment development. Herein, we describe evidence from translational studies arguing for the relevance of the endocannabinoid system in the etiology of PTSD. We also show mechanisms relevant for treatment development. There is convincing evidence from multiple studies for reduced endocannabinoid availability in PTSD. Brain imaging studies show molecular adaptations with elevated cannabinoid type 1 (CB1) receptor availability in PTSD which is linked to abnormal threat processing and anxious arousal symptoms. Of particular relevance is evidence showing reduced levels of the endocannabinoid anandamide and compensatory increase of CB1 receptor availability in PTSD, and an association between increased CB1 receptor availability in the amygdala and abnormal threat processing, as well as increased severity of hyperarousal, but not dysphoric symptomatology, in trauma survivors. Given that hyperarousal symptoms are the key drivers of more disabling aspects of PTSD such as emotional numbing or suicidality, novel, mechanism-based pharmacotherapies that target this particular symptom cluster in patients with PTSD may have utility in mitigating the chronicity and morbidity of the disorder. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Increasing Antiproliferative Properties of Endocannabinoids in N1E-115 Neuroblastoma Cells through Inhibition of Their Metabolism

    PubMed Central

    Hamtiaux, Laurie; Hansoulle, Laurie; Dauguet, Nicolas; Muccioli, Giulio G.; Gallez, Bernard; Lambert, Didier M.

    2011-01-01

    The antitumoral properties of endocannabinoids received a particular attention these last few years. Indeed, these endogenous molecules have been reported to exert cytostatic, apoptotic and antiangiogenic effects in different tumor cell lines and tumor xenografts. Therefore, we investigated the cytotoxicity of three N-acylethanolamines – N-arachidonoylethanolamine (anandamide, AEA), N-palmitoylethanolamine (PEA) and N-oleoylethanolamine (OEA) - which were all able to time- and dose-dependently reduce the viability of murine N1E-115 neuroblastoma cells. Moreover, several inhibitors of FAAH and NAAA, whose presence was confirmed by RT-PCR in the cell line, induced cell cytotoxicity and favored the decrease in cell viability caused by N-acylethanolamines. The most cytotoxic treatment was achieved by the co-incubation of AEA with the selective FAAH inhibitor URB597, which drastically reduced cell viability partly by inhibiting AEA hydrolysis and consequently increasing AEA levels. This combination of molecules synergistically decreased cell proliferation without inducing cell apoptosis or necrosis. We found that these effects are independent of cannabinoid, TRPV1, PPARα, PPARγ or GPR55 receptors activation but seem to occur through a lipid raft-dependent mechanism. These findings further highlight the interest of targeting the endocannabinoid system to treat cancer. More particularly, this emphasizes the great potential benefit of designing novel anti-cancerous therapies based on the association of endocannabinoids and inhibitors of their hydrolysis. PMID:22046372

  17. Endocannabinoids modulate apoptosis in endometriosis and adenomyosis.

    PubMed

    Bilgic, Elif; Guzel, Elif; Kose, Sevil; Aydin, Makbule Cisel; Karaismailoglu, Eda; Akar, Irem; Usubutun, Alp; Korkusuz, Petek

    2017-06-01

    Adenomyosis that is a form of endometriosis is the growth of ectopic endometrial tissue within the muscular wall of the uterus (myometrium), which may cause dysmenorrhea and infertility. Endocannabinoid mediated apoptotic mechanisms of endometriosis and adenomyosis are not known. We hypothesized that the down regulation of endocannabinoid receptors and/or alteration in their regulatory enzymes may have a direct role in the pathogenesis of endometriosis and adenomyosis through apoptosis. Endocannabinoid receptors CB1 and CB2, their synthesizing and catabolizing enzymes (FAAH, NAPE-PLD, DAGL, MAGL) and the apoptotic indexes were immunohistochemically assessed in endometriotic and adenomyotic tissues. Findings were compared to normal endometrium and myometrium. Endometrial adenocarcinoma (Ishikawa) and ovarian endometriosis cyst wall stromal (CRL-7566) cell lines were furthermore cultured with or without cannabinoid receptor agonists. The IC50 value for CB1 and CB2 receptor agonists was quantified. Cannabinoid agonists on cell death were investigated by Annexin-V/Propidium iodide labeling with flow cytometry. CB1 and CB2 receptor levels decreased in endometriotic and adenomyotic tissues compared to the control group (p=0,001 and p=0,001). FAAH, NAPE-PLD, MAGL and DAGL enzyme levels decreased in endometriotic and adenomyotic tissues compared to control (p=0,001, p=0,001, p=0,001 and p=0,002 respectively). Apoptotic cell indexes both in endometriotic and adenomyotic tissues also decreased significantly, compared to the control group (p=0,001 and p=0,001). CB1 and CB2 receptor agonist mediated dose dependent fast anti-proliferative and pro-apoptotic effects were detected in Ishikawa and ovarian endometriosis cyst wall stromal cell lines (CRL-7566). Endocannabinoids are suggested to increase apoptosis mechanisms in endometriosis and adenomyosis. CB1 and CB2 antagonists can be considered as potential medical therapeutic agents for endometriosis and adenomyosis. Copyright

  18. Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures.

    PubMed

    Chen, Kang; Neu, Axel; Howard, Allyson L; Földy, Csaba; Echegoyen, Julio; Hilgenberg, Lutz; Smith, Martin; Mackie, Ken; Soltesz, Ivan

    2007-01-03

    Depolarization-induced suppression of inhibition (DSI) is an endocannabinoid-mediated short-term plasticity mechanism that couples postsynaptic Ca2+ rises to decreased presynaptic GABA release. Whether the gain of this retrograde synaptic mechanism is subject to long-term modulation by glutamatergic excitatory inputs is not known. Here, we demonstrate that activity-dependent long-term DSI potentiation takes place in hippocampal slices after tetanic stimulation of Schaffer collateral synapses. This activity-dependent, long-term plasticity of endocannabinoid signaling was specific to GABAergic synapses, as it occurred without increases in the depolarization-induced suppression of excitation. Induction of tetanus-induced DSI potentiation in vitro required a complex pathway involving AMPA/kainate and metabotropic glutamate receptor as well as CB1 receptor activation. Because DSI potentiation has been suggested to play a role in persistent limbic hyperexcitability after prolonged seizures in the developing brain, we used these mechanistic insights into activity-dependent DSI potentiation to test whether interference with the induction of DSI potentiation prevents seizure-induced long-term hyperexcitability. The results showed that the in vitro, tetanus-induced DSI potentiation was occluded by previous in vivo fever-induced (febrile) seizures, indicating a common pathway. Accordingly, application of CB1 receptor antagonists during febrile seizures in vivo blocked the seizure-induced persistent DSI potentiation, abolished the seizure-induced upregulation of CB1 receptors, and prevented the emergence of long-term limbic hyperexcitability. These results reveal a new form of activity-dependent, long-term plasticity of endocannabinoid signaling at perisomatic GABAergic synapses, and demonstrate that blocking the induction of this plasticity abolishes the long-term effects of prolonged febrile seizures in the developing brain.

  19. Prenatal cannabis exposure - The "first hit" to the endocannabinoid system.

    PubMed

    Richardson, Kimberlei A; Hester, Allison K; McLemore, Gabrielle L

    As more states and countries legalize medical and/or adult recreational marijuana use, the incidences of prenatal cannabis exposure (PCE) will likely increase. While young people increasingly view marijuana as innocuous, marijuana preparations have been growing in potency in recent years, potentially creating global clinical, public health, and workforce concerns. Unlike fetal alcohol spectrum disorder, there is no phenotypic syndrome associated with PCE. There is also no preponderance of evidence that PCE causes lifelong cognitive, behavioral, or functional abnormalities, and/or susceptibility to subsequent addiction. However, there is compelling circumstantial evidence, based on the principles of teratology and fetal malprogramming, suggesting that pregnant women should refrain from smoking marijuana. The usage of marijuana during pregnancy perturbs the fetal endogenous cannabinoid signaling system (ECSS), which is present and active from the early embryonic stage, modulating neurodevelopment and continuing this role into adulthood. The ECSS is present in virtually every brain structure and organ system, and there is also evidence that this system is important in the regulation of cardiovascular processes. Endocannabinoids (eCBs) undergird a broad spectrum of processes, including the early stages of fetal neurodevelopment and uterine implantation. Delta-9-tetrahydrocannabinol (THC), the psychoactive chemical in cannabis, enters maternal circulation, and readily crosses the placental membrane. THC binds to CB receptors of the fetal ECSS, altering neurodevelopment and possibly rewiring ECSS circuitry. In this review, we discuss the Double-Hit Hypothesis as it relates to PCE. We contend that PCE, similar to a neurodevelopmental teratogen, delivers the first hit to the ECSS, which is compromised in such a way that a second hit (i.e., postnatal stressors) will precipitate the emergence of a specific phenotype. In summary, we conclude that perturbations of the

  20. Techniques for the Cellular and Subcellular Localization of Endocannabinoid Receptors and Enzymes in the Mammalian Brain.

    PubMed

    Cristino, Luigia; Imperatore, Roberta; Di Marzo, Vincenzo

    2017-01-01

    This chapter attempts to piece together knowledge about new advanced microscopy techniques to study the neuroanatomical distribution of endocannabinoid receptors and enzymes at the level of cellular and subcellular structures and organelles in the brain. Techniques ranging from light to electron microscopy up to the new advanced LBM, PALM, and STORM super-resolution microscopy will be discussed in the context of their contribution to define the spatial distribution and organization of receptors and enzymes of the endocannabinoid system (ECS), and to better understand ECS brain functions. © 2017 Elsevier Inc. All rights reserved.

  1. Tetrahydrocannabinol and endocannabinoids in feeding and appetite.

    PubMed

    Berry, Elliot M; Mechoulam, Raphael

    2002-08-01

    The physiological control of appetite and satiety, in which numerous neurotransmitters and neuropeptides play a role, is extremely complex. Here we describe the involvement of endocannabinoids in these processes. These endogenous neuromodulators enhance appetite in animals. The same effect is observed in animals and in humans with the psychotropic plant cannabinoid Delta(9)-tetrahydrocannabinol, which is an approved appetite-enhancing drug. The CB(1) cannabinoid receptor antagonist SR141716A blocks the effects on feeding produced by the endocannabinoids. If administered to mice pups, this antagonist blocks suckling. In obese humans, it causes weight reduction. Very little is known about the physiological and biochemical mechanisms involved in the effects of Delta(9)-tetrahydrocannabinol and the cannabinoids in feeding and appetite.

  2. Anandamide and analogous endocannabinoids: a lipid self-assembly study

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sagnella, Sharon M.; Conn, Charlotte E.; Krodkiewska, Irena

    Anandamide, the endogenous agonist of the cannabinoid receptors, has been widely studied for its interesting biological and medicinal properties and is recognized as a highly significant lipid signaling molecule within the nervous system. Few studies have, however, examined the effect of the physical conformation of anandamide on its function. The study presented herein has focused on characterizing the self-assembly behaviour of anandamide and four other endocannabinoid analogues of anandamide, viz., 2-arachidonyl glycerol, arachidonyl dopamine, 2-arachidonyl glycerol ether (noladin ether), and o-arachidonyl ethanolamide (virodhamine). Molecular modeling of the five endocannabinoid lipids indicates that the highly unsaturated arachidonyl chain has a preferencemore » for a U or J shaped conformation. Thermal phase studies of the neat amphiphiles showed that a glass transition was observed for all of the endocannabinoids at {approx} -110 C with the exception of anandamide, with a second glass transition occurring for 2-arachidonyl glycerol, 2-arachidonyl glycerol ether, and virodhamine (-86 C, -95 C, -46 C respectively). Both anandamide and arachidonyl dopamine displayed a crystal-isotropic melting point (-4.8 and -20.4 C respectively), while a liquid crystal-isotropic melting transition was seen for 2-arachidonyl glycerol (-40.7 C) and 2-arachidonyl glycerol ether (-71.2 C). No additional transitions were observed for virodhamine. Small angle X-ray scattering and cross polarized optical microscopy studies as a function of temperature indicated that in the presence of excess water, both 2-arachidonyl glycerol and anandamide form co-existing Q{sub II}{sup G} (gyroid) and Q{sub II}{sup D} (diamond) bicontinuous cubic phases from 0 C to 20 C, which are kinetically stable over a period of weeks but may not represent true thermodynamic equilibrium. Similarly, 2-arachidonyl glycerol ether acquired an inverse hexagonal (HII) phase in excess water from 0 C to 40 C, while

  3. Spinal Endocannabinoids and CB1 Receptors Mediate C-Fiber-Induced Heterosynaptic Pain Plasticity

    PubMed Central

    Pernía-Andrade, Alejandro J.; Kato, Ako; Witschi, Robert; Nyilas, Rita; Katona, István; Freund, Tamás F.; Watanabe, Masahiko; Filitz, Jörg; Koppert, Wolfgang; Schüttler, Jürgen; Ji, Guangchen; Neugebauer, Volker; Marsicano, Giovanni; Lutz, Beat; Vanegas, Horacio; Zeilhofer, Hanns Ulrich

    2010-01-01

    Diminished synaptic inhibition in the spinal dorsal horn is a major contributor to chronic pain. Pathways, which reduce synaptic inhibition in inflammatory and neuropathic pain states, have been identified, but central hyperalgesia and diminished dorsal horn synaptic inhibition also occur in the absence of inflammation or neuropathy, solely triggered by intense nociceptive (C–fiber) input to the spinal dorsal horn. We found that endocannabinoids produced upon strong nociceptive stimulation activated CB1 receptors on inhibitory dorsal horn neurons to reduce the synaptic release of GABA and glycine and thus rendered nociceptive neurons excitable by non-painful stimuli. Spinal endocannabinoids and CB1 receptors on inhibitory dorsal horn interneurons act as mediators of heterosynaptic pain sensitization and play an unexpected role in dorsal horn pain controlling circuits. PMID:19661434

  4. Endocannabinoid signaling enhances visual responses through modulation of intracellular chloride levels in retinal ganglion cells

    PubMed Central

    Miraucourt, Loïs S; Tsui, Jennifer; Gobert, Delphine; Desjardins, Jean-François; Schohl, Anne; Sild, Mari; Spratt, Perry; Castonguay, Annie; De Koninck, Yves; Marsh-Armstrong, Nicholas; Wiseman, Paul W; Ruthazer, Edward S

    2016-01-01

    Type 1 cannabinoid receptors (CB1Rs) are widely expressed in the vertebrate retina, but the role of endocannabinoids in vision is not fully understood. Here, we identified a novel mechanism underlying a CB1R-mediated increase in retinal ganglion cell (RGC) intrinsic excitability acting through AMPK-dependent inhibition of NKCC1 activity. Clomeleon imaging and patch clamp recordings revealed that inhibition of NKCC1 downstream of CB1R activation reduces intracellular Cl− levels in RGCs, hyperpolarizing the resting membrane potential. We confirmed that such hyperpolarization enhances RGC action potential firing in response to subsequent depolarization, consistent with the increased intrinsic excitability of RGCs observed with CB1R activation. Using a dot avoidance assay in freely swimming Xenopus tadpoles, we demonstrate that CB1R activation markedly improves visual contrast sensitivity under low-light conditions. These results highlight a role for endocannabinoids in vision and present a novel mechanism for cannabinoid modulation of neuronal activity through Cl− regulation. DOI: http://dx.doi.org/10.7554/eLife.15932.001 PMID:27501334

  5. Nongenomic Glucocorticoid Suppression of a Postsynaptic Potassium Current via Emergent Autocrine Endocannabinoid Signaling in Hypothalamic Neuroendocrine Cells following Chronic Dehydration

    PubMed Central

    Wu, Ning

    2017-01-01

    Glucocorticoids rapidly stimulate endocannabinoid synthesis and modulation of synaptic transmission in hypothalamic neuroendocrine cells via a nongenomic signaling mechanism. The endocannabinoid actions are synapse-constrained by astrocyte restriction of extracellular spatial domains. Exogenous cannabinoids have been shown to modulate postsynaptic potassium currents, including the A-type potassium current (IA), in different cell types. The activity of magnocellular neuroendocrine cells is shaped by a prominent IA. We tested for a rapid glucocorticoid modulation of the postsynaptic IK and IA in magnocellular neuroendocrine cells of the hypothalamic paraventricular nucleus (PVN) using whole-cell recordings in rat brain slices. Application of the synthetic glucocorticoid dexamethasone (Dex) had no rapid effect on the IK or IA amplitude, voltage dependence, or kinetics in magnocellular neurons in slices from untreated rats. In magnocellular neurons from salt-loaded rats, however, Dex application caused a rapid suppression of the IA and a depolarizing shift in IA voltage dependence. Exogenously applied endocannabinoids mimicked the rapid Dex modulation of the IA, and CB1 receptor antagonists and agonists blocked and occluded the Dex-induced changes in the IA, respectively, suggesting an endocannabinoid dependence of the rapid glucocorticoid effect. Preincubation of control slices in a gliotoxin resulted in the partial recapitulation of the glucocorticoid-induced rapid suppression of the IA. These findings demonstrate a glucocorticoid suppression of the postsynaptic IA in PVN magnocellular neurons via an autocrine endocannabinoid-dependent mechanism following chronic dehydration, and suggest a possible role for astrocytes in the control of the autocrine endocannabinoid actions. PMID:28966975

  6. Sleep Restriction Enhances the Daily Rhythm of Circulating Levels of Endocannabinoid 2-Arachidonoylglycerol.

    PubMed

    Hanlon, Erin C; Tasali, Esra; Leproult, Rachel; Stuhr, Kara L; Doncheck, Elizabeth; de Wit, Harriet; Hillard, Cecilia J; Van Cauter, Eve

    2016-03-01

    Increasing evidence from laboratory and epidemiologic studies indicates that insufficient sleep may be a risk factor for obesity. Sleep curtailment results in stimulation of hunger and food intake that exceeds the energy cost of extended wakefulness, suggesting the involvement of reward mechanisms. The current study tested the hypothesis that sleep restriction is associated with activation of the endocannabinoid (eCB) system, a key component of hedonic pathways involved in modulating appetite and food intake. In a randomized crossover study comparing 4 nights of normal (8.5 h) versus restricted sleep (4.5 h) in healthy young adults, we examined the 24-h profiles of circulating concentrations of the endocannabinoid 2-arachidonoylglycerol (2-AG) and its structural analog 2-oleoylglycerol (2-OG). We concomitantly assessed hunger, appetite, and food intake under controlled conditions. A robust daily variation of 2-AG concentrations with a nadir around the middle of the sleep/overnight fast, followed by a continuous increase culminating in the early afternoon, was evident under both sleep conditions but sleep restriction resulted in an amplification of this rhythm with delayed and extended maximum values. Concentrations of 2-OG followed a similar pattern, but with a lesser amplitude. When sleep deprived, participants reported increases in hunger and appetite concomitant with the afternoon elevation of 2-AG concentrations, and were less able to inhibit intake of palatable snacks. Our findings suggest that activation of the eCB system may be involved in excessive food intake in a state of sleep debt and contribute to the increased risk of obesity associated with insufficient sleep. A commentary on this article appears in this issue on page 495. © 2016 Associated Professional Sleep Societies, LLC.

  7. The endocannabinoid system expression in the female reproductive tract is modulated by estrogen.

    PubMed

    Maia, J; Almada, M; Silva, A; Correia-da-Silva, G; Teixeira, N; Sá, S I; Fonseca, B M

    2017-11-01

    The endocannabinoid system (ECS) is involved in several physiological events that resulted in a growing interest in its modulation. Moreover, the uterine levels of anandamide (AEA), the major endocannabinoid, must be tightly regulated to create proper embryo implantation conditions. However, there are no evidences about the regulation of AEA in uterus by estrogen. Thus, the aim of this study is to elucidate whether estradiol benzoate (EB) and tamoxifen (TAM) administration to ovariectomized (OVX) rats can induce changes in the expression of cannabinoid receptors and AEA-metabolic enzymes in uterus by evaluating gene transcription and protein levels by qPCR, Western blot and immunohistochemistry. Moreover, the plasmatic and uterine levels of AEA and of prostaglandin E 2 (PGE 2 ) and prostaglandin F 2 α (PGF 2α ), the major cyclooxygenase-2 (COX-2) products, were determined by UPLC-MS/MS. The immunohistochemistry showed that cannabinoid receptors, as well as AEA-metabolic enzymes are mainly located in the epithelial cells of both lumen and glands and, to a lesser extent, in the muscle cells. Moreover, EB administration to OVX rats significantly increased CB1, CB2, NAPE-PLD, FAAH and COX-2 expression and transcription. These effects were absent in TAM and TAM+EB treatments showing that this response is estrogen receptor dependent. Additionally, although uterine levels of AEA remained unchanged in EB or TAM treated animals, they showed a rise with EB treatment in plasma. The latter also produced a decrease in uterine PGE 2 levels. In summary, these data collectively indicate that the expression of ECS components, as well as, the AEA and PGE 2 levels in rat uterus is modulated by EB. Thus, estradiol may have a direct regulatory role in the modulation of ECS in female reproductive tissues. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. COX-2-derived endocannabinoid metabolites as novel inflammatory mediators.

    PubMed

    Alhouayek, Mireille; Muccioli, Giulio G

    2014-06-01

    Cyclooxygenase-2 (COX-2) is an enzyme that plays a key role in inflammatory processes. Classically, this enzyme is upregulated in inflammatory situations and is responsible for the generation of prostaglandins (PGs) from arachidonic acid (AA). One lesser-known property of COX-2 is its ability to metabolize the endocannabinoids, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG). Endocannabinoid metabolism by COX-2 is not merely a means to terminate their actions. On the contrary, it generates PG analogs, namely PG-glycerol esters (PG-G) for 2-AG and PG-ethanolamides (PG-EA or prostamides) for AEA. Although the formation of these COX-2-derived metabolites of the endocannabinoids has been known for a while, their biological effects remain to be fully elucidated. Recently, several studies have focused on the role of these PG-G or PG-EA in vivo. In this review we take a closer look at the literature concerning these novel bioactive lipids and their role in inflammation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Activation of endocannabinoid system in the rat basolateral amygdala improved scopolamine-induced memory consolidation impairment.

    PubMed

    Nedaei, Seyed Ershad; Rezayof, Ameneh; Pourmotabbed, Ali; Nasehi, Mohammad; Zarrindast, Mohammad-Reza

    2016-09-15

    The current study was designed to examine the involvement of cannabinoid CB1 receptors in the basolateral amygdala (BLA) in scopolamine-induced memory impairment in adult male Wistar rats. The animals were bilaterally implanted with the cannulas in the BLA and submitted to a step-through type passive avoidance task to measure the memory formation. The results showed that intraperitoneal (i.p.) administration of different doses of scopolamine (0.5-1.5mg/kg) immediately after the training phase (post-training) impaired memory consolidation. Bilateral microinjection of the cannabinoid CB1 receptor agonist, arachydonilcyclopropylamide (ACPA; 1-4ng/rat), into the BLA significantly improved scopolamine-induced memory consolidation impairment. On the other hand, co-administration of AM251, a cannabinoid CB1 receptor antagonist (0.25-1ng/rat, intra-BLA), with an ineffective dose of scopolamine (0.5mg/kg, i.p.), significantly impaired memory consolidation and mimicked the response of a higher dose of scopolamine. It is important to note that post-training intra-BLA microinjections of the same doses of ACPA or AM251 alone had no effect on memory consolidation. Moreover, the blockade of the BLA CB1 receptors by 0.3ng/rat of AM251 prevented ACPA-induced improvement of the scopolamine response. In view of the known actions of the drugs used, the present data pointed to the involvement of the BLA CB1 receptors in scopolamine-induced memory consolidation impairment. Furthermore, it seems that a functional interaction between the BLA endocannabinoid and cholinergic muscarinic systems may be critical for memory formation. Copyright © 2016. Published by Elsevier B.V.

  10. Endocannabinoids in liver disease and hepatic encephalopathy.

    PubMed

    Magen, Iddo; Avraham, Yosefa; Berry, Elliot; Mechoulam, Raphael

    2008-01-01

    Chronic liver disease results from a variety of causes such as hepatitis virus infections, autoimmune processes and alcohol consumption. Its complications include fat deposition, hemodynamic changes and fibrosis. Clinically there may be progression to portal-hypertension and porto-systemic encephalopathy. Pioneering research from the laboratory of Kunos at NIH has stressed the importance of endocannabinoids (ECs) as mediators of some of the pathological processes in chronic liver disease. The present review summarizes the literature on the association between ECs and liver disease, as well as the therapeutic potential of ECs and exogenous cannabinoids in liver disease with emphasis on hepatic encephalopathy.

  11. A Role for 2-Arachidonoylglycerol and Endocannabinoid Signaling in the Locomotor Response to Novelty Induced by Olfactory Bulbectomy

    PubMed Central

    Eisenstein, Sarah A.; Clapper, Joson R.; Holmes, Philip V.; Piomelli, Daniele; Hohmann, Andrea G.

    2010-01-01

    Bilateral olfactory bulbectomy (OBX) in rodents produces behavioral and neurochemical changes associated clinically with depression and schizophrenia. Most notably, OBX induces hyperlocomotion in response to the stress of exposure to a novel environment. We examined the role of the endocannabinoid system in regulating this locomotor response in OBX and sham-operated rats. In our study, OBX-induced hyperactivity was restricted to the first 3 min of the open field test, demonstrating the presence of novelty (0–3 min) and habituation (3–30 min) phases of the open field locomotor response. Levels of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide were decreased in the ventral striatum, a brain region deafferented by OBX, whereas cannabinoid receptor densities were unaltered. In sham-operated rats, 2-AG levels in the ventral striatum were negatively correlated with distance traveled during the novelty phase. Thus, low levels of 2-AG are reflected in a hyperactive open field response. This correlation was not observed in OBX rats. Conversely, 2-AG levels in endocannabinoid-compromised OBX rats correlated with distance traveled during the habituation phase. In OBX rats, pharmacological blockade of cannabinoid CB1 receptors with either AM251 (1 mg kg−1 i.p.) or rimonabant (1 mg kg−1 i.p.) increased distance traveled during the habituation phase. Thus, blockade of endocannabinoid signaling impairs habituation of the hyperlocomotor response in OBX, but not sham-operated, rats. By contrast, in sham-operated rats, effects of CB1 antagonism were restricted to the novelty phase. These findings suggest that dysregulation in the endocannabinoid system, and 2-AG in particular, is implicated in the hyperactive locomotor response induced by OBX. Our studies suggest that drugs that enhance 2-AG signaling, such as 2-AG degradation inhibitors, might be useful in human brain disorders modeled by OBX. PMID:20044005

  12. Neuronal and Astrocytic Monoacylglycerol Lipase Limit the Spread of Endocannabinoid Signaling in the Cerebellum.

    PubMed

    Chen, Yao; Liu, Xiaojie; Vickstrom, Casey R; Liu, Michelle J; Zhao, Li; Viader, Andreu; Cravatt, Benjamin F; Liu, Qing-Song

    2016-01-01

    Endocannabinoids are diffusible lipophilic molecules that may spread to neighboring synapses. Monoacylglycerol lipase (MAGL) is the principal enzyme that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG). Using knock-out mice in which MAGL is deleted globally or selectively in neurons and astrocytes, we investigated the extent to which neuronal and astrocytic MAGL limit the spread of 2-AG-mediated retrograde synaptic depression in cerebellar slices. A brief tetanic stimulation of parallel fibers in the molecular layer induced synaptically evoked suppression of excitation (SSE) in Purkinje cells, and both neuronal and astrocytic MAGL contribute to the termination of this form of endocannabinoid-mediated synaptic depression. The spread of SSE among Purkinje cells occurred only after global knock-out of MAGL or pharmacological blockade of either MAGL or glutamate uptake, but no spread was detected following neuron- or astrocyte-specific deletion of MAGL. The spread of endocannabinoid signaling was also influenced by the spatial pattern of synaptic stimulation, because it did not occur at spatially dispersed parallel fiber synapses induced by stimulating the granular layer. The tetanic stimulation of parallel fibers did not induce endocannabinoid-mediated synaptic suppression in Golgi cells even after disruption of MAGL and glutamate uptake, suggesting that heightened release of 2-AG by Purkinje cells does not spread the retrograde signal to parallel fibers that innervate Golgi cells. These results suggest that both neuronal and astrocytic MAGL limit the spatial diffusion of 2-AG and confer synapse-specificity of endocannabinoid signaling.

  13. Endocannabinoids concentrations in plasma associated with feed efficiency and carcass composition of beef steers

    USDA-ARS?s Scientific Manuscript database

    Endocannabinoids, including anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are a class of endogenous lipid mediators that activate cannabinoids receptors and may be involved in the control of feed intake and energy metabolism. The objective of this study was to quantify AEA and 2-AG in plasma a...

  14. Endocannabinoid concentrations in plasma associated with feed efficiency and carcass composition on crossbreed steers

    USDA-ARS?s Scientific Manuscript database

    Endocannabinoids, including anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are a class of endogenous lipid mediators that activate cannabinoids receptors and may be involved in the control of feed intake and energy metabolism. The objective of this study was to quantify AEA and 2-AG in plasma a...

  15. Dietary DHA reduced downstream endocannabinoid and inflammatory gene expression, epididymal fat mass, and improved aspects of glucose use in muscle in C57BL/6J mice

    USDA-ARS?s Scientific Manuscript database

    Objective: Endocannabinoid system (ECS) overactivation is associated with increased adiposity and likely contributes to type II diabetes risk. Elevated tissue cannabinoid receptor 1 (CB1) and circulating endocannabinoids derived from the n-6 polyunsaturated acid (PUFA) arachidonic acid occur in obes...

  16. The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review.

    PubMed

    Fowler, Christopher J

    2015-01-01

    The endocannabinoids anandamide and 2-arachidonoylglycerol are metabolised by both hydrolytic enzymes (primarily fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL)) and oxygenating enzymes (e.g. cyclooxygenase-2, COX-2). In the present article, the in vivo data for compounds inhibiting endocannabinoid metabolism have been reviewed, focussing on inflammation and pain. Potential reasons for the failure of an FAAH inhibitor in a clinical trial in patients with osteoarthritic pain are discussed. It is concluded that there is a continued potential for compounds inhibiting endocannabinoid metabolism in terms of drug development, but that it is wise not to be unrealistic in terms of expectations of success.

  17. Identification of endocannabinoid system-modulating N-alkylamides from Heliopsis helianthoides var. scabra and Lepidium meyenii.

    PubMed

    Hajdu, Zsanett; Nicolussi, Simon; Rau, Mark; Lorántfy, László; Forgo, Peter; Hohmann, Judit; Csupor, Dezső; Gertsch, Jürg

    2014-07-25

    The discovery of the interaction of plant-derived N-alkylamides (NAAs) and the mammalian endocannabinoid system (ECS) and the existence of a plant endogenous N-acylethanolamine signaling system have led to the re-evaluation of this group of compounds. Herein, the isolation of seven NAAs and the assessment of their effects on major protein targets in the ECS network are reported. Four NAAs, octadeca-2E,4E,8E,10Z,14Z-pentaene-12-ynoic acid isobutylamide (1), octadeca-2E,4E,8E,10Z,14Z-pentaene-12-ynoic acid 2'-methylbutylamide (2), hexadeca-2E,4E,9Z-triene-12,14-diynoic acid isobutylamide (3), and hexadeca-2E,4E,9,12-tetraenoic acid 2'-methylbutylamide (4), were identified from Heliopsis helianthoides var. scabra. Compounds 2-4 are new natural products, while 1 was isolated for the first time from this species. The previously described macamides, N-(3-methoxybenzyl)-(9Z,12Z,15Z)-octadecatrienamide (5), N-benzyl-(9Z,12Z,15Z)-octadecatrienamide (6), and N-benzyl-(9Z,12Z)-octadecadienamide (7), were isolated from Lepidium meyenii (Maca). N-Methylbutylamide 4 and N-benzylamide 7 showed submicromolar and selective binding affinities for the cannabinoid CB1 receptor (Ki values of 0.31 and 0.48 μM, respectively). Notably, compound 7 also exhibited weak fatty acid amide hydrolase (FAAH) inhibition (IC50 = 4 μM) and a potent inhibition of anandamide cellular uptake (IC50 = 0.67 μM) that was stronger than the inhibition obtained with the controls OMDM-2 and UCM707. The pronounced ECS polypharmacology of compound 7 highlights the potential involvement of the arachidonoyl-mimicking 9Z,12Z double-bond system in the linoleoyl group for the overall cannabimimetic action of NAAs. This study provides additional strong evidence of the endocannabinoid substrate mimicking of plant-derived NAAs and uncovers a direct and indirect cannabimimetic action of the Peruvian Maca root.

  18. Effects of the antipsychotic paliperidone on stress-induced changes in the endocannabinoid system in rat prefrontal cortex.

    PubMed

    MacDowell, Karina S; Sayd, Aline; García-Bueno, Borja; Caso, Javier R; Madrigal, José L M; Leza, Juan Carlos

    2017-09-01

    Objectives There is a need to explore novel mechanisms of action of existing/new antipsychotics. One potential candidate is the endocannabinoid system (ECS). The present study tried to elucidate the effects of the antipsychotic paliperidone on stress-induced ECS alterations. Methods Wister rats were submitted to acute/chronic restraint stress. Paliperidone (1 mg/kg) was given prior each stress session. Cannabinoid receptors and endocannabinoids (eCBs) synthesis and degradation enzymes were measured in prefrontal cortex (PFC) samples by RT-PCR and Western Blot. Results In the PFC of rats exposed to acute stress, paliperidone increased CB1 receptor (CB1R) expression. Furthermore, paliperidone increased the expression of the eCB synthesis enzymes N-acylphosphatidylethanolamine- hydrolysing phospholipase D and DAGLα, and blocked the stress-induced increased expression of the degrading enzyme fatty acid amide hydrolase. In chronic conditions, paliperidone prevented the chronic stress-induced down-regulation of CB1R, normalised DAGLα expression and reverted stress-induced down-regulation of the 2-AG degrading enzyme monoacylglycerol lipase. ECS was analysed also in periphery. Acute stress decreased DAGLα expression, an effect prevented by paliperidone. Contrarily, chronic stress increased DAGLα and this effect was potentiated by paliperidone. Conclusions The results obtained described a preventive effect of paliperidone on stress-induced alterations in ECS. Considering the diverse alterations on ECS described in psychotic disease, targeting ECS emerges as a new therapeutic possibility.

  19. Oxylipins, endocannabinoids, and related compounds in human milk: Levels and effects of storage conditions.

    PubMed

    Wu, Junfang; Gouveia-Figueira, Sandra; Domellöf, Magnus; Zivkovic, Angela M; Nording, Malin L

    2016-01-01

    The presence of fatty acid derived oxylipins, endocannabinoids and related compounds in human milk may be of importance to the infant. Presently, clinically relevant protocols for storing and handling human milk that minimize error and variability in oxylipin and endocannabinoid concentrations are lacking. In this study, we compared the individual and combined effects of the following storage conditions on the stability of these fatty acid metabolites in human milk: state (fresh or frozen), storage temperature (4 °C, -20 °C or -80 °C), and duration (1 day, 1 week or 3 months). Thirteen endocannabinoids and related compounds, as well as 37 oxylipins were analyzed simultaneously by liquid chromatography coupled to tandem mass spectrometry. Twelve endocannabinoids and related compounds (2-111 nM) and 31 oxylipins (1.2 pM-1242 nM) were detected, with highest levels being found for 2-arachidonoylglycerol and 17(R)hydroxydocosahexaenoic acid, respectively. The concentrations of most endocannabinoid-related compounds and oxylipins were dependent on storage condition, and especially storage at 4 °C introduced significant variability. Our findings suggest that human milk samples should be analyzed immediately after, or within one day of collection (if stored at 4 °C). Storage at -80 °C is required for long-term preservation, and storage at -20 °C is acceptable for no more than one week. These findings provide a protocol for investigating the oxylipin and endocannabinoid metabolome in human milk, useful for future milk-related clinical studies. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Rescue of Impaired mGluR5-Driven Endocannabinoid Signaling Restores Prefrontal Cortical Output to Inhibit Pain in Arthritic Rats.

    PubMed

    Kiritoshi, Takaki; Ji, Guangchen; Neugebauer, Volker

    2016-01-20

    The medial prefrontal cortex (mPFC) serves executive functions that are impaired in neuropsychiatric disorders and pain. Underlying mechanisms remain to be determined. Here we advance the novel concept that metabotropic glutamate receptor 5 (mGluR5) fails to engage endocannabinoid (2-AG) signaling to overcome abnormal synaptic inhibition in pain, but restoring endocannabinoid signaling allows mGluR5 to increase mPFC output hence inhibit pain behaviors and mitigate cognitive deficits. Whole-cell patch-clamp recordings were made from layer V pyramidal cells in the infralimbic mPFC in rat brain slices. Electrical and optogenetic stimulations were used to analyze amygdala-driven mPFC activity. A selective mGluR5 activator (VU0360172) increased pyramidal output through an endocannabinoid-dependent mechanism because intracellular inhibition of the major 2-AG synthesizing enzyme diacylglycerol lipase or blockade of CB1 receptors abolished the facilitatory effect of VU0360172. In an arthritis pain model mGluR5 activation failed to overcome abnormal synaptic inhibition and increase pyramidal output. mGluR5 function was rescued by restoring 2-AG-CB1 signaling with a CB1 agonist (ACEA) or inhibitors of postsynaptic 2-AG hydrolyzing enzyme ABHD6 (intracellular WWL70) and monoacylglycerol lipase MGL (JZL184) or by blocking GABAergic inhibition with intracellular picrotoxin. CB1-mediated depolarization-induced suppression of synaptic inhibition (DSI) was also impaired in the pain model but could be restored by coapplication of VU0360172 and ACEA. Stereotaxic coadministration of VU0360172 and ACEA into the infralimbic, but not anterior cingulate, cortex mitigated decision-making deficits and pain behaviors of arthritic animals. The results suggest that rescue of impaired endocannabinoid-dependent mGluR5 function in the mPFC can restore mPFC output and cognitive functions and inhibit pain. Significance statement: Dysfunctions in prefrontal cortical interactions with subcortical

  1. Modulation of the Endocannabinoid System: Vulnerability Factor and New Treatment Target for Stimulant Addiction

    PubMed Central

    Olière, Stéphanie; Jolette-Riopel, Antoine; Potvin, Stéphane; Jutras-Aswad, Didier

    2013-01-01

    Cannabis is one of the most widely used illicit substance among users of stimulants such as cocaine and amphetamines. Interestingly, increasing recent evidence points toward the involvement of the endocannabinoid system (ECBS) in the neurobiological processes related to stimulant addiction. This article presents an up-to-date review with deep insights into the pivotal role of the ECBS in the neurobiology of stimulant addiction and the effects of its modulation on addictive behaviors. This article aims to: (1) review the role of cannabis use and ECBS modulation in the neurobiological substrates of psychostimulant addiction and (2) evaluate the potential of cannabinoid-based pharmacological strategies to treat stimulant addiction. A growing number of studies support a critical role of the ECBS and its modulation by synthetic or natural cannabinoids in various neurobiological and behavioral aspects of stimulants addiction. Thus, cannabinoids modulate brain reward systems closely involved in stimulants addiction, and provide further evidence that the cannabinoid system could be explored as a potential drug discovery target for treating addiction across different classes of stimulants. PMID:24069004

  2. Multiple Forms of Endocannabinoid and Endovanilloid Signaling Regulate the Tonic Control of GABA Release

    PubMed Central

    Lee, Sang-Hun; Ledri, Marco; Tóth, Blanka; Marchionni, Ivan; Henstridge, Christopher M.; Dudok, Barna; Kenesei, Kata; Barna, László; Szabó, Szilárd I.; Renkecz, Tibor; Oberoi, Michelle; Watanabe, Masahiko; Limoli, Charles L.; Horvai, George; Soltesz, Ivan

    2015-01-01

    Persistent CB1 cannabinoid receptor activity limits neurotransmitter release at various synapses throughout the brain. However, it is not fully understood how constitutively active CB1 receptors, tonic endocannabinoid signaling, and its regulation by multiple serine hydrolases contribute to the synapse-specific calibration of neurotransmitter release probability. To address this question at perisomatic and dendritic GABAergic synapses in the mouse hippocampus, we used a combination of paired whole-cell patch-clamp recording, liquid chromatography/tandem mass spectrometry, stochastic optical reconstruction microscopy super-resolution imaging, and immunogold electron microscopy. Unexpectedly, application of the CB1 antagonist and inverse agonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide], but not the neutral antagonist NESS0327 [8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-5,6-dihydro-4H-benzo[2,3]cyclohepta[2,4-b]pyrazole-3-carboxamine], significantly increased synaptic transmission between CB1-positive perisomatic interneurons and CA1 pyramidal neurons. JZL184 (4-nitrophenyl 4-[bis(1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate), a selective inhibitor of monoacylglycerol lipase (MGL), the presynaptic degrading enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), elicited a robust increase in 2-AG levels and concomitantly decreased GABAergic transmission. In contrast, inhibition of fatty acid amide hydrolase (FAAH) by PF3845 (N-pyridin-3-yl-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide) elevated endocannabinoid/endovanilloid anandamide levels but did not change GABAergic synaptic activity. However, FAAH inhibitors attenuated tonic 2-AG increase and also decreased its synaptic effects. This antagonistic interaction required the activation of the transient receptor potential vanilloid receptor TRPV1, which was concentrated on postsynaptic

  3. The endocannabinoid system and Post Traumatic Stress Disorder (PTSD): From preclinical findings to innovative therapeutic approaches in clinical settings.

    PubMed

    Berardi, Andrea; Schelling, Gustav; Campolongo, Patrizia

    2016-09-01

    Post-Traumatic Stress Disorder (PTSD) is a psychiatric chronic disease developing in individuals after the experience of an intense and life-threatening traumatic event. The post-traumatic symptomatology encompasses alterations in memory processes, mood, anxiety and arousal. There is now consensus in considering the disease as an aberrant adaptation to traumatic stress. Pharmacological research, aimed at the discovery of new potential effective treatments, has lately directed its attention towards the "so-called" cognitive enhancers. This class of substances, by modulating cognitive processes involved in the development and/or persistence of the post-traumatic symptomatology, could be of great help in improving the outcome of psychotherapies and patients' prognosis. In this perspective, drugs acting on the endocannabinoid system are receiving great attention due to their dual ability to modulate memory processes on one hand, and to reduce anxiety and depression on the other. The purpose of the present review is to offer a thorough overview of both animal and human studies investigating the effects of cannabinoids on memory processes. First, we will briefly describe the characteristics of the endocannabinoid system and the most commonly used animal models of learning and memory. Then, studies investigating cannabinoid modulatory influences on memory consolidation, retrieval and extinction will be separately presented, and the potential benefits associated with each approach will be discussed. In the final section, we will review literature data reporting beneficial effects of cannabinoid drugs in PTSD patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes.

    PubMed

    Russo, Ethan B

    2016-01-01

    Medicine continues to struggle in its approaches to numerous common subjective pain syndromes that lack objective signs and remain treatment resistant. Foremost among these are migraine, fibromyalgia, and irritable bowel syndrome, disorders that may overlap in their affected populations and whose sufferers have all endured the stigma of a psychosomatic label, as well as the failure of endless pharmacotherapeutic interventions with substandard benefit. The commonality in symptomatology in these conditions displaying hyperalgesia and central sensitization with possible common underlying pathophysiology suggests that a clinical endocannabinoid deficiency might characterize their origin. Its base hypothesis is that all humans have an underlying endocannabinoid tone that is a reflection of levels of the endocannabinoids, anandamide (arachidonylethanolamide), and 2-arachidonoylglycerol, their production, metabolism, and the relative abundance and state of cannabinoid receptors. Its theory is that in certain conditions, whether congenital or acquired, endocannabinoid tone becomes deficient and productive of pathophysiological syndromes. When first proposed in 2001 and subsequently, this theory was based on genetic overlap and comorbidity, patterns of symptomatology that could be mediated by the endocannabinoid system (ECS), and the fact that exogenous cannabinoid treatment frequently provided symptomatic benefit. However, objective proof and formal clinical trial data were lacking. Currently, however, statistically significant differences in cerebrospinal fluid anandamide levels have been documented in migraineurs, and advanced imaging studies have demonstrated ECS hypofunction in post-traumatic stress disorder. Additional studies have provided a firmer foundation for the theory, while clinical data have also produced evidence for decreased pain, improved sleep, and other benefits to cannabinoid treatment and adjunctive lifestyle approaches affecting the ECS.

  5. Dose-Specific Effects of Di-Isononyl Phthalate on the Endocannabinoid System and on Liver of Female Zebrafish.

    PubMed

    Forner-Piquer, Isabel; Maradonna, Francesca; Gioacchini, Giorgia; Santangeli, Stefania; Allarà, Marco; Piscitelli, Fabiana; Habibi, Hamid R; Di Marzo, Vincenzo; Carnevali, Oliana

    2017-10-01

    Phthalates, used as plasticizers, have become a ubiquitous contaminant and have been reported for their potential to induce toxicity in living organisms. Among them, di-isononyl phthalate (DiNP) has been recently used to replace di(2-ethylhexyl) phthalate (DEHP). Nowadays, there is evidence that DiNP is an endocrine-disrupting chemical; however, little is known about its effects on the endocannabinoid system (ECS) and lipid metabolism. Hence, the aim of our study was to investigate the effects of DiNP on the ECS in zebrafish liver and brain and on hepatic lipid storage. To do so, adult female zebrafish were exposed to three concentrations (0.42 µg/L, 4.2 µg/L, and 42 µg/L) of DiNP via water for 3 weeks. Afterwards, we investigated transcript levels for genes involved in the ECS of the brain and liver as well as liver histology and image analysis, Fourier-transform infrared spectroscopy imaging, and measurement of endocannabinoid levels. Our results demonstrate that DiNP upregulates orexigenic signals and causes hepatosteatosis together with deregulation of the peripheral ECS and lipid metabolism. A decrease in the levels of ECS components at the central level was observed after exposure to the highest DiNP concentration tested. These findings suggest that replacement of DEHP with DiNP should be considered with caution because of observed adverse DiNP effects on aquatic organisms. Copyright © 2017 Endocrine Society.

  6. Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo

    PubMed Central

    Long, Jonathan Z.; Nomura, Daniel K.; Vann, Robert E.; Walentiny, D. Matthew; Booker, Lamont; Jin, Xin; Burston, James J.; Sim-Selley, Laura J.; Lichtman, Aron H.; Wiley, Jenny L.; Cravatt, Benjamin F.

    2009-01-01

    Δ9-Tetrahydrocannabinol (THC), the psychoactive component of marijuana, and other direct cannabinoid receptor (CB1) agonists produce a number of neurobehavioral effects in mammals that range from the beneficial (analgesia) to the untoward (abuse potential). Why, however, this full spectrum of activities is not observed upon pharmacological inhibition or genetic deletion of either fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), enzymes that regulate the two major endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively, has remained unclear. Here, we describe a selective and efficacious dual FAAH/MAGL inhibitor, JZL195, and show that this agent exhibits broad activity in the tetrad test for CB1 agonism, causing analgesia, hypomotilty, and catalepsy. Comparison of JZL195 to specific FAAH and MAGL inhibitors identified behavioral processes that were regulated by a single endocannabinoid pathway (e.g., hypomotility by the 2-AG/MAGL pathway) and, interestingly, those where disruption of both FAAH and MAGL produced additive effects that were reversed by a CB1 antagonist. Falling into this latter category was drug discrimination behavior, where dual FAAH/MAGL blockade, but not disruption of either FAAH or MAGL alone, produced THC-like responses that were reversed by a CB1 antagonist. These data indicate that AEA and 2-AG signaling pathways interact to regulate specific behavioral processes in vivo, including those relevant to drug abuse, thus providing a potential mechanistic basis for the distinct pharmacological profiles of direct CB1 agonists and inhibitors of individual endocannabinoid degradative enzymes. PMID:19918051

  7. Responses of peripheral endocannabinoids and endocannabinoid-related compounds to hedonic eating in obesity.

    PubMed

    Monteleone, A M; Di Marzo, V; Monteleone, P; Dalle Grave, R; Aveta, T; Ghoch, M El; Piscitelli, F; Volpe, U; Calugi, S; Maj, M

    2016-06-01

    Hedonic eating occurs independently from homeostatic needs prompting the ingestion of pleasurable foods that are typically rich in fat, sugar and/or salt content. In normal weight healthy subjects, we found that before hedonic eating, plasma levels of 2-arachidonoylglycerol (2-AG) were higher than before nonhedonic eating, and although they progressively decreased after food ingestion in both eating conditions, they were significantly higher in hedonic eating. Plasma levels of anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), instead, progressively decreased in both eating conditions without significant differences. In this study, we investigated the responses of AEA, 2-AG, OEA and PEA to hedonic eating in obese individuals. Peripheral levels of AEA, 2-AG, OEA and PEA were measured in 14 obese patients after eating favourite (hedonic eating) and non-favourite (nonhedonic eating) foods in conditions of no homeostatic needs. Plasma levels of 2-AG increased after eating the favourite food, whereas they decreased after eating the non-favourite food, with the production of the endocannabinoid being significantly enhanced in hedonic eating. Plasma levels of AEA decreased progressively in nonhedonic eating, whereas they showed a decrease after the exposure to the favourite food followed by a return to baseline values after eating it. No significant differences emerged in plasma OEA and PEA responses to favourite and non-favourite food. Present findings compared with those obtained in our previously studied normal weight healthy subjects suggest deranged responses of endocannabinoids to food-related reward in obesity.

  8. Dissociating the role of endocannabinoids in the pleasurable and motivational properties of social play behaviour in rats.

    PubMed

    Achterberg, E J Marijke; van Swieten, Maaike M H; Driel, Nina V; Trezza, Viviana; Vanderschuren, Louk J M J

    2016-08-01

    Social play behaviour is a vigorous form of social interaction, abundant during the juvenile and adolescent phases of life in many mammalian species, including humans. Social play is highly rewarding and it is important for social and cognitive development. Being a rewarding activity, social play can be dissociated in its pleasurable and motivational components. We have previously shown that endocannabinoids modulate the expression of social play behaviour in rats. In the present study, we investigated whether endocannabinoids modulate the motivational and pleasurable properties of social play behaviour, using operant and place conditioning paradigms, respectively. Treatment with the anandamide hydrolysis inhibitor URB597 did not affect operant responding or social play-induced conditioned place preference (CPP) when administered at a dose (0.1mg/kg) known to increase the expression of social play behaviour, while it modestly reduced operant responding at a higher dose (0.2mg/kg). The cannabinoid-1 (CB1) receptor antagonist rimonabant reduced operant responding when administered at a dose (1mg/kg) known to decrease the expression of social play behaviour, although this effect may be secondary to concurrent drug-induced stereotypic behaviours (i.e., grooming and scratching). These data demonstrate that enhancing endocannabinoid levels does not differentially affect the motivational and pleasurable aspects of social play behaviour, whereas CB1 receptor blockade reduces the motivational aspects of social play behaviour, possibly due to response competition. Thus, endocannabinoids likely drive the expression of social play behaviour as a whole, without differentially affecting its motivational or pleasurable properties. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Endocannabinoid Release Modulates Electrical Coupling between CCK Cells Connected via Chemical and Electrical Synapses in CA1

    PubMed Central

    Iball, Jonathan; Ali, Afia B.

    2011-01-01

    Electrical coupling between some subclasses of interneurons is thought to promote coordinated firing that generates rhythmic synchronous activity in cortical regions. Synaptic activity of cholecystokinin (CCK) interneurons which co-express cannabinoid type-1 (CB1) receptors are powerful modulators of network activity via the actions of endocannabinoids. We investigated the modulatory actions of endocannabinoids between chemically and electrically connected synapses of CCK cells using paired whole-cell recordings combined with biocytin and double immunofluorescence labeling in acute slices of rat hippocampus at P18–20 days. CA1 stratum radiatum CCK Schaffer collateral-associated cells were coupled electrically with each other as well as CCK basket cells and CCK cells with axonal projections expanding to dentate gyrus. Approximately 50% of electrically coupled cells received facilitating, asynchronously released inhibitory postsynaptic potential (IPSPs) that curtailed the steady-state coupling coefficient by 57%. Tonic CB1 receptor activity which reduces inhibition enhanced electrical coupling between cells that were connected via chemical and electrical synapses. Blocking CB1 receptors with antagonist, AM-251 (5 μM) resulted in the synchronized release of larger IPSPs and this enhanced inhibition further reduced the steady-state coupling coefficient by 85%. Depolarization induced suppression of inhibition (DSI), maintained the asynchronicity of IPSP latency, but reduced IPSP amplitudes by 95% and enhanced the steady-state coupling coefficient by 104% and IPSP duration by 200%. However, DSI did not did not enhance electrical coupling at purely electrical synapses. These data suggest that different morphological subclasses of CCK interneurons are interconnected via gap junctions. The synergy between the chemical and electrical coupling between CCK cells probably plays a role in activity-dependent endocannabinoid modulation of rhythmic synchronization. PMID

  10. A role for the endocannabinoid 2-arachidonoyl-sn-glycerol for social and high-fat food reward in male mice.

    PubMed

    Wei, Don; Lee, DaYeon; Li, Dandan; Daglian, Jennifer; Jung, Kwang-Mook; Piomelli, Daniele

    2016-05-01

    The endocannabinoid system is an important modulator of brain reward signaling. Investigations have focused on cannabinoid (CB1) receptors, because dissection of specific contributions of individual endocannabinoids has been limited by the available toolset. While we recently described an important role for the endocannabinoid anandamide in the regulation of social reward, it remains to be determined whether the other major endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG), serves a similar or different function. To study the role of 2-AG in natural reward, we used a transgenic mouse model (MGL-Tg mice) in which forebrain 2-AG levels are selectively reduced. We complemented behavioral analysis with measurements of brain 2-AG levels. We tested male MGL-Tg mice in conditioned place preference (CPP) tasks for high-fat food, social contact, and cocaine. We measured 2-AG content in the brain regions of interest by liquid chromatography/mass spectrometry. Male MGL-Tg mice are impaired in developing CPP for high-fat food and social interaction, but do develop CPP for cocaine. Furthermore, compared to isolated mice, levels of 2-AG in socially stimulated wild-type mice are higher in the nucleus accumbens and ventral hippocampus (183 and 140 % of controls, respectively), but unchanged in the medial prefrontal cortex. The results suggest that reducing 2-AG-mediated endocannabinoid signaling impairs social and high-fat food reward in male mice, and that social stimulation mobilizes 2-AG in key brain regions implicated in the control of motivated behavior. The time course of this response differentiates 2-AG from anandamide, whose role in mediating social reward was previously documented.

  11. The endocannabinoid gene faah2a modulates stress-associated behavior in zebrafish

    PubMed Central

    Lee, Han B.; El Khoury, Louis Y.; Sigafoos, Ashley N.; Petersen, Morgan O.; Clark, Karl J.

    2018-01-01

    The ability to orchestrate appropriate physiological and behavioral responses to stress is important for survival, and is often dysfunctional in neuropsychiatric disorders that account for leading causes of global disability burden. Numerous studies have shown that the endocannabinoid neurotransmitter system is able to regulate stress responses and could serve as a therapeutic target for the management of these disorders. We used quantitative reverse transcriptase-polymerase chain reactions to show that genes encoding enzymes that synthesize (abhd4, gde1, napepld), enzymes that degrade (faah, faah2a, faah2b), and receptors that bind (cnr1, cnr2, gpr55-like) endocannabinoids are expressed in zebrafish (Danio rerio). These genes are conserved in many other vertebrates, including humans, but fatty acid amide hydrolase 2 has been lost in mice and rats. We engineered transcription activator-like effector nucleases to create zebrafish with mutations in cnr1 and faah2a to test the role of these genes in modulating stress-associated behavior. We showed that disruption of cnr1 potentiated locomotor responses to hyperosmotic stress. The increased response to stress was consistent with rodent literature and served to validate the use of zebrafish in this field. Moreover, we showed for the first time that disruption of faah2a attenuated the locomotor responses to hyperosmotic stress. This later finding suggests that FAAH2 may be an important mediator of stress responses in non-rodent vertebrates. Accordingly, FAAH and FAAH2 modulators could provide distinct therapeutic options for stress-aggravated disorders. PMID:29304078

  12. Changes in the Brain Endocannabinoid System in Rat Models of Depression.

    PubMed

    Smaga, Irena; Jastrzębska, Joanna; Zaniewska, Magdalena; Bystrowska, Beata; Gawliński, Dawid; Faron-Górecka, Agata; Broniowska, Żaneta; Miszkiel, Joanna; Filip, Małgorzata

    2017-04-01

    A growing body of evidence implicates the endocannabinoid (eCB) system in the pathophysiology of depression. The aim of this study was to investigate the influence of changes in the eCB system, such as levels of neuromodulators, eCB synthesizing and degrading enzymes, and cannabinoid (CB) receptors, in different brain structures in animal models of depression using behavioral and biochemical analyses. Both models used, i.e., bulbectomized (OBX) and Wistar Kyoto (WKY) rats, were characterized at the behavioral level by increased immobility time. In the OBX rats, anandamide (AEA) levels were decreased in the prefrontal cortex, hippocampus, and striatum and increased in the nucleus accumbens, while 2-arachidonoylglycerol (2-AG) levels were increased in the prefrontal cortex and decreased in the nucleus accumbens with parallel changes in the expression of eCB metabolizing enzymes in several structures. It was also observed that CB 1 receptor expression decreased in the hippocampus, dorsal striatum, and nucleus accumbens, and CB 2 receptor expression decreased in the prefrontal cortex and hippocampus. In WKY rats, the levels of eCBs were reduced in the prefrontal cortex (2-AG) and dorsal striatum (AEA) and increased in the prefrontal cortex (AEA) with different changes in the expression of eCB metabolizing enzymes, while the CB 1 receptor density was increased in several brain regions. These findings suggest that dysregulation in the eCB system is implicated in the pathogenesis of depression, although neurochemical changes were linked to the particular brain structure and the factor inducing depression (surgical removal of the olfactory bulbs vs. genetic modulation).

  13. Endocannabinoids as biomarkers of human reproduction.

    PubMed

    Rapino, Cinzia; Battista, Natalia; Bari, Monica; Maccarrone, Mauro

    2014-01-01

    Infertility is a condition of the reproductive system that affects ∼10-15% of couples attempting to conceive a baby. More than half of all cases of infertility are a result of female conditions, while the remaining cases can be attributed to male factors, or to a combination of both. The search for suitable biomarkers of pregnancy outcome is a challenging issue in human reproduction, aimed at identifying molecules with predictive significance of the reproductive potential of male and female gametes. Among the various candidates, endocannabinoids (eCBs), and in particular anandamide (AEA), represent potential biomarkers of human fertility disturbances. Any perturbation of the balance between synthesis and degradation of eCBs will result in local changes of their tone in human female and male reproductive tracts, which in turn regulates various pathophysiological processes, oocyte and sperm maturation included. PubMed and Web of Science databases were searched for papers using relevant keywords like 'biomarker', 'endocannabinoid', 'infertility', 'pregnancy' and 'reproduction'. In this review, we discuss different studies on the measurements of AEA and related eCBs in human reproductive cells, tissues and fluids, where the local contribution of these bioactive lipids could be critical in ensuring normal sperm fertilizing ability and pregnancy. Based on the available data, we suggest that the AEA tone has the potential to be exploited as a novel diagnostic biomarker of infertility, to be used in association with assays of conventional hormones (e.g. progesterone, β-chorionic gonadotrophin) and semen analysis. However further quantitative research of its predictive capacity is required. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. The thrifty lipids: Endocannabinoids and the neural control of energy conservation

    PubMed Central

    DiPatrizio, Nicholas V.; Piomelli, Daniele

    2013-01-01

    The “thrifty gene hypothesis” posits that evolution preferentially selects physiological mechanisms that optimize energy storage to increase survival under alternating conditions of abundance and scarcity of food. Recent experiments suggest that endocannabinoids – a class of lipid-derived mediators that activate cannabinoid receptors in many cells of the body – are key agents of energy conservation. The new evidence indicates that these compounds increase energy intake and decrease energy expenditure by controlling the activity of peripheral and central neural pathways involved in the sensing and hedonic processing of sweet and fatty foods, as well as in the storage of their energy content for future use. PMID:22622030

  15. Neuroscience. Stout guards of the central nervous system.

    PubMed

    Mechoulam, R; Lichtman, A H

    2003-10-03

    Endocannabinoids have paradoxical effects on the mammalian nervous system: Sometimes they block neuronal excitability and other times they augment it. In their Perspective, Mechoulam and Lichtman discuss new work (Marsicano et al.) showing that activation of the cannabinoid receptor CB1 by the endocannabinoid anandamide protects against excitotoxic damage in a mouse model of kainic acid-induced epilepsy.

  16. Involvement of the endocannabinoid system in the physiological response to transient common carotid artery occlusion and reperfusion.

    PubMed

    Quartu, Marina; Poddighe, Laura; Melis, Tiziana; Serra, Maria Pina; Boi, Marianna; Lisai, Sara; Carta, Gianfranca; Murru, Elisabetta; Muredda, Laura; Collu, Maria; Banni, Sebastiano

    2017-01-19

    The transient global cerebral hypoperfusion/reperfusion achieved by induction of Bilateral Common Carotid Artery Occlusion followed by Reperfusion (BCCAO/R) may trigger a physiological response in an attempt to preserve tissue and function integrity. There are several candidate molecules among which the endocannabinoid system (ECS) and/or peroxisome-proliferator activated receptor-alpha (PPAR-alpha) may play a role in modulating oxidative stress and inflammation. The aims of the present study are to evaluate whether the ECS, the enzyme cyclooxygenase-2 (COX-2) and PPAR-alpha are involved during BCCAO/R in rat brain, and to identify possible markers of the ongoing BCCAO/R-induced challenge in plasma. Adult Wistar rats underwent BCCAO/R with 30 min hypoperfusion followed by 60 min reperfusion. The frontal and temporal-occipital cortices and plasma were analyzed by high performance liquid chromatography-mass spectrometry (HPLC-MS) to determine concentrations of endocannabinoids (eCBs) and related molecules behaving as ligands of PPAR-alpha, and of oxidative-stress markers such as lipoperoxides, while Western Blot and immunohistochemistry were used to study protein expression of cannabinoid receptors, COX-2 and PPAR-alpha. Unpaired Student's t-test was used to evaluate statistical differences between groups. The acute BCCAO/R procedure is followed by increased brain tissue levels of the eCBs 2-arachidonoylglycerol and anandamide, palmitoylethanolamide, an avid ligand of PPAR-alpha, lipoperoxides, type 1 (CB1) and type 2 (CB2) cannabinoid receptors, and COX-2, and decreased brain tissue concentrations of docosahexaenoic acid (DHA), one of the major targets of lipid peroxidation. In plasma, increased levels of anandamide and lipoperoxides were observed. The BCCAO/R stimulated early molecular changes that can be easily traced in brain tissue and plasma, and that are indicative of the tissue physiological response to the reperfusion-induced oxidative stress and

  17. DIFFERENTIAL EFFECTS OF SINGLE VERSUS REPEATED ALCOHOL WITHDRAWAL ON THE EXPRESSION OF ENDOCANNABINOID SYSTEM-RELATED GENES IN THE RAT AMYGDALA

    PubMed Central

    Serrano, Antonia; Rivera, Patricia; Pavon, Francisco J.; Decara, Juan; Suárez, Juan; de Fonseca, Fernando Rodriguez; Parsons, Loren H.

    2011-01-01

    Background Endogenous cannabinoids such as anandamide and 2-arachidonoylglycerol (2-AG) exert important regulatory influences on neuronal signaling, participate in short- and long-term forms of neuroplasticity, and modulate stress responses and affective behavior in part through the modulation of neurotransmission in the amygdala. Alcohol consumption alters brain endocannabinoid levels, and alcohol dependence is associated with dysregulated amygdalar function, stress responsivity and affective control. Methods The consequence of long-term alcohol consumption on the expression of genes related to endocannabinoid signaling was investigated using quantitative RT-PCR analyses of amygdala tissue. Two groups of ethanol-exposed rats were generated by maintenance on an ethanol liquid diet (10%): one group received continuous access to ethanol for 15 days, while the second group was given intermittent access to the ethanol diet (5 days/week for 3 weeks). Control subjects were maintained on an isocaloric ethanol-free liquid diet. To provide an initial profile of acute withdrawal amygdala tissue was harvested following either 6 or 24 hours of ethanol withdrawal. Results Acute ethanol withdrawal was associated with significant changes in mRNA expression for various components of the endogenous cannabinoid system in the amygdala. Specifically, reductions in mRNA expression for the primary clearance routes for anandamide and 2-AG (FAAH and MAGL, respectively) were evident, as were reductions in mRNA expression for CB1, CB2 and GPR55 receptors. Although similar alterations in FAAH mRNA were evident following either continuous or intermittent ethanol exposure, alterations in MAGL and cannabinoid receptor-related mRNA (e.g. CB1, CB2, GPR55) were more pronounced following intermittent exposure. In general, greater withdrawal-associated deficits in mRNA expression were evident following 24 versus 6 hours of withdrawal. No significant changes in mRNA expression for enzymes involved in

  18. Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome.

    PubMed

    Knani, Ibrahim; Earley, Brian J; Udi, Shiran; Nemirovski, Alina; Hadar, Rivka; Gammal, Asaad; Cinar, Resat; Hirsch, Harry J; Pollak, Yehuda; Gross, Itai; Eldar-Geva, Talia; Reyes-Capo, Daniela P; Han, Joan C; Haqq, Andrea M; Gross-Tsur, Varda; Wevrick, Rachel; Tam, Joseph

    2016-12-01

    Extreme obesity is a core phenotypic feature of Prader-Willi syndrome (PWS). Among numerous metabolic regulators, the endocannabinoid (eCB) system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB 1 R) blockade reverses obesity both in animals and humans. The first-in-class CB 1 R antagonist rimonabant proved effective in inducing weight loss in adults with PWS. However, it is no longer available for clinical use because of its centrally mediated, neuropsychiatric, adverse effects. We studied eCB 'tone' in individuals with PWS and in the Magel2 -null mouse model that recapitulates the major metabolic phenotypes of PWS and determined the efficacy of a peripherally restricted CB 1 R antagonist, JD5037 in treating obesity in these mice. Individuals with PWS had elevated circulating levels of 2-arachidonoylglycerol and its endogenous precursor and breakdown ligand, arachidonic acid. Increased hypothalamic eCB 'tone', manifested by increased eCBs and upregulated CB 1 R, was associated with increased fat mass, reduced energy expenditure, and decreased voluntary activity in Magel2 -null mice. Daily chronic treatment of obese Magel2 -null mice and their littermate wild-type controls with JD5037 (3 mg/kg/d for 28 days) reduced body weight, reversed hyperphagia, and improved metabolic parameters related to their obese phenotype. Dysregulation of the eCB/CB 1 R system may contribute to hyperphagia and obesity in Magel2 -null mice and in individuals with PWS. Our results demonstrate that treatment with peripherally restricted CB 1 R antagonists may be an effective strategy for the management of severe obesity in PWS.

  19. A diet containing a nonfat dry milk matrix significantly alters systemic endocannabinoids and oxylipins in diet-induced obese mice

    USDA-ARS?s Scientific Manuscript database

    BACKGROUND: Diets rich in dairy and/or calcium (Ca) have been associated with reductions in adiposity and inflammation, but the mechanisms underlying this remain to be fully elucidated. Oxylipins and endocannabinoids are bioactive lipids, which influence energy homeostasis, adipose function, insuli...

  20. Consequences of early life stress on the expression of endocannabinoid-related genes in the rat brain.

    PubMed

    Marco, Eva M; Echeverry-Alzate, Victor; López-Moreno, Jose Antonio; Giné, Elena; Peñasco, Sara; Viveros, Maria Paz

    2014-09-01

    The endocannabinoid system is involved in several physiological and pathological states including anxiety, depression, addiction and other neuropsychiatric disorders. Evidence from human and rodent studies suggests that exposure to early life stress may increase the risk of psychopathology later in life. Indeed, maternal deprivation (MD) (24 h at postnatal day 9) in rats induces behavioural alterations associated with depressive-like and psychotic-like symptoms, as well as important changes in the endocannabinoid system. As most neuropsychiatric disorders first appear at adolescence, and show remarkable sexual dimorphisms in their prevalence and severity, in the present study, we analysed the gene expression of the main components of the brain cannabinoid system in adolescent (postnatal day 46) Wistar male and female rats reared under standard conditions or exposed to MD. For this, we analysed, by real-time quantitative PCR, the expression of genes encoding for CB1 and CB2 receptors, TRPV1 and GPR55 (Cnr1, Cnr2a, Cnr2b, Trpv1, and Gpr55), for the major enzymes of synthesis, N-acyl phosphatidyl-ethanolamine phospholipase D (NAPE-PLD) and diacylglycerol lipase (DAGL) (Nape-pld, Dagla and Daglb), and degradation, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) (Faah, Magl and Cox-2), in specific brain regions, that is, the frontal cortex, ventral and dorsal striatum, dorsal hippocampus and amygdala. In males, MD increased the genetic expression of all the genes studied within the frontal cortex, whereas in females such an increase was observed only in the hippocampus. In conclusion, the endocannabinoid system is sensitive to early life stress at the gene expression level in a sex-dependent and region-dependent manner, and these changes are already evident in the adolescent brain.

  1. Association study between alcoholism and endocannabinoid metabolic enzyme genes encoding fatty acid amide hydrolase and monoglyceride lipase in a Japanese population.

    PubMed

    Iwasaki, Shinya; Ishiguro, Hiroki; Higuchi, Susumu; Onaivi, Emmanuel S; Arinami, Tadao

    2007-08-01

    Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGLL) are the major endocannabinoid metabolic enzymes. Owing to the importance of endocannabinoid system in addiction, the Pro129Thr polymorphism in the FAAH gene has reportedly been associated with substance abuse and dependence in a Caucasian population. To determine whether the single nucleodtide polymorphisms of the FAAH and MGLL genes are associated with alcoholism in a Japanese population. We conducted case-control studies for total 14 tag single nucleotide polymorphisms in those two genes using Japanese 729 patients with alcoholism and 799 healthy controls. Genotype and allele frequencies were compared between these groups. None of these genetic markers, however, showed significant association with alcoholism in Japanese. Whereas we examined associations in a larger sample size between alcoholism and tag single nucleotide polymorphisms that covered most regions of these endocannabinoid metabolic enzyme genes, we found that these are not associated with susceptibility to alcoholism in a Japanese population.

  2. Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids

    PubMed Central

    Covey, Dan P.; Bunner, Kendra D.; Schuweiler, Douglas R.; Cheer, Joseph F.; Garris, Paul A.

    2018-01-01

    The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement

  3. Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids.

    PubMed

    Covey, Dan P; Bunner, Kendra D; Schuweiler, Douglas R; Cheer, Joseph F; Garris, Paul A

    2016-06-01

    The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement

  4. Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids

    PubMed Central

    Gunduz-Cinar, Ozge; Flynn, Shaun; Brockway, Emma; Kaugars, Katherine; Baldi, Rita; Ramikie, Teniel S; Cinar, Resat; Kunos, George; Patel, Sachin; Holmes, Andrew

    2016-01-01

    Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1 receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders. PMID:26514583

  5. Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids.

    PubMed

    Gunduz-Cinar, Ozge; Flynn, Shaun; Brockway, Emma; Kaugars, Katherine; Baldi, Rita; Ramikie, Teniel S; Cinar, Resat; Kunos, George; Patel, Sachin; Holmes, Andrew

    2016-05-01

    Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1 receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders.

  6. The Endocannabinoid System Tonically Regulates Inhibitory Transmission and Depresses the Effect of Ethanol in Central Amygdala

    PubMed Central

    Roberto, Marisa; Cruz, Maureen; Bajo, Michal; Siggins, George R; Parsons, Loren H; Schweitzer, Paul

    2010-01-01

    The central amygdala (CeA) has a major role in alcohol dependence and reinforcement, and behavioral and neurochemical evidence suggests a role for the endocannabinoid (eCB) system in ethanol binging and dependence. We used a slice preparation to investigate the physiological role of cannabinoids and their interaction with ethanol on inhibitory synaptic transmission in CeA. Superfusion of the cannabinoid receptor (CB1) agonist WIN55212-2 (WIN2) onto CeA neurons decreased evoked GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs) in a concentration-dependent manner, an effect prevented by the CB1 antagonists Rimonabant (SR141716, SR1) and AM251. SR1 or AM251 applied alone augmented IPSPs, revealing a tonic eCB activity that decreased inhibitory transmission in CeA. Paired-pulse analysis suggested a presynaptic CB1 mechanism. Intracellular BAPTA abolished the ability of AM251 to augment IPSPs, demonstrating the eCB-driven nature and postsynaptic origin of the tonic CB1-dependent control of GABA release. Superfusion of ethanol increased IPSPs and addition of WIN2 reversed the ethanol effect. Similarly, previous superfusion of WIN2 prevented subsequent ethanol effects on GABAergic transmission. The ethanol-induced augmentation of IPSPs was additive to CB1 blockade, ruling out a participation of CB1 in the action of acute ethanol. Our study points to an important role of CB1 in CeA in which the eCBs tonically regulate neuronal activity, and suggests a potent mechanism for modulating CeA tone during challenge with ethanol. PMID:20463657

  7. The Role of Endocannabinoid Signaling in Cortical Inhibitory Neuron Dysfunction in Schizophrenia

    PubMed Central

    Volk, David W.; Lewis, David A.

    2015-01-01

    Cannabis use has been reported to increase the risk of developing schizophrenia and to worsen symptoms of the illness. Both of these outcomes might be attributable to the disruption by cannabis of the endogenous cannabinoid system's spatiotemporal regulation of the inhibitory circuitry in the prefrontal cortex that is essential for core cognitive processes, such as working memory, which are impaired in schizophrenia. In the healthy brain, the endocannabinoid 2-arachidonylglycerol (2-AG) is 1) synthesized by diacylglycerol lipase in pyramidal neurons; 2) travels retrogradely to nearby inhibitory axon terminals that express the primary cannabinoid receptor CB1R; 3) binds to CB1R which inhibits GABA release from the cholecystokinin-containing population of interneurons; and 4) is metabolized by either monoglyceride lipase, which is located in the inhibitory axon terminal, or by α-β-hydrolase domain 6, which is co-localized presynaptically with diacylglycerol lipase. Investigations of the endogenous cannabinoid system in the prefrontal cortex of subjects with schizophrenia have found evidence of higher metabolism of 2-AG, as well as both greater CB1R receptor binding and lower levels of CB1R mRNA and protein. Current views on the potential pathogenesis of these alterations, including disturbances in the development of the endogenous cannabinoid system, are discussed. In addition, how interactions between these alterations in the endocannabinoid system and those in other inhibitory neurons in the prefrontal cortex in subjects with schizophrenia might increase the liability to adverse outcomes with cannabis use is considered. PMID:26210060

  8. Is lipid signaling through cannabinoid 2 receptors part of a protective system?

    PubMed Central

    Pacher, P.; Mechoulam, R.

    2011-01-01

    The mammalian body has a highly developed immune system which guards against continuous invading protein attacks and aims at preventing, attenuating or repairing the inflicted damage. It is conceivable that through evolution analogous biological protective systems have been evolved against non-protein attacks. There is emerging evidence that lipid endocannabinoid signaling through cannabinoid 2 (CB2) receptors may represent an example/part of such a protective system/armamentarium. Inflammation/tissue injury triggers rapid elevations in local endocannabinoid levels, which in turn regulate signaling responses in immune and other cells modulating their critical functions. Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans, ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, auto-immune, lung disorders to pain and cancer, and modulating CB2 receptor activity holds tremendous therapeutic potential in these pathologies. While CB2 receptor activation in general mediates immunosuppressive effects, which limit inflammation and associated tissue injury in large number of pathological conditions, in some disease states activation of the CB2 receptor may enhance or even trigger tissue damage, which will also be discussed alongside the protective actions of the CB2 receptor stimulation with endocannabinoids or synthetic agonists, and the possible biological mechanisms involved in these effects. PMID:21295074

  9. Is lipid signaling through cannabinoid 2 receptors part of a protective system?

    PubMed

    Pacher, P; Mechoulam, R

    2011-04-01

    The mammalian body has a highly developed immune system which guards against continuous invading protein attacks and aims at preventing, attenuating or repairing the inflicted damage. It is conceivable that through evolution analogous biological protective systems have been evolved against non-protein attacks. There is emerging evidence that lipid endocannabinoid signaling through cannabinoid 2 (CB₂) receptors may represent an example/part of such a protective system/armamentarium. Inflammation/tissue injury triggers rapid elevations in local endocannabinoid levels, which in turn regulate signaling responses in immune and other cells modulating their critical functions. Changes in endocannabinoid levels and/or CB₂ receptor expressions have been reported in almost all diseases affecting humans, ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, autoimmune, lung disorders to pain and cancer, and modulating CB₂ receptor activity holds tremendous therapeutic potential in these pathologies. While CB₂ receptor activation in general mediates immunosuppressive effects, which limit inflammation and associated tissue injury in large number of pathological conditions, in some disease states activation of the CB₂ receptor may enhance or even trigger tissue damage, which will also be discussed alongside the protective actions of the CB₂ receptor stimulation with endocannabinoids or synthetic agonists, and the possible biological mechanisms involved in these effects. Published by Elsevier Ltd.

  10. Extinction of avoidance behavior by safety learning depends on endocannabinoid signaling in the hippocampus.

    PubMed

    Micale, Vincenzo; Stepan, Jens; Jurik, Angela; Pamplona, Fabricio A; Marsch, Rudolph; Drago, Filippo; Eder, Matthias; Wotjak, Carsten T

    2017-07-01

    The development of exaggerated avoidance behavior is largely responsible for the decreased quality of life in patients suffering from anxiety disorders. Studies using animal models have contributed to the understanding of the neural mechanisms underlying the acquisition of avoidance responses. However, much less is known about its extinction. Here we provide evidence in mice that learning about the safety of an environment (i.e., safety learning) rather than repeated execution of the avoided response in absence of negative consequences (i.e., response extinction) allowed the animals to overcome their avoidance behavior in a step-down avoidance task. This process was context-dependent and could be blocked by pharmacological (3 mg/kg, s.c.; SR141716) or genetic (lack of cannabinoid CB1 receptors in neurons expressing dopamine D1 receptors) inactivation of CB1 receptors. In turn, the endocannabinoid reuptake inhibitor AM404 (3 mg/kg, i.p.) facilitated safety learning in a CB1-dependent manner and attenuated the relapse of avoidance behavior 28 days after conditioning. Safety learning crucially depended on endocannabinoid signaling at level of the hippocampus, since intrahippocampal SR141716 treatment impaired, whereas AM404 facilitated safety learning. Other than AM404, treatment with diazepam (1 mg/kg, i.p.) impaired safety learning. Drug effects on behavior were directly mirrored by drug effects on evoked activity propagation through the hippocampal trisynaptic circuit in brain slices: As revealed by voltage-sensitive dye imaging, diazepam impaired whereas AM404 facilitated activity propagation to CA1 in a CB1-dependent manner. In line with this, systemic AM404 enhanced safety learning-induced expression of Egr1 at level of CA1. Together, our data render it likely that AM404 promotes safety learning by enhancing information flow through the trisynaptic circuit to CA1. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Acylethanolamides and endocannabinoid signaling system in dorsal striatum of rats exposed to perinatal asphyxia.

    PubMed

    Holubiec, Mariana I; Romero, Juan I; Blanco, Eduardo; Tornatore, Tamara Logica; Suarez, Juan; Rodríguez de Fonseca, Fernando; Galeano, Pablo; Capani, Francisco

    2017-07-13

    Endocannabinoids (eCBs) and acylethanolamides (AEs) have lately received more attention due to their neuroprotective functions in neurological disorders. Here we analyze the alterations induced by perinatal asphyxia (PA) in the main metabolic enzymes and receptors of the eCBs/AEs in the dorsal striatum of rats. To induce PA, we used a model developed by Bjelke et al. (1991). Immunohistochemical techniques were carried out to determine the expression of neuronal and glial markers (NeuN and GFAP), eCBs/AEs synthesis and degradation enzymes (DAGLα, NAPE-PLD and FAAH) and their receptors (CB1 and PPARα). We found a decrease in NAPE-PLD and PPARα expression. Since NAPE-PLD and PPARα take part in the production and reception of biochemical actions of AEs, such as oleoylethanolamide, these results may suggest that PA plays a key role in the regulation of this system. These data agree with previous results obtained in the hippocampus and encourage us to develop further studies using AEs as potential neuroprotective compounds. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Parameters of the Endocannabinoid System as Novel Biomarkers in Sepsis and Septic Shock.

    PubMed

    Lafreniere, J Daniel; Lehmann, Christian

    2017-11-01

    Sepsis represents a dysregulated immune response to infection, with a continuum of severity progressing to septic shock. This dysregulated response generally follows a pattern by which an initial hyperinflammatory phase is followed by a state of sepsis-associated immunosuppression. Major challenges in improving sepsis care include developing strategies to ensure early and accurate identification and diagnosis of the disease process, improving our ability to predict outcomes and stratify patients, and the need for novel sepsis-specific treatments such as immunomodulation. Biomarkers offer promise with all three of these challenges and are likely also to be the solution to determining a patient's immune status; something that is critical in guiding effective and safe immunomodulatory therapy. Currently available biomarkers used in sepsis lack sensitivity and specificity, among other significant shortcomings. The endocannabinoid system (ECS) is an emerging topic of research with evidence suggesting a ubiquitous presence on both central and peripheral tissues, including an intrinsic link with immune function. This review will first discuss the state of sepsis biomarkers and lack of available treatments, followed by an introduction to the ECS and a discussion of its potential to provide novel biomarkers and treatments.

  13. THE ENDOCANNABINOID SYSTEM MODULATES THE VALENCE OF THE EMOTION ASSOCIATED TO FOOD INGESTION

    PubMed Central

    Méndez-Díaz, Mónica; Rueda-Orozco, Pavel Ernesto; Ruiz-Contreras, Alejandra Evelyn; Prospéro-García, O.

    2010-01-01

    Endocannabinoids (eCBs) are mediators of the homeostatic and hedonic systems that modulate food ingestion. Hence, eCBs, by regulating the hedonic system, may be modulating the valence of the emotion associated to food ingestion (positive: pleasant, or negative: unpleasant). Our first goal was to demonstrate that palatable food induces conditioned place preference (CPP), hence a positive valence emotion. Additionally, we analyzed if this CPP is blocked by AM251, inducing a negative valence emotion, meaning avoiding the otherwise pursued compartment. The second goal was to demonstrate that CPP induced by regular food would be strengthened by the simultaneous administration of anandamide or oleamide and if such CPP is blocked by AM251. Finally, we tested the capacity of eCBs (without food) to induce CPP. Our results indicate that rats readily developed CPP to palatable food, which was blocked by AM251. The CPP induced by regular food was strengthened by eCBs and blocked by AM251. Finally, oleamide, unlike anandamide, induced CPP. These results showed that eCBs mediate the positive valence (CPP) of the emotion associated to food ingestion. It was also observed that the blockade of the CB1 receptor causes a loss of correlation between food and CPP (negative valence: avoidance). These data further support the role of eCBs as regulators of the hedonic value of food. PMID:21182571

  14. Deranged endocannabinoid responses to hedonic eating in underweight and recently weight-restored patients with anorexia nervosa.

    PubMed

    Monteleone, Alessio Maria; Di Marzo, Vincenzo; Aveta, Teresa; Piscitelli, Fabiana; Dalle Grave, Riccardo; Scognamiglio, Pasquale; El Ghoch, Marwan; Calugi, Simona; Monteleone, Palmiero; Maj, Mario

    2015-02-01

    A dysregulation of reward mechanisms was suggested in the pathophysiology of anorexia nervosa (AN), but the role of the endogenous mediators of reward has been poorly investigated. Endocannabinoids, including anandamide and 2-arachidonoylglycerol, and the endocannabinoid-related compounds oleoylethanolamide and palmitoylethanolamide modulate food-related and unrelated reward. Hedonic eating, which is the consumption of food just for pleasure and not homeostatic need, is a suitable paradigm to explore food-related reward. We investigated responses of endocannabinoids and endocannabinoid-related compounds to hedonic eating in AN. Peripheral concentrations of anandamide, 2-arachidonoylglycerol, oleoylethanolamide, and palmitoylethanolamide were measured in 7 underweight and 7 weight-restored AN patients after eating favorite and nonfavorite foods in the condition of no homeostatic needs, and these measurements were compared with those of previously studied healthy control subjects. 1) In healthy controls, plasma 2-arachidonoylglycerol concentrations decreased after both types of meals but were significantly higher in hedonic eating; in underweight AN patients, 2-arachidonoylglycerol concentrations did not show specific time patterns after eating either favorite or nonfavorite foods, whereas in weight-restored patients, 2-arachidonoylglycerol concentrations showed similar increases with both types of meals. 2) Anandamide plasma concentrations exhibited no differences in their response patterns to hedonic eating in the groups. 3) Compared with 2-arachidonoylglycerol, palmitoylethanolamide concentrations exhibited an opposite response pattern to hedonic eating in healthy controls; this pattern was partially preserved in underweight AN patients but not in weight-restored ones. 4) Like palmitoylethanolamide, oleoylethanolamide plasma concentrations tended to be higher in nonhedonic eating than in hedonic eating in healthy controls; moreover, no difference between healthy

  15. Endocannabinoids protect the rat isolated heart against ischaemia

    PubMed Central

    Lépicier, Philippe; Bouchard, Jean-François; Lagneux, Caroline; Lamontagne, Daniel

    2003-01-01

    The purpose of this study was to determine whether endocannabinoids can protect the heart against ischaemia and reperfusion. Rat isolated hearts were exposed to low-flow ischaemia (0.5–0.6 ml min−1) and reperfusion. Functional recovery as well as CK and LDH overflow into the coronary effluent were monitored. Infarct size was determined at the end of the experiments. Phosphorylation levels of p38, ERK1/2, and JNK/SAPK kinases were measured by Western blots. None of the untreated hearts recovered from ischaemia during the reperfusion period. Perfusion with either 300 nM palmitoylethanolamide (PEA) or 300 nM 2-arachidonoylglycerol (2-AG), but not anandamide (up to 1 μM), 15 min before and throughout the ischaemic period, improved myocardial recovery and decreased the levels of coronary CK and LDH. PEA and 2-AG also reduced infarct size. The CB2-receptor antagonist, SR144528, blocked completely the cardioprotective effect of both PEA and 2-AG, whereas the CB1-receptor antagonist, SR141716A, blocked partially the effect of 2-AG only. In contrast, both ACEA and JWH015, two selective agonists for CB1- and CB2- receptors, respectively, reduced infarct size at a concentration of 50 nM. PEA enhanced the phosphorylation level of p38 MAP kinase during ischaemia. PEA perfusion doubled the baseline phosphorylation level of ERK1/2, and enhanced its increase upon reperfusion. The cardioprotective effect of PEA was completely blocked by the p38 MAP kinase inhibitor, SB203580, and significantly reduced by the ERK1/2 inhibitor, PD98059, and the PKC inhibitor, chelerythrine. In conclusion, endocannabinoids exert a strong cardioprotective effect in a rat model of ischaemia–reperfusion that is mediated mainly through CB2-receptors, and involves p38, ERK1/2, as well as PKC activation. PMID:12813004

  16. Cannabinoids in the Cardiovascular System.

    PubMed

    Ho, Wing S V; Kelly, Melanie E M

    2017-01-01

    Cannabinoids are known to modulate cardiovascular functions including heart rate, vascular tone, and blood pressure in humans and animal models. Essential components of the endocannabinoid system, namely, the production, degradation, and signaling pathways of endocannabinoids have been described not only in the central and peripheral nervous system but also in myocardium, vasculature, platelets, and immune cells. The mechanisms of cardiovascular responses to endocannabinoids are often complex and may involve cannabinoid CB 1 and CB 2 receptors or non-CB 1/2 receptor targets. Preclinical and some clinical studies have suggested that targeting the endocannabinoid system can improve cardiovascular functions in a number of pathophysiological conditions, including hypertension, metabolic syndrome, sepsis, and atherosclerosis. In this chapter, we summarize the local and systemic cardiovascular effects of cannabinoids and highlight our current knowledge regarding the therapeutic potential of endocannabinoid signaling and modulation. © 2017 Elsevier Inc. All rights reserved.

  17. Training-Associated Emotional Arousal Shapes Endocannabinoid Modulation of Spatial Memory Retrieval in Rats.

    PubMed

    Morena, Maria; De Castro, Valentina; Gray, J Megan; Palmery, Maura; Trezza, Viviana; Roozendaal, Benno; Hill, Matthew N; Campolongo, Patrizia

    2015-10-14

    Variations in environmental aversiveness influence emotional memory processes in rats. We have previously shown that cannabinoid effects on memory are dependent on the stress level at the time of training as well as on the aversiveness of the environmental context. Here, we investigated whether the hippocampal endocannabinoid system modulates memory retrieval depending on the training-associated arousal level. Male adult Sprague Dawley rats were trained on a water maze spatial task at two different water temperatures (19°C and 25°C) to elicit either higher or lower stress levels, respectively. Rats trained under the higher stress condition had better memory and higher corticosterone concentrations than rats trained at the lower stress condition. The cannabinoid receptor agonist WIN55212-2 (10-30 ng/side), the 2-arachidonoyl glycerol (2-AG) hydrolysis inhibitor JZL184 (0.1-1 μg/side), and the anandamide (AEA) hydrolysis inhibitor URB597 (10-30 ng/side) were administered bilaterally into the hippocampus 60 min before probe-trial retention testing. WIN55212-2 or JZL184, but not URB597, impaired probe-trial performances only of rats trained at the higher stressful condition. Furthermore, rats trained under higher stress levels displayed an increase in hippocampal 2-AG, but not AEA, levels at the time of retention testing and a decreased affinity of the main 2-AG-degrading enzyme for its substrate. The present findings indicate that the endocannabinoid 2-AG in the hippocampus plays a key role in the selective regulation of spatial memory retrieval of stressful experience, shedding light on the neurobiological mechanisms involved in the impact of stress effects on memory processing. Endogenous cannabinoids play a central role in the modulation of memory for emotional events. Here we demonstrate that the endocannabinoid 2-arachidonoylglycerol in the hippocampus, a brain region crucially involved in the regulation of memory processes, selectively modulates spatial

  18. Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer's disease and levodopa-induced dyskinesia.

    PubMed

    Navarro, Gemma; Borroto-Escuela, Dasiel; Angelats, Edgar; Etayo, Íñigo; Reyes-Resina, Irene; Pulido-Salgado, Marta; Rodríguez-Pérez, Ana I; Canela, Enric I; Saura, Josep; Lanciego, José Luis; Labandeira-García, José Luis; Saura, Carlos A; Fuxe, Kjell; Franco, Rafael

    2018-01-01

    Endocannabinoids are important regulators of neurotransmission and, acting on activated microglia, they are postulated as neuroprotective agents. Endocannabinoid action is mediated by CB 1 and CB 2 receptors, which may form heteromeric complexes (CB 1 -CB 2 Hets) with unknown function in microglia. We aimed at establishing the expression and signaling properties of cannabinoid receptors in resting and LPS/IFN-γ-activated microglia. In activated microglia mRNA transcripts increased (2 fold for CB 1 and circa 20 fold for CB 2 ), whereas receptor levels were similar for CB 1 and markedly upregulated for CB 2 ; CB 1 -CB 2 Hets were also upregulated. Unlike in resting cells, CB 2 receptors became robustly coupled to G i in activated cells, in which CB 1 -CB 2 Hets mediated a potentiation effect. Hence, resting cells were refractory while activated cells were highly responsive to cannabinoids. Interestingly, similar results were obtained in cultures treated with ß-amyloid (Aß 1-42 ). Microglial activation markers were detected in the striatum of a Parkinson's disease (PD) model and, remarkably, in primary microglia cultures from the hippocampus of mutant β-amyloid precursor protein (APP Sw,Ind ) mice, a transgenic Alzheimer's disease (AD) model. Also of note was the similar cannabinoid receptor signaling found in primary cultures of microglia from APP Sw,Ind and in cells from control animals activated using LPS plus IFN-γ. Expression of CB 1 -CB 2 Hets was increased in the striatum from rats rendered dyskinetic by chronic levodopa treatment. In summary, our results showed sensitivity of activated microglial cells to cannabinoids, increased CB 1 -CB 2 Het expression in activated microglia and in microglia from the hippocampus of an AD model, and a correlation between levodopa-induced dyskinesia and striatal microglial activation in a PD model. Cannabinoid receptors and the CB 1 -CB 2 heteroreceptor complex in activated microglia have potential as targets in the

  19. Endocannabinoids: Multi-scaled, Global Homeostatic Regulators of Cells and Society

    NASA Astrophysics Data System (ADS)

    Melamede, Robert

    Living systems are far from equilibrium open systems that exhibit many scales of emergent behavior. They may be abstractly viewed as a complex weave of dissipative structures that maintain organization by passing electrons from reduced hydrocarbons to oxygen. Free radicals are unavoidable byproducts of biological electron flow. Due to their highly reactive chemical properties, free radicals modify all classes of biological molecules (carbohydrates, lipids, nucleic acids, and proteins). As a result, free radicals are destructive. The generally disruptive nature of free radicals makes them the "friction of life." As such, they are believed to be the etiological agents behind age related illnesses such as cardiovascular, immunological, and neurological diseases, cancer, and ageing itself. Free radicals also play a critical constructive role in living systems. From a thermodynamic perspective, life can only exist if a living system takes in sufficient negative entropy from its environment to overcome the obligatory increase in entropy that would result if the system could not appropriately exchange mass, energy and information with its environment. Free radicals are generated in response to perturbations in the relationship between a living system and its environment. However, evolution has selected for biological response systems to free radicals so that the cellular biochemistry can adapt to environmental perturbations by modifying cellular gene expression and biochemistry. Endocannabinoids are marijuana-like compounds that have their origins hundreds of millions of years in the evolutionary past. They serve as fundamental modulators of energy homeostasis in all vertebrates. Their widespread biological activities may often be attributed to their ability to minimize the negative consequences of free radicals.

  20. The Cannabinoid System and Pain

    PubMed Central

    Woodhams, Stephen G.; Chapman, Victoria; Finn, David P.; Hohmann, Andrea G.; Neugebauer, Volker

    2018-01-01

    Chronic pain states are highly prevalent and yet poorly controlled by currently available analgesics, representing an enormous clinical, societal, and economic burden. Existing pain medications have significant limitations and adverse effects including tolerance, dependence, gastrointestinal dysfunction, cognitive impairment, and a narrow therapeutic window, making the search for novel analgesics ever more important. In this article, we review the role of an important endogenous pain control system, the endocannabinoid (EC) system, in the sensory, emotional, and cognitive aspects of pain. Herein, we briefly cover the discovery of the EC system and its role in pain processing pathways, before concentrating on three areas of current major interest in EC pain research; 1. Pharmacological enhancement of endocannabinoid activity (via blockade of EC metabolism or allosteric modulation of CB1 receptors); 2. The EC System and stress-induced modulation of pain; and 3. The EC system & medial prefrontal cortex (mPFC) dysfunction in pain states. Whilst we focus predominantly on the preclinical data, we also include extensive discussion of recent clinical failures of endocannabinoid-related therapies, the future potential of these approaches, and important directions for future research on the EC system and pain. PMID:28625720

  1. The endocannabinoid system in the baboon (Papio spp.) as a complex framework for developmental pharmacology.

    PubMed

    Rodriguez-Sanchez, Iram P; Guindon, Josee; Ruiz, Marco; Tejero, M Elizabeth; Hubbard, Gene; Martinez-de-Villarreal, Laura E; Barrera-Saldaña, Hugo A; Dick, Edward J; Comuzzie, Anthony G; Schlabritz-Loutsevitch, Natalia E

    The consumption of marijuana (exogenous cannabinoid) almost doubled in adults during last decade. Consumption of exogenous cannabinoids interferes with the endogenous cannabinoid (or "endocannabinoid" (eCB)) system (ECS), which comprises N-arachidonylethanolamide (anandamide, AEA), 2-arachidonoyl glycerol (2-AG), endocannabinoid receptors (cannabinoid receptors 1 and 2 (CB1R and CB2R), encoded by CNR1 and CNR2, respectively), and synthesizing/degrading enzymes (FAAH, fatty-acid amide hydrolase; MAGL, monoacylglycerol lipase; DAGL-α, diacylglycerol lipase-alpha). Reports regarding the toxic and therapeutic effects of pharmacological compounds targeting the ECS are sometimes contradictory. This may be caused by the fact that structure of the eCBs varies in the species studied. First: to clone and characterize the cDNAs of selected members of ECS in a non-human primate (baboon, Papio spp.), and second: to compare those cDNA sequences to known human structural variants (single nucleotide polymorphisms and haplotypes). Polymerase chain reaction-amplified gene products from baboon tissues were transformed into Escherichia coli. Amplicon-positive clones were sequenced, and the obtained sequences were conceptually translated into amino-acid sequences using the genetic code. Among the ECS members, CNR1 was the best conserved gene between humans and baboons. The phenotypes associated with mutations in the untranslated regions of this gene in humans have not been described in baboons. One difference in the structure of CNR2 between humans and baboons was detected in the region with the only known clinically relevant polymorphism in a human receptor. All of the differences in the amino-acid structure of DAGL-α between humans and baboons were located in the hydroxylase domain, close to phosphorylation sites. None of the differences in the amino-acid structure of MAGL observed between baboons and humans were located in the area critical for enzyme function. The evaluation of

  2. The endocannabinoid system modulates the valence of the emotion associated to food ingestion.

    PubMed

    Méndez-Díaz, Mónica; Rueda-Orozco, Pavel Ernesto; Ruiz-Contreras, Alejandra Evelyn; Prospéro-García, Oscar

    2012-07-01

    Endocannabinoids (eCBs) are mediators of the homeostatic and hedonic systems that modulate food ingestion. Hence, eCBs, by regulating the hedonic system, may be modulating the valence of the emotion associated to food ingestion (positive: pleasant or negative: unpleasant). Our first goal was to demonstrate that palatable food induces conditioned place preference (CPP), hence a positive-valence emotion. Additionally, we analyzed if this CPP is blocked by AM251, inducing a negative valence emotion, meaning avoiding the otherwise pursued compartment. The second goal was to demonstrate that CPP induced by regular food would be strengthened by the simultaneous administration of anandamide or oleamide, and if such, CPP is blocked by AM251. Finally, we tested the capacity of eCBs (without food) to induce CPP. Our results indicate that rats readily developed CPP to palatable food, which was blocked by AM251. The CPP induced by regular food was strengthened by eCBs and blocked by AM251. Finally, oleamide, unlike anandamide, induced CPP. These results showed that eCBs mediate the positive valence (CPP) of the emotion associated to food ingestion. It was also observed that the blockade of the CB1 receptor causes a loss of correlation between food and CPP (negative valence: avoidance). These data further support the role of eCBs as regulators of the hedonic value of food. © 2010 The Authors. Addiction Biology © 2010 Society for the Study of Addiction.

  3. Entopeduncular nucleus endocannabinoid system modulates sleep-waking cycle and mood in rats.

    PubMed

    Méndez-Díaz, Mónica; Caynas-Rojas, Seraid; Arteaga Santacruz, Vianney; Ruiz-Contreras, Alejandra E; Aguilar-Roblero, Raúl; Prospéro-García, Oscar

    2013-06-01

    Since the pioneering work of Gadea-Ciria (Gadea-Ciria M, Stadler H, Lloyd KG, Bartholini G. Acetylcholine release within the cat striatum during the sleep-wakefulness cycle. Nature 1973; 243:518-519) indicating pointing to the involvement of acetylcholine and basal ganglia in sleep regulation; extensive literature has suggested that this brain complex participates in the control of the sleep-waking cycle (SWC). On the other hand, it has been demonstrated that the endocannabinoid system (eCBS) is prominently involved in the regulation of the SWC, mood and its related disorders. Since cannabinoid receptor 1 (CB1R) is highly expressed in basal ganglia, in particular in the entopeduncular nucleus (EP), we believe that it is important to know what the role of the EP CB1R is on SWC, depression, and anxiety. To provide insight into the role of the EP CB1R in the regulation of wakefulness (W), non-rapid eye movement sleep (NREMs) and rapid eye movement sleep (REMs), rats were recorded for 24h immediately after a single intra-EP administration of N-arachidonoylethanolamine (AEA) or 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl)pyrazole-3-carboxamide (AM251; CB1 inverse agonist). Likewise, the effect of these drugs on anxiety and depression was tested by means of the elevated plus maze (EPM) and forced swim test (FST), respectively. Results demonstrate that AEA increases NREMs expression, while AM251 increases W and decreases both NREMs and REMs. In addition, administration of AM251 decreases the time rats spent in the open arms and increases immobility time in the FST. It seems that activation of the CB1R in the EP is important to induce sleep, while its blockade promotes W, as well as anxiety and depression, somewhat resembling insomnia in humans. These results suggest that the EP CB1R is modulating sleep and mood. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Endo-cannabinoids system and the toxicity of cannabinoids with a biotechnological approach

    PubMed Central

    Niaz, Kamal; Khan, Fazlullah; Maqbool, Faheem; Momtaz, Saeideh; Ismail Hassan, Fatima; Nobakht-Haghighi, Navid; Rahimifard, Mahban; Abdollahi, Mohammad

    2017-01-01

    Cannabinoids have shown diverse and critical effects on the body systems, which alter the physiological functions. Synthetic cannabinoids are comparatively innovative misuse drugs with respect to their nature of synthesis. Synthetic cannabinoids therapy in healthy, chain smokers, and alcoholic individuals cause damage to the immune and nervous system, eventually leading to intoxication throughout the body. Relevant studies were retrieved using major electronic databases such as PubMed, EMBASE, Medline, Scopus, and Google Scholar. The extensive use of Cannabis Sativa L. (C. Sativa) and its derivatives/analogues such as the nonpsychoactive dimethyl heptyl homolog (CBG-DMH), and tetrahydrocannabivarin (THCV) amongst juveniles and adults have been enhanced in recent years. Cannabinoids play a crucial role in the induction of respiratory, reproductive, immune and carcinogenic effects; however, potential data about mutagenic and developmental effects are still insufficient. The possible toxicity associated with the prolong use of cannabinoids acts as a tumor promoter in animal models and humans. Particular synthetic cannabinoids and analogues have low affinity for CB1 or CB2 receptors, while some synthetic members like Δ9-THC have high affinity towards these receptors. Cannabinoids and their derivatives have a direct or indirect association with acute and long-term toxicity. To reduce/attenuate cannabinoids toxicity, pharmaceutical biotechnology and cloning methods have opened a new window to develop cannabinoids encoding the gene tetrahydrocannabinolic acid (THCA) synthase. Plant revolution and regeneration hindered genetic engineering in C. Sativa. The genetic culture suspension of C. Sativa can be transmuted by the use of Agrobacterium tumefaciens to overcome its toxicity. The main aim of the present review was to collect evidence of the endo-cannabinoid system (ECS), cannabinoids toxicity, and the potential biotechnological approach of cannabinoids synthesis. PMID

  5. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol

    PubMed Central

    Kirkham, Tim C; Williams, Claire M; Fezza, Filomena; Marzo, Vincenzo Di

    2002-01-01

    Endocannabinoids are implicated in appetite and body weight regulation. In rodents, anandamide stimulates eating by actions at central CB1 receptors, and hypothalamic endocannabinoids may be under the negative control of leptin. However, changes to brain endocannabinoid levels in direct relation to feeding or changing nutritional status have not been investigated.We measured anandamide and 2-arachidonoyl glycerol (2-AG) levels in feeding-associated brain regions of rats, during fasting, feeding of a palatable food, or after satiation. Endocannabinoid levels were compared to those in rats fed ad libitum, at a point in their daily cycle when motivation to eat was absent. Fasting increased levels of anandamide and 2-AG in the limbic forebrain and, to a lesser extent, of 2-AG in the hypothalamus. By contrast, hypothalamic 2-AG declined as animals ate. No changes were detected in satiated rats. Endocannabinoid levels in the cerebellum, a control region not directly involved in the control of food intake, were unaffected by any manipulation.As 2-AG was most sensitive to variation during feeding, and to leptin regulation in a previous study, we examined the behavioural effects of 2-AG when injected into the nucleus accumbens shell, a limbic forebrain area strongly linked to eating motivation. 2-AG potently, and dose-dependently, stimulated feeding. This effect was attenuated by the CB1 receptor antagonist SR141716.These findings provide the first direct evidence of altered brain levels of endocannabinoids, and of 2-AG in particular, during fasting and feeding. The nature of these effects supports a role for endocannabinoids in the control of appetitive motivation. PMID:12055133

  6. Diet-induced changes in n-3- and n-6-derived endocannabinoids and reductions in headache pain and psychological distress.

    PubMed

    Ramsden, Christopher E; Zamora, Daisy; Makriyannis, Alexandros; Wood, JodiAnne T; Mann, J Douglas; Faurot, Keturah R; MacIntosh, Beth A; Majchrzak-Hong, Sharon F; Gross, Jacklyn R; Courville, Amber B; Davis, John M; Hibbeln, Joseph R

    2015-08-01

    Omega-3 and omega-6 fatty acids are biosynthetic precursors of endocannabinoids with antinociceptive, anxiolytic, and neurogenic properties. We recently reported that targeted dietary manipulation-increasing omega-3 fatty acids while reducing omega-6 linoleic acid (the H3-L6 intervention)-reduced headache pain and psychological distress among chronic headache patients. It is not yet known whether these clinical improvements were due to changes in endocannabinoids and related mediators derived from omega-3 and omega-6 fatty acids. We therefore used data from this trial (N = 55) to investigate 1) whether the H3-L6 intervention altered omega-3- and omega-6-derived endocannabinoids in plasma and 2) whether diet-induced changes in these bioactive lipids were associated with clinical improvements. The H3-L6 intervention significantly increased the omega-3 docosahexaenoic acid derivatives 2-docosahexaenoylglycerol (+65%, P < .001) and docosahexaenoylethanolamine (+99%, P < .001) and reduced the omega-6 arachidonic acid derivative 2-arachidonoylglycerol (-25%, P = .001). Diet-induced changes in these endocannabinoid derivatives of omega-3 docosahexaenoic acid, but not omega-6 arachidonic acid, correlated with reductions in physical pain and psychological distress. These findings demonstrate that targeted dietary manipulation can alter endocannabinoids derived from omega-3 and omega-6 fatty acids in humans and suggest that 2-docosahexaenoylglycerol and docosahexaenoylethanolamine could have physical and/or psychological pain modulating properties. ClinicalTrials.gov (NCT01157208) PERSPECTIVE: This article demonstrates that targeted dietary manipulation can alter endocannabinoids derived from omega-3 and omega-6 fatty acids and that these changes are related to reductions in headache pain and psychological distress. These findings suggest that dietary interventions could provide an effective, complementary approach for managing chronic pain and related conditions

  7. Song-associated reward correlates with endocannabinoid-related gene expression in male European starlings (Sturnus vulgaris).

    PubMed

    Hahn, Allison H; Merullo, Devin P; Spool, Jeremy A; Angyal, Caroline S; Stevenson, Sharon A; Riters, Lauren V

    2017-03-27

    Vocal communication is required for successful social interactions in numerous species. During the breeding season, songbirds produce songs that are reinforced by behavioral consequences (e.g., copulation). However, some songbirds also produce songs not obviously directed at other individuals. The consequences maintaining or reinforcing these songs are less obvious and the neural mechanisms associated with undirected communication are not well-understood. Previous studies indicate that undirected singing is intrinsically rewarding and mediated by opioid or dopaminergic systems; however, endocannabinoids are also involved in regulating reward and singing behavior. We used a conditioned place preference paradigm to examine song-associated reward in European starlings and quantitative real-time PCR to measure expression of endocannabinoid-related neural markers (CB 1 , FABP7, FABP5, FAAH, DAGLα), in brain regions involved in social behavior, reward and motivation (ventral tegmental area [VTA], periaqueductal gray [PAG], and medial preoptic nucleus [POM]), and a song control region (Area X). Our results indicate that starlings producing high rates of song developed a conditioned place preference, suggesting that undirected song is associated with a positive affective state. We found a significant positive relationship between song-associated reward and CB 1 receptors in VTA and a significant negative relationship between song-associated reward and CB 1 in PAG. There was a significant positive relationship between reward and the cannabinoid transporter FABP7 in POM and a significant negative relationship between reward and FABP7 in PAG. In Area X, FABP5 and DAGLα correlated positively with singing. These results suggest a role for endocannabinoid signaling in vocal production and reward associated with undirected communication. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  8. Song-associated reward correlates with endocannabinoid-related gene expression in male European starlings (Sturnus vulgaris)

    PubMed Central

    Hahn, Allison H.; Merullo, Devin P.; Spool, Jeremy A.; Angyal, Caroline S.; Stevenson, Sharon A.; Riters, Lauren V.

    2017-01-01

    Vocal communication is required for successful social interactions in numerous species. During the breeding season, songbirds produce songs that are reinforced by behavioral consequences (e.g., copulation). However, some songbirds also produce songs not obviously directed at other individuals. The consequences maintaining or reinforcing these songs are less obvious and the neural mechanisms associated with undirected communication are not well-understood. Previous studies indicate that undirected singing is intrinsically rewarding and mediated by opioid or dopaminergic systems; however, endocannabinoids are also involved in regulating reward and singing behavior. We used a conditioned place preference paradigm to examine song-associated reward in European starlings and quantitative real-time PCR to measure expression of endocannabinoid-related neural markers (CB1, FABP7, FABP5, FAAH, DAGLα), in brain regions involved in social behavior, reward and motivation (ventral tegmental area [VTA], periaqueductal gray [PAG], and medial preoptic nucleus [POM]), and a song control region (Area X). Our results indicate that starlings producing high rates of song developed a conditioned place preference, suggesting that undirected song is associated with a positive affective state. We found a significant positive relationship between song-associated reward and CB1 receptors in VTA and a significant negative relationship between song-associated reward and CB1 in PAG. There was a significant positive relationship between reward and the cannabinoid transporter FABP7 in POM and a significant negative relationship between reward and FABP7 in PAG. In Area X, FABP5 and DAGLα correlated positively with singing. These results suggest a role for endocannabinoid signaling in vocal production and reward associated with undirected communication. PMID:28147243

  9. Effects of a Weight Loss Program on Metabolic Syndrome, Eating Disorders and Psychological Outcomes: Mediation by Endocannabinoids?

    PubMed

    Pataky, Zoltan; Carrard, Isabelle; Gay, Valerie; Thomas, Aurélien; Carpentier, Anne; Bobbioni-Harsch, Elisabetta; Golay, Alain

    2018-01-01

    To evaluate the effects of weight loss on endocannabinoids, cardiometabolic and psychological parameters, eating disorders (ED) as well as quality of life (QoL) and to elucidate the role of endocannabinoids in metabolic syndrome (MS). In total, 114 patients with obesity were prospectively included in a 12-month weight loss program. Plasma endocannabinoids were measured by mass spectrometry; ED, psychological and QoL-related parameters were evaluated by self-reported questionnaires; physical activity was measured by accelerometer. Nutritional assessment was done by a 3-day food diary. Among completers (n = 87), body weight decreased in 35 patients (-9.1 ± 8.6 kg), remained stable in 39 patients, and increased in 13 patients (+5.8 ± 3.4 kg). 75% of patients with MS at baseline were free of MS at follow-up, and their baseline plasma N-palmitoylethanolamide (PEA) values were significantly lower when compared to patients with persisting MS. At baseline, there was a positive relationship between PEA and waist circumference (p = 0.005, R2 = 0.08), fasting glucose (p < 0.0001, R2 = 0.12), total cholesterol (p = 0.001, R2 = 0.11), triglycerides (p = 0.001, R2 = 0.11), LDL-cholesterol (p = 0.03, R2 = 0.05) as well as depression score (p = 0.002, R2 = 0.29). Plasma PEA might play a role in metabolic improvement after weight loss. Even in subjects without weight loss, a multidisciplinary intervention improves psychological outcomes, ED, and QoL. © 2018 The Author(s) Published by S. Karger GmbH, Freiburg.

  10. Epigenetic mechanisms associated with addiction-related behavioural effects of nicotine and/or cocaine: implication of the endocannabinoid system.

    PubMed

    Hayase, Tamaki

    2017-10-01

    The addictive use of nicotine (NC) and cocaine (COC) continues to be a major public health problem, and their combined use has been reported, particularly during adolescence. In neural plasticity, commonly induced by NC and COC, as well as behavioural plasticity related to the use of these two drugs, the involvement of epigenetic mechanisms, in which the reversible regulation of gene expression occurs independently of the DNA sequence, has recently been reported. Furthermore, on the basis of intense interactions with the target neurotransmitter systems, the endocannabinoid (ECB) system has been considered pivotal for eliciting the effects of NC or COC. The combined use of marijuana with NC and/or COC has also been reported. This article presents the addiction-related behavioural effects of NC and/or COC, based on the common behavioural/neural plasticity and combined use of NC/COC, and reviews the interacting role of the ECB system. The epigenetic processes inseparable from the effects of NC and/or COC (i.e. DNA methylation, histone modifications and alterations in microRNAs) and the putative therapeutic involvement of the ECB system at the epigenetic level are also discussed.

  11. Circulating levels of endocannabinoids and oxylipins altered by dietary lipids in older women are likely associated with previously identified gene targets

    USDA-ARS?s Scientific Manuscript database

    Postmenopausal women (PMW) report marginal n-3 PUFA intakes and are at risk of chronic diseases associated with the skeletal, muscular, and cardiovascular systems. Our investigation characterized the endocannabinoids (EC), oxylipins (OL), and global metabolites (GM) in white PMW (75 ± 7 y), randomiz...

  12. Impairment of endocannabinoids activity in the dorsolateral striatum delays extinction of behavior in a procedural memory task in rats.

    PubMed

    Rueda-Orozco, Pavel E; Montes-Rodriguez, Corinne J; Soria-Gomez, Edgar; Méndez-Díaz, Mónica; Prospéro-García, Oscar

    2008-07-01

    The dorsolateral striatum (DLS) has been implicated in the learning of habits and procedural memories. Extinction of this kind of memories has been poorly studied. The DLS expresses high levels of the cannabinergic receptor one (CB1), and, lately, it has been suggested that the activation of CB1 in this structure is indispensable for long-term depression (LTD) development. We performed experiments in a T-maze and evaluated the effects of intrastriatal and intrahipocampal administration of the CB1 antagonist AM251 on extinction and on c-Fos expression. We also administered anandamide to evaluate if an artificial increase of endocannabinoids facilitates extinction. Our results indicate clearly a dose-response blockade of extinction induced by AM251 injected into the striatum but a facilitation of extinction when administered into the hippocampus. Anandamide did not induce any observable changes. AM251 effects were accompanied by an increase in c-Fos immunoreactivity in the DLS and its decrease in the hippocampal region, suggesting that the activation of CB1 in the striatum is necessary for the extinction of procedural memories. These findings could be important in some neurological conditions, such as obsessive-compulsive disorder in which striatal activity seems to be abnormal.

  13. Identification of an endocannabinoid system in the rat pars tuberalis-a possible interface in the hypothalamic-pituitary-adrenal system?

    PubMed

    Jafarpour, Arsalan; Dehghani, Faramarz; Korf, Horst-Werner

    2017-04-01

    Endocannabinoids (ECs) are ubiquitous endogenous lipid derivatives and play an important role in intercellular communication either in an autocrine/paracrine or in an endocrine fashion. Recently, an intrinsic EC system has been discovered in the hypophysial pars tuberalis (PT) of hamsters and humans. In hamsters, this EC system is under photoperiodic control and appears to influence the secretion of hormones such as prolactin from the adenohypophysis. We investigate the EC system in the PT of the rat, a frequently used species in endocrine research. By means of immunocytochemistry, enzymes involved in EC biosynthesis, e.g., N-arachidonoyl-phosphatidylethanolamine-phospholipase D (NAPE-PLD) and diacylglycerol lipase α (DAGLα) and enzymes involved in EC degradation, e.g., fatty acid amide hydrolase (FAAH) and cyclooxygenase-2 (COX-2), were demonstrated in PT cells of the rat. Immunoreactions (IR) for FAAH and for the cannabinoid receptor CB 1 were observed in corticotrope cells of the rat adenohypophysis; these cells were identified by antibodies against proopiomelanocortin (POMC) or adrenocorticotrophic hormone (ACTH). In the outer zone of the median eminence, numerous nerve fibers and terminals displayed CB 1 IR. The majority of these were also immunolabeled by an antibody against corticotropin-releasing factor (CRF). These results suggest that the EC system at the hypothalamo-hypophysial interface affects both the CRF-containing nerve fibers and the corticotrope cells in the adenohypophysis. Our data give rise to the hypothesis that, in addition to its well-known role in the reproductive axis, the PT might influence adrenal functions and, thus, the stress response and immune system.

  14. Female Mice are Resistant to Fabp1 Gene Ablation-Induced Alterations in Brain Endocannabinoid Levels.

    PubMed

    Martin, Gregory G; Chung, Sarah; Landrock, Danilo; Landrock, Kerstin K; Dangott, Lawrence J; Peng, Xiaoxue; Kaczocha, Martin; Murphy, Eric J; Kier, Ann B; Schroeder, Friedhelm

    2016-09-01

    Although liver fatty acid binding protein (FABP1, L-FABP) is not detectable in the brain, Fabp1 gene ablation (LKO) markedly increases endocannabinoids (EC) in brains of male mice. Since the brain EC system of females differs significantly from that of males, it was important to determine if LKO differently impacted the brain EC system. LKO did not alter brain levels of arachidonic acid (ARA)-containing EC, i.e. arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), but decreased non-ARA-containing N-acylethanolamides (OEA, PEA) and 2-oleoylglycerol (2-OG) that potentiate the actions of AEA and 2-AG. These changes in brain potentiating EC levels were not associated with: (1) a net decrease in levels of brain membrane proteins associated with fatty acid uptake and EC synthesis; (2) a net increase in brain protein levels of cytosolic EC chaperones and enzymes in EC degradation; or (3) increased brain protein levels of EC receptors (CB1, TRVP1). Instead, the reduced or opposite responsiveness of female brain EC levels to loss of FABP1 (LKO) correlated with intrinsically lower FABP1 level in livers of WT females than males. These data show that female mouse brain endocannabinoid levels were unchanged (AEA, 2-AG) or decreased (OEA, PEA, 2-OG) by complete loss of FABP1 (LKO).

  15. FEMALE MICE ARE RESISTANT TO Fabp1 GENE ABLATION-INDUCED ALTERATIONS IN BRAIN ENDOCANNABINOID LEVELS

    PubMed Central

    Martin, Gregory G.; Chung, Sarah; Landrock, Danilo; Landrock, Kerstin K.; Dangott, Lawrence J.; Peng, Xiaoxue; Kaczocha, Martin; Murphy, Eric J.; Kier, Ann B.; Schroeder, Friedhelm

    2017-01-01

    Although liver fatty acid binding protein (FABP1, L-FABP) is not detectable in brain, Fabp1 gene ablation (LKO) markedly increases endocannabinoids (EC) in brains of male mice. Since the brain EC system of females differs significantly from that of males, it was important to determine if LKO differently impacted the brain EC system. LKO did not alter brain levels of arachidonic acid (ARA)-containing ECs, i.e arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), but decreased non-ARA-containing N-acylethanolamides (OEA, PEA) and 2-oleoylglycerol (2-OG) that potentiate the actions of AEA and 2-AG. These changes in brain potentiating EC levels were not associated with: i) a net decrease in levels of brain membrane proteins associated with fatty acid uptake and EC synthesis; ii) a net increase in brain protein levels of cytosolic EC chaperones and enzymes in EC degradation; or iii) increased brain protein levels of EC receptors (CB1, TRVP1). Instead, the reduced or opposite responsiveness of female brain EC levels to loss of FABP1 (LKO) correlated with intrinsically lower FABP1 level in livers of WT females than males. These data show that female mouse brain endocannabinoid levels were unchanged (AEA, 2-AG) or decreased (OEA, PEA, 2-OG) by complete loss of FABP1 (LKO). PMID:27450559

  16. Cat odour-induced anxiety--a study of the involvement of the endocannabinoid system.

    PubMed

    Sütt, Silva; Raud, Sirli; Areda, Tarmo; Reimets, Ain; Kõks, Sulev; Vasar, Eero

    2008-07-01

    Recent evidence suggests the involvement of the endocannabinoid (EC) system in the regulation of anxiety. The aim of present work was to study the role of the EC system in cat odour-induced anxiety in rats. Materials and methods Male Wistar rats were exposed to cat odour in home and motility cages. Exposure of rats to elevated zero-maze was used to determine changes in anxiety. Effect of rimonabant (0.3-3 mg/kg), antagonist of CB1 receptors, was studied on cat odour-induced alterations in exploratory behaviour. Real-time PCR was used to determine gene expression levels of EC-related genes in the brain. Anxiogenic-like action of cat odour was evident in the elevated zero-maze. Cat odour increased the expression of FAAH, the enzyme responsible for the degradation of anandamide, in the mesolimbic area. By contrast, in the amygdala and periaqueductal grey (PAG) levels of NAPE-PLD, the enzyme related to the synthesis of anandamide, and FAAH were remarkably decreased. Cat odour also decreased the expression of enzymes related to metabolism of 2-archidonoyl-glycerol in the amygdala and PAG. Pre-treatment of rats with rimonabant (0.3-3 mg/kg) reduced the exploratory behaviour of rats, but did not affect cat odour-induced changes. Exposure to cat odour induces anxiogenic-like effect on the behaviour in rats. Cat odour also causes moderate increase in expression of EC-related genes in the mesolimbic area, whereas significant down-regulation is established in the amygdala and PAG. Relation of predator odour-induced anxiety to the inhibition of the EC system in the amygdala and PAG is supported by behavioural studies where blockade of CB1 receptors by rimonabant induces anxiogenic-like action.

  17. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?

    PubMed

    Russo, Ethan B

    2008-04-01

    This study examines the concept of clinical endocannabinoid deficiency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis. Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources. Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, IBS and related disorders. The past and potential clinical utility of cannabis-based medicines in their treatment is discussed, as are further suggestions for experimental investigation of CECD via CSF examination and neuro-imaging. Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.

  18. The Endocannabinoid, Anandamide, Augments Notch-1 Signaling in Cultured Cortical Neurons Exposed to Amyloid-β and in the Cortex of Aged Rats*

    PubMed Central

    Tanveer, Riffat; Gowran, Aoife; Noonan, Janis; Keating, Sinead E.; Bowie, Andrew G.; Campbell, Veronica A.

    2012-01-01

    Aberrant Notch signaling has recently emerged as a possible mechanism for the altered neurogenesis, cognitive impairment, and learning and memory deficits associated with Alzheimer disease (AD). Recently, targeting the endocannabinoid system in models of AD has emerged as a potential approach to slow the progression of the disease process. Although studies have identified neuroprotective roles for endocannabinoids, there is a paucity of information on modulation of the pro-survival Notch pathway by endocannabinoids. In this study the influence of the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol, on the Notch-1 pathway and on its endogenous regulators were investigated in an in vitro model of AD. We report that AEA up-regulates Notch-1 signaling in cultured neurons. We also provide evidence that although Aβ1–42 increases expression of the endogenous inhibitor of Notch-1, numb (Nb), this can be prevented by AEA and 2-arachidonoylglycerol. Interestingly, AEA up-regulated Nct expression, a component of γ-secretase, and this was found to play a crucial role in the enhanced Notch-1 signaling mediated by AEA. The stimulatory effects of AEA on Notch-1 signaling persisted in the presence of Aβ1–42. AEA was found to induce a preferential processing of Notch-1 over amyloid precursor protein to generate Aβ1–40. Aging, a natural process of neurodegeneration, was associated with a reduction in Notch-1 signaling in rat cortex and hippocampus, and this was restored with chronic treatment with URB 597. In summary, AEA has the proclivity to enhance Notch-1 signaling in an in vitro model of AD, which may have relevance for restoring neurogenesis and cognition in AD. PMID:22891244

  19. Characterization of the effects of reuptake and hydrolysis inhibition on interstitial endocannabinoid levels in the brain: an in vivo microdialysis study.

    PubMed

    Wiskerke, Joost; Irimia, Cristina; Cravatt, Benjamin F; De Vries, Taco J; Schoffelmeer, Anton N M; Pattij, Tommy; Parsons, Loren H

    2012-05-16

    The present experiments employed in vivo microdialysis to characterize the effects of commonly used endocannabinoid clearance inhibitors on basal and depolarization-induced alterations in interstitial endocannabinoid levels in the nucleus accumbens of rat brain. Compounds targeting the putative endocannabinoid transporter and hydrolytic enzymes (FAAH and MAGL) were compared. The transporter inhibitor AM404 modestly enhanced depolarization-induced increases in 2-arachidonoyl glycerol (2-AG) levels but did not alter levels of N-arachidonoyl-ethanolamide (anandamide, AEA). The transport inhibitor UCM707 did not alter dialysate levels of either endocannabinoid. The FAAH inhibitors URB597 and PF-3845 robustly increased AEA levels during depolarization without altering 2-AG levels. The MAGL inhibitor URB602 significantly enhanced depolarization-induced increases in 2-AG, but did not alter AEA levels. In contrast, the MAGL inhibitor JZL184 did not alter 2-AG or AEA levels under any condition tested. Finally, the dual FAAH/MAGL inhibitor JZL195 significantly enhanced depolarization-induced increases in both AEA and 2-AG levels. In contrast to the present observations in rats, prior work in mice has demonstrated a robust JZL184-induced enhancement of depolarization-induced increases in dialysate 2-AG. Thus, to further investigate species differences, additional tests with JZL184, PF-3845, and JZL195 were performed in mice. Consistent with prior reports, JZL184 significantly enhanced depolarization-induced increases in 2-AG without altering AEA levels. PF-3845 and JZL195 produced profiles in mouse dialysates comparable to those observed in rats. These findings confirm that interstitial endocannabinoid levels in the brain can be selectively manipulated by endocannabinoid clearance inhibitors. While PF-3845 and JZL195 produce similar effects in both rats and mice, substantial species differences in JZL184 efficacy are evident, which is consistent with previous studies.

  20. Association between plasma endocannabinoids and appetite in hemodialysis patients: a pilot study

    USDA-ARS?s Scientific Manuscript database

    Weight loss is a well-recognized complication in subjects undergoing hemodialysis for impaired kidney function. This pilot study explored whether plasma levels of compounds known to mediate appetite, the endocannabinoids (EC) and EC-like compounds derived from polyunsaturated fatty acids (PUFA), ar...

  1. The endocannabinoid/endovanilloid N-arachidonoyl dopamine (NADA) and synthetic cannabinoid WIN55,212-2 abate the inflammatory activation of human endothelial cells.

    PubMed

    Wilhelmsen, Kevin; Khakpour, Samira; Tran, Alphonso; Sheehan, Kayla; Schumacher, Mark; Xu, Fengyun; Hellman, Judith

    2014-05-09

    Although cannabinoids, such as Δ(9)-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation.

  2. The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine (NADA) and Synthetic Cannabinoid WIN55,212-2 Abate the Inflammatory Activation of Human Endothelial Cells*

    PubMed Central

    Wilhelmsen, Kevin; Khakpour, Samira; Tran, Alphonso; Sheehan, Kayla; Schumacher, Mark; Xu, Fengyun; Hellman, Judith

    2014-01-01

    Although cannabinoids, such as Δ9-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation. PMID:24644287

  3. The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling.

    PubMed

    Fogaça, Manoela V; Campos, Alline C; Coelho, Ludmila D; Duman, Ronald S; Guimarães, Francisco S

    2018-06-01

    Repeated injections of cannabidiol (CBD), the major non-psychotomimetic compound present in the Cannabis sativa plant, attenuate the anxiogenic effects induced by Chronic Unpredictable Stress (CUS). The specific mechanisms remain to be fully understood but seem to involve adult hippocampal neurogenesis and recruitment of endocannabinoids. Here we investigated for the first time if the behavioral and pro-neurogenic effects of CBD administered concomitant the CUS procedure (14 days) are mediated by CB 1 , CB 2 or 5HT 1A receptors, as well as CBD effects on dendritic remodeling and on intracellular/synaptic signaling (fatty acid amide hydrolase - FAAH, Akt, GSK3β and the synaptic proteins Synapsin Ia/b, mGluR1 and PSD95). After 14 days, CBD injections (30 mg/kg) induced anxiolytic responses in stressed animals in the elevated plus-maze and novelty suppressed feeding tests, that were blocked by pre-treatment with a CB 1 (AM251, 0.3 mg/kg) or CB 2 (AM630, 0.3 mg/kg), but not by a 5HT 1A (WAY100635, 0.05 mg/kg) receptor antagonist. Golgi staining and immunofluorescence revealed that these effects were associated with an increase in hippocampal neurogenesis and spine density in the dentate gyrus of the hippocampus. AM251 and AM630 abolished the effects of CBD on spines density. However, AM630 was more effective in attenuating the pro-neurogenic effects of CBD. CBD decreased FAAH and increased p-GSK3β expression in stressed animals, which was also attenuated by AM630. These results indicate that CBD prevents the behavioral effects caused by CUS probably due to a facilitation of endocannabinoid neurotransmission and consequent CB 1 /CB 2 receptors activation, which could recruit intracellular/synaptic proteins involved in neurogenesis and dendritic remodeling. Copyright © 2018 Elsevier Ltd. All rights reserved.

  4. Endocannabinoid system and psychiatry: in search of a neurobiological basis for detrimental and potential therapeutic effects.

    PubMed

    Marco, Eva M; García-Gutiérrez, María S; Bermúdez-Silva, Francisco-Javier; Moreira, Fabricio A; Guimarães, Francisco; Manzanares, Jorge; Viveros, María-Paz

    2011-01-01

    Public concern on mental health has noticeably increased given the high prevalence of neuropsychiatric disorders. Cognition and emotionality are the most affected functions in neuropsychiatric disorders, i.e., anxiety disorders, depression, and schizophrenia. In this review, most relevant literature on the role of the endocannabinoid (eCB) system in neuropsychiatric disorders will be presented. Evidence from clinical and animal studies is provided for the participation of CB1 and CB2 receptors (CB1R and CB2R) in the above mentioned neuropsychiatric disorders. CBRs are crucial in some of the emotional and cognitive impairments reported, although more research is required to understand the specific role of the eCB system in neuropsychiatric disorders. Cannabidiol (CBD), the main non-psychotropic component of the Cannabis sativa plant, has shown therapeutic potential in several neuropsychiatric disorders. Although further studies are needed, recent studies indicate that CBD therapeutic effects may partially depend on facilitation of eCB-mediated neurotransmission. Last but not least, this review includes recent findings on the role of the eCB system in eating disorders. A deregulation of the eCB system has been proposed to be in the bases of several neuropsychiatric disorders, including eating disorders. Cannabis consumption has been related to the appearance of psychotic symptoms and schizophrenia. In contrast, the pharmacological manipulation of this eCB system has been proposed as a potential strategy for the treatment of anxiety disorders, depression, and anorexia nervosa. In conclusion, the eCB system plays a critical role in psychiatry; however, detrimental consequences of manipulating this endogenous system cannot be underestimated over the potential and promising perspectives of its therapeutic manipulation.

  5. Endocannabinoid System and Psychiatry: In Search of a Neurobiological Basis for Detrimental and Potential Therapeutic Effects

    PubMed Central

    Marco, Eva M.; García-Gutiérrez, María S.; Bermúdez-Silva, Francisco-Javier; Moreira, Fabricio A.; Guimarães, Francisco; Manzanares, Jorge; Viveros, María-Paz

    2011-01-01

    Public concern on mental health has noticeably increased given the high prevalence of neuropsychiatric disorders. Cognition and emotionality are the most affected functions in neuropsychiatric disorders, i.e., anxiety disorders, depression, and schizophrenia. In this review, most relevant literature on the role of the endocannabinoid (eCB) system in neuropsychiatric disorders will be presented. Evidence from clinical and animal studies is provided for the participation of CB1 and CB2 receptors (CB1R and CB2R) in the above mentioned neuropsychiatric disorders. CBRs are crucial in some of the emotional and cognitive impairments reported, although more research is required to understand the specific role of the eCB system in neuropsychiatric disorders. Cannabidiol (CBD), the main non-psychotropic component of the Cannabis sativa plant, has shown therapeutic potential in several neuropsychiatric disorders. Although further studies are needed, recent studies indicate that CBD therapeutic effects may partially depend on facilitation of eCB-mediated neurotransmission. Last but not least, this review includes recent findings on the role of the eCB system in eating disorders. A deregulation of the eCB system has been proposed to be in the bases of several neuropsychiatric disorders, including eating disorders. Cannabis consumption has been related to the appearance of psychotic symptoms and schizophrenia. In contrast, the pharmacological manipulation of this eCB system has been proposed as a potential strategy for the treatment of anxiety disorders, depression, and anorexia nervosa. In conclusion, the eCB system plays a critical role in psychiatry; however, detrimental consequences of manipulating this endogenous system cannot be underestimated over the potential and promising perspectives of its therapeutic manipulation. PMID:22007164

  6. Distinct roles of the endocannabinoids anandamide and 2-arachidonoylglycerol in social behavior and emotionality at different developmental ages in rats.

    PubMed

    Manduca, Antonia; Morena, Maria; Campolongo, Patrizia; Servadio, Michela; Palmery, Maura; Trabace, Luigia; Hill, Matthew N; Vanderschuren, Louk J M J; Cuomo, Vincenzo; Trezza, Viviana

    2015-08-01

    To date, our understanding of the relative contribution and potential overlapping roles of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the regulation of brain function and behavior is still limited. To address this issue, we investigated the effects of systemic administration of JZL195, that simultaneously increases AEA and 2-AG signaling by inhibiting their hydrolysis, in the regulation of socio-emotional behavior in adolescent and adult rats. JZL195, administered at the dose of 0.01mg/kg, increased social play behavior, that is the most characteristic social activity displayed by adolescent rats, and increased social interaction in adult animals. At both ages, these behavioral effects were antagonized by the CB1 cannabinoid receptor antagonist SR141716A and were associated with increased brain levels of 2-AG, but not AEA. Conversely, at the dose of 1mg/kg, JZL195 decreased general social exploration in adolescent rats without affecting social play behavior, and induced anxiogenic-like effects in the elevated plus-maze test both in adolescent and adult animals. These effects, mediated by activation of CB1 cannabinoid receptors, were paralleled by simultaneous increase in AEA and 2-AG levels in adolescent rats, and by an increase of only 2-AG levels in adult animals. These findings provide the first evidence for a role of 2-AG in social behavior, highlight the different contributions of AEA and 2-AG in the modulation of emotionality at different developmental ages and suggest that pharmacological inhibition of AEA and 2-AG hydrolysis is a useful approach to investigate the role of these endocannabinoids in neurobehavioral processes. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  7. Effects of Adolescent Intermittent Alcohol Exposure on the Expression of Endocannabinoid Signaling-Related Proteins in the Spleen of Young Adult Rats.

    PubMed

    Pavón, Francisco Javier; Marco, Eva María; Vázquez, Mariam; Sánchez, Laura; Rivera, Patricia; Gavito, Ana; Mela, Virginia; Alén, Francisco; Decara, Juan; Suárez, Juan; Giné, Elena; López-Moreno, José Antonio; Chowen, Julie; Rodríguez-de-Fonseca, Fernando; Serrano, Antonia; Viveros, María Paz

    Intermittent alcohol exposure is a common pattern of alcohol consumption among adolescents and alcohol is known to modulate the expression of the endocannabinoid system (ECS), which is involved in metabolism and inflammation. However, it is unknown whether this pattern may have short-term consequences on the ECS in the spleen. To address this question, we examined the plasma concentrations of metabolic and inflammatory signals and the splenic ECS in early adult rats exposed to alcohol during adolescence. A 4-day drinking in the dark (DID) procedure for 4 weeks was used as a model of intermittent forced-alcohol administration (20%, v/v) in female and male Wistar rats, which were sacrificed 2 weeks after the last DID session. First, there was no liver damage or alterations in plasma metabolic parameters. However, certain plasma inflammatory signals were altered according to sex and alcohol exposition. Whereas fractalkine [chemokine (C-X3-C motif) ligand 1] was only affected by sex with lower concentration in male rats, there was an interaction between sex and alcohol exposure in the TNF-α and interleukin-6 concentrations and only female rats displayed changes. Regarding the mRNA and protein expression of the ECS, the receptors and endocannabinoid-synthesizing enzymes were found to be altered with area-specific expression patterns in the spleen. Overall, whereas the expression of the cannabinoid receptor CB1 and the nuclear peroxisome proliferator-activated receptor PPARα were lower in alcohol-exposed rats compared to control rats, the CB2 expression was higher. Additionally, the N-acyl-phosphatidylethanolamine-specific phospholipase D expression was high in female alcohol-exposed rats and low in male alcohol-exposed rats. In conclusion, intermittent alcohol consumption during adolescence may be sufficient to induce short-term changes in the expression of splenic endocannabinoid signaling-related proteins and plasma pro-inflammatory cytokines in young adult rats

  8. Effects of Adolescent Intermittent Alcohol Exposure on the Expression of Endocannabinoid Signaling-Related Proteins in the Spleen of Young Adult Rats

    PubMed Central

    Vázquez, Mariam; Sánchez, Laura; Rivera, Patricia; Gavito, Ana; Mela, Virginia; Alén, Francisco; Decara, Juan; Suárez, Juan; Giné, Elena; López-Moreno, José Antonio; Chowen, Julie; Rodríguez-de-Fonseca, Fernando; Serrano, Antonia; Viveros, María Paz

    2016-01-01

    Intermittent alcohol exposure is a common pattern of alcohol consumption among adolescents and alcohol is known to modulate the expression of the endocannabinoid system (ECS), which is involved in metabolism and inflammation. However, it is unknown whether this pattern may have short-term consequences on the ECS in the spleen. To address this question, we examined the plasma concentrations of metabolic and inflammatory signals and the splenic ECS in early adult rats exposed to alcohol during adolescence. A 4-day drinking in the dark (DID) procedure for 4 weeks was used as a model of intermittent forced-alcohol administration (20%, v/v) in female and male Wistar rats, which were sacrificed 2 weeks after the last DID session. First, there was no liver damage or alterations in plasma metabolic parameters. However, certain plasma inflammatory signals were altered according to sex and alcohol exposition. Whereas fractalkine [chemokine (C-X3-C motif) ligand 1] was only affected by sex with lower concentration in male rats, there was an interaction between sex and alcohol exposure in the TNF-α and interleukin-6 concentrations and only female rats displayed changes. Regarding the mRNA and protein expression of the ECS, the receptors and endocannabinoid-synthesizing enzymes were found to be altered with area-specific expression patterns in the spleen. Overall, whereas the expression of the cannabinoid receptor CB1 and the nuclear peroxisome proliferator-activated receptor PPARα were lower in alcohol-exposed rats compared to control rats, the CB2 expression was higher. Additionally, the N-acyl-phosphatidylethanolamine-specific phospholipase D expression was high in female alcohol-exposed rats and low in male alcohol-exposed rats. In conclusion, intermittent alcohol consumption during adolescence may be sufficient to induce short-term changes in the expression of splenic endocannabinoid signaling-related proteins and plasma pro-inflammatory cytokines in young adult rats

  9. N-Docosahexaenoyl Dopamine, an Endocannabinoid-like Conjugate of Dopamine and the n-3 Fatty Acid Docosahexaenoic Acid, Attenuates Lipopolysaccharide-Induced Activation of Microglia and Macrophages via COX-2.

    PubMed

    Wang, Ya; Plastina, Pierluigi; Vincken, Jean-Paul; Jansen, Renate; Balvers, Michiel; Ten Klooster, Jean Paul; Gruppen, Harry; Witkamp, Renger; Meijerink, Jocelijn

    2017-03-15

    Several studies indicate that the n-3 long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA) contributes to an attenuated inflammatory status in the development of neurodegenerative disorders, such as Alzheimer's and Parkinson's disease. To explain these effects, different mechanisms are being proposed, including those involving endocannabinoids and related signaling molecules. Many of these compounds belong to the fatty acid amides, conjugates of fatty acids with biogenic amines. Conjugates of DHA with ethanolamine or serotonin have previously been shown to possess anti-inflammatory and potentially neuroprotective properties. Here, we synthesized another amine conjugate of DHA, N-docosahexaenoyl dopamine (DHDA), and tested its immune-modulatory properties in both RAW 264.7 macrophages and BV-2 microglial cells. N-Docosahexaenoyl dopamine significantly suppressed the production of nitric oxide (NO), the cytokine interleukin-6 (IL-6), and the chemokines macrophage-inflammatory protein-3α (CCL20) and monocyte chemoattractant protein-1 (MCP-1), whereas its parent compounds, dopamine and DHA, were ineffective. Further exploration of potential effects of DHDA on key inflammatory mediators revealed that cyclooxygenase-2 (COX-2) mRNA level and production of prostaglandin E 2 (PGE 2 ) were concentration-dependently inhibited in macrophages. In activated BV-2 cells, PGE 2 production was also reduced, without changes in COX-2 mRNA levels. In addition, DHDA did not affect NF-kB activity in a reporter cell line. Finally, the immune-modulatory activities of DHDA were compared with those of N-arachidonoyl dopamine (NADA) and similar potencies were found in both cell types. Taken together, our data suggest that DHDA, a potentially endogenous endocannabinoid, may be an additional member of the group of immune-modulating n-3 fatty acid-derived lipid mediators.

  10. Don't Worry, Be Happy: Endocannabinoids and Cannabis at the Intersection of Stress and Reward.

    PubMed

    Volkow, Nora D; Hampson, Aidan J; Baler, Ruben D

    2017-01-06

    Cannabis enables and enhances the subjective sense of well-being by stimulating the endocannabinoid system (ECS), which plays a key role in modulating the response to stress, reward, and their interactions. However, over time, repeated activation of the ECS by cannabis can trigger neuroadaptations that may impair the sensitivity to stress and reward. This effect, in vulnerable individuals, can lead to addiction and other adverse consequences. The recent shift toward legalization of medical or recreational cannabis has renewed interest in investigating the physiological role of the ECS as well as the potential health effects, both adverse and beneficial, of cannabis. Here we review our current understanding of the ECS and its complex physiological roles. We discuss the implications of this understanding vis-á-vis the ECS's modulation of stress and reward and its relevance to mental disorders in which these processes are disrupted (i.e., addiction, depression, posttraumatic stress disorder, schizophrenia), along with the therapeutic potential of strategies to manipulate the ECS for these conditions.

  11. Endocannabinoid-dependent protection against kainic acid-induced long-term alteration of brain oscillations in guinea pigs.

    PubMed

    Shubina, Liubov; Aliev, Rubin; Kitchigina, Valentina

    2017-04-15

    Changes in rhythmic activity can serve as early biomarkers of pathological alterations, but it remains unclear how different types of rhythmic activity are altered during neurodegenerative processes. Glutamatergic neurotoxicity, evoked by kainic acid (KA), causes hyperexcitation and acute seizures that result in delayed brain damage. We employed wide frequency range (0.1-300Hz) local field potential recordings in guinea pigs to study the oscillatory activity of the hippocampus, entorhinal cortex, medial septum, and amygdala in healthy animals for three months after KA introduction. To clarify whether the activation of endocannabinoid (eCB) system can influence toxic KA action, AM404, an eCB reuptake inhibitor, and URB597, an inhibitor of fatty acid amide hydrolase, were applied. The cannabinoid CB1 receptor antagonist AM251 was also tested. Coadministration of AM404 or URB597 with KA reduced acute behavioral seizures, but electrographic seizures were still registered. During the three months following KA injection, various trends in the oscillatory activities were observed, including an increase in activity power at all frequency bands in the hippocampus and a progressive long-term decrease in the medial septum. In the KA- and KA/AM251-treated animals, disturbances of the oscillatory activities were accompanied by cell loss in the dorsal hippocampus and mossy fiber sprouting in the dentate gyrus. Injections of AM404 or URB597 softened alterations in electrical activity of the brain and prevented hippocampal neuron loss and synaptic reorganization. Our results demonstrate the protective potential of the eCB system during excitotoxic influences. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. N-arachidonoyl l-serine, an endocannabinoid-like brain constituent with vasodilatory properties

    PubMed Central

    Milman, Garry; Maor, Yehoshua; Abu-Lafi, Saleh; Horowitz, Michal; Gallily, Ruth; Batkai, Sandor; Mo, Fong-Ming; Offertaler, Laszlo; Pacher, Pal; Kunos, George; Mechoulam, Raphael

    2006-01-01

    The endocannabinoid N-arachidonoyl ethanolamine (anandamide), found both in the CNS and in the periphery, plays a role in numerous physiological systems. One might expect that the chemically related N-arachidonoyl-l-serine (ARA-S) could also be formed alongside anandamide. We have now isolated ARA-S from bovine brain and elucidated its structure by comparison with synthetic ARA-S. Contrary to anandamide, ARA-S binds very weakly to cannabinoid CB1 and CB2 or vanilloid TRPV1 (transient receptor potential vanilloid 1) receptors. However, it produces endothelium-dependent vasodilation of rat isolated mesenteric arteries and abdominal aorta and stimulates phosphorylation of p44/42 mitogen-activated protein (MAP) kinase and protein kinase B/Akt in cultured endothelial cells. ARA-S also suppresses LPS-induced formation of TNF-α in a murine macrophage cell line and in wild-type mice, as well as in mice deficient in CB1 or CB2 receptors. Many of these effects parallel those reported for abnormal cannabidiol (Abn-CBD), a synthetic agonist of a putative novel cannabinoid-type receptor. Hence, ARA-S may represent an endogenous agonist for this receptor. PMID:16467152

  13. N-arachidonoyl L-serine, an endocannabinoid-like brain constituent with vasodilatory properties.

    PubMed

    Milman, Garry; Maor, Yehoshua; Abu-Lafi, Saleh; Horowitz, Michal; Gallily, Ruth; Batkai, Sandor; Mo, Fong-Ming; Offertaler, Laszlo; Pacher, Pal; Kunos, George; Mechoulam, Raphael

    2006-02-14

    The endocannabinoid N-arachidonoyl ethanolamine (anandamide), found both in the CNS and in the periphery, plays a role in numerous physiological systems. One might expect that the chemically related N-arachidonoyl-L-serine (ARA-S) could also be formed alongside anandamide. We have now isolated ARA-S from bovine brain and elucidated its structure by comparison with synthetic ARA-S. Contrary to anandamide, ARA-S binds very weakly to cannabinoid CB1 and CB2 or vanilloid TRPV1 (transient receptor potential vanilloid 1) receptors. However, it produces endothelium-dependent vasodilation of rat isolated mesenteric arteries and abdominal aorta and stimulates phosphorylation of p44/42 mitogen-activated protein (MAP) kinase and protein kinase B/Akt in cultured endothelial cells. ARA-S also suppresses LPS-induced formation of TNF-alpha in a murine macrophage cell line and in wild-type mice, as well as in mice deficient in CB1 or CB2 receptors. Many of these effects parallel those reported for abnormal cannabidiol (Abn-CBD), a synthetic agonist of a putative novel cannabinoid-type receptor. Hence, ARA-S may represent an endogenous agonist for this receptor.

  14. Sterol Carrier Protein-2: Binding Protein for Endocannabinoids

    PubMed Central

    Liedhegner, Elizabeth Sabens; Vogt, Caleb D.; Sem, Daniel S.; Cunningham, Christopher W.

    2015-01-01

    The endocannabinoid (eCB) system, consisting of eCB ligands and the type 1 cannabinoid receptor (CB1R), subserves retrograde, activity-dependent synaptic plasticity in the brain. eCB signaling occurs “on-demand,” thus the processes regulating synthesis, mobilization and degradation of eCBs are also primary mechanisms for the regulation of CB1R activity. The eCBs, N-arachidonylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), are poorly soluble in water. We hypothesize that their aqueous solubility, and, therefore, their intracellular and transcellular distribution, are facilitated by protein binding. Using in silico docking studies, we have identified the nonspecific lipid binding protein, sterol carrier protein 2 (SCP-2), as a potential AEA binding protein. The docking studies predict that AEA and AM404 associate with SCP-2 at a putative cholesterol binding pocket with ΔG values of −3.6 and −4.6 kcal/mol, respectively. These values are considerably higher than cholesterol (−6.62 kcal/mol) but consistent with a favorable binding interaction. In support of the docking studies, SCP-2-mediated transfer of cholesterol in vitro is inhibited by micromolar concentrations of AEA; and heterologous expression of SCP-2 in HEK 293 cells increases time-related accumulation of AEA in a temperature-dependent fashion. These results suggest that SCP-2 facilitates cellular uptake of AEA. However, there is no effect of SCP-2 transfection on the cellular accumulation of AEA determined at equilibrium or the IC50 values for AEA, AM404 or 2-AG to inhibit steady state accumulation of radiolabelled AEA. We conclude that SCP-2 is a low affinity binding protein for AEA that can facilitate its cellular uptake but does not contribute significantly to intracellular sequestration of AEA. PMID:24510313

  15. Age-dependent plasticity in endocannabinoid modulation of pain processing through postnatal development.

    PubMed

    Kwok, Charlie H-T; Devonshire, Ian M; Imraish, Amer; Greenspon, Charles M; Lockwood, Stevie; Fielden, Catherine; Cooper, Andrew; Woodhams, Stephen; Sarmad, Sarir; Ortori, Catherine A; Barrett, David A; Kendall, David; Bennett, Andrew J; Chapman, Victoria; Hathway, Gareth J

    2017-11-01

    Significant age- and experience-dependent remodelling of spinal and supraspinal neural networks occur, resulting in altered pain responses in early life. In adults, endogenous opioid peptide and endocannabinoid (ECs) pain control systems exist which modify pain responses, but the role they play in acute responses to pain and postnatal neurodevelopment is unknown. Here, we have studied the changing role of the ECs in the brainstem nuclei essential for the control of nociception from birth to adulthood in both rats and humans. Using in vivo electrophysiology, we show that substantial functional changes occur in the effect of microinjection of ECs receptor agonists and antagonists in the periaqueductal grey (PAG) and rostroventral medulla (RVM), both of which play central roles in the supraspinal control of pain and the maintenance of chronic pain states in adulthood. We show that in immature PAG and RVM, the orphan receptor, GPR55, is able to mediate profound analgesia which is absent in adults. We show that tissue levels of endocannabinoid neurotransmitters, anandamide and 2-arachidonoylglycerol, within the PAG and RVM are developmentally regulated (using mass spectrometry). The expression patterns and levels of ECs enzymes and receptors were assessed using quantitative PCR and immunohistochemistry. In human brainstem, we show age-related alterations in the expression of key enzymes and receptors involved in ECs function using PCR and in situ hybridisation. These data reveal that significant changes on ECs that to this point have been unknown and which shed new light into the complex neurochemical changes that permit normal, mature responses to pain.

  16. Differential alterations of the concentrations of endocannabinoids and related lipids in the subcutaneous adipose tissue of obese diabetic patients

    PubMed Central

    2010-01-01

    Background The endocannabinoids, anandamide and 2-AG, are produced by adipocytes, where they stimulate lipogenesis via cannabinoid CB1 receptors and are under the negative control of leptin and insulin. Endocannabinoid levels are elevated in the blood of obese individuals and nonobese type 2 diabetes patients. To date, no study has evaluated endocannabinoid levels in subcutaneous adipose tissue (SAT) of subjects with both obesity and type 2 diabetes (OBT2D), characterised by similar adiposity and whole body insulin resistance and lower plasma leptin levels as compared to non-diabetic obese subjects (OB). Design and Methods The levels of anandamide and 2-AG, and of the anandamide-related PPARα ligands, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), in the SAT obtained by abdominal needle biopsy in 10 OBT2D, 11 OB, and 8 non-diabetic normal-weight (NW) subjects, were measured by liquid chromatography-mass spectrometry. All subjects underwent a hyperinsulinaemic euglycaemic clamp. Results As compared to NW, anandamide, OEA and PEA levels in the SAT were 2-4.4-fold elevated (p < 0.05), and 2-AG levels 2.3-fold reduced (p < .05), in OBT2D but not in OB subjects. Anandamide, OEA and PEA correlated positively (p < .05) with SAT leptin mRNA and free fatty acid during hyperinsulinaemic clamp, and negatively with SAT LPL activity and plasma HDL-cholesterol, which were all specifically altered in OBT2D subjects. Conclusions The observed alterations emphasize, for the first time in humans, the potential different role and regulation of adipose tissue anandamide (and its congeners) and 2-AG in obesity and type 2 diabetes. PMID:20426869

  17. Endocannabinoids and traumatic brain injury.

    PubMed

    Shohami, Esther; Cohen-Yeshurun, Ayelet; Magid, Lital; Algali, Merav; Mechoulam, Raphael

    2011-08-01

    Traumatic brain injury (TBI) represents the leading cause of death in young individuals. It triggers the accumulation of harmful mediators, leading to secondary damage, yet protective mechanisms are also set in motion. The endocannabinoid (eCB) system consists of ligands, such as anandamide and 2-arachidonoyl-glycerol (2-AG), receptors (e.g. CB1, CB2), transporters and enzymes, which are responsible for the 'on-demand' synthesis and degradation of these lipid mediators. There is a large body of evidence showing that eCB are markedly increased in response to pathogenic events. This fact, as well as numerous studies on experimental models of brain toxicity, neuroinflammation and trauma supports the notion that the eCB are part of the brain's compensatory or repair mechanisms. These are mediated via CB receptors signalling pathways that are linked to neuronal survival and repair. The levels of 2-AG, the most highly abundant eCB, are significantly elevated after TBI and when administered to TBI mice, 2-AG decreases brain oedema, inflammation and infarct volume and improves clinical recovery. The role of CB1 in mediating these effects was demonstrated using selective antagonists or CB1 knockout mice. CB2 were shown in other models of brain insults to reduce white blood cell rolling and adhesion, to reduce infarct size and to improve motor function. This review is focused on the role the eCB system plays as a self-neuroprotective mechanism and its potential as a basis for the development of novel therapeutic modality for the treatment of CNS pathologies with special emphasis on TBI. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  18. Exposure to a Highly Caloric Palatable Diet During Pregestational and Gestational Periods Affects Hypothalamic and Hippocampal Endocannabinoid Levels at Birth and Induces Adiposity and Anxiety-Like Behaviors in Male Rat Offspring

    PubMed Central

    Ramírez-López, María Teresa; Vázquez, Mariam; Bindila, Laura; Lomazzo, Ermelinda; Hofmann, Clementine; Blanco, Rosario Noemí; Alén, Francisco; Antón, María; Decara, Juan; Ouro, Daniel; Orio, Laura; Suarez, Juan; Lutz, Beat; Rodríguez de Fonseca, Fernando; Gómez de Heras, Raquel

    2016-01-01

    Exposure to unbalanced diets during pre-gestational and gestational periods may result in long-term alterations in metabolism and behavior. The contribution of the endocannabinoid system to these long-term adaptive responses is unknown. In the present study, we investigated the impact of female rat exposure to a hypercaloric-hypoproteic palatable diet during pre-gestational, gestational and lactational periods on the development of male offspring. In addition, the hypothalamic and hippocampal endocannabinoid contents at birth and the behavioral performance in adulthood were investigated. Exposure to a palatable diet resulted in low weight offspring who exhibited low hypothalamic contents of arachidonic acid and the two major endocannabinoids (anandamide and 2-arachidonoylglycerol) at birth. Palmitoylethanolamide, but not oleoylethanolamide, also decreased. Additionally, pups from palatable diet-fed dams displayed lower levels of anandamide and palmitoylethanolamide in the hippocampus. The low-weight male offspring, born from palatable diet exposed mothers, gained less weight during lactation and although they recovered weight during the post-weaning period, they developed abdominal adiposity in adulthood. These animals exhibited anxiety-like behavior in the elevated plus-maze and open field test and a low preference for a chocolate diet in a food preference test, indicating that maternal exposure to a hypercaloric diet induces long-term behavioral alterations in male offspring. These results suggest that maternal diet alterations in the function of the endogenous cannabinoid system can mediate the observed phenotype of the offspring, since both hypothalamic and hippocampal endocannabinoids regulate feeding, metabolic adaptions to caloric diets, learning, memory, and emotions. PMID:26778987

  19. Peripheral Endocannabinoid Responses to Hedonic Eating in Binge-Eating Disorder

    PubMed Central

    Monteleone, Alessio Maria; Piscitelli, Fabiana; Dalle Grave, Riccardo; El Ghoch, Marwan; Maj, Mario

    2017-01-01

    Reward mechanisms are likely implicated in the pathophysiology of binge-eating behaviour, which is a key symptom of binge-eating disorder (BED). Since endocannabinoids modulate food-related reward, we aimed to investigate the responses of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) to hedonic eating in patients with BED. Peripheral levels of AEA and 2-AG were measured in 7 obese BED patients before and after eating favorite (hedonic eating) and non-favorite (non-hedonic eating) foods. We found that plasma levels of AEA progressively decreased after eating the non-favorite food and significantly increased after eating the favorite food, whereas plasma levels of 2-AG did not differ significantly between the two test conditions, although they showed a trend toward significantly different time patterns. The changes in peripheral AEA levels were positively correlated to the subjects’ sensations of the urge to eat and the pleasantness while eating the presented food, while changes in peripheral 2-AG levels were positively correlated to the subjects’ sensation of the pleasantness while eating the presented food and to the amount of food they would eat. These results suggest the occurrence of distinctive responses of endocannabinoids to food-related reward in BED. The relevance of such findings to the pathophysiology of BED remains to be elucidated. PMID:29261146

  20. Interactions between ethanol and the endocannabinoid system at GABAergic synapses on basolateral amygdala principal neurons

    PubMed Central

    Talani, Giuseppe; Lovinger, David M.

    2015-01-01

    The basolateral amygdala (BLA) plays crucial roles in stimulus value coding, as well as drug and alcohol dependence. Ethanol alters synaptic transmission in the BLA, while endocannabinoids (eCBs) produce presynaptic depression at BLA synapses. Recent studies suggest interactions between ethanol and eCBs that have important consequences for alcohol drinking behavior. To determine how ethanol and eCBs interact in the BLA, we examined the physiology and pharmacology of GABAergic synapses onto BLA pyramidal neurons in neurons from young rats. Application of ethanol at concentrations relevant to intoxication increased, in both young and adult animals, the frequency of spontaneous and miniature GABAergic inhibitory postsynaptic currents, indicating a presynaptic site of ethanol action. The potentiation by ethanol was prevented by inhibition by adenylyl cyclase, and reduced by inhibition by protein kinase A. Activation of type 1 cannabinoid receptors (CB1) in the BLA inhibited GABAergic transmission via an apparent presynaptic mechanism, and prevented ethanol potentiation. Surprisingly, ethanol potentiation was also prevented by CB1 antagonists/inverse agonists. Brief depolarization of BLA pyramidal neurons suppressed GABAergic transmission (depolarization-induced suppression of inhibition [DSI]), an effect previously shown to be mediated by postsynaptic eCB release and presynaptic CB1 activation. A CB1-mediated suppression of GABAergic transmission was also produced by combined afferent stimulation at 0.1 Hz (LFS), and postsynaptic loading with the eCB arachidonoyl ethanolamide (AEA). Both DSI and LFS-induced synaptic depression were prevented by ethanol. Our findings indicate antagonistic interactions between ethanol and eCB/CB1 modulation at GABAergic BLA synapses that may contribute to eCB roles in ethanol seeking and drinking. PMID:26603632

  1. Effects of 2-AG on the reinforcing properties of wheel activity in obese and lean Zucker rats.

    PubMed

    Smith, Shilo L; Rasmussen, Erin B

    2010-07-01

    The endocannabinoid system plays a role in obesity, primarily by its role in food reward. Activity, also involved in obesity, seems to be at least partially controlled by the endocannabinoid system, but the relevant behavioral and neurochemical mechanisms have not been well established. This study represents an attempt to begin elucidating these mechanisms by examining the effects of an endogenous cannabinoid ligand, 2-arachidonoylglycerol (2-AG), on the reinforcing properties of exercise reinforcement in lean and obese Zucker rats. Ten obese and 10 lean Zucker rats pressed a locked door under a progressive ratio schedule of reinforcement that, when unlocked, provided access to a running wheel for 2-min periods. After baseline breakpoints were established, doses of 2-AG (0.3-3 mg/kg) were administered before experimental sessions. Obese rats exhibited lower breakpoints for wheel activity, lower response rates, and fewer revolutions compared with lean rats. 2-AG decreased breakpoints, response rates, and revolutions for obese rats, and revolutions only for lean rats. These data suggest that 2-AG may reduce the reinforcing properties of activity, and that obese Zuckers may show a greater sensitivity to 2-AG. The data also suggest that endocannabinoids may play a role in the reinforcing properties of exercise.

  2. Endocannabinoid signaling at the periphery: 50 years after THC

    PubMed Central

    Maccarrone, Mauro; Bab, Itai; Bíró, Tamás; Cabral, Guy A.; Dey, Sudhansu K.; Di Marzo, Vincenzo; Konje, Justin C.; Kunos, George; Mechoulam, Raphael; Pacher, Pal; Sharkey, Keith A.; Zimmer, Andreas

    2015-01-01

    Fifty years ago (in 1964) the psychoactive ingredient of Cannabis sativa, Δ9-tetrahydrocannabinol (THC), was isolated. Nearly 30 years later the endogenous counterparts of THC, collectively termed endocannabinoids (eCBs), were discovered: N-arachidonoylethanolamine (anandamide, AEA) in 1992, and 2-arachidonoylglycerol (2-AG) in 1995. Since then, considerable research has shed light on the impact of eCBs on human health and disease, identifying an ensemble of proteins that bind, synthesize and degrade them, and that altogether form the eCB system. eCBs control basic biological processes, including cell-choice between survival and death, and progenitor/stem cell proliferation and differentiation. Not surprisingly, in the past two decades, eCBs have been recognized as key mediators of several aspects of human pathophysiology, and thus have emerged among the most widespread and versatile signaling molecules ever discovered. Here, some of the pioneers of this research field review the state-of-the-art of critical eCB functions in peripheral organs. Our community effort is aimed at establishing consensus views on the relevance of the peripheral eCB system for human health and disease pathogenesis, as well as to highlight emerging challenges and therapeutic hopes. PMID:25796370

  3. Kainate Receptors Inhibit Glutamate Release Via Mobilization of Endocannabinoids in Striatal Direct Pathway Spiny Projection Neurons.

    PubMed

    Marshall, John J; Xu, Jian; Contractor, Anis

    2018-04-18

    Kainate receptors are members of the glutamate receptor family that function by both generating ionotropic currents through an integral ion channel pore and coupling to downstream metabotropic signaling pathways. They are highly expressed in the striatum, yet their roles in regulating striatal synapses are not known. Using mice of both sexes, we demonstrate that GluK2-containing kainate receptors expressed in direct pathway spiny projection neurons (dSPNs) inhibit glutamate release at corticostriatal synapses in the dorsolateral striatum. This inhibition requires postsynaptic kainate-receptor-mediated mobilization of a retrograde endocannabinoid (eCB) signal and activation of presynaptic CB1 receptors. This pathway can be activated during repetitive 25 Hz trains of synaptic stimulation, causing short-term depression of corticostriatal synapses. This is the first study to demonstrate a role for kainate receptors in regulating eCB-mediated plasticity at the corticostriatal synapse and demonstrates an important role for these receptors in regulating basal ganglia circuits. SIGNIFICANCE STATEMENT The GRIK2 gene, encoding the GluK2 subunit of the kainate receptor, has been linked to several neuropsychiatric and neurodevelopmental disorders including obsessive compulsive disorder (OCD). Perseverative behaviors associated with OCD are known to result from pathophysiological changes in the striatum and kainate receptor knock-out mice have striatal-dependent phenotypes. However, the role of kainate receptors in striatal synapses is not known. We demonstrate that GluK2-containing kainate receptors regulate corticostriatal synapses by mobilizing endocannabinoids from direct pathway spiny projection neurons. Synaptic activation of GluK2 receptors during trains of synaptic input causes short-term synaptic depression, demonstrating a novel role for these receptors in regulating striatal circuits. Copyright © 2018 the authors 0270-6474/18/383901-10$15.00/0.

  4. Endocannabinoids and traumatic brain injury

    PubMed Central

    Shohami, Esther; Cohen-Yeshurun, Ayelet; Magid, Lital; Algali, Merav; Mechoulam, Raphael

    2011-01-01

    Traumatic brain injury (TBI) represents the leading cause of death in young individuals. It triggers the accumulation of harmful mediators, leading to secondary damage, yet protective mechanisms are also set in motion. The endocannabinoid (eCB) system consists of ligands, such as anandamide and 2-arachidonoyl-glycerol (2-AG), receptors (e.g. CB1, CB2), transporters and enzymes, which are responsible for the ‘on-demand’ synthesis and degradation of these lipid mediators. There is a large body of evidence showing that eCB are markedly increased in response to pathogenic events. This fact, as well as numerous studies on experimental models of brain toxicity, neuroinflammation and trauma supports the notion that the eCB are part of the brain's compensatory or repair mechanisms. These are mediated via CB receptors signalling pathways that are linked to neuronal survival and repair. The levels of 2-AG, the most highly abundant eCB, are significantly elevated after TBI and when administered to TBI mice, 2-AG decreases brain oedema, inflammation and infarct volume and improves clinical recovery. The role of CB1 in mediating these effects was demonstrated using selective antagonists or CB1 knockout mice. CB2 were shown in other models of brain insults to reduce white blood cell rolling and adhesion, to reduce infarct size and to improve motor function. This review is focused on the role the eCB system plays as a self-neuroprotective mechanism and its potential as a basis for the development of novel therapeutic modality for the treatment of CNS pathologies with special emphasis on TBI. LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7 PMID:21418185

  5. Circulating endocannabinoids in insulin sensitive vs. insulin resistant obese postmenopausal women. A MONET group study.

    PubMed

    Abdulnour, Joseph; Yasari, Siham; Rabasa-Lhoret, Rémi; Faraj, May; Petrosino, Stefania; Piscitelli, Fabiana; Prud' Homme, Denis; Di Marzo, Vincenzo

    2014-01-01

    To measure the circulating levels of endocannabinoids and related molecules at fasting, after acute hyperinsulinemia and after weight loss in insulin sensitive vs. insulin resistant obese postmenopausal women. The sample consisted of 30 obese postmenopausal women (age: 58.9 ± 5.2 yrs; BMI: 32.9 ± 3.6 kg/m(2) ). Subjects underwent a 3-hour hyperinsulinaemic-euglycaemic clamp (HEC) (glucose disposal rate (M-value): 10.7 ± 3.3 mg min(-1) kg(-1) FFM) and 6-month weight loss intervention. Participants were classified as insulin sensitive obese (ISO) or insulin resistant obese (IRO) based on a predefined cutoff. Plasma levels of the endocannabinoids, anandamide (AEA), 2-arachidonoylglycerol (2-AG), and of the AEA-related compounds, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), were measured by liquid chromatography-mass spectrometry. IRO presented higher levels of 2-AG (P < 0.05) independently of the HEC and weight loss, whereas the HEC had an independent inhibitory effect on AEA, PEA, and OEA levels (P < 0.05) in both groups. Furthermore, there was an independent stimulatory effect of weight loss only on PEA levels in both groups (P < 0.05). This study is the first to show that higher circulating levels of the endocannabinoid 2-AG are found in IRO compared to ISO postmenopausal women, and that weight loss is associated with an increase in PEA, a PPAR-α ligand. © 2013 The Obesity Society.

  6. Endocannabinoid and cannabinoid-like fatty acid amide levels correlate with pain-related symptoms in patients with IBS-D and IBS-C: a pilot study.

    PubMed

    Fichna, Jakub; Wood, Jodianne T; Papanastasiou, Malvina; Vadivel, Subramanian K; Oprocha, Piotr; Sałaga, Maciej; Sobczak, Marta; Mokrowiecka, Anna; Cygankiewicz, Adam I; Zakrzewski, Piotr K; Małecka-Panas, Ewa; Krajewska, Wanda M; Kościelniak, Piotr; Makriyannis, Alexandros; Storr, Martin A

    2013-01-01

    Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder, associated with alterations of bowel function, abdominal pain and other symptoms related to the GI tract. Recently the endogenous cannabinoid system (ECS) was shown to be involved in the physiological and pathophysiological control of the GI function. The aim of this pilot study was to investigate whether IBS defining symptoms correlate with changes in endocannabinoids or cannabinoid like fatty acid levels in IBS patients. AEA, 2-AG, OEA and PEA plasma levels were determined in diarrhoea-predominant (IBS-D) and constipation-predominant (IBS-C) patients and were compared to healthy subjects, following the establishment of correlations between biolipid contents and disease symptoms. FAAH mRNA levels were evaluated in colonic biopsies from IBS-D and IBS-C patients and matched controls. Patients with IBS-D had higher levels of 2AG and lower levels of OEA and PEA. In contrast, patients with IBS-C had higher levels of OEA. Multivariate analysis found that lower PEA levels are associated with cramping abdominal pain. FAAH mRNA levels were lower in patients with IBS-C. IBS subtypes and their symptoms show distinct alterations of endocannabinoid and endocannabinoid-like fatty acid levels. These changes may partially result from reduced FAAH expression. The here reported changes support the notion that the ECS is involved in the pathophysiology of IBS and the development of IBS symptoms.

  7. Endocannabinoid signaling in hypothalamic circuits regulates arousal from general anesthesia in mice

    PubMed Central

    Zhong, Haixing; Tong, Li; Gu, Ning; Gao, Fang; Lu, Yacheng; Liu, Jingjing; Li, Xin; Bergeron, Richard; Pomeranz, Lisa E.; Wang, Feng; Luo, Chun-Xia; Ren, Yan; Wu, Sheng-Xi; Xie, Zhongcong; Xu, Lin; Li, Jinlian; Dong, Hailong; Xiong, Lize

    2017-01-01

    Consciousness can be defined by two major attributes: awareness of environment and self, and arousal, which reflects the level of awareness. The return of arousal after general anesthesia presents an experimental tool for probing the neural mechanisms that control consciousness. Here we have identified that systemic or intracerebral injection of the cannabinoid CB1 receptor (CB1R) antagonist AM281 into the dorsomedial nucleus of the hypothalamus (DMH) — but not the adjacent perifornical area (Pef) or the ventrolateral preoptic nucleus of the hypothalamus (VLPO) — accelerates arousal in mice recovering from general anesthesia. Anesthetics selectively activated endocannabinoid (eCB) signaling at DMH glutamatergic but not GABAergic synapses, leading to suppression of both glutamatergic DMH-Pef and GABAergic DMH-VLPO projections. Deletion of CB1R from widespread cerebral cortical or prefrontal cortical (PFC) glutamatergic neurons, including those innervating the DMH, mimicked the arousal-accelerating effects of AM281. In contrast, CB1R deletion from brain GABAergic neurons or hypothalamic glutamatergic neurons did not affect recovery time from anesthesia. Inactivation of PFC-DMH, DMH-VLPO, or DMH-Pef projections blocked AM281-accelerated arousal, whereas activation of these projections mimicked the effects of AM281. We propose that decreased eCB signaling at glutamatergic terminals of the PFC-DMH projection accelerates arousal from general anesthesia through enhancement of the excitatory DMH-Pef projection, the inhibitory DMH-VLPO projection, or both. PMID:28463228

  8. Individual differences in frontolimbic circuitry and anxiety emerge with adolescent changes in endocannabinoid signaling across species.

    PubMed

    Gee, Dylan G; Fetcho, Robert N; Jing, Deqiang; Li, Anfei; Glatt, Charles E; Drysdale, Andrew T; Cohen, Alexandra O; Dellarco, Danielle V; Yang, Rui R; Dale, Anders M; Jernigan, Terry L; Lee, Francis S; Casey, B J

    2016-04-19

    Anxiety disorders peak in incidence during adolescence, a developmental window that is marked by dynamic changes in gene expression, endocannabinoid signaling, and frontolimbic circuitry. We tested whether genetic alterations in endocannabinoid signaling related to a common polymorphism in fatty acid amide hydrolase (FAAH), which alters endocannabinoid anandamide (AEA) levels, would impact the development of frontolimbic circuitry implicated in anxiety disorders. In a pediatric imaging sample of over 1,000 3- to 21-y-olds, we show effects of the FAAH genotype specific to frontolimbic connectivity that emerge by ∼12 y of age and are paralleled by changes in anxiety-related behavior. Using a knock-in mouse model of the FAAH polymorphism that controls for genetic and environmental backgrounds, we confirm phenotypic differences in frontoamygdala circuitry and anxiety-related behavior by postnatal day 45 (P45), when AEA levels begin to decrease, and also, at P75 but not before. These results, which converge across species and level of analysis, highlight the importance of underlying developmental neurobiology in the emergence of genetic effects on brain circuitry and function. Moreover, the results have important implications for the identification of risk for disease and precise targeting of treatments to the biological state of the developing brain as a function of developmental changes in gene expression and neural circuit maturation.

  9. Cell-autonomous excitation of midbrain dopamine neurons by endocannabinoid-dependent lipid signaling

    PubMed Central

    Gantz, Stephanie C.; Bean, Bruce P.

    2017-01-01

    SUMMARY The major endocannabinoid in the mammalian brain is the bioactive lipid 2-arachidonoylglycerol (2-AG). The best-known effects of 2-AG are mediated by G protein-coupled cannabinoid receptors. In principle, 2-AG could modify neuronal excitability by acting directly on ion channels, but such mechanisms are poorly understood. Using a preparation of dissociated mouse midbrain dopamine neurons to isolate effects on intrinsic excitability, we found that 100 nM 2-AG accelerated pacemaking and steepened the frequency-current relationship for burst-like firing. In voltage-clamp experiments, 2-AG reduced A-type potassium current (IA) through a cannabinoid receptor-independent mechanism mimicked by arachidonic acid, which has no activity on cannabinoid receptors. Activation of orexin, neurotensin, and metabotropic glutamate Gq/11-linked receptors mimicked the effects of exogenous 2-AG and their actions were prevented by inhibiting the 2-AG-synthesizing enzyme diacylglycerol lipase α. The results show that 2-AG and related lipid signaling molecules can directly tune neuronal excitability in a cell-autonomous manner by modulating IA. PMID:28262417

  10. Restricted vs. unrestricted wheel running in mice: Effects on brain, behavior and endocannabinoids.

    PubMed

    Biedermann, Sarah V; Auer, Matthias K; Bindila, Laura; Ende, Gabriele; Lutz, Beat; Weber-Fahr, Wolfgang; Gass, Peter; Fuss, Johannes

    2016-11-01

    Beneficial effects of voluntary wheel running on hippocampal neurogenesis, morphology and hippocampal-dependent behavior have widely been studied in rodents, but also serious side effects and similarities to stereotypy have been reported. Some mouse strains run excessively when equipped with running wheels, complicating the comparability to human exercise regimes. Here, we investigated how exercise restriction to 6h/day affects hippocampal morphology and metabolism, stereotypic and basal behaviors, as well as the endocannabinoid system in wheel running C57BL/6 mice; the strain most commonly used for behavioral analyses and psychiatric disease models. Restricted and unrestricted wheel running had similar effects on immature hippocampal neuron numbers, thermoregulatory nest building and basal home-cage behaviors. Surprisingly, hippocampal gray matter volume, assessed with magnetic resonance (MR) imaging at 9.4 Tesla, was only increased in unrestricted but not in restricted runners. Moreover, unrestricted runners showed less stereotypic behavior than restricted runners did. However, after blockage of running wheels for 24h stereotypic behavior also increased in unrestricted runners, arguing against a long-term effect of wheel running on stereotypic behavior. Stereotypic behaviors correlated with frontal glutamate and glucose levels assessed by 1 H-MR spectroscopy. While acute running increased plasma levels of the endocannabinoid anandamide in former studies in mice and humans, we found an inverse correlation of anandamide with the daily running distance after long-term running. In conclusion, although there are some diverging effects of restricted and unrestricted running on brain and behavior, restricted running does not per se seem to be a better animal model for aerobic exercise in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Emotional arousal state influences the ability of amygdalar endocannabinoid signaling to modulate anxiety.

    PubMed

    Morena, Maria; Leitl, Kira D; Vecchiarelli, Haley A; Gray, J Megan; Campolongo, Patrizia; Hill, Matthew N

    2016-12-01

    Systemic activation of cannabinoid receptors often induces biphasic effects on emotional memory and anxiety depending on the levels of emotional arousal associated to the experimental context. The basolateral nucleus of the amygdala (BLA) represents a crucial structure for the ability of endocannabinoid (eCB) signaling to modulate emotional behaviour, and receives dense projections from brainstem arousal system nuclei. We examined whether changes in emotional arousal state would influence the ability of acute eCB manipulations within the BLA to modulate anxiety. Rats were tested in an elevated plus maze (EPM) under low or high arousal conditions. The low emotional arousal group was extensively handled and habituated to the experimental room and tested under red light condition, the high emotional arousal group was not handled or habituated and tested under high light condition. We examined amygdalar eCB anandamide (AEA) and 2-arachidonoylglycerol (2-AG) levels immediately after the EPM and the effects of intra-BLA administration of the AEA hydrolysis inhibitor URB597 or the 2-AG hydrolysis inhibitor KML29 on anxiety behaviour. The modulation of anxiety-like behaviour by eCBs in the BLA was strictly dependent on the environmental-associated emotional arousal. Pharmacologically-induced elevations of AEA or 2-AG in the BLA decreased anxiety under conditions of low emotional arousal. Conversely, when the level of emotional arousal increased, local eCB manipulation was ineffective in the modulation of the emotional arousal-induced anxiety response. These findings suggest that, depending on the emotional arousal state, eCB system is differentially activated to regulate the anxiety response in the amygdala and help to understand the state-dependency of many interventions on anxiety. Copyright © 2016. Published by Elsevier Ltd.

  12. Social defeat leads to changes in the endocannabinoid system: An overexpression of calreticulin and motor impairment in mice.

    PubMed

    Tomas-Roig, J; Piscitelli, F; Gil, V; Del Río, J A; Moore, T P; Agbemenyah, H; Salinas-Riester, G; Pommerenke, C; Lorenzen, S; Beißbarth, T; Hoyer-Fender, S; Di Marzo, V; Havemann-Reinecke, U

    2016-04-15

    Prolonged and sustained stimulation of the hypothalamo-pituitary-adrenal axis have adverse effects on numerous brain regions, including the cerebellum. Motor coordination and motor learning are essential for animal and require the regulation of cerebellar neurons. The G-protein-coupled cannabinoid CB1 receptor coordinates synaptic transmission throughout the CNS and is of highest abundance in the cerebellum. Accordingly, the aim of this study was to investigate the long-lasting effects of chronic psychosocial stress on motor coordination and motor learning, CB1 receptor expression, endogenous cannabinoid ligands and gene expression in the cerebellum. After chronic psychosocial stress, motor coordination and motor learning were impaired as indicated the righting reflex and the rota-rod. The amount of the endocannabinoid 2-AG increased while CB1 mRNA and protein expression were downregulated after chronic stress. Transcriptome analysis revealed 319 genes differentially expressed by chronic psychosocial stress in the cerebellum; mainly involved in synaptic transmission, transmission of nerve impulse, and cell-cell signaling. Calreticulin was validated as a stress candidate gene. The present study provides evidence that chronic stress activates calreticulin and might be one of the pathological mechanisms underlying the motor coordination and motor learning dysfunctions seen in social defeat mice. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Monoacylglycerol lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer.

    PubMed

    Nomura, Daniel K; Lombardi, Donald P; Chang, Jae Won; Niessen, Sherry; Ward, Anna M; Long, Jonathan Z; Hoover, Heather H; Cravatt, Benjamin F

    2011-07-29

    Cancer cells couple heightened lipogenesis with lipolysis to produce fatty acid networks that support malignancy. Monoacylglycerol lipase (MAGL) plays a principal role in this process by converting monoglycerides, including the endocannabinoid 2-arachidonoylglycerol (2-AG), to free fatty acids. Here, we show that MAGL is elevated in androgen-independent versus androgen-dependent human prostate cancer cell lines, and that pharmacological or RNA-interference disruption of this enzyme impairs prostate cancer aggressiveness. These effects were partially reversed by treatment with fatty acids or a cannabinoid receptor-1 (CB1) antagonist, and fully reversed by cotreatment with both agents. We further show that MAGL is part of a gene signature correlated with epithelial-to-mesenchymal transition and the stem-like properties of cancer cells, supporting a role for this enzyme in protumorigenic metabolism that, for prostate cancer, involves the dual control of endocannabinoid and fatty acid pathways. Copyright © 2011 Elsevier Ltd. All rights reserved.

  14. Type 2 diabetes associated changes in the plasma non-esterified fatty acids, oxylipins and endocannabinoids

    USDA-ARS?s Scientific Manuscript database

    Type 2 diabetes (T2D) has profound effects on metabolism that can be detected in plasma. While increases in circulating non-esterified fatty acids (NEFA) are well described in T2D, effects on circulating signaling lipids have received little attention. Oxylipins and endocannabinoids are classes of ...

  15. Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors.

    PubMed

    Melis, Miriam; Pillolla, Giuliano; Luchicchi, Antonio; Muntoni, Anna Lisa; Yasar, Sevil; Goldberg, Steven R; Pistis, Marco

    2008-12-17

    Nicotine stimulates the activity of mesolimbic dopamine neurons, which is believed to mediate the rewarding and addictive properties of tobacco use. Accumulating evidence suggests that the endocannabinoid system might play a major role in neuronal mechanisms underlying the rewarding properties of drugs of abuse, including nicotine. Here, we investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area with electrophysiological techniques in vivo and in vitro. We discovered that pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes fatty acid ethanolamides, among which the endocannabinoid anandamide (AEA) is the best known, suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide, the hydrolysis resistant analog of AEA. OEA and PEA are naturally occurring lipid signaling molecules structurally related to AEA, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-alpha triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-alpha in the brain and provide a potential new target for the treatment of nicotine addiction.

  16. Therapeutic potential of cannabinoids in schizophrenia.

    PubMed

    Kucerova, Jana; Tabiova, Katarina; Drago, Filippo; Micale, Vincenzo

    2014-04-01

    Increasing evidence suggests a close relationship between the endocannabinoid system and schizophrenia. The endocannabinoid system comprises of two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuana's psychoactive principle Δ(9)-tetrahydrocannabinol), their endogenous small lipid ligands (namely anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and proteins for endocannabinoid biosynthesis and degradation. It has been suggested to be a pro-homeostatic and pleiotropic signalling system activated in a time- and tissue-specific manner during pathophysiological conditions. In the brain, activation of this system impacts the release of numerous neurotransmitters in various systems and cytokines from glial cells. Hence, the endocannabinoid system is strongly involved in neuropsychiatric disorders, such as schizophrenia. Therefore, adolescence use of Cannabis may alter the endocannabinoid signalling and pose a potential environmental risk to develop psychosis. Consistently, preclinical and clinical studies have found a dysregulation in the endocannabinoid system such as changed expression of CB1 and CB2 receptors or altered levels of AEA and 2-AG . Thus, due to the partial efficacy of actual antipsychotics, compounds which modulate this system may provide a novel therapeutic target for the treatment of schizophrenia. The present article reviews current available knowledge on herbal, synthetic and endogenous cannabinoids with respect to the modulation of schizophrenic symptomatology. Furthermore, this review will be highlighting the therapeutic potential of cannabinoid-related compounds and presenting some promising patents targeting potential treatment options for schizophrenia.

  17. The prefrontal cortical endocannabinoid system modulates fear-pain interactions in a subregion-specific manner.

    PubMed

    Rea, Kieran; McGowan, Fiona; Corcoran, Louise; Roche, Michelle; Finn, David P

    2018-05-30

    The emotional processing and coordination of top-down responses to noxious and conditioned aversive stimuli involves the medial prefrontal cortex (mPFC). Evidence suggests that subregions of the mPFC, (infralimbic (IL), prelimbic (PrL), anterior cingulate (ACC) cortices), differentially alter the expression of contextually-induced fear and nociceptive behaviour. We investigated the role of the endocannabinoid system in the IL, PrL and ACC in formalin-evoked nociceptive behaviour, fear-conditioned analgesia (FCA) and conditioned fear in the presence of nociceptive tone. FCA was modelled in male Lister-hooded rats by assessing formalin-evoked nociceptive behaviour in an arena previously paired with footshock. The effects of intra-mPFC administration of AM251 (CB 1 receptor antagonist/inverse agonist), URB597 (fatty acid amide hydrolase inhibitor) or URB597 + AM251 on FCA and freezing behaviour were assessed. AM251 attenuated FCA when injected into the IL or PrL and reduced contextually induced freezing behaviour when injected intra-IL, but not intra-PrL or intra-ACC. Intra-ACC administration of AM251 alone or in combination with URB597 had no effect on FCA or freezing. URB597 attenuated FCA and freezing behaviour when injected intra-IL, prolonged the expression of FCA when injected intra-PrL and had no effect on these behaviours when injected intra-ACC. These results suggest important and differential roles for FAAH substrates or CB 1 receptors in the PrL, IL and ACC in the expression of FCA and conditioned fear in the presence of nociceptive tone. This article is protected by copyright. All rights reserved.

  18. Ghrelin decreases firing activity of gonadotropin-releasing hormone (GnRH) neurons in an estrous cycle and endocannabinoid signaling dependent manner.

    PubMed

    Farkas, Imre; Vastagh, Csaba; Sárvári, Miklós; Liposits, Zsolt

    2013-01-01

    The orexigenic peptide, ghrelin is known to influence function of GnRH neurons, however, the direct effects of the hormone upon these neurons have not been explored, yet. The present study was undertaken to reveal expression of growth hormone secretagogue receptor (GHS-R) in GnRH neurons and elucidate the mechanisms of ghrelin actions upon them. Ca(2+)-imaging revealed a ghrelin-triggered increase of the Ca(2+)-content in GT1-7 neurons kept in a steroid-free medium, which was abolished by GHS-R-antagonist JMV2959 (10 µM) suggesting direct action of ghrelin. Estradiol (1nM) eliminated the ghrelin-evoked rise of Ca(2+)-content, indicating the estradiol dependency of the process. Expression of GHS-R mRNA was then confirmed in GnRH-GFP neurons of transgenic mice by single cell RT-PCR. Firing rate and burst frequency of GnRH-GFP neurons were lower in metestrous than proestrous mice. Ghrelin (40 nM-4 μM) administration resulted in a decreased firing rate and burst frequency of GnRH neurons in metestrous, but not in proestrous mice. Ghrelin also decreased the firing rate of GnRH neurons in males. The ghrelin-evoked alterations of the firing parameters were prevented by JMV2959, supporting the receptor-specific actions of ghrelin on GnRH neurons. In metestrous mice, ghrelin decreased the frequency of GABAergic mPSCs in GnRH neurons. Effects of ghrelin were abolished by the cannabinoid receptor type-1 (CB1) antagonist AM251 (1µM) and the intracellularly applied DAG-lipase inhibitor THL (10 µM), indicating the involvement of retrograde endocannabinoid signaling. These findings demonstrate that ghrelin exerts direct regulatory effects on GnRH neurons via GHS-R, and modulates the firing of GnRH neurons in an ovarian-cycle and endocannabinoid dependent manner.

  19. Drug-Induced Alterations of Endocannabinoid-Mediated Plasticity in Brain Reward Regions.

    PubMed

    Zlebnik, Natalie E; Cheer, Joseph F

    2016-10-05

    The endocannabinoid (eCB) system has emerged as one of the most important mediators of physiological and pathological reward-related synaptic plasticity. eCBs are retrograde messengers that provide feedback inhibition, resulting in the suppression of neurotransmitter release at both excitatory and inhibitory synapses, and they serve a critical role in the spatiotemporal regulation of both short- and long-term synaptic plasticity that supports adaptive learning of reward-motivated behaviors. However, mechanisms of eCB-mediated synaptic plasticity in reward areas of the brain are impaired following exposure to drugs of abuse. Because of this, it is theorized that maladaptive eCB signaling may contribute to the development and maintenance of addiction-related behavior. Here we review various forms of eCB-mediated synaptic plasticity present in regions of the brain involved in reward and reinforcement and explore the potential physiological relevance of maladaptive eCB signaling to addiction vulnerability. Copyright © 2016 the authors 0270-6474/16/3610230-09$15.00/0.

  20. Developmental regulation of fear learning and anxiety behavior by endocannabinoids.

    PubMed

    Lee, T T-Y; Hill, M N; Lee, F S

    2016-01-01

    The developing brain undergoes substantial maturation into adulthood and the development of specific neural structures occurs on differing timelines. Transient imbalances between developmental trajectories of corticolimbic structures, which are known to contribute to regulation over fear learning and anxiety, can leave an individual susceptible to mental illness, particularly anxiety disorders. There is a substantial body of literature indicating that the endocannabinoid (eCB) system critically regulates stress responsivity and emotional behavior throughout the life span, making this system a novel therapeutic target for stress- and anxiety-related disorders. During early life and adolescence, corticolimbic eCB signaling changes dynamically and coincides with different sensitive periods of fear learning, suggesting that eCB signaling underlies age-specific fear learning responses. Moreover, perturbations to these normative fluctuations in corticolimbic eCB signaling, such as stress or cannabinoid exposure, could serve as a neural substrate contributing to alterations to the normative developmental trajectory of neural structures governing emotional behavior and fear learning. In this review, we first introduce the components of the eCB system and discuss clinical and rodent models showing eCB regulation of fear learning and anxiety in adulthood. Next, we highlight distinct fear learning and regulation profiles throughout development and discuss the ontogeny of the eCB system in the central nervous system, and models of pharmacological augmentation of eCB signaling during development in the context of fear learning and anxiety. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  1. Perinatal maternal high-fat diet induces early obesity and sex-specific alterations of the endocannabinoid system in white and brown adipose tissue of weanling rat offspring.

    PubMed

    Almeida, Mariana M; Dias-Rocha, Camilla P; Souza, André S; Muros, Mariana F; Mendonca, Leonardo S; Pazos-Moura, Carmen C; Trevenzoli, Isis H

    2017-11-01

    Perinatal maternal high-fat (HF) diet programmes offspring obesity. Obesity is associated with overactivation of the endocannabinoid system (ECS) in adult subjects, but the role of the ECS in the developmental origins of obesity is mostly unknown. The ECS consists of endocannabinoids, cannabinoid receptors (cannabinoid type-1 receptor (CB1) and cannabinoid type-2 receptor (CB2)) and metabolising enzymes. We hypothesised that perinatal maternal HF diet would alter the ECS in a sex-dependent manner in white and brown adipose tissue of rat offspring at weaning in parallel to obesity development. Female rats received standard diet (9 % energy content from fat) or HF diet (29 % energy content from fat) before mating, during pregnancy and lactation. At weaning, male and female offspring were killed for tissue harvest. Maternal HF diet induced early obesity, white adipocyte hypertrophy and increased lipid accumulation in brown adipose tissue associated with sex-specific changes of the ECS's components in weanling rats. In male pups, maternal HF diet decreased CB1 and CB2 protein in subcutaneous adipose tissue. In female pups, maternal HF diet increased visceral and decreased subcutaneous CB1. In brown adipose tissue, maternal HF diet increased CB1 regardless of pup sex. In addition, maternal HF diet differentially changed oestrogen receptor across the adipose depots in male and female pups. The ECS and oestrogen signalling play an important role in lipogenesis, adipogenesis and thermogenesis, and we observed early changes in their targets in adipose depots of the offspring. The present findings provide insights into the involvement of the ECS in the developmental origins of metabolic disease induced by inadequate maternal nutrition in early life.

  2. Endocannabinoid signaling at the periphery: 50 years after THC.

    PubMed

    Maccarrone, Mauro; Bab, Itai; Bíró, Tamás; Cabral, Guy A; Dey, Sudhansu K; Di Marzo, Vincenzo; Konje, Justin C; Kunos, George; Mechoulam, Raphael; Pacher, Pal; Sharkey, Keith A; Zimmer, Andreas

    2015-05-01

    In 1964, the psychoactive ingredient of Cannabis sativa, Δ(9)-tetrahydrocannabinol (THC), was isolated. Nearly 30 years later the endogenous counterparts of THC, collectively termed endocannabinoids (eCBs), were discovered: N-arachidonoylethanolamine (anandamide) (AEA) in 1992 and 2-arachidonoylglycerol (2-AG) in 1995. Since then, considerable research has shed light on the impact of eCBs on human health and disease, identifying an ensemble of proteins that bind, synthesize, and degrade them and that together form the eCB system (ECS). eCBs control basic biological processes including cell choice between survival and death and progenitor/stem cell proliferation and differentiation. Unsurprisingly, in the past two decades eCBs have been recognized as key mediators of several aspects of human pathophysiology and thus have emerged to be among the most widespread and versatile signaling molecules ever discovered. Here some of the pioneers of this research field review the state of the art of critical eCB functions in peripheral organs. Our community effort is aimed at establishing consensus views on the relevance of the peripheral ECS for human health and disease pathogenesis, as well as highlighting emerging challenges and therapeutic hopes. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Study of sample preparation for determination of endocannabinoids and analogous compounds in human serum by LC-MS/MS in MRM mode.

    PubMed

    Luque-Córdoba, D; Calderón-Santiago, M; Luque de Castro, M D; Priego-Capote, F

    2018-08-01

    Endocannabinoids are lipids with a key role in physiological processes such as the immune response or the metabolism. This involvement explains their association to pathologies such as cancer, obesity or multiple sclerosis. The determination of endocannabinoids constitutes a challenge for clinical laboratories due to the variety of biological matrices and the wide range of concentrations at which they can be found. This research deals with the comparison of three sample preparation strategies (viz., on-line SPE, off-line SPE for interferents removal, and protein precipitation) for subsequent LC-MS/MS analysis of 14 endocannabinoids and analogous compounds in serum. As a result, the on-line coupling between SPE and LC-MS/MS is proposed as the best approach for this determination. The proposed method allows full automation of the overall process, shortening of the analysis time, and avoidance of errors associated with sample preparation steps. The improvement in sensitivity and selectivity thus achieved allows obtaining quantification limits at the pg mL -1 level, which makes possible the application of the method for clinical studies. Copyright © 2018 Elsevier B.V. All rights reserved.

  4. Anticipatory and consummatory effects of (hedonic) chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults.

    PubMed

    Rigamonti, Antonello E; Piscitelli, Fabiana; Aveta, Teresa; Agosti, Fiorenza; De Col, Alessandra; Bini, Silvia; Cella, Silvano G; Di Marzo, Vincenzo; Sartorio, Alessandro

    2015-01-01

    Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG) in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), anandamide (AEA), 2-AG, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. When motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity.

  5. Anticipatory and consummatory effects of (hedonic) chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults

    PubMed Central

    Rigamonti, Antonello E.; Piscitelli, Fabiana; Aveta, Teresa; Agosti, Fiorenza; De Col, Alessandra; Bini, Silvia; Cella, Silvano G.; Di Marzo, Vincenzo; Sartorio, Alessandro

    2015-01-01

    Background Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG) in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. Methods To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), anandamide (AEA), 2-AG, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. Results The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. Conclusions When motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity. PMID:26546790

  6. Endocannabinoids participate in placental apoptosis induced by hypoxia inducible factor-1.

    PubMed

    Abán, C; Martinez, N; Carou, C; Albamonte, I; Toro, A; Seyahian, A; Franchi, A; Leguizamón, G; Trigubo, D; Damiano, A; Farina, M

    2016-10-01

    During pregnancy, apoptosis is a physiological event critical in the remodeling and aging of the placenta. Increasing evidence has pointed towards the relevance of endocannabinoids (ECs) and hypoxia as modulators of trophoblast cell death. However, the relation between these factors is still unknown. In this report, we evaluated the participation of ECs in placental apoptosis induced by cobalt chloride (CoCl2), a hypoxia mimicking agent that stabilizes the expression of hypoxia inducible factor-1 alpha (HIF-1α). We found that HIF-1α stabilization decreased FAAH mRNA and protein levels, suggesting an increase in ECs tone. Additionally, CoCl2 incubation and Met-AEA treatment reduced cell viability and increased TUNEL-positive staining in syncytiotrophoblast layer. Immunohistochemical analysis demonstrated Bax and Bcl-2 protein expression in the cytoplasm of syncytiotrophoblast. Finally, HIF-1α stabilization produced an increase in Bax/Bcl-2 ratio, activation of caspase 3 and PARP cleavage. All these changes in apoptotic parameters were reversed with AM251, a CB1 antagonist. These results demonstrate that HIF-1α may induce apoptosis in human placenta via intrinsic pathway by a mechanism that involves activation of CB1 receptor suggesting a role of the ECs in this process.

  7. Docosahexaenoyl ethanolamide improves glucose uptake and alters endocannabinoid system gene expression in proliferating and differentiating C2C12 myoblasts

    PubMed Central

    Kim, Jeffrey; Carlson, Morgan E.; Watkins, Bruce A.

    2014-01-01

    Skeletal muscle is a major storage site for glycogen and a focus for understanding insulin resistance and type-2-diabetes. New evidence indicates that overactivation of the peripheral endocannabinoid system (ECS) in skeletal muscle diminishes insulin sensitivity. Specific n-6 and n-3 polyunsaturated fatty acids (PUFA) are precursors for the biosynthesis of ligands that bind to and activate the cannabinoid receptors. The function of the ECS and action of PUFA in skeletal muscle glucose uptake was investigated in proliferating and differentiated C2C12 myoblasts treated with either 25 μM of arachidonate (AA) or docosahexaenoate (DHA), 25 μM of EC [anandamide (AEA), 2-arachidonoylglycerol (2-AG), docosahexaenoylethanolamide (DHEA)], 1 μM of CB1 antagonist NESS0327, and CB2 inverse agonist AM630. Compared to the BSA vehicle control cell cultures in both proliferating and differentiated myoblasts those treated with DHEA, the EC derived from the n-3 PUFA DHA, had higher 24 h glucose uptake, while AEA and 2-AG, the EC derived from the n-6 PUFA AA, had lower basal glucose uptake. Adenylyl cyclase mRNA was higher in myoblasts treated with DHA in both proliferating and differentiated states while those treated with AEA or 2-AG were lower compared to the control cell cultures. Western blot and qPCR analysis showed higher expression of the cannabinoid receptors in differentiated myoblasts treated with DHA while the opposite was observed with AA. These findings indicate a compensatory effect of DHA and DHEA compared to AA-derived ligands on the ECS and associated ECS gene expression and higher glucose uptake in myoblasts. PMID:24711795

  8. Circulating levels of endocannabinoids respond acutely to voluntary exercise, are altered in mice selectively bred for high voluntary wheel running, and differ between the sexes

    PubMed Central

    Thompson, Zoe; Argueta, Donovan; Garland, Theodore; DiPatrizio, Nicholas

    2017-01-01

    The endocannabinoid system serves many physiological roles, including in the regulation of energy balance, food reward, and voluntary locomotion. Signaling at the cannabinoid type 1 receptor has been specifically implicated in motivation for rodent voluntary exercise on wheels. We studied four replicate lines of high runner (HR) mice that have been selectively bred for 81 generations based on average number of wheel revolutions on days five and six of a six-day period of wheel access. Four additional replicate lines are bred without regard to wheel running, and serve as controls (C) for random genetic effects that may cause divergence among lines. On average, mice from HR lines voluntarily run on wheels three times more than C mice on a daily basis. We tested the general hypothesis that circulating levels of endocannabinoids (i.e., 2-arachidonoylglycerol [2-AG] and anandamide [AEA]) differ between HR and C mice in a sex-specific manner. Fifty male and 50 female mice were allowed access to wheels for six days, while another 50 males and 50 females were kept without access to wheels (half HR, half C for all groups). Blood was collected by cardiac puncture during the time of peak running on the sixth night of wheel access or no wheel access, and later analyzed for 2-AG and AEA content by ultra-performance liquid chromatography coupled to tandem mass spectrometry. We observed a significant three-way interaction among sex, linetype, and wheel access for 2-AG concentrations, with females generally having lower levels than males and wheel access lowering 2-AG levels in some but not all subgroups. The number of wheel revolutions in the minutes or hours immediately prior to sampling did not quantitatively predict plasma 2-AG levels within groups. We also observed a trend for a linetype-by-wheel access interaction for AEA levels, with wheel access lowering plasma concentrations of AEA in HR mice, while raising them in C mice. In addition, females tended to have higher AEA

  9. Circulating levels of endocannabinoids respond acutely to voluntary exercise, are altered in mice selectively bred for high voluntary wheel running, and differ between the sexes.

    PubMed

    Thompson, Zoe; Argueta, Donovan; Garland, Theodore; DiPatrizio, Nicholas

    2017-03-01

    The endocannabinoid system serves many physiological roles, including in the regulation of energy balance, food reward, and voluntary locomotion. Signaling at the cannabinoid type 1 receptor has been specifically implicated in motivation for rodent voluntary exercise on wheels. We studied four replicate lines of high runner (HR) mice that have been selectively bred for 81 generations based on average number of wheel revolutions on days five and six of a six-day period of wheel access. Four additional replicate lines are bred without regard to wheel running, and serve as controls (C) for random genetic effects that may cause divergence among lines. On average, mice from HR lines voluntarily run on wheels three times more than C mice on a daily basis. We tested the general hypothesis that circulating levels of endocannabinoids (i.e., 2-arachidonoylglycerol [2-AG] and anandamide [AEA]) differ between HR and C mice in a sex-specific manner. Fifty male and 50 female mice were allowed access to wheels for six days, while another 50 males and 50 females were kept without access to wheels (half HR, half C for all groups). Blood was collected by cardiac puncture during the time of peak running on the sixth night of wheel access or no wheel access, and later analyzed for 2-AG and AEA content by ultra-performance liquid chromatography coupled to tandem mass spectrometry. We observed a significant three-way interaction among sex, linetype, and wheel access for 2-AG concentrations, with females generally having lower levels than males and wheel access lowering 2-AG levels in some but not all subgroups. The number of wheel revolutions in the minutes or hours immediately prior to sampling did not quantitatively predict plasma 2-AG levels within groups. We also observed a trend for a linetype-by-wheel access interaction for AEA levels, with wheel access lowering plasma concentrations of AEA in HR mice, while raising them in C mice. In addition, females tended to have higher AEA

  10. Distinct neuronal activation patterns are associated with PCP-induced social withdrawal and its reversal by the endocannabinoid-enhancing drug URB597.

    PubMed

    Matricon, Julien; Seillier, Alexandre; Giuffrida, Andrea

    2016-09-01

    The fatty acid amide hydrolase inhibitor, URB597, an endocannabinoid enhancing drug, reverses social withdrawal in the sub-chronic PCP rat model of schizophrenia, but reduces social interaction (SI) in controls. To identify the anatomical substrates associated with PCP-induced social withdrawal and the contrasting effects of URB597 on SI in PCP- versus saline-treated rats, we analyzed SI-induced c-Fos expression in 28 brain areas relevant to schizophrenia and/or social behavior following vehicle or URB597 administration. In saline-treated rats, SI was accompanied by changes in c-Fos expression in the infralimbic and orbitofrontal cortices, dorsomedial caudate putamen, ventrolateral nucleus of the septum, dorsolateral periaqueductal gray (dlPAG) and central amygdala. Except for the dlPAG, these changes were not observed in PCP-treated rats or in saline-treated rats receiving URB597. In the dorsomedial part of the bed nucleus of the stria terminalis (dmBNST), SI-induced c-Fos expression was observed only in PCP-treated rats. Interestingly, URB597 in PCP-treated rats restored a similar c-Fos expression pattern as observed in saline-treated rats: activation of the orbitofrontal cortex, inhibition of the central amygdala and suppression of activation of the dmBNST. These data suggest that orbitofrontal cortex, central amygdala and dmBNST play a critical role in the reversal of PCP-induced social withdrawal by URB597. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  11. Cannabinoids and glucocorticoids modulate emotional memory after stress.

    PubMed

    Akirav, Irit

    2013-12-01

    Bidirectional and functional relationships between glucocorticoids and the endocannabinoid system have been demonstrated. Here, I review the interaction between the endocannabinoid and glucocorticoid/stress systems. Specifically, stress is known to produce rapid changes in endocannabinoid signaling in stress-responsive brain regions. In turn, the endocannabinoid system plays an important role in the downregulation and habituation of hypothalamic-pituitary-adrenocortical (HPA) axis activity in response to stress. Glucocorticoids also recruit the endocannabinoid system to exert rapid negative feedback control of the HPA axis during stress. It became increasingly clear, however, that cannabinoid CB1 receptors are also abundantly expressed in the basolateral amygdala (BLA) and other limbic regions where they modulate emotional arousal effects on memory. Enhancing cannabinoids signaling using exogenous CB1 receptor agonists prevent the effects of acute stress on emotional memory. I propose a model suggesting that the ameliorating effects of exogenously administered cannabinoids on emotional learning after acute stress are mediated by the decrease in the activity of the HPA axis via GABAergic mechanisms in the amygdala. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Palmitoyl Serine: An Endogenous Neuroprotective Endocannabinoid-Like Entity After Traumatic Brain Injury.

    PubMed

    Mann, Aniv; Smoum, Reem; Trembovler, Victoria; Alexandrovich, Alexander; Breuer, Aviva; Mechoulam, Raphael; Shohami, Esther

    2015-06-01

    The endocannabinoid (eCB) system helps recovery following traumatic brain injury (TBI). Treatment with 2-arachidonoylglycerol (2-AG), a cerebral eCB ligand, was found to ameliorate the secondary damage. Interestingly, the fatty acid amino acid amide (FAAA) N-arachidonoyl-L-serine (AraS) exerts similar eCB dependent neuroprotective. The present study aimed to investigate the effects of the FAAA palmitoyl-serine (PalmS) following TBI. We utilized the TBI model in mice to examine the therapeutic potential of PalmS, injected 1 h following closed head injury (CHI). We followed the functional recovery of the injured mice for 28 days post-CHI, and evaluated cognitive and motor function, lesion volume, cytokines levels, molecular signaling, and infarct volume at different time points after CHI. PalmS treatment led to a significant improvement of the neurobehavioral outcome of the treated mice, compared with vehicle. This effect was attenuated in the presence of eCBR antagonists and in CB2-/- mice, compared to controls. Unexpectedly, treatment with PalmS did not affect edema and lesion volume, TNFα and IL1β levels, anti-apoptotic mechanisms, nor did it exert improvement in cognitive and motor function. Finally, co-administration of PalmS, AraS and 2-AG, did not enhance the effect of the individual drugs. We suggest that the neuroprotective action of PalmS is mediated by indirect activation of the eCB receptors following TBI. One such mechanism may involve receptor palmitoylation which has been reported to result in structural stabilization of the receptors and to an increase in their activity. Further research is required in order to establish this assumption.

  13. An Endocannabinoid Uptake Inhibitor from Black Pepper Exerts Pronounced Anti-Inflammatory Effects in Mice.

    PubMed

    Reynoso-Moreno, Inés; Najar-Guerrero, Israel; Escareño, Noé; Flores-Soto, Mario Eduardo; Gertsch, Jürg; Viveros-Paredes, Juan Manuel

    2017-11-01

    Guineensine is a dietary N-isobutylamide widely present in black and long pepper (Piper nigrum and Piper longum) previously shown to inhibit cellular endocannabinoid uptake. Given the role of endocannabinoids in inflammation and pain reduction, here we evaluated guineensine in mouse models of acute and inflammatory pain and endotoxemia. Significant dose-dependent anti-inflammatory effects (95.6 ± 3.1% inhibition of inflammatory pain at 2.5 mg/kg ip and 50.0 ± 15.9% inhibition of edema formation at 5 mg/kg ip) and acute analgesia (66.1 ± 28.1% inhibition at 5.0 mg/kg ip) were observed. Moreover, guineensine inhibited proinflammatory cytokine production in endotoxemia. Intriguingly, guineensine and LPS independently induced catalepsy, but in combination this effect was abolished. Both hypothermia and analgesia were blocked by the CB1 receptor inverse agonist rimonabant, but the pronounced hypolocomotion was CB1 receptor-independent. A subsequent screen of 45 CNS-related receptors, ion channels, and transporters revealed apparent interactions of guineensine with the dopamine transporter DAT, 5HT2A, and sigma receptors, uncovering its prospective polypharmacology. The described potent pharmacological effects of guineensine might relate to the reported anti-inflammatory effects of pepper.

  14. A Review of the Interactions between Alcohol and the Endocannabinoid System: Implications for Alcohol Dependence and Future Directions for Research

    PubMed Central

    Pava, Matthew J.; Woodward, John J.

    2012-01-01

    Over the past fifty years a significant body of evidence has been compiled suggesting an interaction between the endocannabinoid (EC) system and alcohol dependence. However, much of this work has been conducted only in the past two decades following the elucidation of the molecular constituents of the EC system that began with the serendipitous discovery of the cannabinoid 1 receptor (CB1). Since then, novel pharmacological and genetic tools have enabled researchers to manipulate select components of the EC system, to determine their contribution to the motivation to consume ethanol. From these preclinical studies, it is evident that CB1 contributes the motivational and reinforcing properties of ethanol, and chronic consumption of ethanol alters EC transmitter levels and CB1 expression in brain nuclei associated with addiction pathways. These results are augmented by in vitro and ex vivo studies showing that acute and chronic treatment with ethanol produces physiologically relevant alterations in the function of the EC system. This report provides a current and comprehensive review of the literature regarding the interactions between ethanol and the EC system. We begin be reviewing the studies published prior to the discovery of the EC system that compared the behavioral and physiological effects of cannabinoids with ethanol in addition to cross-tolerance between these drugs. Next, a brief overview of the molecular constituents of the EC system is provided as context for the subsequent review of more recent studies examining the interaction of ethanol with the EC system. These results are compiled into a summary providing a scheme for the known changes to the components of the EC system in different stages of alcohol dependence. Finally, future directions for research are discussed. PMID:22459871

  15. The Endocannabinoid Reuptake Inhibitor WOBE437 Is Orally Bioavailable and Exerts Indirect Polypharmacological Effects via Different Endocannabinoid Receptors.

    PubMed

    Reynoso-Moreno, Inés; Chicca, Andrea; Flores-Soto, Mario E; Viveros-Paredes, Juan M; Gertsch, Jürg

    2018-01-01

    Different anandamide (AEA) transport inhibitors show antinociceptive and antiinflammatory effects in vivo , but due to their concomitant inhibition of fatty acid amide hydrolase (FAAH) and overall poor bioavailability, they cannot be used unequivocally to study the particular role of endocannabinoid (EC) transport in pathophysiological conditions in vivo . Here, the potent and selective endocannabinoid reuptake inhibitor WOBE437, which inhibits AEA and 2-arachidonoylglycerol (2-AG) transport, was tested for its oral bioavailability to the brain. WOBE437 is assumed to locally increase EC levels in tissues in which facilitated EC reuptake intermediates subsequent hydrolysis. Given the marked polypharmacology of ECs, we hypothesized to see differential effects on distinct EC receptors in animal models of acute and chronic pain/inflammation. In C57BL6/J male mice, WOBE437 was orally bioavailable with an estimated t max value of ≤20 min in plasma (C max ∼ 2000 pmol/mL after 50 mg/kg, p.o.) and brain (C max ∼ 500 pmol/g after 50 mg/kg, p.o.). WOBE437 was cleared from the brain after approximately 180 min. In addition, in BALB/c male mice, acute oral administration of WOBE437 (50 mg/kg) exhibited similar brain concentrations after 60 min and inhibited analgesia in the hot plate test in a cannabinoid CB1 receptor-dependent manner, without inducing catalepsy or affecting locomotion. WOBE437 significantly elevated AEA in the somatosensory cortex, while showing dose-dependent biphasic effects on 2-AG levels in plasma but no significant changes in N -acylethanolamines other than AEA in any of the tissues. In order to explore the presumed polypharmacology mediated via elevated EC levels, we tested this EC reuptake inhibitor in complete Freud's adjuvant induced monoarthritis in BALB/c mice as a model of chronic inflammation. Repetitive doses of WOBE437 (10 mg/kg, i.p.) attenuated allodynia and edema via cannabinoid CB2, CB1, and PPARγ receptors. The allodynia inhibition

  16. The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice.

    PubMed

    Wilkerson, Jenny L; Ghosh, Sudeshna; Mustafa, Mohammed; Abdullah, Rehab A; Niphakis, Micah J; Cabrera, Roberto; Maldonado, Rafael L; Cravatt, Benjamin F; Lichtman, Aron H

    2017-03-01

    Although opioids are highly efficacious analgesics, their abuse potential and other untoward side effects diminish their therapeutic utility. The addition of non-opioid analgesics offers a promising strategy to reduce required antinociceptive opioid doses that concomitantly reduce opioid-related side effects. Inhibitors of the primary endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) show opioid-sparing effects in preclinical models of pain. As simultaneous inhibition of these enzymes elicits enhanced antinociceptive effects compared with single enzyme inhibition, the present study tested whether the dual FAAH-MAGL inhibitor SA-57 [4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester] produces morphine-sparing antinociceptive effects, without major side effects associated with either drug class. SA-57 dose-dependently reversed mechanical allodynia in the constriction injury (CCI) of the sciatic nerve model of neuropathic pain and carrageenan inflammatory pain model. As previously reported, SA-57 was considerably more potent in elevating anandamide (AEA) than 2-arachidonyl glycerol (2-AG) in brain. Its anti-allodynic effects required cannabinoid (CB) 1 and CB 2 receptors; however, only CB 2 receptors were necessary for the anti-edematous effects in the carrageenan assay. Although high doses of SA-57 alone were required to produce antinociception, low doses of this compound, which elevated AEA and did not affect 2-AG brain levels, augmented the antinociceptive effects of morphine, but lacked cannabimimetic side effects. Because of the high abuse liability of opioids and implication of the endocannabinoid system in the reinforcing effects of opioids, the final experiment tested whether SA-57 would alter heroin seeking behavior. Strikingly, SA-57 reduced heroin-reinforced nose poke behavior and the progressive ratio break point for heroin. In conclusion, the results of the present

  17. The Endocannabinoid Hydrolysis Inhibitor SA-57: Intrinsic Antinociceptive Effects, Augmented Morphine-induced Antinociception, and Attenuated Heroin Seeking Behavior in Mice

    PubMed Central

    Wilkerson, Jenny L.; Ghosh, Sudeshna; Mustafa, Mohammed; Abdullah, Rehab A.; Niphakis, Micah J.; Cabrera, Roberto; Maldonado, Rafael L.; Cravatt, Benjamin F.; Lichtman, Aron H.

    2017-01-01

    Although opioids are highly efficacious analgesics, their abuse potential and other untoward side effects diminish their therapeutic utility. The addition of non-opioid analgesics offers a promising strategy to reduce required antinociceptive opioid doses that concomitantly reduce opioid-related side effects. Inhibitors of the primary endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) show opioid-sparing effects in preclinical models of pain. As simultaneous inhibition of these enzymes elicits enhanced antinociceptive effects compared with single enzyme inhibition, the present study tested whether the dual FAAH-MAGL inhibitor SA-57 [4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester] produces morphine-sparing antinociceptive effects, without major side effects associated with either drug class. SA-57 dose-dependently reversed mechanical allodynia in the constriction injury (CCI) of the sciatic nerve model of neuropathic pain and carrageenan inflammatory pain model. As previously reported, SA-57 was considerably more potent in elevating anandamide (AEA) than 2-arachidonyl glycerol (2-AG) in brain. Its anti-allodynic effects required cannabinoid (CB)1 and CB2 receptors; however, only CB2 receptors were necessary for the anti-edematous effects in the carrageenan assay. Although high doses of SA-57 alone were required to produce antinociception, low doses of this compound, which elevated AEA and did not affect 2-AG brain levels, augmented the antinociceptive effects of morphine, but lacked cannabimimetic side effects. Because of the high abuse liability of opioids and implication of the endocannabinoid system in the reinforcing effects of opioids, the final experiment tested whether SA-57 would alter heroin seeking behavior. Strikingly, SA-57 reduced heroin-reinforced nose poke behavior and the progressive ratio break point for heroin. In conclusion, the results of the present

  18. A role for the endocannabinoid system in premature luteal regression and progesterone withdrawal in lipopolysaccharide-induced early pregnancy loss model.

    PubMed

    Schander, Julieta Aylen; Correa, Fernando; Bariani, María Victoria; Blanco, Julieta; Cymeryng, Cora; Jensen, Federico; Wolfson, Manuel Luis; Franchi, Ana María

    2016-11-01

    What is the role of the endocannabinoid system (eCS) in the alterations of the endocrine system in a murine model of lipopolysaccharide (LPS)-induced miscarriage? In 7-days pregnant wild type, but not cannabinoid receptor type 1 knockout (CB1-KO) mice, LPS increased COX-2 expression and prostaglandin F 2α (PGF 2α ) production in the uterus leading to lower expression of prolactin receptor in the ovary and a marked regression of corpora lutea (CL), suggesting that the eCS mediates the deleterious effects of LPS on reproductive events. Appropriate systemic progesterone levels are critical for a successful pregnancy outcome. Precocious loss of luteal progesterone (P4) secretion leads to miscarriage in rodents. We have previously shown that LPS administration to pregnant mice induces embryonic resorption accompanied by a dramatic decrease in systemic progesterone levels in a murine model of inflammatory miscarriage, with the eCS mediating these LPS-induced deleterious effects. CD1 wild-type (WT) and CB1-KO mice were randomly allocated to Vehicle (saline; i.p.) or LPS (0.5 μg/g body weight; i.p.) treated groups: (WT-Vehicle; WT-LPS; CB1-KO-Vehicle and CB1-KO-LPS). A single injection was given on day 7 of pregnancy and tissues (blood, ovary, uterus) were collected 6, 12, 24 and 48 h later. P4 and PGF2α plasma levels were determined by radioimmunoassay. Cyclooxygenase-2 (COX-2) mRNA (RT-PCR) and protein (Western blot) content in uterus was assayed. COX-2 and prolactin receptor (PrlR) mRNA levels in the ovary were assayed by RT-PCR. Tissue morphology of the CL was assessed by haematoxylin-eosin staining. Treatment of 7-day pregnant WT mice with LPS induced a P4 withdrawal (p < 0.05), increased in uterine COX-2 mRNA and protein expression (p < 0.05) as well as an increase in uterine PGF 2α production (p < 0.05). These changes were absent in LPS-treated 7-day pregnant CB1-KO mice. In ovarian tissues, LPS treatment to 7-day pregnant WT mice induced a downregulation

  19. A Preliminary Model for the Protective Role of the Endocannabinoid 2-Arachydonylglycerol in Neuroinflammation

    DTIC Science & Technology

    2015-09-30

    example, Liu et al. (2013) measured the effect of chlorpyrifos (280 mg/kg via subcutaneous (sc) injection) and parathion (27 mg/kg sc) in rats on 2...rats to the organophosphates (OPs) chlorpyrifos (280 mg/kg, sc) and parathion (27 mg/kg, sc), and correspond to 53 and 20 percent predicted inhibition...Effects of Parathion and Chlorpyrifos on Extracellular Endocannabinoid Levels in Rat Hippocampus: Influence on Cholinergic Toxicity. Toxicol Appl

  20. Δ9-Tetrahydrocannabinol and Endocannabinoid Degradative Enzyme Inhibitors Attenuate Intracranial Self-Stimulation in Mice

    PubMed Central

    Grim, Travis W.; Owens, Robert A.; Lazenka, Matthew F.; Sim-Selley, Laura J.; Abdullah, Rehab A.; Niphakis, Micah J.; Vann, Robert E.; Cravatt, Benjamin F.; Wiley, Jenny L.; Negus, S. Stevens; Lichtman, Aron H.

    2015-01-01

    A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle [intracranial self-stimulation (ICSS)], which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 (4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), whereas peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide) and 2-AG. The cannabinoid receptor type 1 receptor antagonist rimonabant, but not the cannabinoid receptor type 2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on ICSS

  1. Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice.

    PubMed

    Wiebelhaus, Jason M; Grim, Travis W; Owens, Robert A; Lazenka, Matthew F; Sim-Selley, Laura J; Abdullah, Rehab A; Niphakis, Micah J; Vann, Robert E; Cravatt, Benjamin F; Wiley, Jenny L; Negus, S Stevens; Lichtman, Aron H

    2015-02-01

    A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle [intracranial self-stimulation (ICSS)], which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 (4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), whereas peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide) and 2-AG. The cannabinoid receptor type 1 receptor antagonist rimonabant, but not the cannabinoid receptor type 2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on

  2. Endocannabinoid signaling and memory dynamics: A synaptic perspective.

    PubMed

    Drumond, Ana; Madeira, Natália; Fonseca, Rosalina

    2017-02-01

    Memory acquisition is a key brain feature in which our human nature relies on. Memories evolve over time. Initially after learning, memories are labile and sensitive to disruption by the interference of concurrent events. Later on, after consolidation, memories are resistant to disruption. However, reactivation of previously consolidated memories renders them again in an unstable state and therefore susceptible to perturbation. Additionally, and depending on the characteristics of the stimuli, a parallel process may be initiated which ultimately leads to the extinction of the previously acquired response. This dynamic aspect of memory maintenance opens the possibility for an updating of previously acquired memories but it also creates several conceptual challenges. What is the time window for memory updating? What determines whether reconsolidation or extinction is triggered? In this review, we tried to re-examine the relationship between consolidation, reconsolidation and extinction, aiming for a unifying view of memory dynamics. Since cellular models of memory share common principles, we present the evidence that similar rules apply to the maintenance of synaptic plasticity. Recently, a new function of the endocannabinoid (eCB) signaling system has been described for associative forms of synaptic plasticity in amygdala synapses. The eCB system has emerged as a key modulator of memory dynamics by adjusting the outcome to stimuli intensity. We propose a key function of eCB in discriminative forms of learning by restricting associative plasticity in amygdala synapses. Since many neuropsychiatric disorders are associated with a dysregulation in memory dynamics, understanding the rules underlying memory maintenance paves the path to better clinical interventions. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Putative Epigenetic Involvement of the Endocannabinoid System in Anxiety- and Depression-Related Behaviors Caused by Nicotine as a Stressor.

    PubMed

    Hayase, Tamaki

    2016-01-01

    Like various stressors, the addictive use of nicotine (NC) is associated with emotional symptoms such as anxiety and depression, although the underlying mechanisms have not yet been fully elucidated due to the complicated involvement of target neurotransmitter systems. In the elicitation of these emotional symptoms, the fundamental involvement of epigenetic mechanisms such as histone acetylation has recently been suggested. Furthermore, among the interacting neurotransmitter systems implicated in the effects of NC and stressors, the endocannabinoid (ECB) system is considered to contribute indispensably to anxiety and depression. In the present study, the epigenetic involvement of histone acetylation induced by histone deacetylase (HDAC) inhibitors was investigated in anxiety- and depression-related behavioral alterations caused by NC and/or immobilization stress (IM). Moreover, based on the contributing roles of the ECB system, the interacting influence of ECB ligands on the effects of HDAC inhibitors was evaluated in order to examine epigenetic therapeutic interventions. Anxiety-like (elevated plus-maze test) and depression-like (forced swimming test) behaviors, which were observed in mice treated with repeated (4 days) NC (subcutaneous 0.8 mg/kg) and/or IM (10 min), were blocked by the HDAC inhibitors sodium butyrate (SB) and valproic acid (VA). The cannabinoid type 1 (CB1) agonist ACPA (arachidonylcyclopropylamide; AC) also antagonized these behaviors. Conversely, the CB1 antagonist SR 141716A (SR), which counteracted the effects of AC, attenuated the anxiolytic-like effects of the HDAC inhibitors commonly in the NC and/or IM groups. SR also attenuated the antidepressant-like effects of the HDAC inhibitors, most notably in the IM group. From these results, the combined involvement of histone acetylation and ECB system was shown in anxiety- and depression-related behaviors. In the NC treatment groups, the limited influence of SR against the HDAC inhibitor

  4. Pharmacological inhibition of 2-arachidonoilglycerol hydrolysis enhances memory consolidation in rats through CB2 receptor activation and mTOR signaling modulation.

    PubMed

    Ratano, Patrizia; Petrella, Carla; Forti, Fabrizio; Passeri, Pamela Petrocchi; Morena, Maria; Palmery, Maura; Trezza, Viviana; Severini, Cinzia; Campolongo, Patrizia

    2018-05-26

    The endocannabinoid system is a key modulator of memory consolidation for aversive experiences. We recently found that the fatty acid amide hydrolase (FAAH) inhibitor URB597, which increases anandamide levels by inhibiting its hydrolysis, facilitates memory consolidation through a concurrent activation of both cannabinoid receptor type 1 (CB1) and 2 (CB2). Here, we investigated the role played on memory consolidation by the other major endocannabinoid, 2-arachidonoylglycerol (2-AG). To this aim, we tested the effects of pharmacological inhibition of monoacylglycerol lipase (MAGL) through systemic administration of the MAGL inhibitor JZL184 to rats immediately after training of the inhibitory avoidance task. Pharmacological enhancement of 2-AG tone facilitated memory consolidation through activation of CB2 receptor signaling. Moreover, we found that increased 2-AG signaling prevented the activation of the mammalian target of rapamycin (mTOR) signaling pathway in the hippocampus through a CB2-dependent mechanism. Our results identify a fundamental role for 2-AG and CB2 receptors in the modulation of memory consolidation for aversive experiences. Copyright © 2018 Elsevier Ltd. All rights reserved.

  5. Endocannabinoid concentrations in plasma during the finishing period are associated with feed efficiency and carcass composition of beef cattle

    USDA-ARS?s Scientific Manuscript database

    We previously have shown that plasma concentrations of endocannabinoids (EC) are positively correlated with feed efficiency and leaner carcasses in finishing steers. However, whether the animal growth during the finishing period affects the concentration of EC is unknown. The objective of this study...

  6. Metabolic Effects of n-3 PUFA as Phospholipids Are Superior to Triglycerides in Mice Fed a High-Fat Diet: Possible Role of Endocannabinoids

    PubMed Central

    Rossmeisl, Martin; Macek Jilkova, Zuzana; Kuda, Ondrej; Jelenik, Tomas; Medrikova, Dasa; Stankova, Barbora; Kristinsson, Björn; Haraldsson, Gudmundur G.; Svensen, Harald; Stoknes, Iren; Sjövall, Peter; Magnusson, Ylva; Balvers, Michiel G. J.; Verhoeckx, Kitty C. M.; Tvrzicka, Eva; Bryhn, Morten; Kopecky, Jan

    2012-01-01

    endocannabinoid system activity in WAT. PMID:22701720

  7. Effects of the novel endocannabinoid uptake inhibitor, LY2183240, on fear-potentiated startle and alcohol-seeking behaviors in mice selectively bred for high alcohol preference.

    PubMed

    Powers, Matthew S; Barrenha, Gustavo D; Mlinac, Nate S; Barker, Eric L; Chester, Julia A

    2010-12-01

    Alcohol-use disorders often occur together with anxiety disorders in humans which may be partly due to common inherited genetic factors. Evidence suggests that the endocannabinoid system (ECS) is a promising therapeutic target for the treatment of individuals with anxiety and/or alcohol-use disorders. The present study assessed the effects of a novel endocannabinoid uptake inhibitor, LY2183240, on anxiety- and alcohol-seeking behaviors in a unique animal model that may represent increased genetic risk to develop co-morbid anxiety and alcohol-use disorders in humans. Mice selectively bred for high alcohol preference (HAP) show greater fear-potentiated startle (FPS) than mice selectively bred for low alcohol preference (LAP). We examined the effects of LY2183240 on the expression of FPS in HAP and LAP mice and on alcohol-induced conditioned place preference (CPP) and limited-access alcohol drinking behavior in HAP mice. Repeated administration of LY2183240 (30 mg/kg) reduced the expression of FPS in HAP but not LAP mice when given prior to a second FPS test 48 h after fear conditioning. Both the 10 and 30 mg/kg doses of LY2183240 enhanced the expression of alcohol-induced CPP and this effect persisted in the absence of the drug. LY2183240 did not alter limited-access alcohol drinking behavior, unconditioned startle responding, or locomotor activity. These findings suggest that ECS modulation influences both conditioned fear and conditioned alcohol reward behavior. LY2183240 may be an effective pharmacotherapy for individuals with anxiety disorders, such as post-traumatic stress disorder, but may not be appropriate for individuals with co-morbid anxiety and alcohol-use disorders.

  8. CRIP1a inhibits endocytosis of G-protein coupled receptors activated by endocannabinoids and glutamate by a common molecular mechanism.

    PubMed

    Mascia, Fabrizio; Klotz, Lisa; Lerch, Judith; Ahmed, Mostafa H; Zhang, Yan; Enz, Ralf

    2017-05-01

    The excitability of the central nervous system depends largely on the surface density of neurotransmitter receptors. The endocannabinoid receptor 1 (CB 1 R) and the metabotropic glutamate receptor mGlu 8 R are expressed pre-synaptically where they reduce glutamate release into the synaptic cleft. Recently, the CB 1 R interacting protein cannabinoid receptor interacting protein 1a (CRIP1a) was identified and characterized to regulate CB 1 R activity in neurons. However, underlying molecular mechanisms are largely unknown. Here, we identified a common mechanism used by CRIP1a to regulate the cell surface density of two different types of G-protein coupled receptors, CB 1 R and mGlu 8a R. Five amino acids within the CB 1 R C-terminus were required and sufficient to reduce constitutive CB 1 R endocytosis by about 72% in the presence of CRIP1a. Interestingly, a similar sequence is present in mGlu 8a R and consistently, endocytosis of mGlu 8a R depended on CRIP1a, as well. Docking analysis and molecular dynamics simulations identified a conserved serine in CB 1 R (S468) and mGlu 8a R (S894) that forms a hydrogen bond with the peptide backbone of CRIP1a at position R82. In contrast to mGlu 8a R, the closely related mGlu 8b R splice-variant carries a lysine (K894) at this position, and indeed, mGlu 8b R endocytosis was not affected by CRIP1a. Chimeric constructs between CB 1 R, mGlu 8a R, and mGlu 8b R underline the role of the identified five CRIP1a sensitive amino acids. In summary, we suggest that CRIP1a negatively regulates endocytosis of two different G-protein coupled receptor types, CB 1 R and mGlu 8a R. © 2017 International Society for Neurochemistry.

  9. Maternal Caloric Restriction Implemented during the Preconceptional and Pregnancy Period Alters Hypothalamic and Hippocampal Endocannabinoid Levels at Birth and Induces Overweight and Increased Adiposity at Adulthood in Male Rat Offspring

    PubMed Central

    Ramírez-López, María Teresa; Vázquez, Mariam; Bindila, Laura; Lomazzo, Ermelinda; Hofmann, Clementine; Blanco, Rosarío Noemí; Alén, Francisco; Antón, María; Decara, Juan; Arco, Rocío; Ouro, Daniel; Orio, Laura; Suárez, Juan; Lutz, Beat; Gómez de Heras, Raquel; Rodríguez de Fonseca, Fernando

    2016-01-01

    Exposure to inadequate nutritional conditions in critical windows of development has been associated to disturbances on metabolism and behavior in the offspring later in life. The role of the endocannabinoid system, a known regulator of energy expenditure and adaptive behaviors, in the modulation of these processes is unknown. In the present study, we investigated the impact of exposing rat dams to diet restriction (20% less calories than standard diet) during pre-gestational and gestational periods on: (a) neonatal outcomes; (b) endocannabinoid content in hypothalamus, hippocampus and olfactory bulb at birth; (c) metabolism-related parameters; and (d) behavior in adult male offspring. We found that calorie-restricted dams tended to have a reduced litter size, although the offspring showed normal weight at birth. Pups from calorie-restricted dams also exhibited a strong decrease in the levels of anandamide (AEA), 2-arachidonoylglycerol (2-AG), arachidonic acid (AA) and palmitoylethanolamide (PEA) in the hypothalamus at birth. Additionally, pups from diet-restricted dams displayed reduced levels of AEA in the hippocampus without significant differences in the olfactory bulb. Moreover, offspring exhibited increased weight gain, body weight and adiposity in adulthood as well as increased anxiety-related responses. We propose that endocannabinoid signaling is altered by a maternal caloric restriction implemented during the preconceptional and pregnancy periods, which might lead to modifications of the hypothalamic and hippocampal circuits, potentially contributing to the long-term effects found in the adult offspring. PMID:27847471

  10. The endocannabinoid system and NGF are involved in the mechanism of action of resveratrol: a multi-target nutraceutical with therapeutic potential in neuropsychiatric disorders.

    PubMed

    Hassanzadeh, Parichehr; Arbabi, Elham; Atyabi, Fatemeh; Dinarvand, Rassoul

    2016-03-01

    Resveratrol is a polyphenolic compound with antioxidant, anti-inflammatory, and neuroprotective effects. It has also shown antidepressant-like effects in the behavioral studies; however, its mechanism(s) of action merit further evaluation. The interaction between the nerve growth factor (NGF) and endocannabinoid system (eCBs) and their contribution to the antidepressant or emotional activity prompted us to evaluate their implications in the mechanism of action of resveratrol. After single and 4-week intraperitoneal (i.p.) once-daily injections of resveratrol (40, 80, and 100 mg/kg), amitriptyline (2.5, 5, and 10 mg/kg), or clonazepam (10, 20, and 40 mg/kg) into male Wistar rats, eCB and NGF contents were quantified in the brain regions implicated in the modulation of emotions by isotope-dilution liquid chromatography/mass spectrometry and Bio-Rad protein assay, respectively. In the case of any significant alteration of brain eCB or NGF level, the effect of pre-treatment with cannabinoid CB1 or CB2 receptor antagonist (AM251 or SR144528) was investigated. Four-week treatment with resveratrol or amitriptyline resulted in a significant and sustained enhancement of NGF and eCB contents in dose-dependent and brain region-specific manner. Neither acute nor 4-week treatment with clonazepam affected brain eCB or NGF contents. Pre-treatment with AM251 (3 mg/kg), but not SR144528, prevented the enhancement of NGF protein levels. AM251 exhibited no effect by itself. Resveratrol like the classical antidepressant, amitriptyline, affects brain NGF and eCB signaling under the regulatory drive of CB1 receptors.

  11. Discovery of endocannabinoids and some random thoughts on their possible roles in neuroprotection and aggression.

    PubMed

    Mechoulam, R

    2002-01-01

    A short history of the discovery of the main plant cannabinoid, Delta(9)-tetrahydrocannabinol and of the endogenous cannabinoids anandamide, 2-arachidonoyl glycerol and 2-arachidonyl glyceryl ether (noladin ether) is presented. The role of the cannabinoids in neuroprotection, with emphasis on the endocannabinoids, is described. The unexpected production of aggression by Cannabis and cannabinoids under stressful conditions, published mainly in the past, is summarized. Copyright 2002 Elsevier Science Ltd. All rights reserved.

  12. Role of beta-catenin and endocannabinoids in the nucleus accumbens in extinction in rats exposed to shock and reminders.

    PubMed

    Korem, Nachshon; Lange, Rachel; Hillard, Cecilia J; Akirav, Irit

    2017-08-15

    The response to a traumatic experience may be rapid recovery or development of psychopathology such as post-traumatic stress disorder (PTSD). Impaired extinction of fear memories is thought to contribute to the development of the persistent trauma memories and avoidance. The Wnt/β-catenin pathway and the endocannabinoid system appear to play significant roles in anxiety and depressive symptoms. Here we examined the involvement of β-catenin in the nucleus accumbens (NAc) in extinction in rats exposed to the shock and reminders model of PTSD. We found that increased β-catenin levels in the NAc were correlated with facilitated extinction kinetics in rats exposed to shock and reminders, suggesting that increased levels of NAc β-catenin are associated with a resilient response to the stressor. Furthermore, downregulating β-catenin expression in the NAc in shocked rats using sulindac (0.0178, 0.178mg/side) impaired extinction whereas upregulating the Wnt/β-catenin pathway using LiCl (2µg/side) facilitated extinction. Exposure to shock and reminders resulted in attenuated levels of the endocannabinoid N-arachidonylethanolamine (AEA) in the NAc; the cannabinoid CB1/2 receptor agonist WIN55,212-2 (5µg/side) microinjected into the NAc facilitated extinction in shocked rats. Importantly, the facilitating effect of WIN55,212-2 on extinction was blocked by co-administration of sulindac in doses that downregulated β-catenin levels. Taken together, the results suggest that β-catenin in the NAc may serve as a protective buffer against the effects of severe stress, and that inhibiting this system in the NAc may prevent the therapeutic effects of cannabinoids against stress-related disorders. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  13. A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects.

    PubMed

    Bisogno, Tiziana; Mahadevan, Anu; Coccurello, Roberto; Chang, Jae Won; Allarà, Marco; Chen, Yugang; Giacovazzo, Giacomo; Lichtman, Aron; Cravatt, Benjamin; Moles, Anna; Di Marzo, Vincenzo

    2013-06-01

    The development of potent and selective inhibitors of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) via DAG lipases (DAGL) α and β is just starting to be considered as a novel and promising source of pharmaceuticals for the treatment of disorders that might benefit from a reduction in endocannabinoid tone, such as hyperphagia in obese subjects. Three new fluorophosphonate compounds O-7458, O-7459 and O-7460 were synthesized and characterized in various enzymatic assays. The effects of O-7460 on high-fat diet intake were tested in mice. Of the new compounds, O-7460 exhibited the highest potency (IC₅₀ = 690 nM) against the human recombinant DAGLα, and selectivity (IC₅₀ > 10 μM) towards COS-7 cell and human monoacylglycerol lipase (MAGL), and rat brain fatty acid amide hydrolase. Competitive activity-based protein profiling confirmed that O-7460 inhibits mouse brain MAGL only at concentrations ≥ 10 μM, and showed that this compound has only one major 'off-target', that is, the serine hydrolase KIAA1363. O-7460 did not exhibit measurable affinity for human recombinant CB₁ or CB₂ cannabinoid receptors (Ki > 10 μM). In mouse neuroblastoma N18TG2 cells stimulated with ionomycin, O-7460 (10 μM) reduced 2-AG levels. When administered to mice, O-7460 dose-dependently (0-12 mg·kg⁻¹, i.p.) inhibited the intake of a high-fat diet over a 14 h observation period, and, subsequently, slightly but significantly reduced body weight. O-7460 might be considered a useful pharmacological tool to investigate further the role played by 2-AG both in vitro and in vivo under physiological as well as pathological conditions. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  14. Insulin induces long-term depression of VTA dopamine neurons via an endocannabinoid-mediated mechanism

    PubMed Central

    Labouèbe, Gwenaël; Liu, Shuai; Dias, Carine; Zou, Haiyan; Wong, Jovi C.Y.; Karunakaran, Subashini; Clee, Susanne M.; Phillips, Anthony; Boutrel, Benjamin; Borgland, Stephanie L.

    2014-01-01

    The prevalence of obesity has drastically increased over the last few decades. Exploration into how hunger and satiety signals influence the reward system can help us to understand non-homeostatic mechanisms of feeding. Evidence suggests that insulin may act in the ventral tegmental area (VTA), a critical site for reward-seeking behavior, to suppress feeding. However, the neural mechanisms underlying insulin effects in the VTA remain unknown. We demonstrate that insulin, a circulating catabolic peptide that inhibits feeding, can induce a long-term depression (LTD) of excitatory synapses onto VTA dopamine neurons. This effect requires endocannabinoid-mediated presynaptic inhibition of glutamate release. Furthermore, after a sweetened high fat meal, which elevates endogenous insulin levels, insulin-induced LTD is occluded. Finally, insulin in the VTA reduces food anticipatory behavior and conditioned place preference for food. Taken together, these results suggest that insulin in the VTA suppresses excitatory synaptic transmission and reduces salience of food-related cues. PMID:23354329

  15. Antidepressants and changes in concentration of endocannabinoids and N-acylethanolamines in rat brain structures.

    PubMed

    Smaga, Irena; Bystrowska, Beata; Gawliński, Dawid; Pomierny, Bartosz; Stankowicz, Piotr; Filip, Małgorzata

    2014-08-01

    The endocannabinoid (eCB) system has recently been implicated in both the pathogenesis of depression and the action of antidepressants. Here, we investigated the effect of acutely or chronically administering antidepressants [imipramine (IMI) (15 mg/kg), escitalopram (ESC) (10 mg/kg), and tianeptine (10 mg/kg)] on the levels of both eCBs [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)] and N-acylethanolamines (NAEs) [palmitoylethanolamide (PEA) and oleoylethanolamide (OEA)] in various rat brain regions. We also examined the ability of the acute and chronic administration of N-acetylcysteine (NAC) (a mucolytic drug; 100 mg/kg) or URB597 (a fatty acid amide hydrolase inhibitor; 0.3 mg/kg), which have both elicited antidepressant activity in preclinical studies, to affect eCB and NAE levels. Next, we determined whether the observed effects are stable 10 days after the chronic administration of these drugs was halted. We report that the chronic administration of all investigated drugs increased AEA levels in the hippocampus and also increased both AEA and 2-AG levels in the dorsal striatum. NAE levels in limbic regions also increased after treatment with IMI (PEA/OEA), ESC (PEA), and NAC (PEA/OEA). Removing chronic ESC treatment for 10 days affected eCB and NAE levels in the frontal cortex, hippocampus, dorsal striatum, and cerebellum, while a similar tianeptine-free period enhanced accumbal NAE levels. All other drugs maintained their effects after the 10-day washout period. Therefore, the eCB system appears to play a significant role in the mechanism of action of clinically effective and potential antidepressants and may serve as a target for drug design and discovery.

  16. Estradiol acutely suppresses inhibition in the hippocampus through a sex-specific endocannabinoid and mGluR dependent mechanism

    PubMed Central

    Huang, Guang Zhe; Woolley, Catherine S.

    2012-01-01

    SUMMARY The steroid, 17β-estradiol (E2), is well known to influence hippocampal functions such as memory, affective behaviors, and epilepsy. There is growing awareness that in addition to responding to ovarian E2, the hippocampus of both males and females synthesizes E2 as a neurosteroid that could acutely modulate synaptic function. Previous work on acute E2 actions in hippocampus has focused on excitatory synapses. Here, we show that E2 rapidly suppresses inhibitory synaptic transmission in hippocampal CA1. E2 acts through the α form of the estrogen receptor to stimulate postsynaptic mGluR1-dependent mobilization of the endocannabinoid, anandamide, which then retrogradely suppresses GABA release from CB1 receptor-containing inhibitory presynaptic boutons. Remarkably, this effect of E2 is sex-specific, occurring in females but not males. Acute E2 modulation of endocannabinoid tone and consequent suppression of inhibition provides a new mechanism by which neurosteroid E2 could modulate hippocampus-dependent behaviors in a sex-specific manner. PMID:22681685

  17. Effects of tumour necrosis factor α upon the metabolism of the endocannabinoid anandamide in prostate cancer cells.

    PubMed

    Karlsson, Jessica; Gouveia-Figueira, Sandra; Alhouayek, Mireille; Fowler, Christopher J

    2017-01-01

    Tumour necrosis factor α (TNFα) is involved in the pathogenesis of prostate cancer, a disease where disturbances in the endocannabinoid system are seen. In the present study we have investigated whether treatment of DU145 human prostate cancer cells affects anandamide (AEA) catabolic pathways. Additionally, we have investigated whether cyclooxygenase-2 (COX-2) can regulate the uptake of AEA into cells. Levels of AEA synthetic and catabolic enzymes were determined by qPCR. AEA uptake and hydrolysis in DU145 and RAW264.7 macrophage cells were assayed using AEA labeled in the arachidonic and ethanolamine portions of the molecule, respectively. Levels of AEA, related N-acylethanolamines (NAEs), prostaglandins (PG) and PG-ethanolamines (PG-EA) in DU145 cells and medium were quantitated by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. TNFα treatment of DU145 cells increased mRNA levels of PTSG2 (gene of COX-2) and decreased the mRNA of the AEA synthetic enzyme N-acyl-phosphatidylethanolamine selective phospholipase D. mRNA levels of the AEA hydrolytic enzymes fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase were not changed. AEA uptake in both DU145 and RAW264.7 cells was inhibited by FAAH inhibition, but not by COX-2 inhibition, even in RAW264.7 cells where the expression of this enzyme had greatly been induced by lipopolysaccharide + interferon γ treatment. AEA and related NAEs were detected in DU145 cells, but PGs and PGE2-EA were only detected when the cells had been preincubated with 100 nM AEA. The data demonstrate that in DU145 cells, TNFα treatment changes the relative expression of the enzymes involved in the hydrolytic and oxygenation catabolic pathways for AEA. In RAW264.7 cells, COX-2, in contrast to FAAH, does not regulate the cellular accumulation of AEA. Further studies are necessary to determine the extent to which inflammatory mediators are involved in the abnormal

  18. Maternal separation and proclivity for ethanol intake: a potential role of the endocannabinoid system in rats.

    PubMed

    Romano-López, A; Méndez-Díaz, M; Ruiz-Contreras, A E; Carrisoza, R; Prospéro-García, O

    2012-10-25

    Maternal separation (MS) during the first postnatal weeks induces alcohol intake and a reduction in the expression of glucocorticoid receptors (GR). Adults' alcohol consumption may depend on changes in the endocannabinoid system (eCBs). Our goal was to evaluate the status of the eCBs before the exposition to alcohol to support the notion that eCBs' alterations prompt rats to drink alcohol. To reach this goal we subjected rats to MS for the first 2 postnatal weeks. Then, we allowed rats to grow with no further manipulation until they reached adulthood. Thereafter, rats were exposed to an alcohol solution (10% of alcohol in water) as the only source of drinking liquid (forced alcohol ingestion). At the end of this period, tap water was added as an option for drinking liquid (voluntary alcohol ingestion) for another 10 days. Different groups of rats (non-MS, and MS) were sacrificed when adult but with no exposition to alcohol whatsoever, to dissect frontal cortex (FCx), ventral striatum (VS) and hippocampus (HIP) to analyze the following: The expression of cannabinoid receptor 1 (CB1R), CB2R, GR and methylated CpG-binding protein 2 (MeCP2). Levels of GABA and glutamate were quantified in the same brain structures. We found CB1 receptor expression increased in the VS while it was decreased in the FCx in MS subjects. No changes in the CB2R or in the MeCP2 were detected. We found GABA levels increased in FCx and HIP but decreased in VS in MS. Likewise, glutamate levels increased in the FCx but decreased in the HIP in MS subjects. These findings suggest that MS induces changes in the CB1R expression, which might contribute to induce a proclivity to ingest alcohol and, potentially, other drugs. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. Effects of Mood Inductions by Meal Ambiance and Moderate Alcohol Consumption on Endocannabinoids and N-Acylethanolamines in Humans: A Randomized Crossover Trial

    PubMed Central

    Schrieks, Ilse C.; Ripken, Dina; Stafleu, Annette; Witkamp, Renger F.; Hendriks, Henk F. J.

    2015-01-01

    Background The endocannabinoid system is suggested to play a regulatory role in mood. However, the response of circulating endocannabinoids (ECs) to mood changes has never been tested in humans. In the present study, we examined the effects of mood changes induced by ambiance and moderate alcohol consumption on plasma ECs 2-arachidonoylglycerol (2-AG), anandamide (AEA), and some N-acylethanolamine (NAE) congeners in humans. Methods Healthy women (n = 28) participated in a randomized cross-over study. They consumed sparkling white wine (340 mL; 30 g alcohol) or alcohol-free sparkling white wine (340 mL; <2 g alcohol) as part of a standard evening meal in a room with either a pleasant or an unpleasant ambiance. Results Plasma concentrations of palmitoylethanolamide (PEA) and stearoylethanolamide (SEA) increased after 30 min in the unpleasant ambiance, while they decreased in the pleasant ambiance. Changes in ECs and their NAE congeners correlated with mood states, such as happiness and fatigue, but in the pleasant ambiance without alcohol only. ECs and their NAE congeners were correlated with serum free fatty acids and cortisol. Conclusion This is the first human study to demonstrate that plasma NAEs are responsive to an unpleasant meal ambiance. Furthermore, associations between mood states and ECs and their NAE congeners were observed. Trial Registration Clinicaltrials.gov NCT01426022 PMID:25962070

  20. Profiling the Oxylipin and Endocannabinoid Metabolome by UPLC-ESI-MS/MS in Human Plasma to Monitor Postprandial Inflammation.

    PubMed

    Gouveia-Figueira, Sandra; Späth, Jana; Zivkovic, Angela M; Nording, Malin L

    2015-01-01

    Bioactive lipids, including oxylipins, endocannabinoids, and related compounds may function as specific biochemical markers of certain aspects of inflammation. However, the postprandial responsiveness of these compounds is largely unknown; therefore, changes in the circulating oxylipin and endocannabinoid metabolome in response to a challenge meal were investigated at six occasions in a subject who freely modified her usual diet. The dietary change, and especially the challenge meal itself, represented a modification of precursor fatty acid status, with expectedly subtle effects on bioactive lipid levels. To detect even the slightest alteration, highly sensitive ultra-performance liquid chromatography (UPLC) coupled to electrospray ionization (ESI) tandem mass spectrometry (MS/MS) methods for bioactive lipid profiling was employed. A previously validated UPLC-ESI-MS/MS method for profiling the endocannabinoid metabolome was used, while validation of an UPLC-ESI-MS/MS method for oxylipin analysis was performed with acceptable outcomes for a majority of the parameters according to the US Food and Drug Administration guidelines for linearity (0.9938 < R2 < 0.9996), limit of detection (0.0005-2.1 pg on column), limit of quantification (0.0005-4.2 pg on column), inter- and intraday accuracy (85-115%) and precision (< 5%), recovery (40-109%) and stability (40-105%). Forty-seven of fifty-two bioactive lipids were detected in plasma samples at fasting and in the postprandial state (0.5, 1, and 3 hours after the meal). Multivariate analysis showed a significant shift of bioactive lipid profiles in the postprandial state due to inclusion of dairy products in the diet, which was in line with univariate analysis revealing seven compounds (NAGly, 9-HODE, 13-oxo-ODE, 9(10)-EpOME, 12(13)-EpOME, 20-HETE, and 11,12-DHET) that were significantly different between background diets in the postprandial state (but not at fasting). The only change in baseline levels at fasting was

  1. Profiling the Oxylipin and Endocannabinoid Metabolome by UPLC-ESI-MS/MS in Human Plasma to Monitor Postprandial Inflammation

    PubMed Central

    Gouveia-Figueira, Sandra; Späth, Jana; Zivkovic, Angela M.; Nording, Malin L.

    2015-01-01

    Bioactive lipids, including oxylipins, endocannabinoids, and related compounds may function as specific biochemical markers of certain aspects of inflammation. However, the postprandial responsiveness of these compounds is largely unknown; therefore, changes in the circulating oxylipin and endocannabinoid metabolome in response to a challenge meal were investigated at six occasions in a subject who freely modified her usual diet. The dietary change, and especially the challenge meal itself, represented a modification of precursor fatty acid status, with expectedly subtle effects on bioactive lipid levels. To detect even the slightest alteration, highly sensitive ultra-performance liquid chromatography (UPLC) coupled to electrospray ionization (ESI) tandem mass spectrometry (MS/MS) methods for bioactive lipid profiling was employed. A previously validated UPLC-ESI-MS/MS method for profiling the endocannabinoid metabolome was used, while validation of an UPLC-ESI-MS/MS method for oxylipin analysis was performed with acceptable outcomes for a majority of the parameters according to the US Food and Drug Administration guidelines for linearity (0.9938 < R2 < 0.9996), limit of detection (0.0005–2.1 pg on column), limit of quantification (0.0005–4.2 pg on column), inter- and intraday accuracy (85–115%) and precision (< 5%), recovery (40–109%) and stability (40–105%). Forty-seven of fifty-two bioactive lipids were detected in plasma samples at fasting and in the postprandial state (0.5, 1, and 3 hours after the meal). Multivariate analysis showed a significant shift of bioactive lipid profiles in the postprandial state due to inclusion of dairy products in the diet, which was in line with univariate analysis revealing seven compounds (NAGly, 9-HODE, 13-oxo-ODE, 9(10)-EpOME, 12(13)-EpOME, 20-HETE, and 11,12-DHET) that were significantly different between background diets in the postprandial state (but not at fasting). The only change in baseline levels at fasting

  2. Glutamate spillover modulates GABAergic synaptic transmission in the rat midbrain periaqueductal grey via metabotropic glutamate receptors and endocannabinoid signaling.

    PubMed

    Drew, Geoffrey M; Mitchell, Vanessa A; Vaughan, Christopher W

    2008-01-23

    Glutamate spillover regulates GABAergic synaptic transmission at several CNS synapses via presynaptic ionotropic and metabotropic glutamate receptors (mGluRs). We have previously demonstrated that activation of group I-III mGluRs inhibits GABAergic transmission in the midbrain periaqueductal gray (PAG), a region involved in organizing behavioral responses to threat, stress, and pain. Here, we examined the role of glutamate spillover in the modulation of GABAergic transmission in the PAG. Using whole-cell recordings from rat PAG slices, we found that evoked IPSCs were reduced by the nonspecific glutamate transport blockers DL-threo-beta-benzyloxyaspartic acid (TBOA) and L-trans-pyrrolidine-2,4-dicarboxylic acid, but not by the glial GLT1-specific blocker dihydrokainate. In contrast, TBOA had no effect on evoked IPSCs when glutamate uptake into the postsynaptic neuron was selectively impaired. TBOA increased the paired-pulse ratio of evoked IPSCs and reduced the rate but not the amplitude of spontaneous miniature IPSCs. The effect of TBOA on evoked IPSCs was abolished by the broad-spectrum mGluR antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (100 microM), reduced by the mGluR5-specific antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and mimicked by the mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG). Furthermore, the effects of both TBOA and DHPG were reduced by the cannabinoid CB1 receptor antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251). Finally, although MPEP and AM251 had no effect on single evoked IPSCs, they increased evoked IPSCs during repetitive stimulation. These results indicate that neuronal glutamate transporters limit mGluR5 activation and endocannabinoid signaling, but may be overwhelmed during conditions of elevated glutamate release. Thus, neuronal glutamate transporters play a key role in regulating endocannabinoid

  3. Endocannabinoids in Body Weight Control.

    PubMed

    Horn, Henrike; Böhme, Beatrice; Dietrich, Laura; Koch, Marco

    2018-05-30

    Maintenance of body weight is fundamental to maintain one's health and to promote longevity. Nevertheless, it appears that the global obesity epidemic is still constantly increasing. Endocannabinoids (eCBs) are lipid messengers that are involved in overall body weight control by interfering with manifold central and peripheral regulatory circuits that orchestrate energy homeostasis. Initially, blocking of eCB signaling by first generation cannabinoid type 1 receptor (CB1) inverse agonists such as rimonabant revealed body weight-reducing effects in laboratory animals and men. Unfortunately, rimonabant also induced severe psychiatric side effects. At this point, it became clear that future cannabinoid research has to decipher more precisely the underlying central and peripheral mechanisms behind eCB-driven control of feeding behavior and whole body energy metabolism. Here, we will summarize the most recent advances in understanding how central eCBs interfere with circuits in the brain that control food intake and energy expenditure. Next, we will focus on how peripheral eCBs affect food digestion, nutrient transformation and energy expenditure by interfering with signaling cascades in the gastrointestinal tract, liver, pancreas, fat depots and endocrine glands. To finally outline the safe future potential of cannabinoids as medicines, our overall goal is to address the molecular, cellular and pharmacological logic behind central and peripheral eCB-mediated body weight control, and to figure out how these precise mechanistic insights are currently transferred into the development of next generation cannabinoid medicines displaying clearly improved safety profiles, such as significantly reduced side effects.

  4. Computational search for hypotheses concerning the endocannabinoid contribution to the extinction of fear conditioning.

    PubMed

    Anastasio, Thomas J

    2013-01-01

    Fear conditioning, in which a cue is conditioned to elicit a fear response, and extinction, in which a previously conditioned cue no longer elicits a fear response, depend on neural plasticity occurring within the amygdala. Projection neurons in the basolateral amygdala (BLA) learn to respond to the cue during fear conditioning, and they mediate fear responding by transferring cue signals to the output stage of the amygdala. Some BLA projection neurons retain their cue responses after extinction. Recent work shows that activation of the endocannabinoid system is necessary for extinction, and it leads to long-term depression (LTD) of the GABAergic synapses that inhibitory interneurons make onto BLA projection neurons. Such GABAergic LTD would enhance the responses of the BLA projection neurons that mediate fear responding, so it would seem to oppose, rather than promote, extinction. To address this paradox, a computational analysis of two well-known conceptual models of amygdaloid plasticity was undertaken. The analysis employed exhaustive state-space search conducted within a declarative programming environment. The analysis reveals that GABAergic LTD actually increases the number of synaptic strength configurations that achieve extinction while preserving the cue responses of some BLA projection neurons in both models. The results suggest that GABAergic LTD helps the amygdala retain cue memory during extinction even as the amygdala learns to suppress the previously conditioned response. The analysis also reveals which features of both models are essential for their ability to achieve extinction with some cue memory preservation, and suggests experimental tests of those features.

  5. Computational search for hypotheses concerning the endocannabinoid contribution to the extinction of fear conditioning

    PubMed Central

    Anastasio, Thomas J.

    2013-01-01

    Fear conditioning, in which a cue is conditioned to elicit a fear response, and extinction, in which a previously conditioned cue no longer elicits a fear response, depend on neural plasticity occurring within the amygdala. Projection neurons in the basolateral amygdala (BLA) learn to respond to the cue during fear conditioning, and they mediate fear responding by transferring cue signals to the output stage of the amygdala. Some BLA projection neurons retain their cue responses after extinction. Recent work shows that activation of the endocannabinoid system is necessary for extinction, and it leads to long-term depression (LTD) of the GABAergic synapses that inhibitory interneurons make onto BLA projection neurons. Such GABAergic LTD would enhance the responses of the BLA projection neurons that mediate fear responding, so it would seem to oppose, rather than promote, extinction. To address this paradox, a computational analysis of two well-known conceptual models of amygdaloid plasticity was undertaken. The analysis employed exhaustive state-space search conducted within a declarative programming environment. The analysis reveals that GABAergic LTD actually increases the number of synaptic strength configurations that achieve extinction while preserving the cue responses of some BLA projection neurons in both models. The results suggest that GABAergic LTD helps the amygdala retain cue memory during extinction even as the amygdala learns to suppress the previously conditioned response. The analysis also reveals which features of both models are essential for their ability to achieve extinction with some cue memory preservation, and suggests experimental tests of those features. PMID:23761759

  6. Prenatal Stress and Peripubertal Stimulation of the Endocannabinoid System Differentially Regulate Emotional Responses and Brain Metabolism in Mice

    PubMed Central

    Macrì, Simone; Ceci, Chiara; Canese, Rossella; Laviola, Giovanni

    2012-01-01

    The central endocannabinoid system (ECS) and the hypothalamic-pituitary-adrenal-axis mediate individual responses to emotionally salient stimuli. Their altered developmental adjustment may relate to the emergence of emotional disturbances. Although environmental influences regulate the individual phenotype throughout the entire lifespan, their effects may result particularly persistent during plastic developmental stages (e.g. prenatal life and adolescence). Here, we investigated whether prenatal stress – in the form of gestational exposure to corticosterone supplemented in the maternal drinking water (100 mg/l) during the last week of pregnancy – combined with a pharmacological stimulation of the ECS during adolescence (daily fatty acid amide hydrolase URB597 i.p. administration - 0.4 mg/kg - between postnatal days 29–38), influenced adult mouse emotional behaviour and brain metabolism measured through in vivo quantitative magnetic resonance spectroscopy. Compared to control mice, URB597-treated subjects showed, in the short-term, reduced locomotion and, in the long term, reduced motivation to execute operant responses to obtain palatable rewards paralleled by reduced levels of inositol and taurine in the prefrontal cortex. Adult mice exposed to prenatal corticosterone showed increased behavioural anxiety and reduced locomotion in the elevated zero maze, and altered brain metabolism (increased glutamate and reduced taurine in the hippocampus; reduced inositol and N-Acetyl-Aspartate in the hypothalamus). Present data further corroborate the view that prenatal stress and pharmacological ECS stimulation during adolescence persistently regulate emotional responses in adulthood. Yet, whilst we hypothesized these factors to be interactive in nature, we observed that the consequences of prenatal corticosterone administration were independent from those of ECS drug-induced stimulation during adolescence. PMID:22848620

  7. Blockade of Endocannabinoid Hydrolytic Enzymes Attenuates Precipitated Opioid Withdrawal Symptoms in MiceS⃞

    PubMed Central

    Ramesh, Divya; Ross, Gracious R.; Schlosburg, Joel E.; Owens, Robert A.; Abdullah, Rehab A.; Kinsey, Steven G.; Long, Jonathan Z.; Nomura, Daniel K.; Sim-Selley, Laura J.; Cravatt, Benjamin F.; Akbarali, Hamid I.

    2011-01-01

    Δ9-Tetrahydrocannbinol (THC), the primary active constituent of Cannabis sativa, has long been known to reduce opioid withdrawal symptoms. Although THC produces most of its pharmacological actions through the activation of CB1 and CB2 cannabinoid receptors, the role these receptors play in reducing the variety of opioid withdrawal symptoms remains unknown. The endogenous cannabinoids, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), activate both cannabinoid receptors but are rapidly metabolized by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The objective of this study was to test whether increasing AEA or 2-AG, via inhibition of their respective hydrolytic enzymes, reduces naloxone-precipitated morphine withdrawal symptoms in in vivo and in vitro models of opioid dependence. Morphine-dependent mice challenged with naloxone reliably displayed a profound withdrawal syndrome, consisting of jumping, paw tremors, diarrhea, and weight loss. THC and the MAGL inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) dose dependently reduced the intensity of most measures through the activation of CB1 receptors. JZL184 also attenuated spontaneous withdrawal signs in morphine-dependent mice. The FAAH inhibitor N-(pyridin-3-yl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)benzyl)-piperdine-1-carboxamide (PF-3845) reduced the intensity of naloxone-precipitated jumps and paw flutters through the activation of CB1 receptors but did not ameliorate incidence of diarrhea or weight loss. In the final series of experiments, we investigated whether JZL184 or PF-3845 would attenuate naloxone-precipitated contractions in morphine-dependent ilea. Both enzyme inhibitors attenuated the intensity of naloxone-induced contractions, although this model does not account mechanistically for the autonomic withdrawal responses (i.e., diarrhea) observed in vivo. These results indicate

  8. Negative Regulation of Leptin-induced Reactive Oxygen Species (ROS) Formation by Cannabinoid CB1 Receptor Activation in Hypothalamic Neurons.

    PubMed

    Palomba, Letizia; Silvestri, Cristoforo; Imperatore, Roberta; Morello, Giovanna; Piscitelli, Fabiana; Martella, Andrea; Cristino, Luigia; Di Marzo, Vincenzo

    2015-05-29

    The adipocyte-derived, anorectic hormone leptin was recently shown to owe part of its regulatory effects on appetite-regulating hypothalamic neuropeptides to the elevation of reactive oxygen species (ROS) levels in arcuate nucleus (ARC) neurons. Leptin is also known to exert a negative regulation on hypothalamic endocannabinoid levels and hence on cannabinoid CB1 receptor activity. Here we investigated the possibility of a negative regulation by CB1 receptors of leptin-mediated ROS formation in the ARC. Through pharmacological and molecular biology experiments we report data showing that leptin-induced ROS accumulation is 1) blunted by arachidonyl-2'-chloroethylamide (ACEA) in a CB1-dependent manner in both the mouse hypothalamic cell line mHypoE-N41 and ARC neuron primary cultures, 2) likewise blocked by a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, troglitazone, in a manner inhibited by T0070907, a PPAR-γ antagonist that also inhibited the ACEA effect on leptin, 3) blunted under conditions of increased endocannabinoid tone due to either pharmacological or genetic inhibition of endocannabinoid degradation in mHypoE-N41 and primary ARC neuronal cultures from MAGL(-/-) mice, respectively, and 4) associated with reduction of both PPAR-γ and catalase activity, which are reversed by both ACEA and troglitazone. We conclude that CB1 activation reverses leptin-induced ROS formation and hence possibly some of the ROS-mediated effects of the hormone by preventing PPAR-γ inhibition by leptin, with subsequent increase of catalase activity. This mechanism might underlie in part CB1 orexigenic actions under physiopathological conditions accompanied by elevated hypothalamic endocannabinoid levels. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Transient increase of interleukin-1β after prolonged febrile seizures promotes adult epileptogenesis through long-lasting upregulating endocannabinoid signaling

    PubMed Central

    Feng, Bo; Tang, Yangshun; Chen, Bin; Xu, Cenglin; Wang, Yi; Dai, Yunjian; Wu, Dengchang; Zhu, Junmin; Wang, Shuang; Zhou, Yudong; Shi, Liyun; Hu, Weiwei; Zhang, Xia; Chen, Zhong

    2016-01-01

    It remains unclear how infantile febrile seizures (FS) enhance adult seizure susceptibility. Here we showed that the transient increase of interleukin-1β (IL-1β) after prolonged FS promoted adult seizure susceptibility, which was blocked by interleukin-1 receptor antagonist (IL-1Ra) within a critical time window. Postnatal administered IL-1β alone mimicked the effect of FS on adult seizure susceptibility. IL-1R1 knockout mice were not susceptible to adult seizure after prolonged FS or IL-1β treatment. Prolonged FS or early-life IL-1β treatment increased the expression of cannabinoid type 1 receptor (CB1R) for over 50 days, which was blocked by IL-1Ra or was absent in IL-1R1 knockout mice. CB1R antagonist, knockdown and endocannabinoid synthesis inhibitor abolished FS or IL-1β-enhanced seizure susceptibility. Thus, this work identifies a pathogenic role of postnatal IL-1β/IL-1R1 pathway and subsequent prolonged prominent increase of endocannabinoid signaling in adult seizure susceptibility following prolonged FS, and highlights IL-1R1 as a potential therapeutic target for preventing the development of epilepsy after infantile FS. PMID:26902320

  10. Long-term depression of inhibitory synaptic transmission induced by spike-timing dependent plasticity requires coactivation of endocannabinoid and muscarinic receptors.

    PubMed

    Ahumada, Juan; Fernández de Sevilla, David; Couve, Alejandro; Buño, Washington; Fuenzalida, Marco

    2013-12-01

    The precise timing of pre-postsynaptic activity is vital for the induction of long-term potentiation (LTP) or depression (LTD) at many central synapses. We show in synapses of rat CA1 pyramidal neurons in vitro that spike timing dependent plasticity (STDP) protocols that induce LTP at glutamatergic synapses can evoke LTD of inhibitory postsynaptic currents or STDP-iLTD. The STDP-iLTD requires a postsynaptic Ca(2+) increase, a release of endocannabinoids (eCBs), the activation of type-1 endocananabinoid receptors and presynaptic muscarinic receptors that mediate a decreased probability of GABA release. In contrast, the STDP-iLTD is independent of the activation of nicotinic receptors, GABAB Rs and G protein-coupled postsynaptic receptors at pyramidal neurons. We determine that the downregulation of presynaptic Cyclic adenosine monophosphate/protein Kinase A pathways is essential for the induction of STDP-iLTD. These results suggest a novel mechanism by which the activation of cholinergic neurons and retrograde signaling by eCBs can modulate the efficacy of GABAergic synaptic transmission in ways that may contribute to information processing and storage in the hippocampus. Copyright © 2013 Wiley Periodicals, Inc.

  11. The Endocannabinoid System in the Baboon (Papio SPP.) as a Complex Framework for Developmental Pharmacology

    PubMed Central

    Rodriguez-Sanchez, Iram P.; Guindon, Josee; Ruiz, Marco; Tejero, Maria E.; Hubbard, Gene; Martinez-De-Villarreal, Laura E.; Barrera-Saldaña, Hugo A.; Dick, Edward J.; Commuzzie, Anthony G; Schlabritz-Loutsevitch, Natalia E

    2017-01-01

    Introduction The consumption of marijuana (exogenous cannabinoid) almost doubled in adults during last decade. Consumption of exogenous cannabinoids interferes with the endogenous cannabinoid (or “endocannabinoid” (eCB)) system (ECS), which comprises N-arachidonylethanolamide (anandamide, AEA), 2-arachidonoyl glycerol (2-AG), endocannabinoid receptors (cannabinoid receptors 1 and 2 (CB1R and CB2R), encoded by CNR1 and CNR2, respectively), and synthesizing/degrading enzymes (FAAH, fatty-acid amide hydrolase; MAGL, monoacylglycerol lipase; DAGL-α, diacylglycerol lipase-alpha). Reports regarding the toxic and therapeutic effects of pharmacological compounds targeting the ECS are sometimes contradictory. This may be caused by the fact that structure of the eCBs varies in the species studied. Objectives First: to clone and characterize the cDNAs of selected members of ECS in a non-human primate (baboon, Papio spp.), and second: to compare those cDNA sequences to known human structural variants (single nucleotide polymorphisms and haplotypes). Materials and methods Polymerase chain reaction-amplified gene products from baboon tissues were transformed into Escherichia coli. Amplicon-positive clones were sequenced, and the obtained sequences were conceptually translated into amino-acid sequences using the genetic code. Results Among the ECS members, CNR1 was the best conserved gene between humans and baboons. The phenotypes associated with mutations in the untranslated regions of this gene in humans have not been described in baboons. One difference in the structure of CNR2 between humans and baboons was detected in the region with the only known clinically relevant polymorphism in a human receptor. All of the differences in the amino-acid structure of DAGL-α between humans and baboons were located in the hydroxylase domain, close to phosphorylation sites. None of the differences in the amino-acid structure of MAGL observed between baboons and humans were located in

  12. Activity-Based Protein Profiling of Organophosphorus and Thiocarbamate Pesticides Reveals Multiple Serine Hydrolase Targets in Mouse Brain

    PubMed Central

    NOMURA, DANIEL K.; CASIDA, JOHN E.

    2010-01-01

    Organophosphorus (OP) and thiocarbamate (TC) agrochemicals are used worldwide as insecticides, herbicides, and fungicides, but their safety assessment in terms of potential off-targets remains incomplete. In this study, we used a chemoproteomic platform, termed activity-based protein profiling, to broadly define serine hydrolase targets in mouse brain of a panel of 29 OP and TC pesticides. Among the secondary targets identified, enzymes involved in degradation of endocannabinoid signaling lipids, monoacylglycerol lipase and fatty acid amide hydrolase, were inhibited by several OP and TC pesticides. Blockade of these two enzymes led to elevations in brain endocannabinoid levels and dysregulated brain arachidonate metabolism. Other secondary targets include enzymes thought to also play important roles in the nervous system and unannotated proteins. This study reveals a multitude of secondary targets for OP and TC pesticides and underscores the utility of chemoproteomic platforms in gaining insights into biochemical pathways that are perturbed by these toxicants. PMID:21341672

  13. From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology.

    PubMed

    Ligresti, Alessia; De Petrocellis, Luciano; Di Marzo, Vincenzo

    2016-10-01

    Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one Δ(9)-tetrahydrocannabinol, and 2) the adaptive pro-homeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field. Copyright © 2016 the American Physiological Society.

  14. Role of Endocannabinoids on Sweet Taste Perception, Food Preference, and Obesity-related Disorders.

    PubMed

    Tarragon, Ernesto; Moreno, Juan José

    2017-12-25

    The prevalence of obesity and obesity-related disorders such as type 2 diabetes (T2D) and metabolic syndrome has increased significantly in the past decades, reaching epidemic levels and therefore becoming a major health issue worldwide. Chronic overeating of highly palatable foods is one of the main responsible aspects behind overweight. Food choice is driven by food preference, which is influenced by environmental and internal factors, from availability to rewarding properties of food. Consequently, the acquisition of a dietary habit that may lead to metabolic alterations is the result of a learning process in which many variables take place. From genetics to socioeconomic status, the response to food and how this food affects energy metabolism is heavily influenced, even before birth. In this work, we review how food preference is acquired and established, particularly as regards sweet taste; towards which flavors and tastes we are positively predisposed by our genetic background, our early experience, further lifestyle, and our surroundings; and, especially, the role that the endocannabinoid system (ECS) plays in all of this. Ultimately, we try to summarize why this system is relevant for health purposes and how this is linked to important aspects of eating behavior, as its function as a modulator of energy homeostasis affects, and is affected by, physiological responses directly associated with obesity. © The Author(s) 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. Monoacylglycerol lipase (MGLL) polymorphism rs604300 interacts with childhood adversity to predict cannabis dependence symptoms and amygdala habituation: Evidence from an endocannabinoid system-level analysis

    PubMed Central

    Carey, Caitlin E.; Agrawal, Arpana; Zhang, Bo; Conley, Emily D.; Degenhardt, Louisa; Heath, Andrew C.; Li, Daofeng; Lynskey, Michael T.; Martin, Nicholas G.; Montgomery, Grant W.; Wang, Ting; Bierut, Laura J.; Hariri, Ahmad R.; Nelson, Elliot C.; Bogdan, Ryan

    2015-01-01

    Despite evidence for heritable variation in cannabis involvement and the discovery of cannabinoid receptors and their endogenous ligands, no consistent patterns have emerged from candidate endocannabinoid (eCB) genetic association studies of cannabis involvement. Given interactions between eCB and stress systems and associations between childhood stress and cannabis involvement, it may be important to consider childhood adversity in the context of eCB-related genetic variation. We employed a system-level gene-based analysis of data from the Comorbidity and Trauma Study (N = 1,558) to examine whether genetic variation in 6 eCB genes (anabolism: DAGLA, DAGLB, NAPEPLD, catabolism: MGLL, FAAH, binding: CNR1; SNPs N = 65) and childhood sexual abuse (CSA) predicts cannabis dependence symptoms. Significant interactions with CSA emerged for MGLL at the gene-level (p = .009), and for rs604300 within MGLL (ΔR2 = .007, p < .001), the latter of which survived SNP-level Bonferroni correction and was significant in an additional sample with similar directional effects (N = 859; ΔR2 = .005, p = .026). Furthermore, in a third sample (N = 312), there was evidence that rs604300 genotype interacts with early life adversity to predict threat-related basolateral amygdala habituation, a neural phenotype linked to the eCB system and addiction (ΔR2 = .013, p = .047). Rs604300 may be related to epigenetic modulation of MGLL expression. These results are consistent with rodent models implicating 2-arachidonoylglycerol (2-AG), an endogenous cannabinoid metabolized by the enzyme encoded by MGLL, in the etiology of stress adaptation related to cannabis dependence, but require further replication. PMID:26595473

  16. Enhanced vasorelaxant effects of the endocannabinoid-like mediator, oleamide, in hypertension.

    PubMed

    Hopps, Jamie J; Dunn, William R; Randall, Michael D

    2012-06-05

    Oleamide is an endocannabinoid-like, fatty acid amide with structural similarities to anandamide. The cardiovascular effects of anandamide are enhanced in hypertension and we have now examined how hypertension affects responses to oleamide. Vasorelaxant responses to oleamide were significantly (P<0.001) enhanced in aortic rings from spontaneously hypertensive rats (SHRs), such that the maximal relaxation to oleamide was 40.3 ± 3.5%, compared to 15.7 ± 3.9% in normotensive Wistar Kyoto (WKY) controls. The augmented responses to oleamide in SHR arteries were unaffected by either inhibition of nitric oxide synthase (300 μM l-NAME) or fatty acid amide hydrolase (1 μM URB597) and independent of cannabinoid CB(1) receptors or the endothelium. The enhanced responses to oleamide were opposed by pre-treatment with capsaicin (such that R(max) was reduced to 9.8 ± 1.5%) and this occurred independently of TRPV1 receptor and sensory nerve activity, as the TRPV1 antagonist capsazepine (1-5 μM) and the cation channel inhibitor ruthenium red (10 μM) had no effect on the responses to oleamide. However, inhibition of cyclooxygenase (10 μM indomethacin) enhanced the responses in the WKY aortae, such that the responses were comparable to those in the SHR. The results suggest that the cyclooxygenase pathway has a role in modulating vasorelaxation caused by oleamide in normotensive aortae and that this is lost in hypertension, possibly as an adaptation to the increase in blood pressure. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Endocannabinoid receptor blockade reduces alanine aminotransferase in polycystic ovary syndrome independent of weight loss.

    PubMed

    Dawson, Alison J; Kilpatrick, Eric S; Coady, Anne-Marie; Elshewehy, Abeer M M; Dakroury, Youssra; Ahmed, Lina; Atkin, Stephen L; Sathyapalan, Thozhukat

    2017-07-14

    Evidence suggests that endocannabinoid system activation through the cannabinoid receptor 1 (CB1) is associated with enhanced liver injury, and CB1 antagonism may be beneficial. The aim of this study was to determine the impact of rimonabant (CB1 antagonist) on alanine aminotransferase (ALT), a hepatocellular injury marker, and a hepatic inflammatory cytokine profile. Post hoc review of 2 studies involving 50 obese women with PCOS and well matched for weight, randomised to weight reducing therapy; rimonabant (20 mg od) or orlistat (120 mg tds), or to insulin sensitising therapy metformin, (500 mg tds), or pioglitazone (45 mg od). No subject had non-alcoholic fatty liver disease (NAFLD). Treatment with rimonabant for 12 weeks reduced both ALT and weight (p < 0.01), and there was a negative correlation between Δ ALT and Δ HOMA-IR (p < 0.001), but not between Δ ALT and Δ weight. There was a significant reduction of weight with orlistat (p < 0.01); however, orlistat, metformin and pioglitazone had no effect on ALT. The free androgen index fell in all groups (p < 0.05). The inflammatory marker hs-CRP was reduced by pioglitazone (p < 0.001) alone and did not correlate with changes in ALT. The inflammatory cytokine profile for IL-1β, IL-6, IL-7, IL-10, IL12, TNF-α, MCP-1 and INF-γ did not differ between groups. None of the interventions had an effect on biological variability of ALT. Rimonabant through CB1 receptor blockade decreased serum ALT that was independent of weight loss and hepatic inflammatory markers in obese women with PCOS without NAFLD. ISRCTN58369615 (February 2007; retrospectively registered) ISRCTN75758249 (October 2007; retrospectively registered).

  18. Endocannabinoid-Dependent Long-Term Potentiation of Synaptic Transmission at Rat Barrel Cortex.

    PubMed

    Maglio, Laura Eva; Noriega-Prieto, José Antonio; Maraver, Maria Jesús; Fernández de Sevilla, David

    2018-05-01

    Brain-derived neurotrophic factor (BDNF) plays a critical role in modulating plasticity in sensory cortices. Indeed, a BDNF-dependent long-term potentiation (LTP) at distal basal excitatory synapses of Layer 5 pyramidal neurons (L5PNs) has been demonstrated in disinhibited rat barrel cortex slices. Although it is well established that this LTP requires the pairing of excitatory postsynaptic potentials (PSPs) with Ca2+ spikes, its induction when synaptic inhibition is working remains unexplored. Here we show that low-frequency stimulation at basal dendrites of L5PNs is able to trigger a PSP followed by an action potential (AP) and a slow depolarization (termed PSP-Ca2+ response) in thalamocortical slices without blocking synaptic inhibition. We demonstrate that AP barrage-mediated release of endocannabinoids (eCBs) from the recorded L5PNs induces PSP-Ca2+ response facilitation and BDNF-dependent LTP. Indeed, this LTP requires the type 1 cannabinoid receptors activation, is prevented by postsynaptic intracellular 1,2-bis(2-aminophenoxy) ethane-N,N,N,N'-tetraacetic acid (BAPTA) or the anandamide membrane transporter inhibitor AM404, and only occurs in L5PNs neurons showing depolarization-induced suppression of inhibition. Additionally, electrical stimulation at the posteromedial thalamic nucleus induced similar response and LTP. These results reveal a novel form of eCB-dependent LTP at L5PNs that could be relevant in the processing of sensory information in the barrel cortex.

  19. Clinical endocannabinoid deficiency (CECD) revisited: can this concept explain the therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?

    PubMed

    Smith, Steele Clarke; Wagner, Mark S

    2014-01-01

    Ethan B. Russo's paper of December 1, 2003 explored the concept of a clinical endocannabinoid deficiency (CECD) underlying the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome and other functional conditions alleviated by clinical cannabis. Available literature was reviewed, including searches via the National Library of medicine database and other sources. A review of the literature indicates that significant progress has been made since Dr. Ethan B. Russo's landmark paper, just ten years ago (February 2, 2004). Investigation at that time suggested that cannabinoids can block spinal, peripheral and gastrointestional mechanisms that promote pain in headache, fibromyalgia, irritable bowel syndrome and muscle spasm. Subsequent research has confirmed that underlying endocannabinoid deficiencies indeed play a role in migraine, fibromyalgia, irritable bowel syndrome and a growing list of other medical conditions. Clinical experience is bearing this out. Further research and especially, clinical trials will further demonstrate the usefulness of medical cannabis. As legal barriers fall and scientific bias fades this will become more apparent.

  20. Phencyclidine-induced social withdrawal results from deficient stimulation of cannabinoid CB₁ receptors: implications for schizophrenia.

    PubMed

    Seillier, Alexandre; Martinez, Alex A; Giuffrida, Andrea

    2013-08-01

    The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB₁-dependent manner, whereas pharmacological blockade of CB₁ receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB₁ receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB₁-mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP- and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB₁ receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission.

  1. Phyto and endocannabinoids exert complex actions on calcium and zinc signaling in mouse cortical neurons.

    PubMed

    Bouron, Alexandre

    2018-06-01

    Live-cell imaging experiments were performed with the fluorescent Ca 2+ and Zn 2+ probes Fluo-4 and FluoZin-3 on cultured cortical neurons dissociated from embryonic mice to investigate the effects of the cannabinoids anandamide (AEA), cannabidiol (CBD), and N-arachidonoyl glycine (NAGly) on neuronal store-operated Ca 2+ entry (SOCE). When tested individually AEA, CBD or NAGly inhibited SOCE. CBD and NAGly also released Ca 2+ from the endoplasmic reticulum. Furthermore, NAGly mobilized Zn 2+ from a store distinct from the endoplasmic reticulum and mitochondria, and up-regulated the thapsigargin-evoked Ca 2+ release. All these effects developed in a cannabinoid receptor CB1/2 independent manner via an intracellular pathway sensitive to the GPR55 antagonist ML193. Evidence is presented that cannabinoids influence Ca 2+ and Zn 2+ signaling in central nervous system neurons. The lipid sensing receptor GPR55 seems to be a central actor governing these responses. In addition, the alteration of the cytosolic Zn 2+ levels produced by NAGly provides support for the existence of a connection between endocannabinoids and Zn 2+ signaling in the brain. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Testosterone Rapidly Augments Retrograde Endocannabinoid Signaling in Proopiomelanocortin Neurons to Suppress Glutamatergic Input from Steroidogenic Factor 1 Neurons via Upregulation of Diacylglycerol Lipase-α

    PubMed Central

    Conde, Kristie; Fabelo, Carolina; Krause, William C.; Propst, Robert; Goethel, Jordan; Fischer, Daniel; Hur, Jin; Meza, Cecilia; Ingraham, Holly A.; Wagner, Edward J.

    2018-01-01

    Testosterone exerts profound effects on reproduction and energy homeostasis. Like other orexigenic hormones, it increases endocannabinoid tone within the hypothalamic feeding circuitry. Therefore, we tested the hypothesis that testosterone upregulates the expression of diacylglycerol lipase (DAGL)α in the hypothalamic arcuate nucleus (ARC) to increase energy intake via enhanced endocannabinoid-mediated retrograde inhibition of anorexigenic proopiomelanocortin (POMC) neurons. Energy intake, meal patterns, and energy expenditure were evaluated in orchidectomized, male guinea pigs treated subcutaneously with testosterone propionate (TP; 400 μg) or its sesame oil vehicle (0.1 mL). TP rapidly increased energy intake, meal size, O2 consumption, CO2 production, and metabolic heat production, all of which were antagonized by prior administration of the DAGL inhibitor orlistat (3 μg) into the third ventricle. These orlistat-sensitive, TP-induced increases in energy intake and expenditure were temporally associated with a significant elevation in ARC DAGLα expression. Electrophysiological recordings in hypothalamic slices revealed that TP potentiated depolarization-induced suppression of excitatory glutamatergic input onto identified ARC POMC neurons, which was also abolished by orlistat (3 μM), the CB1 receptor antagonist AM251 (1 μM), and the AMP-activated protein kinase inhibitor compound C (30 μM) and simulated by transient bath application of the dihydrotestosterone mimetic Cl-4AS-1 (100 nM) and testosterone-conjugated bovine serum albumin (100 nM). Thus, testosterone boosts DAGLα expression to augment retrograde, presynaptic inhibition of glutamate release onto ARC POMC neurons that, in turn, increases energy intake and expenditure. These studies advance our understanding of how androgens work within the hypothalamic feeding circuitry to affect changes in energy balance. PMID:27871072

  3. Redox system and phospholipid metabolism in the kidney of hypertensive rats after FAAH inhibitor URB597 administration.

    PubMed

    Biernacki, Michał; Ambrożewicz, Ewa; Gęgotek, Agnieszka; Toczek, Marek; Bielawska, Katarzyna; Skrzydlewska, Elżbieta

    2018-05-01

    Primary and secondary hypertension is associated with kidney redox imbalance resulting in enhanced reactive oxygen species (ROS) and enzymes dependent phospholipid metabolism. The fatty acid amide hydrolase inhibitor, URB597, modulates the levels of endocannabinoids, particularly of anandamide, which is responsible for controlling blood pressure and regulating redox balance. Therefore, this study aimed to compare the effects of chronic URB597 administration to spontaneously hypertensive rats (SHR) and rats with secondary hypertension (DOCA-salt rats) on the kidney metabolism associated with the redox and endocannabinoid systems. It was shown fatty acid amide hydrolase (FAAH) inhibitor decreased the activity of ROS-generated enzymes what resulted in a reduction of ROS level. Moreover varied changes in antioxidant parameters were observed with tendency to improve antioxidant defense in SHR kidney. Moreover, URB597 administration to hypertensive rats decreased pro-inflammatory response, particularly in the kidneys of DOCA-salt hypertensive rats. URB597 had tendency to enhance ROS-dependent phospholipid oxidation, estimated by changes in neuroprostanes in the kidney of SHR and reactive aldehydes (4-hydroxynonenal and malondialdehyde) in DOCA-salt rats, in particular. The administration of FAAH inhibitor resulted in increased level of endocannabinoids in kidney of both groups of hypertensive rats led to enhanced expression of the cannabinoid receptors type 1 and 2 in SHR as well as vanilloid receptor 1 receptors in DOCA-salt rats. URB597 given to normotensive rats also affected kidney oxidative metabolism, resulting in enhanced level of neuroprostanes in Wistar Kyoto rats and reactive aldehydes in Wistar rats. Moreover, the level of endocannabinoids and cannabinoid receptors were significantly higher in both control groups of rats after URB597 administration. In conclusion, because URB597 disturbed the kidney redox system and phospholipid ROS-dependent and enzymatic

  4. Endocannabinoid/GABA interactions in the entopeduncular nucleus modulates alcohol intake in rats.

    PubMed

    Méndez-Díaz, Mónica; Caynas Rojas, Seraid; Gómez Armas, David; Ruiz-Contreras, Alejandra E; Aguilar-Roblero, Raúl; Prospéro-García, Oscar

    2013-02-01

    Alcohol use disorder is a compulsive behavior driven by motivational systems and by a poor control of consummatory behavior. The entopeduncular nucleus (EP) seems to be involved in the regulation of executive mechanisms, hence, in the expression of behavior. Endocannabinoids (eCB) are involved in alcohol intake mechanisms. The eCB receptor name cannabinoid receptor 1 (CB1R) is expressed in the EP in GABAergic terminals. The role of the eCB system (eCBs) of the EP in the modulation of alcohol seeking and intake behavior is unknown. Therefore, we decided to investigate the role of the eCBs and its interaction with GABA transmission in rat EP, in the regulation of alcohol intake behavior. Rats were submitted to a 10-day period of moderate alcohol (10% in tap water) ingestion. No tap water was available. On day 11, either anandamide (AEA, CB1 receptor agonist), AM251 (CB1R inverse agonist), baclofen (BAC, GABAB receptor agonist), or CGP35348 (GABAB receptor antagonist) was administered into the EP. One bottle of water and one of alcohol (10% in water) were available ad libitum for the following 24 h, and consumption was quantified at the end of this period. Results show that administration of AEA into the EP decreased alcohol consumption while AM251 and BAC administered independently increased alcohol consumption. AEA prevented the increase induced by AM251 or BAC. Likewise, CGP35348 prevented alcohol ingestion induced by AM251. These data suggest that eCBs dysfunction in the EP may be playing a crucial role in the abuse and dependence of alcohol and other drugs. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Are the endocannabinoid-like compounds N-acyl aminoacids neuroprotective after traumatic brain injury?

    PubMed

    Mann, Aniv; Cohen-Yeshurun, Ayelet; Trembovler, Victoria; Mechoulam, Raphael; Shohami, Esther

    2016-05-01

    In recent years, a library of approx. 70 N-acyl aminoacids (NAAAs) was discovered in the rat brain. A particular member of this family of compounds is arachidonoyl serine (AraS), which has generated special interest as a potential therapy for traumatic brain injury (TBI). This is due to its structural similarity to the endocannabinoid (eCB) 2-arachidonoyl glycerol (2-AG), which was previously shown to be beneficial in the recovery in a closed head injury model of TBI. Indeed, AraS exerted eCB-mediated neuroprotection, which was evident in numerous aspects related to the secondary damage characterizing TBI. These findings promoted broadening of the research to additional compounds of the NAAA family that share a structural similarity to AraS, namely, palmitoyl serine (PalmS) and oleoyl serine. The latter did not exhibit any improvement in recovery, whereas the former displayed some neuroprotection, albeit inferior to 2-AG and AraS, via unknown mechanisms. Interestingly, when a combined treatment of 2-AG, AraS and PalmS was tested, the overall effect on the severity score was inferior to their individual effects, suggesting not only a lack of direct or indirect synergism, but also possibly some spatial hindrance. Taken together, the complexity of the damage caused by TBI and the many open questions concerning the role of the eCB system in health and disease, the findings so far may serve as a small trace to the understanding of the eCB system, as well as of the mechanisms underlying TBI.

  6. Molecular model of cannabis sensitivity in developing neuronal circuits

    PubMed Central

    Keimpema, Erik; Mackie, Ken; Harkany, Tibor

    2011-01-01

    Prenatal cannabis exposure can complicate in utero development of the nervous system. Cannabis impacts the formation and functions of neuronal circuitries by targeting cannabinoid receptors. Endocannabinoid signaling emerges as a signaling cassette to orchestrate neuronal differentiation programs through the precisely timed interaction of endocannabinoid ligands with their cognate cannabinoid receptors. By indiscriminately prolonging the ‘switched-on’ period of cannabinoid receptors, cannabis can hijack endocannabinoid signals to evoke molecular rearrangements, leading to the erroneous wiring of neuronal networks. Here, we formulate a hierarchical network design necessary and sufficient to describe molecular underpinnings of cannabis-induced neural growth defects. We integrate signalosome components deduced from genome- and proteome-wide arrays and candidate analyses to propose a mechanistic hypothesis on how cannabis-induced ectopic cannabinoid receptor activity overrides physiological neurodevelopmental endocannabinoid signals, affecting the timely formation of synapses. PMID:21757242

  7. Role of Cannabinoids in Gastrointestinal Mucosal Defense and Inflammation

    PubMed Central

    Gyires, Klára; Zádori, Zoltán S.

    2016-01-01

    Modulating the activity of the endocannabinoid system influences various gastrointestinal physiological and pathophysiological processes, and cannabinoid receptors as well as regulatory enzymes responsible for the synthesis or degradation of endocannabinoids representing potential targets to reduce the development of gastrointestinal mucosal lesions, hemorrhage and inflammation. Direct activation of CB1 receptors by plant-derived, endogenous or synthetic cannabinoids effectively reduces both gastric acid secretion and gastric motor activity, and decreases the formation of gastric mucosal lesions induced by stress, pylorus ligation, nonsteroidal anti-inflammatory drugs (NSAIDs) or alcohol, partly by peripheral, partly by central mechanisms. Similarly, indirect activation of cannabinoid receptors through elevation of endocannabinoid levels by globally acting or peripherally restricted inhibitors of their metabolizing enzymes (FAAH, MAGL) or by inhibitors of their cellular uptake reduces the gastric mucosal lesions induced by NSAIDs in a CB1 receptor-dependent fashion. Dual inhibition of FAAH and cyclooxygenase enzymes induces protection against both NSAID-induced gastrointestinal damage and intestinal inflammation. Moreover, in intestinal inflammation direct or indirect activation of CB1 and CB2 receptors exerts also multiple beneficial effects. Namely, activation of both CB receptors was shown to ameliorate intestinal inflammation in various murine colitis models, to decrease visceral hypersensitivity and abdominal pain, as well as to reduce colitis-associated hypermotility and diarrhea. In addition, CB1 receptors suppress secretory processes and also modulate intestinal epithelial barrier functions. Thus, experimental data suggest that the endocannabinoid system represents a promising target in the treatment of inflammatory bowel diseases, and this assumption is also confirmed by preliminary clinical studies. PMID:26935536

  8. Behavioral alterations in cystic fibrosis mice are prevented by cannabinoid treatment in infancy.

    PubMed

    Bregman, Tatiana; Fride, Ester

    2011-06-17

    Substantial data have been accumulated regarding the molecular basis of cystic fibrosis (CF) pathogenesis, whereas the influence of biochemical impairments on brain processes has been the focus of much less attention. We have studied some behavioral parameters, such as motor activity and anxiety level, in a mice model of CF. We have assumed that functioning of the endocannabinoid system could be impaired in CF (endocannabinoids are fatty acid derivatives, and fatty acid deficiency is considered a major factor in CF etiology). We have suggested that chronic treatment with cannabinoid receptors agonist during infancy would balance cannabinoid levels and prevent CF-related behavioral alterations. Motor activity and anxiety level were studied in naïve adult CF mice (cftr-deficient mice) and compared with wild-type mice and to CF mice treated chronically with Δ9-tetrahydrocannabinol (Δ9-THC; endocannabinoid receptor agonist) during infancy (from days 7 to 28). Motor activity was tested in the tetrad, and level of anxiety in the plus maze, a month after cessation of treatment. Motor activity decrease and elevated anxiety level were found in adult naïve CF mice compared with wild-type mice. CF mice treated with THC in infancy showed normal motor activity and anxiety levels in adulthood. Motor function alteration and elevated anxiety levels in CF can result from lack of CFTR-channel in neurons and disturbed activity of various brain areas, as well as being secondary and mediated by fatty acids deficiency, altered levels of endocannabinoids and their receptors. It can be suggested that chronic treatment during infancy restores endocannabinoid function and thus prevents behavioral alterations.

  9. Phencyclidine-Induced Social Withdrawal Results from Deficient Stimulation of Cannabinoid CB1 Receptors: Implications for Schizophrenia

    PubMed Central

    Seillier, Alexandre; Martinez, Alex A; Giuffrida, Andrea

    2013-01-01

    The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB1-dependent manner, whereas pharmacological blockade of CB1 receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB1 receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB1-mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP- and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB1 receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission. PMID:23563893

  10. Molecular model of cannabis sensitivity in developing neuronal circuits.

    PubMed

    Keimpema, Erik; Mackie, Ken; Harkany, Tibor

    2011-09-01

    Prenatal cannabis exposure can complicate in utero development of the nervous system. Cannabis impacts the formation and functions of neuronal circuitries by targeting cannabinoid receptors. Endocannabinoid signaling emerges as a signaling cassette that orchestrates neuronal differentiation programs through the precisely timed interaction of endocannabinoid ligands with their cognate cannabinoid receptors. By indiscriminately prolonging the 'switched-on' period of cannabinoid receptors, cannabis can hijack endocannabinoid signals to evoke molecular rearrangements, leading to the erroneous wiring of neuronal networks. Here, we formulate a hierarchical network design necessary and sufficient to describe the molecular underpinnings of cannabis-induced neural growth defects. We integrate signalosome components, deduced from genome- and proteome-wide arrays and candidate analyses, to propose a mechanistic hypothesis of how cannabis-induced ectopic cannabinoid receptor activity overrides physiological neurodevelopmental endocannabinoid signals, affecting the timely formation of synapses. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?

    PubMed Central

    Fernández-Ruiz, Javier; Sagredo, Onintza; Pazos, M Ruth; García, Concepción; Pertwee, Roger; Mechoulam, Raphael; Martínez-Orgado, José

    2013-01-01

    Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, anti-oxidant, anti-emetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and anti-oxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with Δ9-tetrahydrocannabinol is already under clinical evaluation in patients with Huntington's disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ9-tetrahydrocannabinol, i.e. CB1 and CB2 receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB2 receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels. PMID:22625422

  12. Glutamate spillover drives endocannabinoid production and inhibits GABAergic transmission in the Substantia Nigra pars compacta.

    PubMed

    Freestone, Peter S; Guatteo, Ezia; Piscitelli, Fabiana; di Marzo, Vincenzo; Lipski, Janusz; Mercuri, Nicola B

    2014-04-01

    Endocannabinoids (eCBs) modulate synaptic transmission in the brain, but little is known of their regulatory role in nigral dopaminergic neurons, and whether transmission to these neurons is tonically inhibited by eCBs as seen in some other brain regions. Using whole-cell recording in midbrain slices, we observed potentiation of evoked IPSCs (eIPSCs) in these neurons after blocking CB1 receptors with rimonabant or LY-320,135, indicating the presence of an eCB tone reducing inhibitory synaptic transmission. Increased postsynaptic calcium buffering and block of mGluR1 or postsynaptic G-protein coupled receptors prevented this potentiation. Increasing spillover of endogenous glutamate by inhibiting uptake attenuated eIPSC amplitude, while enhancing the potentiation by rimonabant. Group I mGluR activation transiently inhibited eIPSCs, which could be prevented by GDP-β-S, increased calcium buffering or rimonabant. We explored the possibility that the dopamine-derived eCB N-arachidonoyl dopamine (NADA) is involved. The eCB tone was abolished by preventing dopamine synthesis, and enhanced by l-DOPA. It was not detected in adjacent non-dopaminergic neurons. Preventing 2-AG synthesis did not affect the tone, while inhibition of NADA production abolished it. Quantification of ventral midbrain NADA suggested a basal level that increased following prolonged depolarization or mGluR activation. Since block of the tone was not always accompanied by attenuation of depolarization-induced suppression of inhibition (DSI) and vice versa, our results indicate DSI and the eCB tone are mediated by distinct eCBs. This study provides evidence that dopamine modulates the activity of SNc neurons not only by conventional dopamine receptors, but also by CB1 receptors, potentially via NADA. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Corticotropin-Releasing Hormone Drives Anandamide Hydrolysis in the Amygdala to Promote Anxiety

    PubMed Central

    Gray, J. Megan; Vecchiarelli, Haley A.; Morena, Maria; Lee, Tiffany T.Y.; Hermanson, Daniel J.; Kim, Alexander B.; McLaughlin, Ryan J.; Hassan, Kowther I.; Kühne, Claudia; Wotjak, Carsten T.; Deussing, Jan M.; Patel, Sachin

    2015-01-01

    Corticotropin-releasing hormone (CRH) is a central integrator in the brain of endocrine and behavioral stress responses, whereas activation of the endocannabinoid CB1 receptor suppresses these responses. Although these systems regulate overlapping functions, few studies have investigated whether these systems interact. Here we demonstrate a novel mechanism of CRH-induced anxiety that relies on modulation of endocannabinoids. Specifically, we found that CRH, through activation of the CRH receptor type 1 (CRHR1), evokes a rapid induction of the enzyme fatty acid amide hydrolase (FAAH), which causes a reduction in the endocannabinoid anandamide (AEA), within the amygdala. Similarly, the ability of acute stress to modulate amygdala FAAH and AEA in both rats and mice is also mediated through CRHR1 activation. This interaction occurs specifically in amygdala pyramidal neurons and represents a novel mechanism of endocannabinoid–CRH interactions in regulating amygdala output. Functionally, we found that CRH signaling in the amygdala promotes an anxious phenotype that is prevented by FAAH inhibition. Together, this work suggests that rapid reductions in amygdala AEA signaling following stress may prime the amygdala and facilitate the generation of downstream stress-linked behaviors. Given that endocannabinoid signaling is thought to exert “tonic” regulation on stress and anxiety responses, these data suggest that CRH signaling coordinates a disruption of tonic AEA activity to promote a state of anxiety, which in turn may represent an endogenous mechanism by which stress enhances anxiety. These data suggest that FAAH inhibitors may represent a novel class of anxiolytics that specifically target stress-induced anxiety. PMID:25740517

  14. A Lower Olfactory Capacity Is Related to Higher Circulating Concentrations of Endocannabinoid 2-Arachidonoylglycerol and Higher Body Mass Index in Women.

    PubMed

    Pastor, Antoni; Fernández-Aranda, Fernando; Fitó, Montserrat; Jiménez-Murcia, Susana; Botella, Cristina; Fernández-Real, Jose M; Frühbeck, Gema; Tinahones, Francisco J; Fagundo, Ana B; Rodriguez, Joan; Agüera, Zaida; Langohr, Klaus; Casanueva, Felipe F; de la Torre, Rafael

    2016-01-01

    The endocannabinoid (eCB) system can promote food intake by increasing odor detection in mice. The eCB system is over-active in human obesity. Our aim is to measure circulating eCB concentrations and olfactory capacity in a human sample that includes people with obesity and explore the possible interaction between olfaction, obesity and the eCB system. The study sample was made up of 161 females with five groups of body mass index sub-categories ranging from under-weight to morbidly obese. We assessed olfactory capacity with the "Sniffin´Sticks" test, which measures olfactory threshold-discrimination-identification (TDI) capacity. We measured plasma concentrations of the eCBs 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine or anandamide (AEA), and several eCB-related compounds, 2-acylglycerols and N-acylethanolamines. 2-AG and other 2-acylglycerols fasting plasma circulating plasma concentrations were higher in obese and morbidly obese subjects. AEA and other N-acylethanolamine circulating concentrations were lower in under-weight subjects. Olfactory TDI scores were lower in obese and morbidly obese subjects. Lower TDI scores were independently associated with higher 2-AG fasting plasma circulating concentrations, higher %body fat, and higher body mass index, after controlling for age, smoking, menstruation, and use of contraceptives. Our results show that obese subjects have a lower olfactory capacity than non-obese ones and that elevated fasting plasma circulating 2-AG concentrations in obesity are linked to a lower olfactory capacity. In agreement with previous studies we show that eCBs AEA and 2-AG, and their respective congeners have a distinct profile in relation to body mass index. The present report is the first study in humans in which olfactory capacity and circulating eCB concentrations have been measured in the same subjects.

  15. The cannabinoid WIN55,212-2 protects against oxidized LDL-induced inflammatory response in murine macrophages[S

    PubMed Central

    Hao, Ming-xiu; Jiang, Li-sheng; Fang, Ning-yuan; Pu, Jun; Hu, Liu-hua; Shen, Ling-Hong; Song, Wei; He, Ben

    2010-01-01

    The endocannabinoid system has recently been attracted interest for its anti-inflammatory and anti-oxidative properties. In this study, we investigated the role of the endocannabinoid system in regulating the oxidized low-density lipoprotein (oxLDL)-induced inflammatory response in macrophages. RAW264.7 mouse macrophages and peritoneal macrophages isolated from Sprague-Dawley (SD) rats were exposed to oxLDL with or without the synthetic cannabinoid WIN55,212-2. To assess the inflammatory response, reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF- α) levels were determined, and activation of the mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappa B signaling pathways were assessed. We observed that: i) oxLDL strongly induced ROS generation and TNF- α secretion in murine macrophages; ii) oxLDL-induced TNF- α and ROS levels could be lowered considerably by WIN55,212-2 via inhibition of MAPK (ERK1/2) signaling and NF-kappa B activity; and iii) the effects of WIN55212-2 were attenuated by the selective CB2 receptor antagonist AM630. These results demonstrate the involvement of the endocannabinoid system in regulating the oxLDL-induced inflammatory response in macrophages, and indicate that the CB2 receptor may offer a novel pharmaceutical target for treating atherosclerosis. PMID:20305287

  16. The administration of endocannabinoid uptake inhibitors OMDM-2 or VDM-11 promotes sleep and decreases extracellular levels of dopamine in rats.

    PubMed

    Murillo-Rodríguez, Eric; Palomero-Rivero, Marcela; Millán-Aldaco, Diana; Di Marzo, Vincenzo

    2013-01-17

    The family of the endocannabinoid system comprises endogenous lipids (such as anandamide [ANA]), receptors (CB(1)/CB(2) cannabinoid receptors), metabolic enzymes (fatty acid amide hydrolase [FAAH]) and a putative membrane transporter (anandamide membrane transporter [AMT]). Although the role of ANA, FAAH or the CB(1) cannabinoid receptor in sleep modulation has been reported, the effects of the inhibition of AMT on sleep remain unclear. In the present study, we show that microdialysis perfusion in rats of AMT inhibitors, (9Z)-N-[1-((R)-4-hydroxbenzyl)-2-hydroxyethyl]-9-octadecenamide (OMDM-2) or N-(4-hydroxy-2-methylphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (VDM-11; 10, 20 or 30 μM; each compound) delivered into the paraventricular thalamic nucleus (PVA) increased sleep and decreased waking. In addition, the infusion of compounds reduced the extracellular levels of dopamine collected from nucleus accumbens. Taken together, these findings illustrate a critical role of AMT in sleep modulation. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?

    PubMed

    Fernández-Ruiz, Javier; Sagredo, Onintza; Pazos, M Ruth; García, Concepción; Pertwee, Roger; Mechoulam, Raphael; Martínez-Orgado, José

    2013-02-01

    Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, anti-oxidant, anti-emetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and anti-oxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with Δ(9)-tetrahydrocannabinol is already under clinical evaluation in patients with Huntington's disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ(9)-tetrahydrocannabinol, i.e. CB(1) and CB(2) receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB(2) receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

  18. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes

    PubMed Central

    De Petrocellis, Luciano; Ligresti, Alessia; Moriello, Aniello Schiano; Allarà, Marco; Bisogno, Tiziana; Petrosino, Stefania; Stott, Colin G; Di Marzo, Vincenzo

    2011-01-01

    BACKGROUND AND PURPOSE Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) interact with transient receptor potential (TRP) channels and enzymes of the endocannabinoid system. EXPERIMENTAL APPROACH The effects of 11 pure cannabinoids and botanical extracts [botanical drug substance (BDS)] from Cannabis varieties selected to contain a more abundant cannabinoid, on TRPV1, TRPV2, TRPM8, TRPA1, human recombinant diacylglycerol lipase α (DAGLα), rat brain fatty acid amide hydrolase (FAAH), COS cell monoacylglycerol lipase (MAGL), human recombinant N-acylethanolamine acid amide hydrolase (NAAA) and anandamide cellular uptake (ACU) by RBL-2H3 cells, were studied using fluorescence-based calcium assays in transfected cells and radiolabelled substrate-based enzymatic assays. Cannabinol (CBN), cannabichromene (CBC), the acids (CBDA, CBGA, THCA) and propyl homologues (CBDV, CBGV, THCV) of CBD, cannabigerol (CBG) and THC, and tetrahydrocannabivarin acid (THCVA) were also tested. KEY RESULTS CBD, CBG, CBGV and THCV stimulated and desensitized human TRPV1. CBC, CBD and CBN were potent rat TRPA1 agonists and desensitizers, but THCV-BDS was the most potent compound at this target. CBG-BDS and THCV-BDS were the most potent rat TRPM8 antagonists. All non-acid cannabinoids, except CBC and CBN, potently activated and desensitized rat TRPV2. CBDV and all the acids inhibited DAGLα. Some BDS, but not the pure compounds, inhibited MAGL. CBD was the only compound to inhibit FAAH, whereas the BDS of CBC > CBG > CBGV inhibited NAAA. CBC = CBG > CBD inhibited ACU, as did the BDS of THCVA, CBGV, CBDA and THCA, but the latter extracts were more potent inhibitors. CONCLUSIONS AND IMPLICATIONS These results are relevant to the analgesic, anti-inflammatory and anti-cancer effects of cannabinoids and Cannabis extracts. LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011

  19. A restricted population of CB1 cannabinoid receptors with neuroprotective activity.

    PubMed

    Chiarlone, Anna; Bellocchio, Luigi; Blázquez, Cristina; Resel, Eva; Soria-Gómez, Edgar; Cannich, Astrid; Ferrero, José J; Sagredo, Onintza; Benito, Cristina; Romero, Julián; Sánchez-Prieto, José; Lutz, Beat; Fernández-Ruiz, Javier; Galve-Roperh, Ismael; Guzmán, Manuel

    2014-06-03

    The CB1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. Of note, CB1 receptors are expressed at the synapses of two opposing (i.e., GABAergic/inhibitory and glutamatergic/excitatory) neuronal populations, so the activation of one and/or another receptor population may conceivably evoke different effects. Despite the widely reported neuroprotective activity of the CB1 receptor in animal models, the precise pathophysiological relevance of those two CB1 receptor pools in neurodegenerative processes is unknown. Here, we first induced excitotoxic damage in the mouse brain by (i) administering quinolinic acid to conditional mutant animals lacking CB1 receptors selectively in GABAergic or glutamatergic neurons, and (ii) manipulating corticostriatal glutamatergic projections remotely with a designer receptor exclusively activated by designer drug pharmacogenetic approach. We next examined the alterations that occur in the R6/2 mouse, a well-established model of Huntington disease, upon (i) fully knocking out CB1 receptors, and (ii) deleting CB1 receptors selectively in corticostriatal glutamatergic or striatal GABAergic neurons. The data unequivocally identify the restricted population of CB1 receptors located on glutamatergic terminals as an indispensable player in the neuroprotective activity of (endo)cannabinoids, therefore suggesting that this precise receptor pool constitutes a promising target for neuroprotective therapeutic strategies.

  20. Oleamide: a fatty acid amide signaling molecule in the cardiovascular system?

    PubMed

    Hiley, C Robin; Hoi, Pui Man

    2007-01-01

    Oleamide (cis-9,10-octadecenoamide), a fatty acid primary amide discovered in the cerebrospinal fluid of sleep-deprived cats, has a variety of actions that give it potential as a signaling molecule, although these actions have not been extensively investigated in the cardiovascular system. The synthetic pathway probably involves synthesis of oleoylglycine and then conversion to oleamide by peptidylglycine alpha-amidating monooxygenase (PAM); breakdown of oleamide is by fatty acid amide hydrolase (FAAH). Oleamide interacts with voltage-gated Na(+) channels and allosterically with GABA(A) and 5-HT(7) receptors as well as having cannabinoid-like actions. The latter have been suggested to be due to potentiation of the effects of endocannabinoids such as anandamide by inhibiting FAAH-mediated hydrolysis. This might underlie an "entourage effect" whereby co-released endogenous nonagonist congeners of endocannabinoids protect the active molecule from hydrolysis by FAAH. However, oleamide has direct agonist actions at CB(1) cannabinoid receptors and also activates the TRPV1 vanilloid receptor. Other actions include inhibition of gap-junctional communication, and this might give oleamide a role in myocardial development. Many of these actions are absent from the trans isomer of 9,10-octadecenoamide. One of the most potent actions of oleamide is vasodilation. In rat small mesenteric artery the response does not involve CB(1) cannabinoid receptors but another pertussis toxin-sensitive, G protein-coupled receptor, as yet unidentified. This receptor is sensitive to rimonabant and O-1918, an antagonist at the putative "abnormal-cannabidiol" or endothelial "anandamide" receptors. Vasodilation is mediated by endothelium-derived nitric oxide, endothelium-dependent hyperpolarization, and also through activation of TRPV1 receptors. A physiological role for oleamide in the heart and circulation has yet to be demonstrated, as has production by cells of the cardiovascular system, but

  1. Endocannabinoid receptor deficiency affects maternal care and alters the dam's hippocampal oxytocin receptor and brain-derived neurotrophic factor expression.

    PubMed

    Schechter, M; Weller, A; Pittel, Z; Gross, M; Zimmer, A; Pinhasov, A

    2013-10-01

    Maternal care is the newborn's first experience of social interaction, and this influences infant survival, development and social competences throughout life. We recently found that postpartum blocking of the endocannabinoid receptor-1 (CB1R) altered maternal behaviour. In the present study, maternal care was assessed by the time taken to retrieve pups, pups' ultrasonic vocalisations (USVs) and pup body weight, comparing CB1R deleted (CB1R KO) versus wild-type (WT) mice. After culling on postpartum day 8, hippocampal expression of oxytocin receptor (OXTR), brain-derived neurotrophic factor (BDNF) and stress-mediating factors were evaluated in CB1R KO and WT dams. Comparisons were also performed with nulliparous (NP) CB1R KO and WT mice. Compared to WT, CB1R KO dams were slower to retrieve their pups. Although the body weight of the KO pups did not differ from the weight of WT pups, they emitted fewer USVs. This impairment of the dam-pup relationship correlated with a significant reduction of OXTR mRNA and protein levels among CB1R KO dams compared to WT dams. Furthermore, WT dams exhibited elevated OXTR mRNA expression, as well as increased levels of mineralocorticoid and glucocorticoid receptors, compared to WT NP mice. By contrast, CB1R KO dams showed no such elevation of OXTR expression, alongside lower BDNF and mineralocorticoid receptors, as well as elevated corticotrophin-releasing hormone mRNA levels, when compared to CB1R KO NP. Thus, it appears that the disruption of endocannabinoid signalling by CB1R deletion alters expression of the OXTR, apparently leading to deleterious effects upon maternal behaviour. © 2013 British Society for Neuroendocrinology.

  2. Cannabinoid Regulation of Brain Reward Processing with an Emphasis on the Role of CB1 Receptors: A Step Back into the Future.

    PubMed

    Panagis, George; Mackey, Brian; Vlachou, Styliani

    2014-01-01

    Over the last decades, the endocannabinoid system has been implicated in a large variety of functions, including a crucial modulation of brain-reward circuits and the regulation of motivational processes. Importantly, behavioral studies have shown that cannabinoid compounds activate brain reward mechanisms and circuits in a similar manner to other drugs of abuse, such as nicotine, alcohol, cocaine, and heroin, although the conditions under which cannabinoids exert their rewarding effects may be more limited. Furthermore, there is evidence on the involvement of the endocannabinoid system in the regulation of cue- and drug-induced relapsing phenomena in animal models. The aim of this review is to briefly present the available data obtained using diverse behavioral experimental approaches in experimental animals, namely, the intracranial self-stimulation paradigm, the self-administration procedure, the conditioned place preference procedure, and the reinstatement of drug-seeking behavior procedure, to provide a comprehensive picture of the current status of what is known about the endocannabinoid system mechanisms that underlie modification of brain-reward processes. Emphasis is placed on the effects of cannabinoid 1 (CB1) receptor agonists, antagonists, and endocannabinoid modulators. Further, the role of CB1 receptors in reward processes is investigated through presentation of respective genetic ablation studies in mice. The vast majority of studies in the existing literature suggest that the endocannabinoid system plays a major role in modulating motivation and reward processes. However, much remains to be done before we fully understand these interactions. Further research in the future will shed more light on these processes and, thus, could lead to the development of potential pharmacotherapies designed to treat reward-dysfunction-related disorders.

  3. Plasma endocannabinoid levels in lean, overweight and obese humans: relationships with intestinal permeability markers, inflammation and incretin secretion.

    PubMed

    Little, Tanya J; Cvijanovic, Nada; DiPatrizio, Nicholas V; Argueta, Donovan A; Rayner, Christopher K; Feinle-Bisset, Christine; Young, Richard L

    2018-02-13

    Intestinal production of endocannabinoid and oleoylethanolamide (OEA) is impaired in high-fat diet/obese rodents, leading to reduced satiety. Such diets also alter the intestinal microbiome in association with enhanced intestinal permeability and inflammation, however little is known of these effects in humans. This study aimed to: (i) evaluate effects of lipid on plasma anandamide (AEA), 2-arachidonyl-sn-glycerol (2-AG) and OEA in humans, and (ii) examine relationships with intestinal permeability, inflammation markers and incretin hormone secretion. 20 lean, 18 overweight and 19 obese participants underwent intraduodenal Intralipid® infusion (2 kcal/min) with collection of endoscopic duodenal biopsies and blood. Plasma AEA, 2-AG, and OEA (HPLC/tandem mass spectrometry), tumour necrosis factor-α (TNF-α), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) (multiplex), and duodenal expression of occludin, zona-occludin-1 (ZO-1), intestinal-alkaline-phosphatase (IAP), and toll-like receptor-4 (TLR4) (RT-PCR), were assessed. Fasting plasma AEA was increased in obese, compared with lean and overweight (P<0.05), with no effect of BMI group or ID lipid infusion on plasma 2-AG or OEA. Duodenal expression of IAP and ZO-1 was reduced in obese, compared with lean (P<0.05), and these levels related negatively to plasma AEA (P<0.05). The iAUC for AEA was positively related to iAUC GIP (r=0.384, P=0.005). Obese individuals have increased plasma AEA and decreased duodenal expression of ZO-1 and IAP, in comparison to lean and overweight. The relationships between plasma AEA with duodenal ZO-1 and IAP, and GIP, suggest that altered endocannabinoid signalling may contribute to changes in intestinal permeability, inflammation and incretin release in human obesity.

  4. Phytocannabinoids for Cancer Therapeutics: Recent Updates and Future Prospects.

    PubMed

    Patil, K R; Goyal, S N; Sharma, C; Patil, C R; Ojha, S

    2015-01-01

    Phytocannabinoids (pCBs) are lipid-soluble phytochemicals present in the plant, Cannabis sativa L. and non-cannabis plants which have a long history in recreation and traditional medicine. The plant and the constituents isolated were central in the discovery of the endocannabinoid system (ECS), the most new target for drug discovery. The ECS includes two G-protein-coupled receptors; the cannabinoid receptors-1 and -2 (CB1 and CB2) for marijuana's psychoactive principle Δ(9)-tetrahydrocannabinol (Δ(9)-THC), their endogenous small lipid ligands; namely anandamide (AEA) and 2-arachidonoylglycerol (2-AG), also known as endocannabinoids and the enzymes for endocannabinoid biosynthesis and degradation such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The ECS has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during pathological conditions including cancer. Targeting the CB1 receptors becomes a concern because of adverse psychotropic reactions. Hence, targeting the CB2 receptors or the endocannabinoid metabolizing enzymes by pCBs obtained from plants lacking psychotropic adverse reactions has garnered interest in drug discovery. These pCBs derived from plants appear safe and effective with a wider access and availability. In the recent years, several pCBs derived other than non-cannabinoid plants have been reported to bind to and functionally interact with cannabinoid receptors and appear promising candidate for drug development including cancer therapeutics. Several of them also targets the endocannabinoid metabolizing enzymes that control endocannabinoid levels. In this article, we summarize and critically discuss the updates and future prospects of the pCBs as novel and promising candidates for cancer therapeutics.

  5. Effects of centrally administered endocannabinoids and opioids on orofacial pain perception in rats.

    PubMed

    Zubrzycki, Marek; Janecka, Anna; Liebold, Andreas; Ziegler, Mechthild; Zubrzycka, Maria

    2017-11-01

    Endocannabinoids and opioids play a vital role in mediating pain-induced analgesia. The specific effects of these compounds within the orofacial region are largely unknown. In this study, we tried to determine whether an increase in cannabinoid and opioid concentration in the CSF affects impulse transmission between the motor centres localized in the vicinity of the third and fourth cerebral ventricles. The study objectives were realized on rats using a method that allows the recording of the amplitude of evoked tongue jerks (ETJ) in response to noxious tooth pulp stimulation. The amplitude of ETJ was a measure of the effect of neurotransmitters on neural structures. Perfusion of cerebral ventricles with anandamide (AEA), endomorphin-2 (EM-2), URB597, an inhibitor of fatty acid amide hydrolase (FAAH) and JZL195, a dual inhibitor of FAAH and monoacylglycerol lipase (MAGL) reduced the ETJ amplitude. The antinociceptive effect of AEA, EM-2, URB597 and JZL195 was blocked by CB 1 receptor antagonist, AM251 and by μ receptor-antagonist, β-funaltrexamine. In contrast to AEA, 2-arachidonoylglycerol alone did not decrease ETJ amplitude. We demonstrated that in the orofacial area, analgesic activity is modulated by AEA and that EM-2-induced antinociception was mediated by μ and CB 1 receptors. The action of AEA and EM-2 is tightly regulated by FAAH and FAAH/MAGL, by preventing the breakdown of endogenous cannabinoids in regions where they are produced on demand. Therefore, the current findings support the therapeutic potential of FAAH and FAAH/MAGL inhibitors as novel pharmacotherapeutic agents for orofacial pain. © 2017 The British Pharmacological Society.

  6. On the pharmacological properties of Delta9-tetrahydrocannabinol (THC).

    PubMed

    Costa, Barbara

    2007-08-01

    Cannabis is one of the first plants used as medicine, and the notion that it has potentially valuable therapeutic properties is a matter of current debate. The isolation of its main constituent, Delta9-tetrahydrocannabinol (THC), and the discovery of the endocannabinoid system (cannabinoid receptors CB1 and CB2 and their endogenous ligands) made possible studies concerning the pharmacological activity of cannabinoids. This paper reviews some of the most-important findings in the field of THC pharmacology. Clinical trials, anecdotal reports, and experiments employing animal models strongly support the idea that THC and its derivatives exhibit a wide variety of therapeutic applications. However, the psychotropic effects observed in laboratory animals and the adverse reactions reported during human trials, as well as the risk of tolerance development and potential dependence, limit the application of THC in therapy. Nowadays, researchers focus on other therapeutic strategies by which the endocannabinoid system might be modulated to clinical advantage (inhibitor or activator of endocannabinoid biosynthesis, cellular uptake, or metabolism). However, emerging evidence highlights the beneficial effects of the whole cannabis extract over those observed with single components, indicating cannabis-based medicines as new perspective to revisit the pharmacology of this plant.

  7. The dual FAAH/MAGL inhibitor JZL195 has enhanced effects on endocannabinoid transmission and motor behavior in rats as compared to those of the MAGL inhibitor JZL184

    PubMed Central

    Seillier, Alexandre; Aguilar, David Dominguez; Giuffrida, Andrea

    2014-01-01

    The biological actions of the endocannabinoids anandamide and 2-arachidonoyl glycerol (2-AG) are terminated by enzymatic hydrolysis of these lipids via fatty acid amide hydrolase (FAAH ) and monoacylglycerol lipase (MAGL), respectively. While several selective FAAH inhibitors have been developed and characterized in vitro and in vivo, none of the initial MAGL blockers have shown adequate potency and specificity for in vivo applications. More recently, a selective MAGL inhibitor, JZL184, has been shown to produce a long-lasting elevation of brain 2-AG, as well as cannabinoid-like behavioral responses in mice. However, its effectiveness in rats remains controversial. Indeed, although JZL184 can elicit behavioral responses that are mediated, at least in part, via activation of cannabinoid CB1 receptors, several reports indicate that this compound does not alter 2-AG levels in this species. In this study we compared the behavioral and neurochemical effects of JZL 184 with those of the dual FAAH/MAGL inhibitor JZL195, and showed that systemic administration of the former can selectively elevate brain 2-AG in rats and produce motor suppression through a CB1-independent mechanism. These findings indicate that, despite its lower potency against rat MAGL, JZL184 can be used to enhance 2-AG transmission and elicit behavioral responses in rodents. PMID:24911644

  8. CB1 Cannabinoid Receptors Couple to Focal Adhesion Kinase to Control Insulin Release*

    PubMed Central

    Malenczyk, Katarzyna; Jazurek, Magdalena; Keimpema, Erik; Silvestri, Cristoforo; Janikiewicz, Justyna; Mackie, Ken; Di Marzo, Vincenzo; Redowicz, Maria J.; Harkany, Tibor; Dobrzyn, Agnieszka

    2013-01-01

    Endocannabinoid signaling has been implicated in modulating insulin release from β cells of the endocrine pancreas. β Cells express CB1 cannabinoid receptors (CB1Rs), and the enzymatic machinery regulating anandamide and 2-arachidonoylglycerol bioavailability. However, the molecular cascade coupling agonist-induced cannabinoid receptor activation to insulin release remains unknown. By combining molecular pharmacology and genetic tools in INS-1E cells and in vivo, we show that CB1R activation by endocannabinoids (anandamide and 2-arachidonoylglycerol) or synthetic agonists acutely or after prolonged exposure induces insulin hypersecretion. In doing so, CB1Rs recruit Akt/PKB and extracellular signal-regulated kinases 1/2 to phosphorylate focal adhesion kinase (FAK). FAK activation induces the formation of focal adhesion plaques, multimolecular platforms for second-phase insulin release. Inhibition of endocannabinoid synthesis or FAK activity precluded insulin release. We conclude that FAK downstream from CB1Rs mediates endocannabinoid-induced insulin release by allowing cytoskeletal reorganization that is required for the exocytosis of secretory vesicles. These findings suggest a mechanistic link between increased circulating and tissue endocannabinoid levels and hyperinsulinemia in type 2 diabetes. PMID:24089517

  9. Antitumorigenic targets of cannabinoids - current status and implications.

    PubMed

    Ramer, Robert; Hinz, Burkhard

    2016-10-01

    Molecular structures of the endocannabinoid system have gained interest as potential pharmacotherapeutical targets for systemic cancer treatment. The present review covers the contribution of the endocannabinoid system to cancer progression. Particular focus will be set on the accumulating preclinical data concerning antimetastatic, anti-invasive and anti-angiogenic mechanisms induced by cannabinoids. The main goal of targeting endocannabinoid structures for systemic anticancer treatment is the comparatively good safety profile of cannabinoid compounds. In addition, antitumorigenic mechanisms of cannabinoids are not restricted to a single molecular cascade but involve multiple effects on various levels of cancer progression such as angiogenesis and metastasis. Particularly the latter effect has gained interest for pharmacological interventions. Thus, drugs aiming at the endocannabinoid system may represent potential 'antimetastatics' for an upgrade of a future armamentarium against cancer diseases.

  10. Endocannabinoid 2-arachidonoylglycerol protects inflammatory insults from sulfur dioxide inhalation via cannabinoid receptors in the brain.

    PubMed

    Li, Ben; Chen, Minjun; Guo, Lin; Yun, Yang; Li, Guangke; Sang, Nan

    2017-01-01

    Sulfur dioxide (SO 2 ) pollution in the atmospheric environment causes brain inflammatory insult and inflammatory-related microvasculature dysfunction. However, there are currently no effective medications targeting the harmful outcomes from chemical inhalation. Endocannabinoids (eCBs) are involved in neuronal protection against inflammation-induced neuronal injury. The 2-arachidonoylglycerol (2-AG), the most abundant eCBs and a full agonist for cannabinoid receptors (CB1 and CB2), is also capable of suppressing proinflammatory stimuli and improving microvasculature dysfunction. Here, we indicated that endogenous 2-AG protected against neuroinflammation in response to SO 2 inhalation by inhibiting the activation of microglia and astrocytes and attenuating the overexpression of inflammatory cytokines, including tumor necrosis factor alpha (TNF-a), interleukin (IL)-1β, and inducible nitric oxide synthase (iNOS). In addition, endogenous 2-AG prevented cerebral vasculature dysfunction following SO 2 inhalation by inhibiting endothelin 1 (ET-1), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) expression, elevating endothelial nitric oxide synthase (eNOS) level, and restoring the imbalance between thromboxane A2 (TXA2) and prostaglandin I2 (PGI2). In addition, the action of endogenous 2-AG on the suppression of inflammatory insult and inflammatory-related microvasculature dysfunction appeared to be mainly mediated by CB1 and CB2 receptors. Our results provided a mechanistic basis for the development of new therapeutic approaches for protecting brain injuries from SO 2 inhalation. Copyright © 2016. Published by Elsevier B.V.

  11. The putative endocannabinoid transport blocker LY2183240 is a potent inhibitor of FAAH and several other brain serine hydrolases.

    PubMed

    Alexander, Jessica P; Cravatt, Benjamin F

    2006-08-02

    How lipid transmitters move within and between cells to communicate signals remains an important and largely unanswered question. Integral membrane transporters, soluble lipid-binding proteins, and metabolic enzymes have all been proposed to collaboratively regulate lipid signaling dynamics in vivo. Assignment of the relative contributions made by each of these classes of proteins requires selective pharmacological agents to perturb their individual functions. Recently, LY2183240, a heterocyclic urea inhibitor of the putative endocannabinoid (EC) transporter, was shown to disrupt the cellular uptake of the lipid EC anandamide and promote analgesia in vivo. Here, we show that LY2183240 is a potent, covalent inhibitor of the EC-degrading enzyme fatty acid amide hydrolase (FAAH). LY2183240 inactivates FAAH by carbamylation of the enzyme's serine nucleophile. More global screens using activity-based proteomic probes identified several additional serine hydrolases that are also inhibited by LY2183240. These results indicate that the blockade of anandamide uptake observed with LY2183240 may be due primarily to the inactivation of FAAH, providing further evidence that this enzyme serves as a metabolic driving force that promotes the diffusion of anandamide into cells. More generally, the proteome-wide target promiscuity of LY2183240 designates the heterocyclic urea as a chemotype with potentially excessive protein reactivity for drug design.

  12. Implantation failure in mice with a disruption in Phospholipase C beta 1 gene: lack of embryonic attachment, aberrant steroid hormone signalling and defective endocannabinoid metabolism

    PubMed Central

    Filis, Panayiotis; Kind, Peter C.; Spears, Norah

    2013-01-01

    Phospholipase C beta 1 (PLCβ1) is a downstream effector of G-protein-coupled receptor signalling and holds central roles in reproductive physiology. Mice with a disruption in the Plcβ1 gene are infertile with pleiotropic reproductive defects, the major reproductive block in females being implantation failure. Here, PLCβ1 was demonstrated at the luminal and glandular epithelia throughout the pre- and peri-implantation period, with transient stromal expression during 0.5–1.5 days post coitum (dpc). Examination of implantation sites at 4.5 dpc showed that in females lacking functional PLCβ1 (knock-out (KO) females), embryos failed to establish proper contact with the uterine epithelium. Proliferating luminal epithelial cells were evident in KO implantation sites, indicating failure to establish a receptive uterus. Real-time PCR demonstrated that KO implantation sites had aberrant ovarian steroid signalling, with high levels of estrogen receptor α, lactoferrin and amphiregulin mRNA, while immunohistochemistry revealed very low levels of estrogen receptor α protein, possibly due to rapid receptor turnover. KO implantation sites expressed markedly less fatty acid amide hydrolase and monoacylglycerol lipase, indicating that endocannabinoid metabolism was also affected. Collectively, our results show that PLCβ1 is essential for uterine preparation for implantation, and that defective PLCβ1-mediated signalling during implantation is associated with aberrant ovarian steroid signalling and endocannabinoid metabolism. PMID:23295235

  13. Acute inhibition of diacylglycerol lipase blocks endocannabinoid-mediated retrograde signalling: evidence for on-demand biosynthesis of 2-arachidonoylglycerol

    PubMed Central

    Hashimotodani, Yuki; Ohno-Shosaku, Takako; Tanimura, Asami; Kita, Yoshihiro; Sano, Yoshikazu; Shimizu, Takao; Di Marzo, Vincenzo; Kano, Masanobu

    2013-01-01

    The endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) produced by diacylglycerol lipase α (DGLα) is one of the best-characterized retrograde messengers at central synapses. It has been thought that 2-AG is produced ‘on demand’ upon activation of postsynaptic neurons. However, recent studies propose that 2-AG is pre-synthesized by DGLα and stored in neurons, and that 2-AG is released from such ‘pre-formed pools’ without the participation of DGLα. To address whether the 2-AG source for retrograde signalling is the on-demand biosynthesis by DGLα or the mobilization from pre-formed pools, we examined the effects of acute pharmacological inhibition of DGL by a novel potent DGL inhibitor, OMDM-188, on retrograde eCB signalling triggered by Ca2+ elevation, Gq/11 protein-coupled receptor activation or synergy of these two stimuli in postsynaptic neurons. We found that pretreatment for 1 h with OMDM-188 effectively blocked depolarization-induced suppression of inhibition (DSI), a purely Ca2+-dependent form of eCB signalling, in slices from the hippocampus, striatum and cerebellum. We also found that at parallel fibre–Purkinje cell synapses in the cerebellum OMDM-188 abolished synaptically induced retrograde eCB signalling, which is known to be caused by the synergy of postsynaptic Ca2+ elevation and group I metabotropic glutamate receptor (I-mGluR) activation. Moreover, brief OMDM-188 treatments for several minutes were sufficient to suppress both DSI and the I-mGluR-induced retrograde eCB signalling in cultured hippocampal neurons. These results are consistent with the hypothesis that 2-AG for synaptic retrograde signalling is supplied as a result of on-demand biosynthesis by DGLα rather than mobilization from presumptive pre-formed pools. PMID:23858009

  14. The neurobiology of social play and its rewarding value in rats

    PubMed Central

    Vanderschuren, Louk J.M.J.; Achterberg, E.J. Marijke; Trezza, Viviana

    2016-01-01

    In the young of many mammalian species, including humans, a vigorous and highly rewarding social activity is abundantly expressed, known as social play behaviour. Social play is thought to be important for the development of social, cognitive and emotional processes and their neural underpinnings, and it is disrupted in pediatric psychiatric disorders. Here, we summarize recent progress in our understanding of the brain mechanisms of social play behaviour, with a focus on its rewarding properties. Opioid, endocannabinoid, dopamine and noradrenaline systems play a prominent role in the modulation of social play. Of these, dopamine is particularly important for the motivational properties of social play. The nucleus accumbens has been identified as a key site for opioid and dopamine modulation of social play. Endocannabinoid influences on social play rely on the basolateral amygdala, whereas noradrenaline modulates social play through the basolateral amygdala, habenula and prefrontal cortex. In sum, social play behaviour is the result of coordinated activity in a network of corticolimbic structures, and its monoamine, opioid and endocannabinoid innervation. PMID:27587003

  15. Dose-response effects of systemic anandamide administration in mice sequentially submitted to the open field and elevated plus-maze tests.

    PubMed

    Ribeiro, A; Ferraz-de-Paula, V; Pinheiro, M L; Palermo-Neto, J

    2009-06-01

    The endocannabinoid system is involved in the control of many physiological functions, including the control of emotional states. In rodents, previous exposure to an open field increases the anxiety-like behavior in the elevated plus-maze. Anxiolytic-like effects of pharmacological compounds that increase endocannabinoid levels have been well documented. However, these effects are more evident in animals with high anxiety levels. Several studies have described characteristic inverted U-shaped dose-response effects of drugs that modulate the endocannabinoid levels. However, there are no studies showing the effects of different doses of exogenous anandamide, an endocannabinoid, in animal models of anxiety. Thus, in the present study, we determined the dose-response effects of exogenous anandamide at doses of 0.01, 0.1, and 1.0 mg/kg in C57BL/6 mice (N = 10/group) sequentially submitted to the open field and elevated plus-maze. Anandamide was diluted in 0.9% saline, ethyl alcohol, Emulphor (18:1:1) and administered ip (0.1 mL/10 g body weight); control animals received the same volume of anandamide vehicle. Anandamide at the dose of 0.1 mg/kg (but not of 0.01 or 1 mg/kg) increased (P < 0.05) the time spent and the distance covered in the central zone of the open field, as well as the exploration of the open arms of the elevated plus-maze. Thus, exogenous anandamide, like pharmacological compounds that increase endocannabinoid levels, promoted a characteristic inverted U-shaped dose-response effect in animal models of anxiety. Furthermore, anandamide (0.1 mg/kg) induced an anxiolytic-like effect in the elevated plus-maze (P < 0.05) after exposing the animals to the open field test.

  16. Cannabinoids and Pain: Sites and Mechanisms of Action.

    PubMed

    Starowicz, Katarzyna; Finn, David P

    2017-01-01

    The endocannabinoid system, consisting of the cannabinoid 1 receptor (CB 1 R) and cannabinoid 2 receptor (CB 2 R), endogenous cannabinoid ligands (endocannabinoids), and metabolizing enzymes, is present throughout the pain pathways. Endocannabinoids, phytocannabinoids, and synthetic cannabinoid receptor agonists have antinociceptive effects in animal models of acute, inflammatory, and neuropathic pain. CB 1 R and CB 2 R located at peripheral, spinal, or supraspinal sites are important targets mediating these antinociceptive effects. The mechanisms underlying the analgesic effects of cannabinoids likely include inhibition of presynaptic neurotransmitter and neuropeptide release, modulation of postsynaptic neuronal excitability, activation of the descending inhibitory pain pathway, and reductions in neuroinflammatory signaling. Strategies to dissociate the psychoactive effects of cannabinoids from their analgesic effects have focused on peripherally restricted CB 1 R agonists, CB 2 R agonists, inhibitors of endocannabinoid catabolism or uptake, and modulation of other non-CB 1 R/non-CB 2 R targets of cannabinoids including TRPV1, GPR55, and PPARs. The large body of preclinical evidence in support of cannabinoids as potential analgesic agents is supported by clinical studies demonstrating their efficacy across a variety of pain disorders. © 2017 Elsevier Inc. All rights reserved.

  17. Activation of cannabinoid CB1 receptors in the dorsolateral periaqueductal gray induces anxiolytic effects in rats submitted to the Vogel conflict test.

    PubMed

    Lisboa, Sabrina F; Resstel, Leonardo B M; Aguiar, Daniele C; Guimarães, Francisco S

    2008-09-28

    There are contradictory results concerning the effects of systemic injections of cannabinoid agonists in anxiety-induced behavioral changes. Direct drug administration into brain structures related to defensive responses could help to clarify the role of cannabinoids in these changes. Activation of cannabinoid CB(1) receptors in the dorsolateral periaqueductal gray induces anxiolytic-like effects in the elevated plus maze. The aim of this work was to verify if facilitation of endocannabinoid-mediated neurotransmission in this region would also produce anxiolytic-like effects in another model of anxiety, the Vogel conflict test. Male Wistar rats (n=5-9/group) with cannulae aimed at the dorsolateral periaqueductal gray were water deprived for 24 h and pre-exposed to the apparatus where they were allowed to drink for 3 min. After another 24 h-period of water deprivation, they received the microinjections and, 10 min later, were placed into the experimental box. In this box an electrical shock (0.5 mA, 2 s) was delivered in the spout of a drinking bottle at every twenty licks. The animals received a first microinjection of vehicle (0.2 microl) or AM251 (a cannabinoid CB(1) receptor antagonist; 100 pmol) followed, 5 min later, by a second microinjection of vehicle, anandamide (an endocannabinoid, 5 pmol), AM404 (an inhibitor of anandamide uptake, 50 pmol) or URB597 (an inhibitor of Fatty Acid Amide Hydrolase, 0.01 or 0.1 nmol). Anandamide, AM404 and URB597 (0.01 nmol) increased the total number of punished licks. These effects were prevented by AM251. The results give further support to the proposal that facilitation of CB(1) receptor-mediated endocannabinoid neurotransmission in the dorsolateral periaqueductal gray modulates defensive responses.

  18. Anticonvulsive effects of endocannabinoids; an investigation to determine the role of regulatory components of endocannabinoid metabolism in the Pentylenetetrazol induced tonic- clonic seizures.

    PubMed

    Zareie, Parisa; Sadegh, Mehdi; Palizvan, Mohammad Reza; Moradi-Chameh, Homeira

    2018-06-01

    2-Arachidonoylglycerol (2-AG) and anandamide are two major endocannabinoids produced, released and eliminated by metabolic pathways. Anticonvulsive effect of 2-AG and CB1 receptor is well-established. Herein, we designed to investigate the anticonvulsive influence of key components of the 2-AG and anandamide metabolism. Tonic-clonic seizures were induced by an injection of Pentylenetetrazol (80 mg/kg, i.p.) in adult male Wistar rats. Delay and duration for the seizure stages were considered for analysis. Monoacylglycerol lipase blocker (JJKK048; 1 mg/kg) or alpha/beta hydroxylase domain 6 blocker (WWL70; 5 mg/kg) were administrated alone or with 2-AG to evaluate the anticonvulsive potential of these enzymes. To determine the CB1 receptor involvement, its blocker (MJ15; 3 mg/kg) was administrated associated with JJKK048 or WWL70. To assess anandamide anticonvulsive effect, anandamide membrane transporter blocker (LY21813240; 2.5 mg/kg) was used alone or associated with MJ15. Also, fatty acid amide hydrolase blocker (URB597; 1 mg/kg; to prevent intracellular anandamide hydrolysis) were used alone or with AMG21629 (transient receptor potential vanilloid; TRPV1 antagonist; 3 mg/kg). All compounds were dissolved in DMSO and injected i.p., before the Pentylenetetrazol. Both JJKK048 and WWL70 revealed anticonvulsive effect. Anticonvulsive effect of JJKK048 but not WWL70 was CB1 receptor dependent. LY2183240 showed CB1 receptor dependent anticonvulsive effect. However, URB597 revealed a TRPV1 dependent proconvulsive effect. It seems extracellular accumulation of 2-AG or anandamide has anticonvulsive effect through the CB1 receptor, while intracellular anandamide accumulation is proconvulsive through TRPV1.

  19. Platform for systems medicine research and diagnostic applications in psychotic disorders-The METSY project.

    PubMed

    Frank, Elisabeth; Maier, Dieter; Pajula, Juha; Suvitaival, Tommi; Borgan, Faith; Butz-Ostendorf, Markus; Fischer, Alexander; Hietala, Jarmo; Howes, Oliver; Hyötyläinen, Tuulia; Janssen, Joost; Laurikainen, Heikki; Moreno, Carmen; Suvisaari, Jaana; Van Gils, Mark; Orešič, Matej

    2018-04-01

    Psychotic disorders are associated with metabolic abnormalities including alterations in glucose and lipid metabolism. A major challenge in the treatment of psychosis is to identify patients with vulnerable metabolic profiles who may be at risk of developing cardiometabolic co-morbidities. It is established that both central and peripheral metabolic organs use lipids to control energy balance and regulate peripheral insulin sensitivity. The endocannabinoid system, implicated in the regulation of glucose and lipid metabolism, has been shown to be dysregulated in psychosis. It is currently unclear how these endocannabinoid abnormalities relate to metabolic changes in psychosis. Here we review recent research in the field of metabolic co-morbidities in psychotic disorders as well as the methods to study them and potential links to the endocannabinoid system. We also describe the bioinformatics platforms developed in the EU project METSY for the investigations of the biological etiology in patients at risk of psychosis and in first episode psychosis patients. The METSY project was established with the aim to identify and evaluate multi-modal peripheral and neuroimaging markers that may be able to predict the onset and prognosis of psychiatric and metabolic symptoms in patients at risk of developing psychosis and first episode psychosis patients. Given the intrinsic complexity and widespread role of lipid metabolism, a systems biology approach which combines molecular, structural and functional neuroimaging methods with detailed metabolic characterisation and multi-variate network analysis is essential in order to identify how lipid dysregulation may contribute to psychotic disorders. A decision support system, integrating clinical, neuropsychological and neuroimaging data, was also developed in order to aid clinical decision making in psychosis. Knowledge of common and specific mechanisms may aid the etiopathogenic understanding of psychotic and metabolic disorders

  20. Selective activation of cannabinoid receptor-2 reduces neuroinflammation after traumatic brain injury via alternative macrophage polarization.

    PubMed

    Braun, Molly; Khan, Zenab T; Khan, Mohammad B; Kumar, Manish; Ward, Ayobami; Achyut, Bhagelu R; Arbab, Ali S; Hess, David C; Hoda, Md Nasrul; Baban, Babak; Dhandapani, Krishnan M; Vaibhav, Kumar

    2018-02-01

    Inflammation is an important mediator of secondary neurological injury after traumatic brain injury (TBI). Endocannabinoids, endogenously produced arachidonate based lipids, have recently emerged as powerful anti-inflammatory compounds, yet the molecular and cellular mechanisms underlying these effects are poorly defined. Endocannabinoids are physiological ligands for two known cannabinoid receptors, CB1R and CB2R. In the present study, we hypothesized that selective activation of CB2R attenuates neuroinflammation and reduces neurovascular injury after TBI. Using a murine controlled cortical impact (CCI) model of TBI, we observed a dramatic upregulation of CB2R within infiltrating myeloid cells beginning at 72 h. Administration of the selective CB2R agonist, GP1a (1-5 mg/kg), attenuated pro-inflammatory M1 macrophage polarization, increased anti-inflammatory M2 polarization, reduced edema development, enhanced cerebral blood flow, and improved neurobehavioral outcomes after TBI. In contrast, the CB2R antagonist, AM630, worsened outcomes. Taken together, our findings support the development of selective CB2R agonists as a therapeutic strategy to improve TBI outcomes while avoiding the psychoactive effects of CB1R activation. Published by Elsevier Inc.