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Sample records for activity dopaminergic systems

  1. Differential activation of dopaminergic systems in rat brain basal ganglia by morphine and methamphetamine.

    PubMed

    Mori, T; Iwase, Y; Saeki, T; Iwata, N; Murata, A; Masukawa, D; Suzuki, T

    2016-05-13

    Typical abused drug-induced behavioral changes are ordinarily mediated by the mesolimbic dopaminergic system and even the phenotypes of behavior are different from each other. However, the mechanisms that underlie the behavioral changes induced by these abused drugs have not yet been elucidated. The present study was designed to investigate the mechanisms that underlie how abused drugs induce distinct behavioral changes using neurochemical as well as behavioral techniques in rats. Methamphetamine (2mg/kg) more potently increased dopamine release from the striatum more than that from the nucleus accumbens. In contrast, the administration of morphine (10mg/kg) produced a significant increase in the release of dopamine from the nucleus accumbens, but not the striatum, which is accompanied by a decrease in the release of GABA in the ventral tegmental area. These findings indicate that morphine and methamphetamine differentially regulate dopaminergic systems to produce behavioral changes, even though both drugs have abuse potential through activation of the mesolimbic dopaminergic system. PMID:26820597

  2. Repeated exposure to the herbicide atrazine alters locomotor activity and the nigrostriatal dopaminergic system of the albino rat.

    PubMed

    Rodríguez, Verónica M; Limón-Pacheco, Jorge H; Mendoza-Trejo, Maria Soledad; González-Gallardo, Adriana; Hernández-Plata, Isela; Giordano, Magda

    2013-01-01

    Atrazine (ATR) is used as a pre- and post-emergent herbicide; although banned in several countries of the European Community, it is still used extensively around the world. A recent study in rats has shown that chronic, daily exposure to 10 mg ATR/kg BW causes hyperactivity, disrupts motor coordination and learning of behavioral tasks, and decreases dopamine levels in the brain. In order to evaluate the short-term effect of ATR exposure on locomotor activity, monoamine markers, and antioxidants, adult male Sprague-Dawley rats received six IP injections of 100 mg ATR/kg BW or vehicle over two weeks. After every ATR injection we found hypoactivity that lasted up to five days, and it was accompanied by reductions in levels of striatal DA, DOPAC, and HVA without any alteration in the striatal expression of the mRNAs for Mn-SOD, Trx-1, DAR-D(1), or DAR-D(2). In contrast, in the nucleus accumbens no changes in monoamine markers were observed, and a down-regulation of Trx-1 expression was detected shortly after the ATR treatment. Moreover, in the ventral midbrain, we found that ATR induced a down-regulation of mRNA for Th and DAT, but it increased VMAT2 mRNA expression. Decreases of monoamine levels and of locomotor activity disappeared three months after ATR treatment; however, an amphetamine challenge (1 mg/kg) given two months after the ATR treatment resulted in a significant stimulation in the exposed group, revealing hidden effects of ATR on dopaminergic systems. These results indicate that ATR exposure differentially modifies the dopaminergic systems, and these modifications may underlie the behavioral changes observed. PMID:23123945

  3. Renalase regulates peripheral and central dopaminergic activities

    PubMed Central

    Serrão, Maria Paula; Soares-Silva, Isabel; Fernandes-Cerqueira, Cátia; Simões-Silva, Liliana; Pinho, Maria João; Remião, Fernando; Sampaio-Maia, Benedita; Desir, Gary V.; Pestana, Manuel

    2014-01-01

    Renalase is a recently identified FAD/NADH-dependent amine oxidase mainly expressed in kidney that is secreted into blood and urine where it was suggested to metabolize catecholamines. The present study evaluated central and peripheral dopaminergic activities in the renalase knockout (KO) mouse model and examined the changes induced by recombinant renalase (RR) administration on plasma and urine catecholamine levels. Compared with wild-type (WT) mice, KO mice presented increased plasma levels of epinephrine (Epi), norepinephrine (NE), and dopamine (DA) that were accompanied by increases in the urinary excretion of Epi, NE, DA. In addition, the KO mice presented an increase in urinary DA-to-l-3,4-dihydroxyphenylalanine (l-DOPA) ratios without changes in renal tubular aromatic-l-amino acid decarboxylase (AADC) activity. By contrast, the in vivo administration of RR (1.5 mg/kg sc) to KO mice was accompanied by significant decreases in plasma levels of Epi, DA, and l-DOPA as well as in urinary excretion of Epi, DA, and DA-to-l-DOPA ratios notwithstanding the accompanied increase in renal AADC activity. In addition, the increase in renal DA output observed in renalase KO mice was accompanied by an increase in the expression of the L-type amino acid transporter like (LAT) 1 that is reversed by the administration of RR in these animals. These results suggest that the overexpression of LAT1 in the renal cortex of the renalase KO mice might contribute to the enhanced l-DOPA availability/uptake and consequently to the activation of the renal dopaminergic system in the presence of renalase deficiency. PMID:25411385

  4. Brain renin-angiotensin system and dopaminergic cell vulnerability

    PubMed Central

    Labandeira-García, Jose L.; Garrido-Gil, Pablo; Rodriguez-Pallares, Jannette; Valenzuela, Rita; Borrajo, Ana; Rodríguez-Perez, Ana I.

    2014-01-01

    Although the renin-angiotensin system (RAS) was classically considered as a circulating system that regulates blood pressure, many tissues are now known to have a local RAS. Angiotensin, via type 1 receptors, is a major activator of the NADPH-oxidase complex, which mediates several key events in oxidative stress (OS) and inflammatory processes involved in the pathogenesis of major aging-related diseases. Several studies have demonstrated the presence of RAS components in the basal ganglia, and particularly in the nigrostriatal system. In the nigrostriatal system, RAS hyperactivation, via NADPH-oxidase complex activation, exacerbates OS and the microglial inflammatory response and contributes to progression of dopaminergic degeneration, which is inhibited by angiotensin receptor blockers and angiotensin converting enzyme (ACE) inhibitors. Several factors may induce an increase in RAS activity in the dopaminergic system. A decrease in dopaminergic activity induces compensatory upregulation of local RAS function in both dopaminergic neurons and glia. In addition to its role as an essential neurotransmitter, dopamine may also modulate microglial inflammatory responses and neuronal OS via RAS. Important counterregulatory interactions between angiotensin and dopamine have also been observed in several peripheral tissues. Neurotoxins and proinflammatory factors may also act on astrocytes to induce an increase in RAS activity, either independently of or before the loss of dopamine. Consistent with a major role of RAS in dopaminergic vulnerability, increased RAS activity has been observed in the nigra of animal models of aging, menopause and chronic cerebral hypoperfusion, which also showed higher dopaminergic vulnerability. Manipulation of the brain RAS may constitute an effective neuroprotective strategy against dopaminergic vulnerability and progression of Parkinson’s disease. PMID:25071471

  5. The Dopaminergic System in Autoimmune Diseases

    PubMed Central

    Pacheco, Rodrigo; Contreras, Francisco; Zouali, Moncef

    2014-01-01

    Bidirectional interactions between the immune and the nervous systems are of considerable interest both for deciphering their functioning and for designing novel therapeutic strategies. The past decade has brought a burst of insights into the molecular mechanisms involved in neuroimmune communications mediated by dopamine. Studies of dendritic cells (DCs) revealed that they express the whole machinery to synthesize and store dopamine, which may act in an autocrine manner to stimulate dopamine receptors (DARs). Depending on specific DARs stimulated on DCs and T cells, dopamine may differentially favor CD4+ T cell differentiation into Th1 or Th17 inflammatory cells. Regulatory T cells can also release high amounts of dopamine that acts in an autocrine DAR-mediated manner to inhibit their suppressive activity. These dopaminergic regulations could represent a driving force during autoimmunity. Indeed, dopamine levels are altered in the brain of mouse models of multiple sclerosis (MS) and lupus, and in inflamed tissues of patients with inflammatory bowel diseases or rheumatoid arthritis (RA). The distorted expression of DARs in peripheral lymphocytes of lupus and MS patients also supports the importance of dopaminergic regulations in autoimmunity. Moreover, dopamine analogs had beneficial therapeutic effects in animal models, and in patients with lupus or RA. We propose models that may underlie key roles of dopamine and its receptors in autoimmune diseases. PMID:24711809

  6. Human neuromelanin: an endogenous microglial activator for dopaminergic neuron death

    PubMed Central

    Zhang, Wei; Zecca, Luigi; Wilson, Belinda; Ren, RW; Wang, Yong-jun; Wang, Xiao-min; Hong, Jau-Shyong

    2013-01-01

    Substantial evidence indicates that neuroinflammation caused by over-activation of microglial in the substantia nigra is critical in the pathogenesis of dopaminergic neurodegeneration in Parkinson’s disease (PD). Increasing data demonstrates that environmental factors such as rotenone, paraquat play pivotal roles in the death of dopaminergic neurons. Here, potential role and mechanism of neuromelanin (NM), a major endogenous component in dopaminergic neurons of the substantia nigra, on microglial activation and associated dopaminergic neurotoxicity were investigated. Using multiple well-established primary mesencephalic cultures, we tested whether human NM (HNM) could activate microglia, thereby provoking dopaminergic neurodegeneration. The results demonstrated that in primary mesencephalic neuron-glia cultures, HNM caused dopaminergic neuronal damage characterized by the decreased dopamine uptake and reduced numbers and shorted dendrites of dopaminergic neurons. HNM-induced degeneration was relatively selective to dopaminergic neurons since the other types of neurons determined by either gamma-aminobutyric acid uptake and total neuronal numbers after staining showed smaller decrease. We demonstrated that HNM produced modest dopaminergic neurotoxicity in neuron-enriched cultures; in contrast, much greater neurotoxicity was observed in the presence of microglia. HNM-induced microglial activation was shown by morphological changes and production of proinflammatory and neurotoxic factors. These results suggest that HNM, once released from damaged dopaminergic neurons, can be an potent endogenous activator involved in the reactivation of microglia, which may mediate disease progression. Thus, inhibition of reactive microglia can be a useful strategy for PD therapy. PMID:23276965

  7. [Anhedonia--a general nosology surmounting correlate of a dysfunctional dopaminergic reward system?].

    PubMed

    Heinz, A

    1999-05-01

    The dopaminergic reward system is activated by primary rewarding factors such as food, sexual activity and parental care. Its activation enhances the occurrence of behaviors which induced the stimulation of dopaminergic neurotransmission. Indications of a dysfunction of the dopaminergic reward system are found in major depression, schizophrenia, and addictive disorders. It has been hypothesized that dysfunction of the dopaminergic reward system is associated with anhedonia, the inability to experience pleasure. However, animal studies indicate that a reduction of central dopaminergic neurotransmission is associated with a decrease in incentive salience of reward-indicating stimuli and not with anhedonia per se. Sensitization of dopaminergic neurotransmission, on the other hand, seems to induce cue-dependent craving in addicted patients. In schizophrenia, phasic, stimulus-dependent dopamine release in the striatum may play a role in the abnormal attribution of salience to previously neutral stimuli. PMID:10407834

  8. Hemispheric differences in the mesostriatal dopaminergic system

    PubMed Central

    Molochnikov, Ilana; Cohen, Dana

    2014-01-01

    The mesostriatal dopaminergic system, which comprises the mesolimbic and the nigrostriatal pathways, plays a major role in neural processing underlying motor and limbic functions. Multiple reports suggest that these processes are influenced by hemispheric differences in striatal dopamine (DA) levels, DA turnover and its receptor activity. Here, we review studies which measured the concentration of DA and its metabolites to examine the relationship between DA imbalance and animal behavior under different conditions. Specifically, we assess evidence in support of endogenous, inter-hemispheric DA imbalance; determine whether the known anatomy provides a suitable substrate for this imbalance; examine the relationship between DA imbalance and animal behavior; and characterize the symmetry of the observed inter-hemispheric laterality in the nigrostriatal and the mesolimbic DA systems. We conclude that many studies provide supporting evidence for the occurrence of experience-dependent endogenous DA imbalance which is controlled by a dedicated regulatory/compensatory mechanism. Additionally, it seems that the link between DA imbalance and animal behavior is better characterized in the nigrostriatal than in the mesolimbic system. Nonetheless, a variety of brain and behavioral manipulations demonstrate that the nigrostriatal system displays symmetrical laterality whereas the mesolimbic system displays asymmetrical laterality which supports hemispheric specialization in rodents. The reciprocity of the relationship between DA imbalance and animal behavior (i.e., the capacity of animal training to alter DA imbalance for prolonged time periods) remains controversial, however, if confirmed, it may provide a valuable non-invasive therapeutic means for treating abnormal DA imbalance. PMID:24966817

  9. Assessment of renal dopaminergic system activity in the nitric oxide-deprived hypertensive rat model.

    PubMed Central

    Soares-da-Silva, P; Pestana, M; Vieira-Coelho, M A; Fernandes, M H; Albino-Teixeira, A

    1995-01-01

    1. The present paper reports changes in the urinary excretion of dopamine, 5-hydroxytryptamine and amine metabolites in nitric oxide deprived hypertensive rats during long-term administration of NG-nitro-L-arginine methyl ester (L-NAME). Aromatic L-amino acid decarboxylase (AAAD) activity in renal tissues and the ability of newly-formed dopamine to leave the cellular compartment where the synthesis of the amine has occurred were also determined. 2. Twenty four hours after exposure to L-NAME, both systolic (SBP) and diastolic (DBP) blood pressure were increased by 20 mmHg; heart rate was slightly decreased. During the next 13 days both SBP and DBP increased progressively reaching 170 +/- 3 and 116 +/- 3 mmHg, respectively. 3. Baseline urinary excretion of L-DOPA, dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) and homovanillic acid (HVA) during the 4 day period of stabilization averaged 4.4 +/- 0.5, 13.8 +/- 0.3, 37.4 +/- 0.8, 180.0 +/- 2.7 and 206.1 +/- 6.7 nmol day-1, respectively. The urinary excretion of L-DOPA, dopamine and DOPAC, but not that of 3-MT and HVA, were increased from day 6-8 of L-NAME administration onwards (L-DOPA, up to 13.4 +/- 2.1; dopamine, up to 23.0 +/- 1.6; DOPAC, up to 62.8 +/- 3.7 nmol day-1). Baseline daily urinary excretion of 5-hydroxytryptamine and 5-hydroxyindolacetic acid (5-HIAA) averaged 73.5 +/- 1.1 and 241.7 +/- 5.4 nmol day-1, respectively. During the first week of L-NAME administration, the urinary excretion of both 5-hydroxytryptamine and 5-HIAA did not change significantly; however, as was found with dopamine and DOPAC, changes in the urinary excretion of 5-hydroxytryptamine were evident during the second week of L-NAME administration. 4. In experiments performed on homogenates of isolated renal tubules, the decarboxylation of L-DOPA to dopamine was dependent on the concentration of L-DOPA used (10 to 5000 microM) and saturable at 1000 microM. AAAD activity as determined in homogenates (Vmax, in

  10. Dopaminergic System Dysfunction in Recreational Dexamphetamine Users

    PubMed Central

    Schrantee, Anouk; Václavů, Lena; Heijtel, Dennis F R; Caan, Matthan W A; Gsell, Willy; Lucassen, Paul J; Nederveen, Aart J; Booij, Jan; Reneman, Liesbeth

    2015-01-01

    Dexamphetamine (dAMPH) is a stimulant drug that is widely used recreationally as well as for the treatment of attention-deficit hyperactivity disorder (ADHD). Although animal studies have shown neurotoxic effects of dAMPH on the dopaminergic system, little is known about such effects on the human brain. Here, we studied the dopaminergic system at multiple physiological levels in recreational dAMPH users and age, gender, and IQ-matched dAMPH-naïve healthy controls. We assessed baseline D2/3 receptor availability, in addition to changes in dopamine (DA) release using single-photon emission computed tomography and DA functionality using pharmacological magnetic resonance imaging, following a dAMPH challenge. Also, the subjective responses to the challenge were determined. dAMPH users displayed significantly lower striatal DA D2/3 receptor binding compared with healthy controls. In dAMPH users, we further observed a blunted DA release and DA functionality to an acute dAMPH challenge, as well as a blunted subjective response. Finally, the lower D2/3 availability, the more pleasant the dAMPH administration was experienced by control subjects, but not by dAMPH users. Thus, in agreement with preclinical studies, we show that the recreational use of dAMPH in human subjects is associated with dopaminergic system dysfunction. These findings warrant further (longitudinal) investigations and call for caution when using this drug recreationally and for ADHD. PMID:25394786

  11. Decoding of dopaminergic mesolimbic activity and depressive behavior.

    PubMed

    Friedman, Alexander; Deri, Ilana; Friedman, Yaakov; Dremencov, Eliyahu; Goutkin, Sophia; Kravchinsky, Elizabeth; Mintz, Matti; Levi, Dino; Overstreet, David H; Yadid, Gal

    2007-01-01

    Dopaminergic mesolimbic and mesocortical systems are involved in hedonia and motivation, two core symptoms of depression. However, their role in the pathophysiology of depression and their manipulation to treat depression has received little attention. Previously, we showed decreased limbic dopamine (DA) neurotransmission in an animal model of depression, Flinder sensitive line (FSL) rats. Here we describe a high correlation between phase-space algorithm of bursting-like activity of DA cells in the ventral tegmental area (VTA) and efficiency of DA release in the accumbens. This bursting-like activity of VTA DA cells of FSL rats is characterized by a low dimension complexity. Treatment with the antidepressant desipramine affected both the dimension complexity of cell firing in the VTA and rate of DA release in the accumbens, as well as alleviating depressive-like behavior. Our findings indicate the potential usefulness of monitoring limbic dopaminergic dynamics in combination with non-linear analysis. Decoding the functionality of the dopaminergic system may help in development of future antidepressant drugs. PMID:17873290

  12. Effects of dopaminergic system activation on feeding behavior and growth performance of the sea bass (Dicentrarchus labrax): a self-feeding approach.

    PubMed

    Leal, Esther; Fernández-Durán, Begoña; Agulleiro, Maria Josep; Conde-Siera, Marta; Míguez, Jesús Manuel; Cerdá-Reverter, José Miguel

    2013-06-01

    Dopamine is synthesized from l-dopa and subsequently processed into norepinephrine and epinephrine. Any excess neurotransmitter can be taken up again by the neurons to be broken down enzymatically into DOPAC. The effect of dopamine on mammalian food intake is controversial. Mice unable to synthesize central dopamine die of starvation. However, studies have also shown that central injection of dopamine inhibits food intake. The effect of dopaminergic system in the fish feeding behavior has been scarcely explored. We report that the inclusion of l-dopa in the diets results in the activation of sea bass central dopaminergic system but also in the significant increase of the hypothalamic serotonin levels. Dietary l-dopa induces a decrease of food intake and feed conversion efficiency that drives a decline of all growth parameters tested. No behavioral effects were observed after l-dopa treatment. l-dopa treatment stimulated central expression of NPY and CRF. It suggests that CRF might mediate l-dopa effects on food intake but also that CRF neurons lie downstream of NPY neurons in the hierarchical forebrain system, thus controlling energy balance. Unexpectedly, dietary administration of haloperidol, a D2-receptor antagonist, cannot block dopamine effects but also induces a decline of the food intake. This decrease seems to be a side effect of haloperidol treatment since fish exhibited a decreased locomotor activity. We conclude that oral l-dopa inhibits sea bass food intake and growth. Mechanism could also involve an increase of hypothalamic serotoninergic tone. PMID:23747830

  13. Cross interaction of melanocortinergic and dopaminergic systems in neural modulation

    PubMed Central

    He, Zhi-Gang; Liu, Bao-Wen; Xiang, Hong-Bing

    2015-01-01

    Melanocortinergic and dopaminergic systems are widely distributed in the CNS and have been established as a crucial regulatory component in diverse physiological functions. The pharmacology of both melanocortinergic and dopaminergic systems including their individual receptors, signaling mechanisms, agonists and antagonists has been extensively studied. Several lines of evidence showed that there existed a cross interaction between the receptors of melanocortinergic and dopaminergic systems. The data available at present had expanded our understanding of melanocortinergic and dopaminergic system interaction in neural modulation, which will be main discussed in this paper. PMID:26823964

  14. Establishing diversity in the dopaminergic system.

    PubMed

    Bodea, Gabriela O; Blaess, Sandra

    2015-12-21

    Midbrain dopaminergic neurons (MbDNs) modulate cognitive processes, regulate voluntary movement, and encode reward prediction errors and aversive stimuli. While the degeneration of MbDNs underlies the motor defects in Parkinson's disease, imbalances in dopamine levels are associated with neuropsychiatric disorders such as depression, schizophrenia and substance abuse. In recent years, progress has been made in understanding how MbDNs, which constitute a relatively small neuronal population in the brain, can contribute to such diverse functions and dysfunctions. In particular, important insights have been gained regarding the distinct molecular, neurochemical and network properties of MbDNs. How this diversity of MbDNs is established during brain development is only starting to be unraveled. In this review, we summarize the current knowledge on the diversity in MbDN progenitors and differentiated MbDNs in the developing rodent brain. We discuss the signaling pathways, transcription factors and transmembrane receptors that contribute to setting up these diverse MbDN subpopulations. A better insight into the processes that establish diversity in MbDNs will ultimately improve the understanding of the architecture and function of the dopaminergic system in the adult brain. PMID:26431946

  15. Desire, disease, and the origins of the dopaminergic system.

    PubMed

    Sillitoe, Roy V; Vogel, Michael W

    2008-03-01

    The dopaminergic neurons in the midbrain region of the central nervous system project an extensive network of connections throughout the forebrain, including the neocortex. The midbrain-forebrain dopaminergic circuits are thought to regulate a diverse set of behaviors, from the control of movement to modulation of cognition and desire--because they relate to mood, attention, reward, and addiction. Defects in these pathways, including neurodegeneration, are implicated in a variety of psychiatric and neurological diseases, such as schizophrenia, attention-deficit/hyperactivity disorder, drug addiction, and Parkinson disease. Based on the importance of the midbrain dopaminergic neurons to normal and pathological brain function, there is considerable interest in the molecular mechanisms that regulate their development. The goal of this short review is to outline new methods and recent advances in identifying the molecular networks that regulate midbrain dopaminergic neuron differentiation and fate. Midbrain dopaminergic neurons are descended from progenitor cells located near the ventral midline of the neural tube floor plate around the cephalic flexure. It is now clear that their initial formation is dependent on interactions between the signaling molecules Sonic hedgehog, WINGLESS 1, and FIBROBLAST growth factor 8, but there is still an extensive wider network of molecular interactions that must be resolved before the complete picture of dopaminergic neuron development can be described. PMID:18283047

  16. Renal dopaminergic system: Pathophysiological implications and clinical perspectives

    PubMed Central

    Choi, Marcelo Roberto; Kouyoumdzian, Nicolás Martín; Rukavina Mikusic, Natalia Lucía; Kravetz, María Cecilia; Rosón, María Inés; Rodríguez Fermepin, Martín; Fernández, Belisario Enrique

    2015-01-01

    Fluid homeostasis, blood pressure and redox balance in the kidney are regulated by an intricate interaction between local and systemic anti-natriuretic and natriuretic systems. Intrarenal dopamine plays a central role on this interactive network. By activating specific receptors, dopamine promotes sodium excretion and stimulates anti-oxidant and anti-inflammatory pathways. Different pathological scenarios where renal sodium excretion is dysregulated, as in nephrotic syndrome, hypertension and renal inflammation, can be associated with impaired action of renal dopamine including alteration in biosynthesis, dopamine receptor expression and signal transduction. Given its properties on the regulation of renal blood flow and sodium excretion, exogenous dopamine has been postulated as a potential therapeutic strategy to prevent renal failure in critically ill patients. The aim of this review is to update and discuss on the most recent findings about renal dopaminergic system and its role in several diseases involving the kidneys and the potential use of dopamine as a nephroprotective agent. PMID:25949933

  17. Chronic exposure to low levels of inorganic arsenic causes alterations in locomotor activity and in the expression of dopaminergic and antioxidant systems in the albino rat.

    PubMed

    Rodríguez, Verónica Mireya; Limón-Pacheco, Jorge Humberto; Carrizales, Leticia; Mendoza-Trejo, María Soledad; Giordano, Magda

    2010-01-01

    Several studies have associated chronic arsenicism with decreases in IQ and sensory and motor alterations in humans. Likewise, studies of rodents exposed to inorganic arsenic ((i)As) have found changes in locomotor activity, brain neurochemistry, behavioral tasks, oxidative stress, and in sensory and motor nerves. In the current study, male Sprague-Dawley rats were exposed to environmentally relevant doses of (i)As (0.05, 0.5 mg (i)As/L) and to a high dose (50 mg (i)As/L) in drinking water for one year. Hypoactivity and increases in the striatal dopamine content were found in the group treated with 50 mg (i)As/L. Exposure to 0.5 and 50 mg (i)As/L increased the total brain content of As. Furthermore, (i)As exposure produced a dose-dependent up-regulation of mRNA for Mn-SOD and Trx-1 and a down-regulation of DAR-D₂ mRNA levels in the nucleus accumbens. DAR-D₁ and Nrf2 mRNA expression were down-regulated in nucleus accumbens in the group exposed to 50 mg (i)As/L. Trx-1 mRNA levels were up-regulated in the cortex in an (i)As dose-dependent manner, while DAR-D₁ mRNA expression was increased in striatum in the 0.5 mg (i)As/L group. These results show that chronic exposure to low levels of arsenic causes subtle but region-specific changes in the nervous system, especially in antioxidant systems and dopaminergic elements. These changes became behaviorally evident only in the group exposed to 50 mg (i)As/L. PMID:20699118

  18. The dopaminergic system and aggression in laying hens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The dopaminergic system regulates aggression in humans and other mammals. To investigate if birds with genetic propensity for high and low aggressiveness may exhibit distinctly different aggressive mediation via dopamine (DA) D1 and D2 receptor pathways, two high aggressive (DXL and LGPS) and one lo...

  19. Dynamics of the dopaminergic system as a key component to the understanding of depression.

    PubMed

    Yadid, Gal; Friedman, Alexander

    2008-01-01

    For decades, clinical treatment of depression has usually involved antidepressants that target noradrenergic and serotonergic neurotransmission. Over the past half century, no genuinely ground-breaking progress has been made in the pharmacological development of antidepressant drugs. Dopaminergic mesolimbic and mesocortical systems are involved in hedonia and motivation, two core symptoms of depression. However, their role in the pathophysiology of depression and their manipulation to treat depression has received little attention. Recent findings indicate the potential usefulness of monitoring limbic dopaminergic dynamics in combination with mathematical analysis. In this chapter comprehensive review of data from animal models, genetics, neuroimaging and human clinical trials that strengthen the case for dopaminergic dysfunction in the pathophysiology of major depression. This chapter focuses on recent convergence of data describing the fluctuation in activity of the mesolimbic dopaminergic system, and discusses its crucial role in manifestation of depressive-like behavior. Decoding the functionality of the dopaminergic system is important to the understanding of depression and the development of future efficient antidepressant treatments. PMID:18772037

  20. Imbalance between thyroid hormones and the dopaminergic system might be central to the pathophysiology of restless legs syndrome: a hypothesis.

    PubMed

    Pereira, Jose Carlos; Pradella-Hallinan, Marcia; Lins Pessoa, Hugo de

    2010-05-01

    Data collected from medical literature indicate that dopaminergic agonists alleviate Restless Legs Syndrome symptoms while dopaminergic agonists antagonists aggravate them. Dopaminergic agonists is a physiological regulator of thyroid-stimulating hormone. Dopaminergic agonists infusion diminishes the levels of thyroid hormones, which have the ability to provoke restlessness, hyperkinetic states, tremors, and insomnia. Conditions associated with higher levels of thyroid hormones, such as pregnancy or hyperthyroidism, have a higher prevalence of Restless Legs Syndrome symptoms. Low iron levels can cause secondary Restless Legs Syndrome or aggravate symptoms of primary disease as well as diminish enzymatic activities that are involved in dopaminergic agonists production and the degradation of thyroid hormones. Moreover, as a result of low iron levels, dopaminergic agonists diminishes and thyroid hormones increase. Iron therapy improves Restless Legs Syndrome symptoms in iron deprived patients. Medical hypothesis. To discuss the theory that thyroid hormones, when not counterbalanced by dopaminergic agonists, may precipitate the signs and symptoms underpinning Restless Legs Syndrome. The main cause of Restless Legs Syndrome might be an imbalance between the dopaminergic agonists system and thyroid hormones. PMID:20535374

  1. Nicotine-induced acute hyperactivity is mediated by dopaminergic system in a sexually dimorphic manner.

    PubMed

    Zhang, Yunpeng; Guo, Jing; Guo, Aike; Li, Yan

    2016-09-22

    Short-term exposure to nicotine induces positive effects in mice, monkeys and humans, including mild euphoria, hyperactivity, and enhanced cognition. However, the underlying neural basis and molecular mechanisms for these effects remain poorly understood. Here, using a video recording system, we find that acute nicotine administration induces locomotor hyperactivity in Drosophila, similar to observations made in higher model organisms. Suppressing dopaminergic neurons or down-regulating dopamine 1-like receptor (DopR) abolishes this acute nicotine response, but surprisingly, does so only in male flies. Using a GFP reconstitution across synaptic partners (GRASP) approach, we show that dopaminergic neurons possess potential synaptic connections with acetylcholinergic neurons in wide regions of the brain. Furthermore, dopaminergic neurons are widely activated upon nicotine perfusion in both sexes, while the response curve differs significantly between the sexes. Moreover, knockdown of the β1 nicotine acetylcholine receptor (nAChR) in dopaminergic neurons abolishes the acute nicotine response only in male flies, while panneural knock-down occurs in both sexes. Taken together, our results reveal that in fruit flies, dopaminergic neurons mediate nicotine-induced acute locomotor hyperactivity in a sexually dimorphic manner, and Drosophila β1 nAChR subunit plays a crucial role in this nicotine response. These findings provide important insights into the molecular and neural basis of acute nicotine effects, and the underlying mechanisms may play conserved roles across species. PMID:27365175

  2. Dopaminergic correlates of metabolic network activity in Parkinson's disease.

    PubMed

    Holtbernd, Florian; Ma, Yilong; Peng, Shichun; Schwartz, Frank; Timmermann, Lars; Kracht, Lutz; Fink, Gereon R; Tang, Chris C; Eidelberg, David; Eggers, Carsten

    2015-09-01

    Parkinson's disease (PD) is associated with distinct metabolic covariance patterns that relate to the motor and cognitive manifestations of the disorder. It is not known, however, how the expression of these patterns relates to measurements of nigrostriatal dopaminergic activity from the same individuals. To explore these associations, we studied 106 PD subjects who underwent cerebral PET with both (18) F-fluorodeoxyglucose (FDG) and (18) F-fluoro-L-dopa (FDOPA). Expression values for the PD motor- and cognition-related metabolic patterns (PDRP and PDCP, respectively) were computed for each subject; these measures were correlated with FDOPA uptake on a voxel-by-voxel basis. To explore the relationship between dopaminergic function and local metabolic activity, caudate and putamen FDOPA PET signal was correlated voxel-wise with FDG uptake over the entire brain. PDRP expression correlated with FDOPA uptake in caudate and putamen (P < 0.001), while PDCP expression correlated with uptake in the anterior striatum (P < 0.001). While statistically significant, the correlations were only of modest size, accounting for less than 20% of the overall variation in these measures. After controlling for PDCP expression, PDRP correlations were significant only in the posterior putamen. Of note, voxel-wise correlations between caudate/putamen FDOPA uptake and whole-brain FDG uptake were significant almost exclusively in PDRP regions. Overall, the data indicate that PDRP and PDCP expression correlates significantly with PET indices of presynaptic dopaminergic functioning obtained in the same individuals. Even so, the modest size of these correlations suggests that in PD patients, individual differences in network activity cannot be explained solely by nigrostriatal dopamine loss. PMID:26037537

  3. Manganese nanoparticle activates mitochondrial dependent apoptotic signaling and autophagy in dopaminergic neuronal cells

    SciTech Connect

    Afeseh Ngwa, Hilary; Kanthasamy, Arthi; Gu, Yan; Fang, Ning; Anantharam, Vellareddy; Kanthasamy, Anumantha G.

    2011-11-15

    activate mitochondrial cell death signaling in dopaminergic neuron. Black-Right-Pointing-Pointer Mn nanoparticles activate caspase-mediated proteolytic cleavage of PKC{delta} cascade. Black-Right-Pointing-Pointer Mn nanoparticles induce autophagy in dopaminergic neuronal cells. Black-Right-Pointing-Pointer Mn nanoparticles induce loss of TH{sup +} neurons in primary mesencephalic cultures. Black-Right-Pointing-Pointer Study emphasizes neurotoxic risks of Mn nanoparticles to nigral dopaminergic system.

  4. Effects of manganese on tyrosine hydroxylase (TH) activity and TH-phosphorylation in a dopaminergic neural cell line

    SciTech Connect

    Zhang Danhui; Kanthasamy, Arthi; Anantharam, Vellareddy; Kanthasamy, Anumantha

    2011-07-15

    Manganese (Mn) exposure causes manganism, a neurological disorder similar to Parkinson's disease. However, the cellular mechanism by which Mn impairs the dopaminergic neurotransmitter system remains unclear. We previously demonstrated that caspase-3-dependent proteolytic activation of protein kinase C delta (PKC{delta}) plays a key role in Mn-induced apoptotic cell death in dopaminergic neurons. Recently, we showed that PKC{delta} negatively regulates tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, by enhancing protein phosphatase-2A activity in dopaminergic neurons. Here, we report that Mn exposure can affect the enzymatic activity of TH, the rate-limiting enzyme in dopamine synthesis, by activating PKC{delta}-PP2A signaling pathway in a dopaminergic cell model. Low dose Mn (3-10 {mu}M) exposure to differentiated mesencephalic dopaminergic neuronal cells for 3 h induced a significant increase in TH activity and phosphorylation of TH-Ser40. The PKC{delta} specific inhibitor rottlerin did not prevent Mn-induced TH activity or TH-Ser40 phosphorylation. On the contrary, chronic exposure to 0.1-1 {mu}M Mn for 24 h induced a dose-dependent decrease in TH activity. Interestingly, chronic Mn treatment significantly increased PKC{delta} kinase activity and protein phosphatase 2A (PP2A) enzyme activity. Treatment with the PKC{delta} inhibitor rottlerin almost completely prevented chronic Mn-induced reduction in TH activity, as well as increased PP2A activity. Neither acute nor chronic Mn exposures induced any cytotoxic cell death or altered TH protein levels. Collectively, these results demonstrate that low dose Mn exposure impairs TH activity in dopaminergic cells through activation of PKC{delta} and PP2A activity.

  5. Chronic low-level arsenic exposure causes gender-specific alterations in locomotor activity, dopaminergic systems, and thioredoxin expression in mice.

    PubMed

    Bardullas, U; Limón-Pacheco, J H; Giordano, M; Carrizales, L; Mendoza-Trejo, M S; Rodríguez, V M

    2009-09-01

    Arsenic (As) is a toxic metalloid widely present in the environment. Human exposure to As has been associated with the development of skin and internal organ cancers and cardiovascular disorders, among other diseases. A few studies report decreases in intelligence quotient (IQ), and sensory and motor alterations after chronic As exposure in humans. On the other hand, studies of rodents exposed to high doses of As have found alterations in locomotor activity, brain neurochemistry, behavioral tasks, and oxidative stress. In the present study both male and female C57Bl/6J mice were exposed to environmentally relevant doses of As such as 0.05, 0.5, 5.0, or 50 mg As/L of drinking water for 4 months, and locomotor activity was assessed every month. Male mice presented hyperactivity in the group exposed to 0.5 mg As/L and hypoactivity in the group exposed to 50 mg As/L after 4 months of As exposure, whereas female mice exposed to 0.05, 0.5, and 5.0 mg As/L exhibited hyperactivity in every monthly test during As exposure. Furthermore, striatal and hypothalamic dopamine content was decreased only in female mice. Also decreases in tyrosine hydroxylase (TH) and cytosolic thioredoxin (Trx-1) mRNA expression in striatum and nucleus accumbens were observed in male and female mice, respectively. These results indicate that chronic As exposure leads to gender-dependent alterations in dopaminergic markers and spontaneous locomotor activity, and down-regulation of the antioxidant capacity of the brain. PMID:19121333

  6. Chronic low-level arsenic exposure causes gender-specific alterations in locomotor activity, dopaminergic systems, and thioredoxin expression in mice

    SciTech Connect

    Bardullas, U.; Limon-Pacheco, J.H.; Giordano, M.; Carrizales, L.; Mendoza-Trejo, M.S.; Rodriguez, V.M.

    2009-09-01

    Arsenic (As) is a toxic metalloid widely present in the environment. Human exposure to As has been associated with the development of skin and internal organ cancers and cardiovascular disorders, among other diseases. A few studies report decreases in intelligence quotient (IQ), and sensory and motor alterations after chronic As exposure in humans. On the other hand, studies of rodents exposed to high doses of As have found alterations in locomotor activity, brain neurochemistry, behavioral tasks, and oxidative stress. In the present study both male and female C57Bl/6J mice were exposed to environmentally relevant doses of As such as 0.05, 0.5, 5.0, or 50 mg As/L of drinking water for 4 months, and locomotor activity was assessed every month. Male mice presented hyperactivity in the group exposed to 0.5 mg As/L and hypoactivity in the group exposed to 50 mg As/L after 4 months of As exposure, whereas female mice exposed to 0.05, 0.5, and 5.0 mg As/L exhibited hyperactivity in every monthly test during As exposure. Furthermore, striatal and hypothalamic dopamine content was decreased only in female mice. Also decreases in tyrosine hydroxylase (TH) and cytosolic thioredoxin (Trx-1) mRNA expression in striatum and nucleus accumbens were observed in male and female mice, respectively. These results indicate that chronic As exposure leads to gender-dependent alterations in dopaminergic markers and spontaneous locomotor activity, and down-regulation of the antioxidant capacity of the brain.

  7. The Dopaminergic System in the Aging Brain of Drosophila

    PubMed Central

    White, Katherine E.; Humphrey, Dickon M.; Hirth, Frank

    2010-01-01

    Drosophila models of Parkinson's disease are characterized by two principal phenotypes: the specific loss of dopaminergic (DA) neurons in the aging brain and defects in motor behavior. However, an age-related analysis of these baseline parameters in wildtype Drosophila is lacking. Here we analyzed the DA system and motor behavior in aging Drosophila. DA neurons in the adult brain can be grouped into bilateral symmetric clusters, each comprising a stereotypical number of cells. Analysis of TH > mCD8::GFP and cell type-specific MARCM clones revealed that DA neurons show cluster-specific, stereotypical projection patterns with terminal arborization in target regions that represent distinct functional areas of the adult brain. Target areas include the mushroom bodies, involved in memory formation and motivation, and the central complex, involved in the control of motor behavior, indicating that similar to the mammalian brain, DA neurons in the fly brain are involved in the regulation of specific behaviors. Behavioral analysis revealed that Drosophila show an age-related decline in startle-induced locomotion and negative geotaxis. Motion tracking however, revealed that walking activity, and exploration behavior, but not centrophobism increase at late stages of life. Analysis of TH > Dcr2, mCD8::GFP revealed a specific effect of Dcr2 expression on walking activity but not on exploratory or centrophobic behavior, indicating that the siRNA pathway may modulate distinct DA behaviors in Drosophila. Moreover, DA neurons were maintained between early- and late life, as quantified by TH > mCD8::GFP and anti-TH labeling, indicating that adult onset, age-related degeneration of DA neurons does not occur in the aging brain of Drosophila. Taken together, our data establish baseline parameters in Drosophila for the study of Parkinson's disease as well as other disorders affecting DA neurons and movement control. PMID:21165178

  8. The dopaminergic projection system, basal forebrain macrosystems, and conditioned stimuli

    PubMed Central

    Zahm, Daniel S.

    2011-01-01

    This review begins with a description of some problems that in recent years have beset an influential circuit model of fear-conditioning and goes on to look at neuroanatomy that might subserve conditioning viewed in a broader perspective, including not only fear, but also appetitive, conditioning. The paper then focuses on basal forebrain functional-anatomical systems, or macrosystems, as they have come to be called, which Lennart Heimer and colleagues described beginning in the 1970’s. Yet more specific attention is then given to the relationships of the dorsal and ventral striatopallidal systems and extended amygdala with the dopaminergic mesotelencephalic projection systems, culminating with the hypothesis that all macrosystems contribute to behavioral conditioning. PMID:18204412

  9. Modulation of the basal ganglia dopaminergic system in a transgenic mouse exhibiting dystonia-like features

    PubMed Central

    Giannakopoulou, D.; Armata, I. A.; Mitsacos, A.; Shashidharan, P.; Giompres, P.

    2011-01-01

    Dystonia is a movement disorder characterized by involuntary excessive muscle activity and abnormal postures. There are data supporting the hypothesis that basal ganglia dysfunction, and specifically dopaminergic system dysfunction, plays a role in dystonia. In the present study, we used hyperkinetic transgenic mice generated as a model of DYT1 dystonia and compared the basal ganglia dopaminergic system between transgenic mice exhibiting hyperkinesia (affected) transgenic mice not showing movement abnormalities (unaffected), and non-transgenic littermates A decrease in the density of striatal D2 binding sites, measured by [3H]raclopride binding, and D2 mRNA expression in substantia nigra pars compacta (SNpc) was revealed in affected an unaffected transgenic mice when compared with non-transgenic. No difference in D1 receptor binding and DAT binding, measured by [3H]SCH23390 and [3H]WIN35428 binding, respectively, was found in striatum of transgenic animals. In SNpc, increased levels of DAT binding sites were observed in affected and unaffected animals compared to non-transgenic, whereas no change in DAT mRNA expression was found. Our results show selective neurochemical changes in the basal ganglia dopaminergic system, suggesting a possible involvement in the pathophysiology of dystonialike motor hyperactivity. PMID:21136125

  10. Atrial Natriuretic Peptide and Renal Dopaminergic System: A Positive Friendly Relationship?

    PubMed Central

    Choi, Marcelo Roberto; Rukavina Mikusic, Natalia Lucía; Kouyoumdzian, Nicolás Martín; Kravetz, María Cecilia; Fernández, Belisario Enrique

    2014-01-01

    Sodium metabolism by the kidney is accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Renal dopamine plays a central role in this interactive network. The natriuretic hormones, such as the atrial natriuretic peptide, mediate some of their effects by affecting the renal dopaminergic system. Renal dopaminergic tonus can be modulated at different steps of dopamine metabolism (synthesis, uptake, release, catabolism, and receptor sensitization) which can be regulated by the atrial natriuretic peptide. At tubular level, dopamine and atrial natriuretic peptide act together in a concerted manner to promote sodium excretion, especially through the overinhibition of Na+, K+-ATPase activity. In this way, different pathological scenarios where renal sodium excretion is dysregulated, as in nephrotic syndrome or hypertension, are associated with impaired action of renal dopamine and/or atrial natriuretic peptide, or as a result of impaired interaction between these two natriuretic systems. The aim of this review is to update and comment on the most recent evidences demonstrating how the renal dopaminergic system interacts with atrial natriuretic peptide to control renal physiology and blood pressure through different regulatory pathways. PMID:25013796

  11. Clinical Investigation of the Dopaminergic System with PET and FLUORINE-18-FLUORO-L-DOPA.

    NASA Astrophysics Data System (ADS)

    Oakes, Terrence Rayford

    1995-01-01

    Positron Emission Tomography (PET) is a tool that provides quantitative physiological information. It is valuable both in a clinical environment, where information is sought for an individual, and in a research environment, to answer more fundamental questions about physiology and disease states. PET is particularly attractive compared to other nuclear medicine imaging techniques in cases where the anatomical regions of interest are small or when true metabolic rate constants are required. One example with both of these requirements is the investigation of Parkinson's Disease, which is characterized as a presynaptic motor function deficit affecting the striatum. As dopaminergic neurons die, the ability of the striatum to affect motor function decreases. The extent of functional neuronal damage in the small sub-structures may be ascertained by measuring the ability of the caudate and putamen to trap and store dopamine, a neurotransmitter. PET is able to utilize a tracer of dopamine activity, ^ {18}F- scL-DOPA, to quantitate the viability of the striatum. This thesis work deals with implementing and optimizing the many different elements that compose a PET study of the dopaminergic system, including: radioisotope production; conversion of aqueous ^{18}F ^-into [^ {18}F]-F2; synthesis of ^{18}F- scL -DOPA; details of the PET scan itself; measurements to estimate the radiation dosimetry; accurate measurement of a plasma input function; and the quantitation of dopaminergic activity in normal human subjects as well as in Parkinson's Disease patients.

  12. Pentadecapeptide BPC 157 interactions with adrenergic and dopaminergic systems in mucosal protection in stress.

    PubMed

    Sikirić, P; Mazul, B; Seiwerth, S; Grabarević, Z; Rucman, R; Petek, M; Jagić, V; Turković, B; Rotkvić, I; Mise, S; Zoricić, I; Jurina, L; Konjevoda, P; Hanzevacki, M; Gjurasin, M; Separović, J; Ljubanović, D; Artuković, B; Bratulić, M; Tisljar, M; Miklić, P; Sumajstorcić, J

    1997-03-01

    Since superior protection against different gastrointestinal and liver lesions and antiinflammatory and analgesic activities were noted for pentadecapeptide BPC (an essential fragment of an organoprotective gastric juice protein named BPC), the beneficial mechanism of BPC 157 and its likely interactions with other systems were studied. Hence its beneficial effects would be abolished by adrenal gland medullectomy, the influence of different agents affecting alpha, beta, and dopamine receptors on BPC 157 gastroprotection in 48 h restraint stress was further investigated. Animals were pretreated (1 hr before stress) with saline (controls) or BPC 157 (dissolved in saline) (10 microg or 10 ng/kg body wt intraperitoneally or intragastrically) applied either alone to establish basal conditions or, when manipulating the adrenergic or dopaminergic system, a simultaneous administration was carried out with various agents with specific effects on adrenergic or dopaminergic receptors [given in milligrams per kilogram intraperitoneally except for atenolol, which was given subcutaneously] phentolamine (10.0), prazosin (0.5), yohimbine (5.0), clonidine (0.1) (alpha-adrenergic domain), propranolol (1.0), atenolol (20.0) (beta-adrenergic domain), domperidone (5.0), and haloperidol (5.0) (peripheral/central dopamine system). Alternatively, agents stimulating adrenergic or dopaminergic systems--adrenaline (5.0) or bromocriptine (10.0)--were applied. A strong protection, noted following intragastric or intraperitoneal administration of BPC 157, was fully abolished by coadministration of phentolamine, clonidine, and haloperidol, and consistently not affected by prazosin, yohimbine, or domperidone. Atenolol abolished only intraperitoneal BPC 157 protection, whereas propranolol affected specifically intragastric BPC 157 protection. Interestingly, the severe course of lesion development obtained in basal conditions, unlike BPC 157 gastroprotection, was not influenced by the application of

  13. White noise improves learning by modulating activity in dopaminergic midbrain regions and right superior temporal sulcus.

    PubMed

    Rausch, Vanessa H; Bauch, Eva M; Bunzeck, Nico

    2014-07-01

    In neural systems, information processing can be facilitated by adding an optimal level of white noise. Although this phenomenon, the so-called stochastic resonance, has traditionally been linked with perception, recent evidence indicates that white noise may also exert positive effects on cognitive functions, such as learning and memory. The underlying neural mechanisms, however, remain unclear. Here, on the basis of recent theories, we tested the hypothesis that auditory white noise, when presented during the encoding of scene images, enhances subsequent recognition memory performance and modulates activity within the dopaminergic midbrain (i.e., substantia nigra/ventral tegmental area, SN/VTA). Indeed, in a behavioral experiment, we can show in healthy humans that auditory white noise-but not control sounds, such as a sinus tone-slightly improves recognition memory. In an fMRI experiment, white noise selectively enhances stimulus-driven phasic activity in the SN/VTA and auditory cortex. Moreover, it induces stronger connectivity between SN/VTA and right STS, which, in addition, exhibited a positive correlation with subsequent memory improvement by white noise. Our results suggest that the beneficial effects of auditory white noise on learning depend on dopaminergic neuromodulation and enhanced connectivity between midbrain regions and the STS-a key player in attention modulation. Moreover, they indicate that white noise could be particularly useful to facilitate learning in conditions where changes of the mesolimbic system are causally related to memory deficits including healthy and pathological aging. PMID:24345178

  14. JNK-mediated activation of ATF2 contributes to dopaminergic neurodegeneration in the MPTP mouse model of Parkinson's disease.

    PubMed

    Huang, Qiaoying; Du, Xiaoxiao; He, Xin; Yu, Qing; Hu, Kunhua; Breitwieser, Wolfgang; Shen, Qingyu; Ma, Shanshan; Li, Mingtao

    2016-03-01

    The c-Jun N-terminal kinase (JNK)/c-Jun pathway is a known critical regulator of dopaminergic neuronal death in Parkinson's disease (PD) and is considered a potential target for neuroprotective therapy. However, whether JNK is activated within dopaminergic neurons remains controversial, and whether JNK acts through downstream effectors other than c-Jun to promote dopaminergic neuronal death remains unclear. In this study, we confirm that JNK but not p38 is activated in dopaminergic neurons after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxication. Furthermore, within the dopaminergic neurons of the substantia nigra in MPTP-treated mice, JNK2/3 phosphorylates threonine 69 (Thr69) of Activating transcription factor-2 (ATF2), a transcription factor of the ATF/CREB family, whereas the phosphorylation of Thr71 is constitutive and remains unchanged. The increased phosphorylation of ATF2 on Thr69 by JNK in the MPTP mouse model suggests a functional relationship between the transcriptional activation of ATF2 and dopaminergic neuron death. By using dopaminergic neuron-specific conditional ATF2 mutant mice, we found that either partial or complete deletion of the ATF2 DNA-binding domain in dopaminergic neurons markedly alleviates the MPTP-induced dopaminergic neurodegeneration, indicating that the activation of ATF2 plays a detrimental role in neuropathogenesis in PD. Taken together, our findings demonstrate that JNK-mediated ATF2 activation contributes to dopaminergic neuronal death in an MPTP model of PD. PMID:26515688

  15. GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function.

    PubMed

    Kumar, Anmol; Kopra, Jaakko; Varendi, Kärt; Porokuokka, Lauriina L; Panhelainen, Anne; Kuure, Satu; Marshall, Pepin; Karalija, Nina; Härma, Mari-Anne; Vilenius, Carolina; Lilleväli, Kersti; Tekko, Triin; Mijatovic, Jelena; Pulkkinen, Nita; Jakobson, Madis; Jakobson, Maili; Ola, Roxana; Palm, Erik; Lindahl, Maria; Strömberg, Ingrid; Võikar, Vootele; Piepponen, T Petteri; Saarma, Mart; Andressoo, Jaan-Olle

    2015-12-01

    Degeneration of nigrostriatal dopaminergic system is the principal lesion in Parkinson's disease. Because glial cell line-derived neurotrophic factor (GDNF) promotes survival of dopamine neurons in vitro and in vivo, intracranial delivery of GDNF has been attempted for Parkinson's disease treatment but with variable success. For improving GDNF-based therapies, knowledge on physiological role of endogenous GDNF at the sites of its expression is important. However, due to limitations of existing genetic model systems, such knowledge is scarce. Here, we report that prevention of transcription of Gdnf 3'UTR in Gdnf endogenous locus yields GDNF hypermorphic mice with increased, but spatially unchanged GDNF expression, enabling analysis of postnatal GDNF function. We found that increased level of GDNF in the central nervous system increases the number of adult dopamine neurons in the substantia nigra pars compacta and the number of dopaminergic terminals in the dorsal striatum. At the functional level, GDNF levels increased striatal tissue dopamine levels and augmented striatal dopamine release and re-uptake. In a proteasome inhibitor lactacystin-induced model of Parkinson's disease GDNF hypermorphic mice were protected from the reduction in striatal dopamine and failure of dopaminergic system function. Importantly, adverse phenotypic effects associated with spatially unregulated GDNF applications were not observed. Enhanced GDNF levels up-regulated striatal dopamine transporter activity by at least five fold resulting in enhanced susceptibility to 6-OHDA, a toxin transported into dopamine neurons by DAT. Further, we report how GDNF levels regulate kidney development and identify microRNAs miR-9, miR-96, miR-133, and miR-146a as negative regulators of GDNF expression via interaction with Gdnf 3'UTR in vitro. Our results reveal the role of GDNF in nigrostriatal dopamine system postnatal development and adult function, and highlight the importance of correct spatial

  16. Developmental Deltamethrin Exposure Causes Persistent Changes in Dopaminergic Gene Expression, Neurochemistry, and Locomotor Activity in Zebrafish.

    PubMed

    Kung, Tiffany S; Richardson, Jason R; Cooper, Keith R; White, Lori A

    2015-08-01

    Pyrethroids are commonly used insecticides that are considered to pose little risk to human health. However, there is an increasing concern that children are more susceptible to the adverse effects of pesticides. We used the zebrafish model to test the hypothesis that developmental exposure to low doses of the pyrethroid deltamethrin results in persistent alterations in dopaminergic gene expression, neurochemistry, and locomotor activity. Zebrafish embryos were treated with deltamethrin (0.25-0.50 μg/l), at concentrations below the LOAEL, during the embryonic period [3-72 h postfertilization (hpf)], after which transferred to fresh water until the larval stage (2-weeks postfertilization). Deltamethrin exposure resulted in decreased transcript levels of the D1 dopamine (DA) receptor (drd1) and increased levels of tyrosine hydroxylase at 72 hpf. The reduction in drd1 transcripts persisted to the larval stage and was associated with decreased D2 dopamine receptor transcripts. Larval fish, exposed developmentally to deltamethrin, had increased levels of homovanillic acid, a DA metabolite. Since the DA system is involved in locomotor activity, we measured the swim activity of larval fish following a transition to darkness. Developmental exposure to deltamethrin significantly increased larval swim activity which was attenuated by concomitant knockdown of the DA transporter. Acute exposure to methylphenidate, a DA transporter inhibitor, increased swim activity in control larva, while reducing swim activity in larva developmentally exposed to deltamethrin. Developmental exposure to deltamethrin causes locomotor deficits in larval zebrafish, which is likely mediated by dopaminergic dysfunction. This highlights the need to understand the persistent effects of low-dose neurotoxicant exposure during development. PMID:25912032

  17. Developmental Deltamethrin Exposure Causes Persistent Changes in Dopaminergic Gene Expression, Neurochemistry, and Locomotor Activity in Zebrafish

    PubMed Central

    Kung, Tiffany S.; Richardson, Jason R.; Cooper, Keith R.; White, Lori A.

    2015-01-01

    Pyrethroids are commonly used insecticides that are considered to pose little risk to human health. However, there is an increasing concern that children are more susceptible to the adverse effects of pesticides. We used the zebrafish model to test the hypothesis that developmental exposure to low doses of the pyrethroid deltamethrin results in persistent alterations in dopaminergic gene expression, neurochemistry, and locomotor activity. Zebrafish embryos were treated with deltamethrin (0.25–0.50 μg/l), at concentrations below the LOAEL, during the embryonic period [3–72 h postfertilization (hpf)], after which transferred to fresh water until the larval stage (2-weeks postfertilization). Deltamethrin exposure resulted in decreased transcript levels of the D1 dopamine (DA) receptor (drd1) and increased levels of tyrosine hydroxylase at 72 hpf. The reduction in drd1 transcripts persisted to the larval stage and was associated with decreased D2 dopamine receptor transcripts. Larval fish, exposed developmentally to deltamethrin, had increased levels of homovanillic acid, a DA metabolite. Since the DA system is involved in locomotor activity, we measured the swim activity of larval fish following a transition to darkness. Developmental exposure to deltamethrin significantly increased larval swim activity which was attenuated by concomitant knockdown of the DA transporter. Acute exposure to methylphenidate, a DA transporter inhibitor, increased swim activity in control larva, while reducing swim activity in larva developmentally exposed to deltamethrin. Developmental exposure to deltamethrin causes locomotor deficits in larval zebrafish, which is likely mediated by dopaminergic dysfunction. This highlights the need to understand the persistent effects of low-dose neurotoxicant exposure during development. PMID:25912032

  18. Role and Mechanism of Microglial Activation in Iron-Induced Selective and Progressive Dopaminergic Neurodegeneration

    PubMed Central

    Yan, Zhao-fen; Gao, Jun-hua; Sun, Li; Huang, Xi-yan; Liu, Zhuo; Yu, Shu-yang; Cao, Chen-Jie; Zuo, Li-jun; Chen, Ze-Jie; Hu, Yang; Wang, Fang; Hong, Jau-shyong; Wang, Xiao-min

    2016-01-01

    Parkinson’s disease (PD) patients have excessive iron depositions in substantia nigra (SN). Neuroinflammation characterized by microglial activation is pivotal for dopaminergic neurodegeneration in PD. However, the role and mechanism of microglial activation in iron-induced dopaminergic neurodegeneration in SN remain unclear yet. This study aimed to investigate the role and mechanism of microglial β-nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) activation in iron-induced selective and progressive dopaminergic neurodegeneration. Multiple primary midbrain cultures from rat, NOX2+/+ and NOX2−/− mice were used. Dopaminergic neurons, total neurons, and microglia were visualized by immunostainings. Cell viability was measured by MTT assay. Superoxide (O2·−) and intracellular reactive oxygen species (iROS) were determined by measuring SOD-inhibitable reduction of tetrazolium salt WST-1 and DCFH-DA assay. mRNA and protein were detected by real-time PCR and Western blot. Iron induces selective and progressive dopaminergic neurotoxicity in rat neuron–microglia–astroglia cultures and microglial activation potentiates the neurotoxicity. Activated microglia produce a magnitude of O2·− and iROS, and display morphological alteration. NOX2 inhibitor diphenylene iodonium protects against iron-elicited dopaminergic neurotoxicity through decreasing microglial O2·− generation, and NOX2−/− mice are resistant to the neurotoxicity by reducing microglial O2·− production, indicating that iron-elicited dopaminergic neurotoxicity is dependent of NOX2, a O2·−-generating enzyme. NOX2 activation is indicated by the increased mRNA and protein levels of subunits P47 and gp91. Molecules relevant to NOX2 activation include PKC-σ, P38, ERK1/2, JNK, and NF-ΚBP65 as their mRNA and protein levels are enhanced by NOX2 activation. Iron causes selective and progressive dopaminergic neurodegeneration, and microglial NOX2 activation potentiates the

  19. Aldrin-induced locomotor activity: possible involvement of the central GABAergic-cholinergic-dopaminergic interaction.

    PubMed

    Jamaluddin, S; Poddar, M K

    2001-01-01

    Aldrin (5 mg/kg/day, p.o.) under nontolerant condition, administered either for a single day or for 12 consecutive days, enhanced locomotor activity (LA) of rats. The increase in LA was greater in rats treated with aldrin for 12 consecutive days than that observed with a single dose. The aim of the present study is to evaluate the involvement of possible interactions of central GABAergic, cholinergic and dopaminergic systems using their agonist(s) and antagonist(s) in the regulation of LA in aldrin nontolerant rats. Administration of either L-DOPA along with carbidopa or bicuculline potentiated aldrin-induced increase in LA under nontolerant condition as well as LA of the control rats. Treatment with muscimol, haloperidol, atropine or physostigmine all decreased the LA of both aldrin nontolerant and control rats. Further, the application of (a) haloperidol along with bicuculline, atropine or physostigmine and (b) physostigmine along with bicuculline or L-DOPA + carbidopa significantly reduced LA but L-DOPA + carbidopa along with atropine or bicuculline increased LA of the control rats. These agonist(s)/antagonist(s)-induced decrease or increase in LA of the control rats were attenuated or potentiated, respectively, when those agonist(s)/antagonist(s) under abovementioned condition were administered to aldrin nontolerant rats. The attenuating or potentiating effects of aldrin on agonist(s)/antagonist(s) (either individually or in different combinations)-induced change in LA were greater in rats treated with aldrin for 12 consecutive days than that observed with a single-dose aldrin treatment. These results suggest that aldrin, under nontolerant condition, reduces central GABAergic activity and increases LA by activating dopaminergic system via inhibition of cholinergic activity. The treatment with aldrin for 12 consecutive days produces greater effect than that caused by a single-day treatment. PMID:11785907

  20. Neurotoxicity effects of atrazine-induced SH-SY5Y human dopaminergic neuroblastoma cells via microglial activation.

    PubMed

    Ma, Kun; Wu, Hao-Yu; Zhang, Bo; He, Xi; Li, Bai-Xiang

    2015-11-01

    Atrazine (2-chloro-4-ethytlamino-6-isopropylamine-1,3,5-triazine; ATR) is a broad-spectrum herbicide with a wide range of applications worldwide. However, ATR is neurotoxic; it reduces dopamine levels in the substantia nigra and corpus striatum in the midbrain, affects the absorption of synaptic vesicles and synaptic bodies, and interferes with dopamine storage and uptake in synaptic vesicles, leading to neurodegenerative disorders. Microglia are resident immunocompetent and phagocytic cells that regulate and participate in the microenvironment in the central nervous system. They demonstrate macrophage characteristics after activation by releasing inflammatory cytokines and neurotoxic substances to increase the inflammatory response, and are thus involved in neurodegeneration. The aim of this study was to investigate the neurotoxic effects of ATR-activated microglia-mediated neuronal damage in terms of human dopaminergic neuroblastoma SH-SY5Y cell death. ATR was administered to BV-2 microglial cells at 12.5, 25, and 50 μM for 1, 6, 12, 24 and 48 h, respectively. ATR increased activated-microglia-induced overexpression of reactive oxygen species, inducible nitric oxide synthase, nitric oxide, gp91(phox), p47(phox), and the inflammatory cytokines tumor necrosis factor α and interleukin-1β, thus reducing SH-SY5Y cell viability. These results suggest that activated microglia may play a critical role in inflammation-mediated dopaminergic neuronal death, and provide the basis for further studies on the mechanisms of ATR-induced dopaminergic system toxicity. PMID:26256823

  1. GABA-mediated regulation of the activity-dependent olfactory bulb dopaminergic phenotype

    PubMed Central

    Akiba, Yosuke; Sasaki, Hayato; Huerta, Patricio T.; Estevez, Alvaro G.; Baker, Harriet; Cave, John W.

    2009-01-01

    Gamma-amino-butyric acid (GABA) regulates the proliferation and migration of olfactory bulb (OB) interneuron progenitors derived from the subventricular zone (SVZ), but the role of GABA in the differentiation of these progenitors has been largely unexplored. This study examined the role of GABA in the differentiation of OB dopaminergic interneurons using neonatal forebrain organotypic slice cultures prepared from transgenic mice expressing GFP under the control of the tyrosine hydroxylase (Th) gene promoter (ThGFP). KCl-mediated depolarization of the slices induced ThGFP expression. The addition of GABA to the depolarized slices further increased GFP fluorescence by inducing ThGFP expression in an additional set of periglomerular cells. These findings showed that GABA promoted differentiation of SVZ-derived OB dopaminergic interneurons and suggested that GABA indirectly regulated Th expression and OB dopaminergic neuron differentiation through an acceleration of the maturation rate for the dopaminergic progenitors. Additional studies revealed that the effect of GABA on ThGFP expression required activation of L- and P/Q-type Ca+2 channels as well as GABAA and GABAB receptors. These voltage-gated Ca+2 channels and GABA receptors have previously been shown to be required for the co-expressed GABAergic phenotype in the OB interneurons. Together, these findings suggest that Th expression and the differentiation of OB dopaminergic interneurons are coupled to the co-expressed GABAergic phenotype, and demonstrate a novel role for GABA in neurogenesis. PMID:19301430

  2. 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

  3. 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'. PMID:24709540

  4. The Dopaminergic Reward System and Leisure Time Exercise Behavior: A Candidate Allele Study

    PubMed Central

    Huppertz, Charlotte; Bartels, Meike; Groen-Blokhuis, Maria M.; Dolan, Conor V.; de Moor, Marleen H. M.; Abdellaoui, Abdel; van Beijsterveldt, Catharina E. M.; Ehli, Erik A.; Hottenga, Jouke-Jan; Willemsen, Gonneke; Xiao, Xiangjun; Scheet, Paul; Davies, Gareth E.; Boomsma, Dorret I.; Hudziak, James J.; de Geus, Eco J. C.

    2014-01-01

    Purpose. Twin studies provide evidence that genetic influences contribute strongly to individual differences in exercise behavior. We hypothesize that part of this heritability is explained by genetic variation in the dopaminergic reward system. Eight single nucleotide polymorphisms (SNPs in DRD1: rs265981, DRD2: rs6275, rs1800497, DRD3: rs6280, DRD4: rs1800955, DBH: rs1611115, rs2519152, and in COMT: rs4680) and three variable number of tandem repeats (VNTRs in DRD4, upstream of DRD5, and in DAT1) were investigated for an association with regular leisure time exercise behavior. Materials and Methods. Data on exercise activities and at least one SNP/VNTR were available for 8,768 individuals aged 7 to 50 years old that were part of the Netherlands Twin Register. Exercise behavior was quantified as weekly metabolic equivalents of task (MET) spent on exercise activities. Mixed models were fitted in SPSS with genetic relatedness as a random effect. Results. None of the genetic variants were associated with exercise behavior (P > .02), despite sufficient power to detect small effects. Discussion and Conclusions. We did not confirm that allelic variants involved in dopaminergic function play a role in creating individual differences in exercise behavior. A plea is made for large genome-wide association studies to unravel the genetic pathways that affect this health-enhancing behavior. PMID:24734235

  5. Hesr1 knockout mice exhibit behavioral alterations through the dopaminergic nervous system.

    PubMed

    Fuke, Satoshi; Minami, Natsumi; Kokubo, Hiroki; Yoshikawa, Ayumu; Yasumatsu, Hiroshi; Sasagawa, Noboru; Saga, Yumiko; Tsukahara, Toshifumi; Ishiura, Shoichi

    2006-11-15

    The basic helix-loop-helix (bHLH) transcriptional factor Hesr1 gene (hairy and enhancer of split-related 1, also called Hey1/HRT1/CHF2/HERP2) has been identified and characterized as a member of the subfamily of hairy/Enhancer of split, and shown to be involved in cardiovascular and neural development. We report that HESR1 binds directly to a part of the 3' non-coding region of the human dopamine transporter (DAT1) gene and represses the endogenous DAT1 gene in HEK293 cells. To investigate functions of the HESR1 gene in the dopaminergic nervous system in vivo, we analyzed the expressions of dopamine-related genes in the postnatal day 0 whole brains of Hesr1 knockout mice by real-time RT-PCR analysis. Several dopamine-related genes, such as DAT, dopamine receptors D1, D2, D4, and D5, were significantly upregulated. Moreover, young adults of Hesr1 knockout mice showed a decrease in spontaneous locomotor activity and a reduction in exploratory behavior or behavioral responses to novelty in the open-field, and elevated plus-maze tests. These results indicate that the HESR1 gene is related to neuropsychiatric disorders and behavioral traits through the dopaminergic nervous system. PMID:16998899

  6. NANOMETER DIESEL EXHAUST PARTICLES ARE NEUROTOXIC TO DOPAMINERGIC NEURONS THROUGH MICROGLIAL ACTIVATION.

    EPA Science Inventory

    NANOMETER DIESEL EXHAUST PARTICLES ARE NEUROTOXIC TO DOPAMINERGIC NEURONS THROUGH MICROGLIAL ACTIVATION. M.L. Block1,2, X. Wu1, P. Zhong1, G. Li1, T. Wang1, J.S. Hong1 & B.Veronesi.2
    1The Laboratory of Pharmacology and Chemistry, NIEHS, RTP, NC and 2 National Health and Envi...

  7. Changes in dopamine availability in the nigrostriatal and mesocortical dopaminergic systems by gait in Parkinson's disease.

    PubMed

    Ouchi, Y; Kanno, T; Okada, H; Yoshikawa, E; Futatsubashi, M; Nobezawa, S; Torizuka, T; Tanaka, K

    2001-04-01

    The basal ganglia play a role in controlling movement during gait. The aim of the present study was to investigate changes in dopamine transporter (DAT) availability in the striatum and extrastriatal region in association with walking exercise in six normal subjects and seven age-matched unmedicated patients with Parkinson's disease. This was done by comparing DAT radioligand uptake in the dopaminergic projection areas after gait with that under the resting condition using a DAT probe, 11C-labelled 2-beta-carbomethoxy-3beta-(4-fluorophenyl) tropane ([11C]CFT) and PET. Physiological parameters were stable during and after gait in both groups. The regions of interest method for measuring differences in [11C]CFT uptake level and voxel-based statistical parametric mapping (SPM96) showed that [11C]CFT uptake in the striatum (specifically the putamen) was decreased by gait to a greater extent in normal subjects, whereas a significant reduction in [11C]CFT uptake was not found in the putamen but in the caudate and orbitofrontal cortex in Parkinson's disease patients. These results are the first in vivo evidence that DAT availability is reduced in the nigrostriatal projection area by basic human behaviour, i.e. gait. Alterations in this availability in Parkinson's disease suggested that shifted activation in the medial striatum and the mesocortical dopaminergic system might reflect the pathophysiology of parkinsonian gait. PMID:11287377

  8. Selenoprotein T Exerts an Essential Oxidoreductase Activity That Protects Dopaminergic Neurons in Mouse Models of Parkinson's Disease

    PubMed Central

    Boukhzar, Loubna; Hamieh, Abdallah; Cartier, Dorthe; Tanguy, Yannick; Alsharif, Ifat; Castex, Matthieu; Arabo, Arnaud; Hajji, Sana El; Bonnet, Jean-Jacques; Errami, Mohammed; Falluel-Morel, Anthony; Chagraoui, Abdeslam; Lihrmann, Isabelle

    2016-01-01

    Abstract Aims: Oxidative stress is central to the pathogenesis of Parkinson's disease (PD), but the mechanisms involved in the control of this stress in dopaminergic cells are not fully understood. There is increasing evidence that selenoproteins play a central role in the control of redox homeostasis and cell defense, but the precise contribution of members of this family of proteins during the course of neurodegenerative diseases is still elusive. Results: We demonstrated first that selenoprotein T (SelT) whose gene disruption is lethal during embryogenesis, exerts a potent oxidoreductase activity. In the SH-SY5Y cell model of dopaminergic neurons, both silencing and overexpression of SelT affected oxidative stress and cell survival. Treatment with PD-inducing neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone triggered SelT expression in the nigrostriatal pathway of wild-type mice, but provoked rapid and severe parkinsonian-like motor defects in conditional brain SelT-deficient mice. This motor impairment was associated with marked oxidative stress and neurodegeneration and decreased tyrosine hydroxylase activity and dopamine levels in the nigrostriatal system. Finally, in PD patients, we report that SelT is tremendously increased in the caudate putamen tissue. Innovation: These results reveal the activity of a novel selenoprotein enzyme that protects dopaminergic neurons against oxidative stress and prevents early and severe movement impairment in animal models of PD. Conclusions: Our findings indicate that selenoproteins such as SelT play a crucial role in the protection of dopaminergic neurons against oxidative stress and cell death, providing insight into the molecular underpinnings of this stress in PD. Antioxid. Redox Signal. 24, 557–574. PMID:26866473

  9. Association of gene polymorphisms encoding dopaminergic system components and platelet MAO-B activity with alcohol dependence and alcohol dependence-related phenotypes.

    PubMed

    Nedic Erjavec, Gordana; Nenadic Sviglin, Korona; Nikolac Perkovic, Matea; Muck-Seler, Dorotea; Jovanovic, Tanja; Pivac, Nela

    2014-10-01

    The present study aimed to evaluate the association of alcohol dependence and alcohol dependence-related phenotypes with platelet monoamine oxidase type B (MAO-B) activity, Val108/158Met of catechol-o-methyltransferase (COMT), variable number of tandem repeats (VNTR) in the third exon of dopamine receptor D4 (DRD4) gene, VNTR in the 3'-untranslated region of dopamine transporter (DAT) gene, -1021C/T of dopamine beta-hydroxylase (DBH) and MAO-B intron 13 polymorphisms. The study included 1270 Caucasian men and women of Croatian origin: 690 patients with alcohol dependence and 580 healthy controls. Patients with alcohol dependence were subdivided according to the presence or absence of withdrawal symptoms, aggressive behavior, severity of alcohol dependence, delirium tremens, comorbid depression, suicidal behavior, lifetime suicide attempt and early/late onset of alcohol abuse. The results, corrected for multiple testing, revealed increased platelet MAO-B activity in patients with alcohol dependence, subdivided into those with or without alcohol-related liver diseases, compared to control subjects (P<0.001). In addition, we found an increased frequency of the COMT Met/Met genotype among suicidal (P=0.002) and patients who attempted suicide (P<0.001) and an increased frequency of COMT Val/Val genotype in patients with an early onset of alcohol dependence (P=0.004). This study provides data from a sample of ethnically homogeneous unrelated Caucasian subjects for future meta-analyses and suggests that the increased platelet MAO-B activity might be used as independent peripheral indicator of alcohol dependence, while COMT Val108/158Met polymorphism is associated with increased suicidality and early onset of alcohol dependence. PMID:25035107

  10. Tiagabine Protects Dopaminergic Neurons against Neurotoxins by Inhibiting Microglial Activation

    PubMed Central

    Liu, Jie; Huang, Dongping; Xu, Jing; Tong, Jiabin; Wang, Zishan; Huang, Li; Yang, Yufang; Bai, Xiaochen; Wang, Pan; Suo, Haiyun; Ma, Yuanyuan; Yu, Mei; Fei, Jian; Huang, Fang

    2015-01-01

    Microglial activation and inflammation are associated with progressive neuronal apoptosis in neurodegenerative disorders such as Parkinson’s disease (PD). γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, has recently been shown to play an inhibitory role in the immune system. Tiagabine, a piperidine derivative, enhances GABAergic transmission by inhibiting GABA transporter 1 (GAT 1). In the present study, we found that tiagabine pretreatment attenuated microglial activation, provided partial protection to the nigrostriatal axis and improved motor deficits in a methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. The protective function of tiagabine was abolished in GAT 1 knockout mice that were challenged with MPTP. In an alternative PD model, induced by intranigral infusion of lipopolysaccharide (LPS), microglial suppression and subsequent neuroprotective effects of tiagabine were demonstrated. Furthermore, the LPS-induced inflammatory activation of BV-2 microglial cells and the toxicity of conditioned medium toward SH-SY5Y cells were inhibited by pretreatment with GABAergic drugs. The attenuation of the nuclear translocation of nuclear factor κB (NF-κB) and the inhibition of the generation of inflammatory mediators were the underlying mechanisms. Our results suggest that tiagabine acts as a brake for nigrostriatal microglial activation and that it might be a novel therapeutic approach for PD. PMID:26499517

  11. Endogenous 17β-estradiol is required for activity-dependent long-term potentiation in the striatum: interaction with the dopaminergic system

    PubMed Central

    Tozzi, Alessandro; de Iure, Antonio; Tantucci, Michela; Durante, Valentina; Quiroga-Varela, Ana; Giampà, Carmela; Di Mauro, Michela; Mazzocchetti, Petra; Costa, Cinzia; Di Filippo, Massimiliano; Grassi, Silvarosa; Pettorossi, Vito Enrico; Calabresi, Paolo

    2015-01-01

    17β-estradiol (E2), a neurosteroid synthesized by P450-aromatase (ARO), modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs) and dopamine (DA) receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP) in both medium spiny neurons (MSNs) and cholinergic interneurons (ChIs). Activation of a D1-like DA receptor/cAMP/PKA-dependent pathway restored LTP. In MSNs exogenous E2 reversed the effect of ARO inhibition. Also antagonism of M1 muscarinic receptors prevented the D1-like receptor-mediated restoration of LTP confirming a role for ChIs in controlling the E2-mediated LTP of MSNs. A novel striatal interaction, occurring between ERs and D1-like receptors in both MSNs and ChIs, might be critical to regulate basal ganglia physiology and to compensate synaptic alterations in Parkinson’s disease. PMID:26074768

  12. Endogenous 17β-estradiol is required for activity-dependent long-term potentiation in the striatum: interaction with the dopaminergic system.

    PubMed

    Tozzi, Alessandro; de Iure, Antonio; Tantucci, Michela; Durante, Valentina; Quiroga-Varela, Ana; Giampà, Carmela; Di Mauro, Michela; Mazzocchetti, Petra; Costa, Cinzia; Di Filippo, Massimiliano; Grassi, Silvarosa; Pettorossi, Vito Enrico; Calabresi, Paolo

    2015-01-01

    17β-estradiol (E2), a neurosteroid synthesized by P450-aromatase (ARO), modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs) and dopamine (DA) receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP) in both medium spiny neurons (MSNs) and cholinergic interneurons (ChIs). Activation of a D1-like DA receptor/cAMP/PKA-dependent pathway restored LTP. In MSNs exogenous E2 reversed the effect of ARO inhibition. Also antagonism of M1 muscarinic receptors prevented the D1-like receptor-mediated restoration of LTP confirming a role for ChIs in controlling the E2-mediated LTP of MSNs. A novel striatal interaction, occurring between ERs and D1-like receptors in both MSNs and ChIs, might be critical to regulate basal ganglia physiology and to compensate synaptic alterations in Parkinson's disease. PMID:26074768

  13. Substance P Exacerbates Dopaminergic Neurodegeneration through Neurokinin-1 Receptor-Independent Activation of Microglial NADPH Oxidase

    PubMed Central

    Chu, Chun-Hsien; Qian, Li; Chen, Shih-Heng; Wilson, Belinda; Oyarzabal, Esteban; Jiang, Lulu; Ali, Syed; Robinson, Bonnie; Kim, Hyoung-Chun

    2014-01-01

    Although dysregulated substance P (SP) has been implicated in the pathophysiology of Parkinson's disease (PD), how SP affects the survival of dopaminergic neurons remains unclear. Here, we found that mice lacking endogenous SP (TAC1−/−), but not those deficient in the SP receptor (neurokinin-1 receptor, NK1R), were more resistant to lipopolysaccharide (LPS)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigral dopaminergic neurodegeneration than wild-type controls, suggesting a NK1R-independent toxic action of SP. In vitro dose–response studies revealed that exogenous SP enhanced LPS- and 1-methyl-4-phenylpyridinium (MPP+)-induced dopaminergic neurodegeneration in a bimodal manner, peaking at submicromolar and subpicomolar concentrations, but was substantially less effective at intermediate concentrations. Mechanistically, the actions of submicromolar levels of SP were NK1R-dependent, whereas subpicomolar SP-elicited actions required microglial NADPH oxidase (NOX2), the key superoxide-producing enzyme, but not NK1R. Subpicomolar concentrations of SP activated NOX2 by binding to the catalytic subunit gp91phox and inducing membrane translocation of the cytosolic subunits p47phox and p67phox. The importance of NOX2 was further corroborated by showing that inhibition or disruption of NOX2 blocked subpicomolar SP-exacerbated neurotoxicity. Together, our findings revealed a critical role of microglial NOX2 in mediating the neuroinflammatory and dopaminergic neurodegenerative effects of SP, which may provide new insights into the pathogenesis of PD. PMID:25209287

  14. Histamine impairs midbrain dopaminergic development in vivo by activating histamine type 1 receptors

    PubMed Central

    2014-01-01

    Background Histamine (HA) regulates the sleep-wake cycle, synaptic plasticity and memory in adult mammals. Dopaminergic specification in the embryonic ventral midbrain (VM) coincides with increased HA brain levels. To study the effect of HA receptor stimulation on dopamine neuron generation, we administered HA to dopamine progenitors, both in vitro and in vivo. Results Cultured embryonic day 12 (E12) VM neural stem/progenitor cells expressed transcripts for HA receptors H1R, H2R and H3R. These undifferentiated progenitors increased intracellular calcium upon HA addition. In HA-treated cultures, dopamine neurons significantly decreased after activation of H1R. We performed intrauterine injections in the developing VM to investigate HA effects in vivo. HA administration to E12 rat embryos notably reduced VM Tyrosine Hydroxylase (TH) staining 2 days later, without affecting GABA neurons in the midbrain, or serotonin neurons in the mid-hindbrain boundary. qRT-PCR and Western blot analyses confirmed that several markers important for the generation and maintenance of dopaminergic lineage such as TH, Lmx1a and Lmx1b were significantly diminished. To identify the cell type susceptible to HA action, we injected embryos of different developmental stages, and found that neural progenitors (E10 and E12) were responsive, whereas differentiated dopaminergic neurons (E14 and E16) were not susceptible to HA actions. Proliferation was significantly diminished, whereas neuronal death was not increased in the VM after HA administration. We injected H1R or H2R antagonists to identify the receptor responsible for the detrimental effect of HA on dopaminergic lineage and found that activation of H1R was required. Conclusion These results reveal a novel action of HA affecting dopaminergic lineage during VM development. PMID:25112718

  15. GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function

    PubMed Central

    Porokuokka, Lauriina L.; Panhelainen, Anne; Kuure, Satu; Marshall, Pepin; Karalija, Nina; Härma, Mari-Anne; Vilenius, Carolina; Lilleväli, Kersti; Tekko, Triin; Mijatovic, Jelena; Pulkkinen, Nita; Jakobson, Madis; Jakobson, Maili; Ola, Roxana; Palm, Erik; Lindahl, Maria; Strömberg, Ingrid; Võikar, Vootele; Piepponen, T. Petteri; Saarma, Mart; Andressoo, Jaan-Olle

    2015-01-01

    Degeneration of nigrostriatal dopaminergic system is the principal lesion in Parkinson’s disease. Because glial cell line-derived neurotrophic factor (GDNF) promotes survival of dopamine neurons in vitro and in vivo, intracranial delivery of GDNF has been attempted for Parkinson’s disease treatment but with variable success. For improving GDNF-based therapies, knowledge on physiological role of endogenous GDNF at the sites of its expression is important. However, due to limitations of existing genetic model systems, such knowledge is scarce. Here, we report that prevention of transcription of Gdnf 3’UTR in Gdnf endogenous locus yields GDNF hypermorphic mice with increased, but spatially unchanged GDNF expression, enabling analysis of postnatal GDNF function. We found that increased level of GDNF in the central nervous system increases the number of adult dopamine neurons in the substantia nigra pars compacta and the number of dopaminergic terminals in the dorsal striatum. At the functional level, GDNF levels increased striatal tissue dopamine levels and augmented striatal dopamine release and re-uptake. In a proteasome inhibitor lactacystin-induced model of Parkinson’s disease GDNF hypermorphic mice were protected from the reduction in striatal dopamine and failure of dopaminergic system function. Importantly, adverse phenotypic effects associated with spatially unregulated GDNF applications were not observed. Enhanced GDNF levels up-regulated striatal dopamine transporter activity by at least five fold resulting in enhanced susceptibility to 6-OHDA, a toxin transported into dopamine neurons by DAT. Further, we report how GDNF levels regulate kidney development and identify microRNAs miR-9, miR-96, miR-133, and miR-146a as negative regulators of GDNF expression via interaction with Gdnf 3’UTR in vitro. Our results reveal the role of GDNF in nigrostriatal dopamine system postnatal development and adult function, and highlight the importance of correct

  16. Cocaine Increases Dopaminergic Neuron and Motor Activity via Midbrain α1 Adrenergic Signaling

    PubMed Central

    Goertz, Richard Brandon; Wanat, Matthew J; Gomez, Jorge A; Brown, Zeliene J; Phillips, Paul EM; Paladini, Carlos A

    2015-01-01

    Cocaine reinforcement is mediated by increased extracellular dopamine levels in the forebrain. This neurochemical effect was thought to require inhibition of dopamine reuptake, but cocaine is still reinforcing even in the absence of the dopamine transporter. Here, we demonstrate that the rapid elevation in dopamine levels and motor activity elicited by cocaine involves α1 receptor activation within the ventral midbrain. Activation of α1 receptors increases dopaminergic neuron burst firing by decreasing the calcium-activated potassium channel current (SK), as well as elevates dopaminergic neuron pacemaker firing through modulation of both SK and the hyperpolarization-activated cation currents (Ih). Furthermore, we found that cocaine increases both the pacemaker and burst-firing frequency of rat ventral-midbrain dopaminergic neurons through an α1 adrenergic receptor-dependent mechanism within the ventral tegmental area and substantia nigra pars compacta. These results demonstrate the mechanism underlying the critical role of α1 adrenergic receptors in the regulation of dopamine neurotransmission and behavior by cocaine. PMID:25374094

  17. Dopaminergic modulation of motor neuron activity and neuromuscular function in Drosophila melanogaster.

    PubMed

    Cooper, R L; Neckameyer, W S

    1999-02-01

    Dopamine is found in both neuronal and non-neuronal tissues in the larval stage of the fruit fly, Drosophila melanogaster, and functions as a signaling molecule in the nervous system. Although dopaminergic neurons in the central nervous system (CNS) were previously thought solely to be interneurons, recent studies suggest that dopamine may also act as a neuromodulator in humoral pathways. We examined both application of dopamine on intact larval CNS-segmental preparations and isolated neuromuscular junctions (NMJs). Dopamine rapidly decreased the rhythmicity of the CNS motor activity. Application of dopamine on neuromuscular preparations of the segmental muscles 6 and 7 resulted in a dose-responsive decrease in the excitatory junction potentials (EJPs). With the use of focal, macro-patch synaptic current recordings the quantal evoked transmission showed a depression of vesicular release at concentrations of 10 microM. Higher concentrations (1 mM) produced a rapid decrement in evoked vesicular release. Dopamine did not alter the shape of the spontaneous synaptic currents, suggesting that dopamine does not alter the postsynaptic muscle fiber receptiveness to the glutaminergic motor nerve transmission. The effects are presynaptic in causing a reduction in the number of vesicles that are stimulated to be released due to neural activity. PMID:10327610

  18. Subchronic Polychlorinated Biphenyl (Aroclor 1254) Exposure Produces Oxidative Damage and Neuronal Death of Ventral Midbrain Dopaminergic Systems

    PubMed Central

    Lee, Donna W.; Notter, Sarah A.; Thiruchelvam, Mona; Dever, Daniel P.; Fitzpatrick, Richard; Kostyniak, Paul J.; Cory-Slechta, Deborah A.; Opanashuk, Lisa A.

    2012-01-01

    Recent epidemiologic studies have demonstrated a link between organochlorine and pesticide exposure to an enhanced risk for neurodegenerative disorders such as Parkinson’s disease (PD). A common biological phenomenon underlying cell injury associated with both polychlorinated biphenyl (PCB) exposure and dopaminergic neurodegeneration during aging is oxidative stress (OS). In this study, we tested the hypothesis that oral PCB exposure, via food ingestion, impairs dopamine systems in the adult murine brain. We determined whether PCB exposure was associated with OS in dopaminergic neurons, a population of cells that selectively degenerate in PD. After 4 weeks of oral exposure to the PCB mixture Aroclor 1254, several congeners, mostly ortho substituted, accumulated throughout the brain. Significant increases in locomotor activity were observed within 2 weeks, which persisted after cessation of PCB exposure. Stereologic analyses revealed a significant loss of dopaminergic neurons within the substantia nigra and ventral tegmental area. However, striatal dopamine levels were elevated, suggesting that compensatory mechanisms exist to maintain dopamine homeostasis, which could contribute to the observed increases in locomotor activity following PCB exposure. Biochemical experiments revealed alterations in OS markers, including increases in SOD and HO-1 levels and the presence of oxidatively modified lipids and proteins. These findings were accompanied by elevated iron levels within the striatal and midbrain regions, perhaps due to the observed dysregulation of transferrin receptors and ferritin levels following PCB exposure. In this study, we suggest that both OS and the uncoupling of iron regulation contribute to dopamine neuron degeneration and hyperactivity following PCB exposure. PMID:22094459

  19. COUP-TFI controls activity-dependent tyrosine hydroxylase expression in adult dopaminergic olfactory bulb interneurons.

    PubMed

    Bovetti, Serena; Bonzano, Sara; Garzotto, Donatella; Giannelli, Serena Gea; Iannielli, Angelo; Armentano, Maria; Studer, Michèle; De Marchis, Silvia

    2013-12-01

    COUP-TFI is an orphan nuclear receptor acting as a strong transcriptional regulator in different aspects of forebrain embryonic development. In this study, we investigated COUP-TFI expression and function in the mouse olfactory bulb (OB), a highly plastic telencephalic region in which continuous integration of newly generated inhibitory interneurons occurs throughout life. OB interneurons belong to different populations that originate from distinct progenitor lineages. Here, we show that COUP-TFI is highly expressed in tyrosine hydroxylase (TH)-positive dopaminergic interneurons in the adult OB glomerular layer (GL). We found that odour deprivation, which is known to downregulate TH expression in the OB, also downregulates COUP-TFI in dopaminergic cells, indicating a possible correlation between TH- and COUP-TFI-activity-dependent action. Moreover, we demonstrate that conditional inactivation of COUP-TFI in the EMX1 lineage results in a significant reduction of both TH and ZIF268 expression in the GL. Finally, lentiviral vector-mediated COUP-TFI deletion in adult-generated interneurons confirmed that COUP-TFI acts cell-autonomously in the control of TH and ZIF268 expression. These data indicate that COUP-TFI regulates TH expression in OB cells through an activity-dependent mechanism involving ZIF268 induction and strongly argue for a maintenance rather than establishment function of COUP-TFI in dopaminergic commitment. Our study reveals a previously unknown role for COUP-TFI in the adult brain as a key regulator in the control of sensory-dependent plasticity in olfactory dopaminergic neurons. PMID:24227652

  20. Organotypic slice co-culture systems to study axon regeneration in the dopaminergic system ex vivo.

    PubMed

    Heine, Claudia; Franke, Heike

    2014-01-01

    Organotypic slice co-cultures are suitable tools to study axonal regeneration and development (growth or regrowth) of different projection systems of the CNS under ex vivo conditions.In this chapter, we describe in detail the reconstruction of the mesocortical and nigrostriatal dopaminergic projection system culturing tissue slices from the ventral tegmental area/substantia nigra (VTA/SN) with the prefrontal cortex (PFC) or the striatum (STR). The protocol includes the detailed slice preparation and incubation. Moreover, different application possibilities of the ex vivo model are mentioned; as an example, the substance treatment procedure and biocytin tracing are described to reveal the effect of applied substances on fiber outgrowth. PMID:24838961

  1. New facts and the concept of physiological regulation of the dopaminergic system function and its disorders.

    PubMed

    Krzymowski, T; Stefanczyk-Krzymowska, S

    2015-06-01

    We present the main results of the study and justification of our opinion on the role of dopamine (DA) retrograde transfer in the cavernous sinus in the regulation of the dopaminergic (DArgic) system activity. We are convinced that under physiological conditions DA - which is continuously retrograde transferred in the cavernous sinus from venous brain effluent to arterial blood supplying the brain and carried by the arterial blood to endothelial cells and perivascular astrocytes of striatal DArgic cell groups - can inhibit dopamine transporter (DAT) expression by a down-regulation mechanism. A new concept of the genesis of DArgic system dysfunction with involvement of DA retrograde transfer in the cavernous sinus is presented. We suggest that future research that aims to explain the genesis of hypo- or hyperfunction of the DArgic system, and DArgic system dysfunction causing Parkinson's disease, attention deficit hyperactivity disorder (ADHD), schizophrenia, and many other psychiatric disorders, must involve two areas: 1) the cavernous sinus, where DA is taken up, and transferred from the venous blood of the cavernous sinus to the arterial blood supplying the brain. To regulate this process pharmacologically, understanding the mechanism and explanation of what determines its course is necessary; 2) brain DArgic structures, whose activity is regulated primarily by the action of DAT. It is essential to clarify whether the expression of the DAT is regulated directly by DA reaching the presynaptic membrane or by any factor secreted by specific perivascular glial cells (astrocytes) under the influence of DA and DA metabolites. PMID:26084215

  2. HIV Subtypes B and C gp120 and Methamphetamine Interaction: Dopaminergic System Implicates Differential Neuronal Toxicity.

    PubMed

    Samikkannu, Thangavel; Rao, Kurapati V K; Salam, Abdul Ajees Abdul; Atluri, Venkata S R; Kaftanovskaya, Elena M; Agudelo, Marisela; Perez, Suray; Yoo, Changwon; Raymond, Andrea D; Ding, Hong; Nair, Madhavan P N

    2015-01-01

    HIV subtypes or clades differentially induce HIV-associated neurocognitive disorders (HAND) and substance abuse is known to accelerate HIV disease progression. The HIV-1 envelope protein gp120 plays a major role in binding and budding in the central nervous system (CNS) and impacts dopaminergic functions. However, the mechanisms utilized by HIV-1 clades to exert differential effects and the methamphetamine (METH)-associated dopaminergic dysfunction are poorly understood. We hypothesized that clade B and C gp120 structural sequences, modeling based analysis, dopaminergic effect, and METH potentiate neuronal toxicity in astrocytes. We evaluated the effect of clade B and C gp120 and/or METH on the DRD-2, DAT, CaMKs and CREBP transcription. Both the structural sequence and modeling studies demonstrated that clade B gp120 in V1-V4, α -2 and N-glycosylated sites are distinct from clade C gp120. The distinct structure and sequence variation of clade B gp120 differentially impact DRD-2, DAT, CaMK II and CaMK IV mRNA, protein and intracellular expression compared to clade C gp120. However, CREB transcription is upregulated by both clade B and C gp120, and METH co-treatment potentiated these effects. In conclusion, distinct structural sequences of HIV-1 clade B and C gp120 differentially regulate the dopaminergic pathway and METH potentiates neurotoxicity. PMID:26057350

  3. HIV Subtypes B and C gp120 and Methamphetamine Interaction: Dopaminergic System Implicates Differential Neuronal Toxicity

    PubMed Central

    Samikkannu, Thangavel; Rao, Kurapati V. K.; Salam, Abdul Ajees Abdul; Atluri, Venkata S. R.; Kaftanovskaya, Elena M.; Agudelo, Marisela; Perez, Suray; Yoo, Changwon; Raymond, Andrea D.; Ding, Hong; Nair, Madhavan P. N.

    2015-01-01

    HIV subtypes or clades differentially induce HIV-associated neurocognitive disorders (HAND) and substance abuse is known to accelerate HIV disease progression. The HIV-1 envelope protein gp120 plays a major role in binding and budding in the central nervous system (CNS) and impacts dopaminergic functions. However, the mechanisms utilized by HIV-1 clades to exert differential effects and the methamphetamine (METH)-associated dopaminergic dysfunction are poorly understood. We hypothesized that clade B and C gp120 structural sequences, modeling based analysis, dopaminergic effect, and METH potentiate neuronal toxicity in astrocytes. We evaluated the effect of clade B and C gp120 and/or METH on the DRD-2, DAT, CaMKs and CREBP transcription. Both the structural sequence and modeling studies demonstrated that clade B gp120 in V1-V4, α -2 and N-glycosylated sites are distinct from clade C gp120. The distinct structure and sequence variation of clade B gp120 differentially impact DRD-2, DAT, CaMK II and CaMK IV mRNA, protein and intracellular expression compared to clade C gp120. However, CREB transcription is upregulated by both clade B and C gp120, and METH co-treatment potentiated these effects. In conclusion, distinct structural sequences of HIV-1 clade B and C gp120 differentially regulate the dopaminergic pathway and METH potentiates neurotoxicity. PMID:26057350

  4. Activity enhances dopaminergic long-duration response in Parkinson disease

    PubMed Central

    Auinger, Peggy; Fahn, Stanley; Oakes, David; Shoulson, Ira; Kieburtz, Karl; Rudolph, Alice; Marek, Kenneth; Seibyl, John; Lang, Anthony; Olanow, C. Warren; Tanner, Caroline; Schifitto, Giovanni; Zhao, Hongwei; Reyes, Lydia; Shinaman, Aileen; Comella, Cynthia L.; Goetz, Christopher; Blasucci, Lucia M.; Samanta, Johan; Stacy, Mark; Williamson, Kelli; Harrigan, Mary; Greene, Paul; Ford, Blair; Moskowitz, Carol; Truong, Daniel D.; Pathak, Mayank; Jankovic, Joseph; Ondo, William; Atassi, Farah; Hunter, Christine; Jacques, Carol; Friedman, Joseph H.; Lannon, Margaret; Russell, David S.; Jennings, Danna; Fussell, Barbara; Standaert, David; Schwarzschild, Michael A.; Growdon, John H.; Tennis, Marsha; Gauthier, Serge; Panisset, Michel; Hall, Jean; Gancher, Stephen; Hammerstad, John P.; Stone, Claudia; Alexander-Brown, Barbara; Factor, Stewart A.; Molho, Eric; Brown, Diane; Evans, Sharon; Clark, Jeffrey; Manyam, Bala; Simpson, Patricia; Wulbrecht, Brian; Whetteckey, Jacqueline; Martin, Wayne; Roberts, Ted; King, Pamela; Hauser, Robert; Zesiewicz, Theresa; Gauger, Lisa; Trugman, Joel; Wooten, G. Frederick; Rost-Ruffner, Elke; Perlmutter, Joel; Racette, Brad A.; Suchowersky, Oksana; Ranawaya, Ranjit; Wood, Susan; Pantella, Carol; Kurlan, Roger; Richard, Irene; Pearson, Nancy; Caviness, John N.; Adler, Charles; Lind, Marlene; Simuni, Tanya; Siderowf, Andrew; Colcher, Amy; Lloyd, Mary; Weiner, William; Shulman, Lisa; Koller, William; Lyons, Kelly; Feldman, Robert G.; Saint-Hilaire, Marie H.; Ellias, Samuel; Thomas, Cathi-Ann; Juncos, Jorge; Watts, Ray; Partlow, Anna; Tetrud, James; Togasaki, Daniel M.; Stewart, Tracy; Mark, Margery H.; Sage, Jacob I.; Caputo, Debbie; Gould, Harry; Rao, Jayaraman; McKendrick, Ann; Brin, Mitchell; Danisi, Fabio; Benabou, Reina; Hubble, Jean; Paulson, George W.; Reider, Carson; Birnbaum, Alex; Miyasaki, Janis; Johnston, Lisa; So, Julie; Pahwa, Rajesh; Dubinsky, Richard M.; Wszolek, Zbigniew; Uitti, Ryan; Turk, Margaret; Tuite, Paul; Rottenberg, David; Hansen, Joy; Ramos, Serrano; Waters, Cheryl; Lew, Mark; Welsh, Mickie; Kawai, Connie; O'Brien, Christopher; Kumar, Rajeev; Seeberger, Lauren; Judd, Deborah; Barclay, C. Lynn; Grimes, David A.; Sutherland, Laura; Dawson, Ted; Reich, Stephen; Dunlop, Rebecca; Albin, Roger; Frey, Kirk; Wernette, Kristine; Fahn, Stanley; Oakes, David; Shoulson, Ira; Kieburtz, Karl; Rudolph, Alice; Marek, Kenneth; Seibyl, John; Lang, Anthony; Olanow, C. Warren; Tanner, Caroline; Schifitto, Giovanni; Zhao, Hongwei; Reyes, Lydia; Shinaman, Aileen; Comella, Cynthia L.; Goetz, Christopher; Blasucci, Lucia M.; Samanta, Johan; Stacy, Mark; Williamson, Kelli; Harrigan, Mary; Greene, Paul; Ford, Blair; Moskowitz, Carol; Truong, Daniel D.; Pathak, Mayank; Jankovic, Joseph; Ondo, William; Atassi, Farah; Hunter, Christine; Jacques, Carol; Friedman, Joseph H.; Lannon, Margaret; Russell, David S.; Jennings, Danna; Fussell, Barbara; Standaert, David; Schwarzschild, Michael A.; Growdon, John H.; Tennis, Marsha; Gauthier, Serge; Panisset, Michel; Hall, Jean; Gancher, Stephen; Hammerstad, John P.; Stone, Claudia; Alexander-Brown, Barbara; Factor, Stewart A.; Molho, Eric; Brown, Diane; Evans, Sharon; Clark, Jeffrey; Manyam, Bala; Simpson, Patricia; Wulbrecht, Brian; Whetteckey, Jacqueline; Martin, Wayne; Roberts, Ted; King, Pamela; Hauser, Robert; Zesiewicz, Theresa; Gauger, Lisa; Trugman, Joel; Wooten, G. Frederick; Rost-Ruffner, Elke; Perlmutter, Joel; Racette, Brad A.; Suchowersky, Oksana; Ranawaya, Ranjit; Wood, Susan; Pantella, Carol; Kurlan, Roger; Richard, Irene; Pearson, Nancy; Caviness, John N.; Adler, Charles; Lind, Marlene; Simuni, Tanya; Siderowf, Andrew; Colcher, Amy; Lloyd, Mary; Weiner, William; Shulman, Lisa; Koller, William; Lyons, Kelly; Feldman, Robert G.; Saint-Hilaire, Marie H.; Ellias, Samuel; Thomas, Cathi-Ann; Juncos, Jorge; Watts, Ray; Partlow, Anna; Tetrud, James; Togasaki, Daniel M.; Stewart, Tracy; Mark, Margery H.; Sage, Jacob I.; Caputo, Debbie; Gould, Harry; Rao, Jayaraman; McKendrick, Ann; Brin, Mitchell; Danisi, Fabio; Benabou, Reina; Hubble, Jean; Paulson, George W.; Reider, Carson; Birnbaum, Alex; Miyasaki, Janis; Johnston, Lisa; So, Julie; Pahwa, Rajesh; Dubinsky, Richard M.; Wszolek, Zbigniew; Uitti, Ryan; Turk, Margaret; Tuite, Paul; Rottenberg, David; Hansen, Joy; Ramos, Serrano; Waters, Cheryl; Lew, Mark; Welsh, Mickie; Kawai, Connie; O'Brien, Christopher; Kumar, Rajeev; Seeberger, Lauren; Judd, Deborah; Barclay, C. Lynn; Grimes, David A.; Sutherland, Laura; Dawson, Ted; Reich, Stephen; Dunlop, Rebecca; Albin, Roger; Frey, Kirk; Wernette, Kristine; Mendis, Tilak

    2012-01-01

    Objective: We tested the hypothesis that dopamine-dependent motor learning mechanism underlies the long-duration response to levodopa in Parkinson disease (PD) based on our studies in a mouse model. By data-mining the motor task performance in dominant and nondominant hands of the subjects in a double-blind randomized trial of levodopa therapy, the effects of activity and dopamine therapy were examined. Methods: We data-mined the Earlier versus Later Levodopa Therapy in Parkinson's Disease (ELLDOPA) study published in 2005 and performed statistical analysis comparing the effects of levodopa and dominance of handedness over 42 weeks. Results: The mean change in finger-tapping counts from baseline before the initiation of therapy to predose at 9 weeks and 40 weeks increased more in the dominant compared to nondominant hand in levodopa-treated subjects in a dose-dependent fashion. There was no significant difference in dominant vs nondominant hands in the placebo group. The short-duration response assessed by the difference of postdose performance compared to predose performance at the same visit did not show any significant difference between dominant vs nondominant hands. Conclusions: Active use of the dominant hand and dopamine replacement therapy produces synergistic effect on long-lasting motor task performance during “off” medication state. Such effect was confined to dopamine-responsive symptoms and not seen in dopamine-resistant symptoms such as gait and balance. We propose that long-lasting motor learning facilitated by activity and dopamine is a form of disease modification that is often seen in trials of medications that have symptomatic effects. PMID:22459675

  5. Functional Interplay between Dopaminergic and Serotonergic Neuronal Systems during Development and Adulthood

    PubMed Central

    Dymecki, Susan M.

    2016-01-01

    The complex integration of neurotransmitter signals in the nervous system contributes to the shaping of behavioral and emotional constitutions throughout development. Imbalance among these signals may result in pathological behaviors and psychiatric illnesses. Therefore, a better understanding of the interplay between neurotransmitter systems holds potential to facilitate therapeutic development. Of particular clinical interest are the dopaminergic and serotonergic systems, as both modulate a broad array of behaviors and emotions and have been implicated in a wide range of affective disorders. Here we review evidence speaking to an interaction between the dopaminergic and serotonergic neuronal systems across development. We highlight data stemming from developmental, functional, and clinical studies, reflecting the importance of this transmonoaminergic interplay. PMID:25747116

  6. Activation of CNTF/CNTFRα signaling pathway by hRheb(S16H) transduction of dopaminergic neurons in vivo.

    PubMed

    Jeong, Kyoung Hoon; Nam, Jin Han; Jin, Byung Kwan; Kim, Sang Ryong

    2015-01-01

    Ciliary neurotrophic factor (CNTF) is one of representative neurotrophic factors for the survival of dopaminergic neurons. Its effects are primarily mediated via CNTF receptor α (CNTFRα). It is still unclear whether the levels of CNTFRα change in the substantia nigra of Parkinson's disease (PD) patients, but CNTF expression shows the remarkable decrease in dopaminergic neurons in the substantia nigra pars compacta (SNpc), suggesting that the support of CNTF/CNTFRα signaling pathway may be a useful neuroprotective strategy for the nigrostriatal dopaminergic projection in the adult brain. Here, we report that transduction of rat SNpc dopaminergic neurons by adeno-associated virus with a gene encoding human ras homolog enriched in brain (hRheb), with an S16H mutation [hRheb(S16H)], significantly upregulated the levels of both CNTF and CNTFRα in dopaminergic neurons. Moreover, the hRheb(S16H)-activated CNTF/CNTFRα signaling pathway was protective against 1-methyl-4-phenylpyridinium-induced neurotoxicity in the nigrostriatal dopaminergic projections. These results suggest that activation of CNTF/CNTFRα signaling pathway by specific gene delivery such as hRheb(S16H) may have therapeutic potential in the treatment of PD. PMID:25799580

  7. Activity-dependent regulation of NMDA receptors in substantia nigra dopaminergic neurones.

    PubMed

    Wild, Angela R; Jones, Susan; Gibb, Alasdair J

    2014-02-15

    N-Methyl-d-aspartate receptors (NMDARs) are Ca(2+)-permeable glutamate receptors that play a critical role in synaptic plasticity and promoting cell survival. However, overactive NMDARs can trigger cell death signalling pathways and have been implicated in substantia nigra pars compacta (SNc) pathology in Parkinson's disease. Calcium ion influx through NMDARs recruits Ca(2+)-dependent proteins that can regulate NMDAR activity. The surface density of NMDARs can also be regulated dynamically in response to receptor activity via Ca(2+)-independent mechanisms. We have investigated the activity-dependent regulation of NMDARs in SNc dopaminergic neurones. Repeated whole-cell agonist applications resulted in a decline in the amplitude of NMDAR currents (current run-down) that was use dependent and not readily reversible. Run-down was reduced by increasing intracellular Ca(2+) buffering or by reducing Ca(2+) influx but did not appear to be mediated by the same regulatory proteins that cause Ca(2+)-dependent run-down in hippocampal neurones. The NMDAR current run-down may be mediated in part by a Ca(2+)-independent mechanism, because intracellular dialysis with a dynamin-inhibitory peptide reduced run-down, suggesting a role for clathrin-mediated endocytosis in the regulation of the surface density of receptors. Synaptic NMDARs were also subject to current run-down during repeated low-frequency synaptic stimulation in a Ca(2+)-dependent but dynamin-independent manner. Thus, we report, for the first time, regulation of NMDARs in SNc dopaminergic neurones by changes in intracellular Ca(2+) at both synaptic and extrasynaptic sites and provide evidence for activity-dependent changes in receptor trafficking. These mechanisms may contribute to intracellular Ca(2+) homeostasis in dopaminergic neurones by limiting Ca(2+) influx through the NMDAR. PMID:24344168

  8. Effects of HZE particle on the nigrostriatal dopaminergic system in a future Mars mission.

    PubMed

    Koike, Yu; Frey, M A; Sahiar, F; Dodge, R; Mohler, S

    2005-02-01

    Because of long duration travel outside the Earth's magnetic field, the effect of iron-rich high charge and energy (HZE) particles in Galactic Cosmic Rays on human body is the major concern in radiation protection. Recently attention has been directed to effects on the central nervous system in addition to mutagenic effects. In particular, a reduction in striatal dopamine content on nigrostriatal dopaminergic system has been reported by investigators using accelerated iron ions in ground-based mammalian studies. In addition, studies of the pathophysiology of Parkinson's disease demonstrated that excess iron cause a reduction in the dopamine content in the substantia nigra. This suggests an intriguing possibility to explain the selective detrimental effects of HZE particles on the dopaminergic system. Should these particles have biochemical effects, possible options for countermeasures are: (1) nutritional prevention, (2) medication, and (3) surgical placement of a stimulator electrode at a specific anatomic site in the basal ganglia. PMID:15754475

  9. Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice.

    PubMed

    Sidor, M M; Spencer, S M; Dzirasa, K; Parekh, P K; Tye, K M; Warden, M R; Arey, R N; Enwright, J F; Jacobsen, J P R; Kumar, S; Remillard, E M; Caron, M G; Deisseroth, K; McClung, C A

    2015-11-01

    Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here, we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night. Mood-cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels and dopamine synthesis. To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviors in ClockΔ19 mice. Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behavior. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder. PMID:25560763

  10. Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice

    PubMed Central

    Sidor, Michelle M.; Spencer, Sade M.; Dzirasa, Kafui; Parekh, Puja K.; Tye, Kay M.; Warden, Melissa R.; Arey, Rachel N.; Enwright, John F; Jacobsen, Jacob PR; Kumar, Sunil; Remillard, Erin M; Caron, Marc G.; Deisseroth, Karl; McClung, Colleen A

    2014-01-01

    Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night. Mood cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels, and dopamine synthesis. To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviours in ClockΔ19 mice. Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behaviour. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder. PMID:25560763

  11. Behavioral Functions of the Mesolimbic Dopaminergic System: an Affective Neuroethological Perspective

    PubMed Central

    Alcaro, Antonio; Huber, Robert; Panksepp, Jaak

    2008-01-01

    The mesolimbic dopaminergic (ML-DA) system has been recognized for its central role in motivated behaviors, various types of reward, and, more recently, in cognitive processes. Functional theories have emphasized DA's involvement in the orchestration of goal-directed behaviors, and in the promotion and reinforcement of learning. The affective neuroethological perspective presented here, views the ML-DA system in terms of its ability to activate an instinctual emotional appetitive state (SEEKING) evolved to induce organisms to search for all varieties of life-supporting stimuli and to avoid harms. A description of the anatomical framework in which the ML system is embedded is followed by the argument that the SEEKING disposition emerges through functional integration of ventral basal ganglia (BG) into thalamocortical activities. Filtering cortical and limbic input that spread into BG, DA transmission promotes the “release” of neural activity patterns that induce active SEEKING behaviors when expressed at the motor level. Reverberation of these patterns constitutes a neurodynamic process for the inclusion of cognitive and perceptual representations within the extended networks of the SEEKING urge. In this way, the SEEKING disposition influences attention, incentive salience, associative learning, and anticipatory predictions. In our view, the rewarding properties of drugs of abuse are, in part, caused by the activation of the SEEKING disposition, ranging from appetitive drive to persistent craving depending on the intensity of the affect. The implications of such a view for understanding addiction are considered, with particular emphasis on factors predisposing individuals to develop compulsive drug seeking behaviors. PMID:17905440

  12. Evidence That GABA Mediates Dopaminergic and Serotonergic Pathways Associated with Locomotor Activity in Juvenile Chinook Salmon (Oncorhynchus tshawytscha)

    USGS Publications Warehouse

    Clements, S.; Schreck, C.B.

    2004-01-01

    The authors examined the control of locomotor activity in juvenile salmon (Oncorhynchus tshawytscha) by manipulating 3 neurotransmitter systems-gamma-amino-n-butyric acid (GABA), dopamine, and serotonin-as well as the neuropeptide corticotropin releasing hormone (CRH). Intracerebroventricular (ICV) injections of CRH and the GABAAagonist muscimol stimulated locomotor activity. The effect of muscimol was attenuated by administration of a dopamine receptor antagonist, haloperidol. Conversely, the administration of a dopamine uptake inhibitor (4???,4??? -difluoro-3-alpha-[diphenylmethoxy] tropane hydrochloride [DUI]) potentiated the effect of muscimol. They found no evidence that CRH-induced hyperactivity is mediated by dopaminergic systems following concurrent injections of haloperidol or DUI with CRH. Administration of muscimol either had no effect or attenuated the locomotor response to concurrent injections of CRH and fluoxetine, whereas the GABAA antagonist bicuculline methiodide potentiated the effect of CRH and fluoxetine.

  13. In Search of Concomitant Alterations of Dopaminergic and Neurotensinergic Systems in Stress Conditions.

    PubMed

    Rodríguez de Lores Arnaiz, Georgina; Antonelli, Marta C

    2016-02-01

    The aim of the present article is to review experimental evidence which suggest joint involvement of both the dopaminergic and neurotensinergic systems in stress conditions. At present, the concept of stress refers to an environmental demand exceeding the normal regulatory ability of an organism, particularly during unpredictable and uncontrollable situations. Chronic stress yields devastating effects including cognitive and working memory dysfunctions, for which neurotransmission mediated by the catecholamines dopamine and noradrenaline is crucial. Catecholamine synthesis depends on the rate-limiting enzyme, tyrosine hydroxylase, whose expression is associated with working memory and the response to chronic stress. Neurotensin is a tridecapeptide widely distributed in the nervous system, at both central and peripheral levels, which behaves as a neurotransmitter or neuromodulator. It mediates diverse biological actions including reward, locomotion, pain modulation and stress. Neurotensin and its high affinity NTS1 receptor are densely localized in areas that process emotion (amygdala nucleus), cognition (such as hippocampal nuclei and cortical areas) and the response to stress (hypothalamic nucleus). Experimental evidence indicates a crosstalk between the dopaminergic and the neurotensinergic systems either from an anatomical or a biochemical point of view. It is suggested that a concomitant alteration of dopaminergic and neurotensinergic systems takes place in diverse stress conditions. PMID:26869038

  14. Prothrombin Kringle-2: A Potential Inflammatory Pathogen in the Parkinsonian Dopaminergic System

    PubMed Central

    Leem, Eunju; Jeong, Kyoung Hoon; Won, So-Yoon

    2016-01-01

    Although accumulating evidence suggests that microglia-mediated neuroinflammation may be crucial for the initiation and progression of Parkinson's disease (PD), and that the control of neuroinflammation may be a useful strategy for preventing the degeneration of nigrostriatal dopaminergic (DA) projections in the adult brain, it is still unclear what kinds of endogenous biomolecules initiate microglial activation, consequently resulting in neurodegeneration. Recently, we reported that the increase in the levels of prothrombin kringle-2 (pKr-2), which is a domain of prothrombin that is generated by active thrombin, can lead to disruption of the nigrostriatal DA projection. This disruption is mediated by neurotoxic inflammatory events via the induction of microglial Toll-like receptor 4 (TLR4) in vivo , thereby resulting in less neurotoxicity in TLR4-deficient mice. Moreover, inhibition of microglial activation following minocycline treatment, which has anti-inflammatory activity, protects DA neurons from pKr-2-induced neurotoxicity in the substantia nigra (SN) in vivo. We also found that the levels of pKr-2 and microglial TLR4 were significantly increased in the SN of PD patients compared to those of age-matched controls. These observations suggest that there may be a correlation between pKr-2 and microglial TLR4 in the initiation and progression of PD, and that inhibition of pKr-2-induced microglial activation may be protective against the degeneration of the nigrostriatal DA system in vivo. To describe the significance of pKr-2 overexpression, which may have a role in the pathogenesis of PD, we have reviewed the mechanisms of pKr-2-induced microglial activation, which results in neurodegeneration in the SN of the adult brain. PMID:27574481

  15. Prothrombin Kringle-2: A Potential Inflammatory Pathogen in the Parkinsonian Dopaminergic System.

    PubMed

    Leem, Eunju; Jeong, Kyoung Hoon; Won, So-Yoon; Shin, Won-Ho; Kim, Sang Ryong

    2016-08-01

    Although accumulating evidence suggests that microglia-mediated neuroinflammation may be crucial for the initiation and progression of Parkinson's disease (PD), and that the control of neuroinflammation may be a useful strategy for preventing the degeneration of nigrostriatal dopaminergic (DA) projections in the adult brain, it is still unclear what kinds of endogenous biomolecules initiate microglial activation, consequently resulting in neurodegeneration. Recently, we reported that the increase in the levels of prothrombin kringle-2 (pKr-2), which is a domain of prothrombin that is generated by active thrombin, can lead to disruption of the nigrostriatal DA projection. This disruption is mediated by neurotoxic inflammatory events via the induction of microglial Toll-like receptor 4 (TLR4) in vivo , thereby resulting in less neurotoxicity in TLR4-deficient mice. Moreover, inhibition of microglial activation following minocycline treatment, which has anti-inflammatory activity, protects DA neurons from pKr-2-induced neurotoxicity in the substantia nigra (SN) in vivo. We also found that the levels of pKr-2 and microglial TLR4 were significantly increased in the SN of PD patients compared to those of age-matched controls. These observations suggest that there may be a correlation between pKr-2 and microglial TLR4 in the initiation and progression of PD, and that inhibition of pKr-2-induced microglial activation may be protective against the degeneration of the nigrostriatal DA system in vivo. To describe the significance of pKr-2 overexpression, which may have a role in the pathogenesis of PD, we have reviewed the mechanisms of pKr-2-induced microglial activation, which results in neurodegeneration in the SN of the adult brain. PMID:27574481

  16. The effects of dihydropyridine compounds in behavioural tests of dopaminergic activity.

    PubMed Central

    Bourson, A.; Gower, A. J.; Mir, A. K.; Moser, P. C.

    1989-01-01

    1. The effects of the dihydropyridine calcium channel blocker nifedipine and the activator Bay K 8644 were investigated in different behavioural tests involving dopaminergic systems. These were the discriminative stimulus induced by amphetamine, rotational behaviour in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions and apomorphine-induced yawning in rats. 2. The yawning induced by apomorphine (40 micrograms kg-1 s.c.) was significantly potentiated by nifedipine (5-10 mgkg-1 i.p.). Bay K 8644 (0.05-0.5 mgkg-1 i.p.) dose-dependently inhibited yawning induced by apomorphine (80 micrograms kg-1 s.c.) and, at 0.4 mgkg-1, inhibited the nifedipine potentiation of apomorphine-induced yawning. In contrast to their effects on apomorphine-induced yawning, nifedipine and Bay K 8644 had no effect on apomorphine-induced penile erection. 3. Bay K 8644 (0.06-0.5 mgkg-1 i.p.) and nifedipine (5-20 mgkg-1 i.p.) had no dose-related effect on the discrimination performance of rats trained to discriminate amphetamine from saline. However, nifedipine dose-dependently reduced the response rate of amphetamine-treated rats. Bay K 8644 had no effect on this measure except at high doses that also caused disruption. 4. Neither nifedipine (5-10 mgkg-1 i.p.) nor Bay K 8644 (0.06-0.5 mgkg-1 i.p.) affected the turning behaviour induced by amphetamine (1 mgkg-1 i.p.) in rats with unilateral 6-OHDA lesion of the medial forebrain bundle, and did not induce turning themselves. 5. As the dihydropyridine compounds affected apomorphine-induced yawning but not penile erection, and did not affect amphetamine-induced rotation or drug discrimination, it seems unlikely that they are affecting dopamine release in vivo. PMID:2482105

  17. Working memory training impacts the mean diffusivity in the dopaminergic system.

    PubMed

    Takeuchi, Hikaru; Taki, Yasuyuki; Nouchi, Rui; Hashizume, Hiroshi; Sekiguchi, Atsushi; Kotozaki, Yuka; Nakagawa, Seishu; Miyauchi, Carlos Makoto; Sassa, Yuko; Kawashima, Ryuta

    2015-11-01

    Dopaminergic transmission plays a critical role in working memory (WM). Mean diffusivity (MD) is a sensitive and unique neuroimaging tool for detecting microstructural differences particularly in the areas of the dopaminergic system. Despite previous investigation of the effects of WM training (WMT) on dopamine receptor binding potentials, the effects of WMT on MD remain unknown. In this study, we investigated these effects in young adult subjects who either underwent WMT or received no intervention for 4 weeks. Before and after the intervention or no-intervention periods, subjects underwent scanning sessions in diffusion-weighted imaging to measure MD. Compared with no intervention, WMT resulted in an increase in MD in the bilateral caudate, right putamen, left dorsolateral prefrontal cortex (DLPFC), right anterior cingulate cortex (ACC), right substantia nigra, and ventral tegmental area. Furthermore, the increase in performance on WMT tasks was significantly positively correlated with the mean increase in MD in the clusters of the left DLPFC and of the right ACC. These results suggest that WMT caused microstructural changes in the regions of the dopaminergic system in a way that is usually interpreted as a reduction in neural components. PMID:25023736

  18. GABAergic Afferents activate both GABAA and GABAB receptors in mouse substantia nigra dopaminergic neurons in vivo

    PubMed Central

    Brazhnik, Elena; Shah, Fulva; Tepper, James M.

    2008-01-01

    Most in vivo electrophysiological studies of substantia nigra have employed rats. With the recent proliferation of the use of mice for in vitro neurophysiological studies due to the availability of various genetically modified strains to identify the roles of various channels and proteins in neuronal function, it is crucial to obtain data on in vivo responses in mice to verify that the in vitro results reflect functioning of systems comparable to those that have been well studied in rat. Inhibitory responses of rat nigral dopaminergic neurons by stimulation of afferents from striatum, globus pallidus or pars reticulata have been shown to be mediated predominantly or exclusively by GABAA receptors. This is puzzling given the substantial expression of GABAB receptors and the ubiquitous appearance of GABAB synaptic responses in rat dopaminergic neurons in vitro. In the present study we studied electrically evoked GABAergic inhibition in nigral dopaminergic neurons in C57BL/6J mice. Stimulation of the three major GABAergic inputs elicited stronger and longer lasting inhibitory responses than those seen in rats. The early inhibition was GABAA mediated, whereas the later component, absent in rats, was GABAB mediated and selectively enhanced by GABA uptake inhibition. Striatal-evoked inhibition exhibited a slower onset and a weaker initial component compared to inhibition from globus pallidus or substantia nigra pars reticulata. These results are discussed with respect to differences in the size and neuronal density of the rat and mouse brain, and the different sites of synaptic contact of the synapses from the three GABAergic afferents. PMID:18842898

  19. Neuromelanin activates microglia and induces degeneration of dopaminergic neurons: implications for progression of Parkinson's disease

    PubMed Central

    Zhang, Wei; Phillips, Kester; Wielgus, Albert R.; Liu, Jie; Albertini, Alberto; Zucca, Fabio A.; Faust, Rudolph; Qian, Steven Y.; Miller, David S.; Chignell, Colin F.; Wilson, Belinda; Jackson-Lewis, Vernice; Przedborski, Serge; Joset, Danielle; Loike, John; Hong, Jau-Shyong; Sulzer, David; Zecca, Luigi

    2013-01-01

    In Parkinson's disease (PD), there is a progressive loss of neuromelanin (NM)-containing dopamine (DA) neurons in substantia nigra (SN) which is associated with microgliosis and presence of extracellular NM. Herein, we have investigated the interplay between microglia and human NM on the degeneration of SN dopaminergic neurons. Although NM particles are phagocytised and degraded by microglia within minutes in vitro, extracellular NM particles induce microglial activation and ensuing production of superoxide, nitric oxide (NO), hydrogen peroxide (H2O2), and pro-inflammatory factors. Furthermore, NM produces, in a microglia-depended manner, neurodegeneration in primary ventral midbrain cultures. Neurodegeneration was effectively attenuated with microglia derived from mice deficient in macrophage antigen complex-1 (Mac-1), a microglial integrin receptor involved in the initiation of phagocytosis. Neuronal loss was also attenuated with microglia derived from mice deficient in phagocytic oxidase (PHOX), a subunit of NADPH oxidase, that is responsible for superoxide and H2O2 production, or apocyanin, a NADPH oxidase inhibitor. In vivo, NM injected into rat SN produces microgliosis and a loss of tyrosine hydroxylase (TH) neurons. Thus, these results show that extracellular NM can activate microglia, which in turn, may induce dopaminergic neurodegeneration in PD. Our study may have far-reaching implications, both pathogenic and therapeutic. PMID:19957214

  20. Synergistic effect of 5-HT1A and σ1 receptor activation on prefrontal dopaminergic transmission under circulating steroid deficiency.

    PubMed

    Hiramatsu, Naoki; Ago, Yukio; Hasebe, Shigeru; Nishimura, Akira; Mori, Kazuya; Takuma, Kazuhiro; Matsuda, Toshio

    2013-12-01

    Serotonin (5-HT)1A and σ1 receptors have been implicated in psychiatric disorders. We previously found that combined 5-HT reuptake inhibition and σ1 receptor activation has a synergistic effect on prefrontal dopaminergic transmission in adrenalectomized/castrated mice lacking circulating steroid hormones. In the present study, we examined the mechanisms underlying this neurochemical synergism. Systemic administration of fluvoxamine, a selective 5-HT reuptake inhibitor with agonistic activity towards the σ1 receptor, increased prefrontal dopamine (DA) levels, and adrenalectomy/castration potentiated this fluvoxamine-induced increase in DA. This enhancement of DA release was blocked by WAY100635 (a 5-HT1A receptor antagonist), but not by ritanserin (a 5-HT2 receptor antagonist), azasetron (a 5-HT3 receptor antagonist) or SB269970 (a 5-HT7 receptor antagonist). Individually, osemozotan (a 5-HT1A receptor agonist) and (+)-SKF-10,047 (a σ1 receptor agonist) did not alter prefrontal monoamine levels in adrenalectomized/castrated and sham-operated mice differentially. In contrast, co-administration of these drugs increased prefrontal DA levels to a greater extent in adrenalectomized/castrated mice than in sham-operated animals. Furthermore, co-administration of osemozotan and (+)-SKF-10,047 increased expression of the neuronal activity marker c-Fos in the ventral tegmental area of adrenalectomized/castrated mice, but not in sham-operated animals. These findings suggest that combined activation of 5-HT1A and σ1 receptors has a synergistic effect on prefrontal dopaminergic transmission under circulating steroid deficiency, and that this interaction may play an important role in the regulation of the prefrontal DA system. PMID:23851260

  1. Motor impairments and neurochemical changes after unilateral 6-hydroxydopamine lesion of the nigrostriatal dopaminergic system in monkeys.

    PubMed

    Apicella, P; Trouche, E; Nieoullon, A; Legallet, E; Dusticier, N

    1990-01-01

    Unilateral lesions of the nigrostriatal dopaminergic system were induced in five monkeys by intranigral injections of the neurotoxin 6-hydroxydopamine. Following the lesion, all monkeys showed a transient reluctance in using the contralateral forelimb, accompanied, in two monkeys by semi-flexed posture of the disabled forelimb. Three of the monkeys that had been conditioned to perform a visually triggered goal-directed arm movement, showed an increase in latency and duration of contralateral arm movements. Task performance recovered spontaneously to preoperative levels within four months in two monkeys despite significant reductions of endogenous dopamine and dihydroxyphenylacetic acid contents in the caudate nucleus, putamen and globus pallidus ipsilateral to the neurotoxic nigral injection. The third monkey exhibited a persistent increase in movement latency associated with a near complete loss of dopamine in both the putamen and the caudate nucleus. In all cases, an increase the dihydroxyphenyl-acetic acid to dopamine ratio was detected in the striatum and pallidum suggesting a compensatory increase in dopamine turnover in remaining intact dopaminergic nerve terminals. The level of serotonin was changed in all monkeys consisting of either a decrease or an increase, depending on the striatopallidal regions studied. Changes in choline acetyltransferase and glutamic acid decarboxylase activities in the same regions were only seen in some cases. The present results show that 6-hydroxydopamine-induced partial unilateral lesion of nigral dopaminergic neurons produced predominantly contralateral hypokinesia, accompanied by reductions of dopamine content in the ipsilateral striatum and pallidum. The use of this locally applied neurotoxin appears to be a suitable method for investigating neurophysiological mechanisms underlying hypokinesia since deficits in both initiating and executing movements can be expressed independently of other behavioral symptoms. The results

  2. Chronic stress enhances microglia activation and exacerbates death of nigral dopaminergic neurons under conditions of inflammation

    PubMed Central

    2014-01-01

    Background Parkinson’s disease is an irreversible neurodegenerative disease linked to progressive movement disorders and is accompanied by an inflammatory reaction that is believed to contribute to its pathogenesis. Since sensitivity to inflammation is not the same in all brain structures, the aim of this work was to test whether physiological conditions as stress could enhance susceptibility to inflammation in the substantia nigra, where death of dopaminergic neurons takes place in Parkinson’s disease. Methods To achieve our aim, we induced an inflammatory process in nonstressed and stressed rats (subject to a chronic variate stress) by a single intranigral injection of lipopolysaccharide, a potent proinflammogen. The effect of this treatment was evaluated on inflammatory markers as well as on neuronal and glial populations. Results Data showed a synergistic effect between inflammation and stress, thus resulting in higher microglial activation and expression of proinflammatory markers. More important, the higher inflammatory response seen in stressed animals was associated with a higher rate of death of dopaminergic neurons in the substantia nigra, the most characteristic feature seen in Parkinson’s disease. This effect was dependent on glucocorticoids. Conclusions Our data demonstrate that stress sensitises midbrain microglia to further inflammatory stimulus. This suggests that stress may be an important risk factor in the degenerative processes and symptoms of Parkinson’s disease. PMID:24565378

  3. Suppressed tyrosine hydroxylase gene expression in the tuberoinfundibular dopaminergic system during lactation.

    PubMed

    Wang, H J; Hoffman, G E; Smith, M S

    1993-10-01

    Suckling-induced PRL secretion is regulated in part by a reduction in tuberoinfundibular dopamine (TIDA) neuronal activity. We have examined the effects of suckling on TIDA activity in the arcuate nucleus by measuring changes in gene expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. TH gene expression was assessed by performing in situ hybridization, using a 35S-labeled antisense riboprobe for quantitating TH mRNA and analyzing grain density with the aid of an Optimas Bioscan image analysis system. Lactating rats suckled by eight pups were studied on postpartum day 10, and diestrous day 1 rats were used as controls. The results showed that lactation suppressed TH mRNA content throughout the arcuate nucleus to about 10% of diestrous levels. The dramatic reduction in TH mRNA during lactation was specific to the arcuate nucleus, as TH mRNA levels in the zona incerta were similar during lactation and diestrus. The suckling stimulus was the primary signal responsible for the suppression of TH mRNA in the arcuate nucleus, as removal of the pups for 6 h restored TH mRNA content to diestrous levels. By 24 h after pup removal, TH mRNA had reached almost twice diestrous levels. In view of the dramatic reduction in TH mRNA levels during lactation, we examined whether TH protein in the arcuate nucleus was similarly diminished. TH protein was detected by immunocytochemistry using a monoclonal antibody to TH. Qualitatively, TH staining was heavier in cell bodies, nerve fibers, and median eminence during diestrus. There was a small, but significant, decrease in TH-positive cell numbers during lactation (14% reduction) compared to those on diestrus. These data provide clear evidence that TH expression is suppressed during lactation, as evidenced by the decrease in TH mRNA and TH protein. The reduction in TH expression most likely contributes to the decrease in dopaminergic tone during lactation. PMID:8104777

  4. Inhibition of Drp1 mitochondrial translocation provides neural protection in dopaminergic system in a Parkinson's disease model induced by MPTP.

    PubMed

    Filichia, Emily; Hoffer, Barry; Qi, Xin; Luo, Yu

    2016-01-01

    Accumulating evidence suggest mitochondria-mediated pathways play an important role in dopaminergic neuronal cell death in Parkinson's disease (PD). Drp1, a key regulator of mitochondrial fission, has been shown to be activated and translocated to mitochondria under stress, leading to excessive mitochondria fission and dopaminergic neuronal death in vitro. However, whether Drp1 inhibition can lead to long term stable preservation of dopaminergic neurons in PD-related mouse models remains unknown. In this study, using a classical MPTP animal PD model, we showed for the first time Drp1 activation and mitochondrial translocation in vivo after MPTP administration. Inhibition of Drp1 activation by a selective peptide inhibitor P110, blocked MPTP-induced Drp1 mitochondrial translocation and attenuated dopaminergic neuronal loss, dopaminergic nerve terminal damage and behavioral deficits caused by MPTP. MPTP-induced microglial activation and astrogliosis were not affected by P110 treatment. Instead, inhibition of Drp1 mitochondrial translocation diminished MPTP-induced p53, BAX and PUMA mitochondrial translocation. This study demonstrates that inhibition of Drp1 hyperactivation by a Drp1 peptide inhibitor P110 is neuroprotective in a MPTP animal model. Our data also suggest that the protective effects of P110 treatment might be mediated by inhibiting the p53 mediated apoptotic pathways in neurons through inhibition of Drp1-dependent p53 mitochondrial translocation. PMID:27619562

  5. Modulation of the action of stress by ethanol on dopaminergic activity in the rat prefrontal cortex

    SciTech Connect

    Hegarty, A.A.; Vogel, W.H. )

    1992-02-26

    Both stress and ethanol, when administered individually, have been shown to affect dopamine (DA) and its metabolite (DOPAC) in the central nervous system. Stress can increase DA efflux in several areas of the brain, whereas ethanol has been shown to have variable effects on extracellular DA, either increasing DA or having no apparent effect. Furthermore, ethanol has been shown in microdissection studies to antagonize the effect of stress on the dopaminergic system, indicating an anxiety-reducing property of ethanol. However, the influence of the combination of stress and ethanol on the dopaminergic system has not been studied extensively with the newer technique of microdialysis. In this study, microdialysis was again used to characterize the interaction of immobilization stress and ethanol in the prefrontal cortex. Two groups of rats received either ethanol or saline in the resting state. A third group was immobilization stress and ethanol in the prefrontal cortex. Two groups of rats received either ethanol or saline in the resting state. A third group was immobilization Saline-treated animals showed essentially no changes in levels of DA or DOPAC. Ethanol had no effect on DA overflow in resting animals and caused only a small increase in DOPAC levels. Immobilization caused marked increases in DA levels and smaller increases in DOPAC. Ethanol pretreatment strongly reduced and antagonized the stress-induced increases in DA. However, ethanol potentiated the stress-induced increase in extracellular DOPAC. The authors data add biochemical evidence to the tension-reduction hypothesis of ethanol by perhaps implicating a reduction in the DA stress response by ethanol as a contributing factor in the development of alcoholism.

  6. Brain dopaminergic system changes in drug addiction: a review of positron emission tomography findings.

    PubMed

    Hou, Haifeng; Wang, Chunyan; Jia, Shaowei; Hu, Shu; Tian, Mei

    2014-10-01

    Dopamine (DA) is considered crucial for the rewarding effects of drugs of abuse, but its role in addiction remains unclear. Positron emission tomography (PET) is the first technology used for in vivo measurement of components of the dopaminergic system in the human brain. In this article, we review the major findings from PET imaging studies on the involvement of DA in drug addiction, including presynaptic DA synthesis, vesicular monoamine transporter 2, the DA transporter, and postsynaptic DA receptors. These results have corroborated the role of DA in addiction and increased the understanding of its underlying mechanisms. PMID:25260796

  7. Estrogen-related receptor gamma regulates dopaminergic neuronal phenotype by activating GSK3β/NFAT signaling in SH-SY5Y cells.

    PubMed

    Lim, Juhee; Choi, Hueng-Sik; Choi, Hyun Jin

    2015-05-01

    The orphan nuclear receptor estrogen-related receptor gamma (ERRγ) is highly expressed in the nervous system during embryogenesis and in adult brains, but its physiological role in neuronal development remains unknown. In this study, we evaluated the relevance of ERRγ in regulating dopaminergic (DAergic) phenotype and the corresponding signaling pathway. We used retinoic acid (RA) to differentiate human neuroblastoma SH-SY5Y cells. RA induced neurite outgrowth of SH-SY5Y cells with an increase in DAergic neuron-like properties, including up-regulation of tyrosine hydroxylase, dopamine transporter, and vesicular monoamine transporter 2. ERRγ, but not ERRα, was up-regulated by RA, and participated in RA effect on SH-SY5Y cells. ERRγ over-expression enhanced mature DAergic neuronal phenotype with neurite outgrowth as with RA treatment; and RA-induced increase in DAergic phenotype was attenuated by silencing ERRγ expression. ERRγ appears to have a crucial role in morphological and functional regulation of cells that is selective for DAergic neurons. Polo-like kinase 2 was up-regulated in ERRγ-over-expressing SH-SY5Y cells, which was involved in phosphorylation of glycogen synthase kinase 3β and resulting downstream activation of nuclear factor of activated T cells. The likely involvement of ERRγ in regulating the DAergic neuronal phenotype makes this orphan nuclear receptor a novel target for understanding DAergic neuronal differentiation. We propose the relevance of estrogen-related receptor gamma (ERRγ) in regulating dopaminergic neuronal phenotype: ERRγ is up-regulated by retinoic acid in SH-SY5Y cells, and enhances dopaminergic phenotypes and induces neurite outgrowth; Polo-like kinase 2 (PLK2) and glycogen synthase kinase 3 beta/nuclear factor of activated T cells (GSK3β/NFAT) signaling are responsible for the ERRγ effect. Our findings provide the first insights into the role of ERRγ in the brain, as a novel approach toward understanding

  8. Involvement of the dopaminergic system in the consolidation of fear conditioning in hippocampal CA3 subregion.

    PubMed

    Wen, Jia-Ling; Xue, Li; Wang, Run-Hua; Chen, Zi-Xiang; Shi, Yan-Wei; Zhao, Hu

    2015-02-01

    The hippocampus, the primary brain structure related to learning and memory, receives sparse but comprehensive dopamine innervations and contains dopamine D1 and D2 receptors. Systematic hippocampal dopaminergic dysfunction can cause deficits in spatial working memory and impair consolidation of contextual fear memories. CA3 is involved in the rapid acquisition of new memories and has extensive nerve fibre connections with other brain structures such as CA1, the amygdala, and the medial prefrontal cortex (mPFC). A bidirectional fibrous connection between CA3 and the amygdala reflects the importance of CA3 in fear conditioning. The present study evaluated the effects of a 6-OHDA lesion in CA3 on the acquisition and expression of conditioned fear. The results showed CA3 involvement in the expression but not the acquisition of conditioned fear. Injection of SCH23390 and quinpirole into the bilateral CA3 attenuated a conditioned fear-related freezing response, whereas SKF38393 and sulpiride were not associated with this effect. The present study found that a 6-OHDA lesion in CA3 up-regulated the expression of GluR1 in BLA and down-regulated NR2B in CA1 and the basolateral amygdala (BLA). Our data suggest that dopamine depletion in hippocampal subdivision CA3 may not be necessary for the acquisition of conditioned fear, but the expression of conditioned fear is likely dependent on the integrity of mesohippocampal dopaminergic connections. It is probable that both D1 and D2 dopaminergic receptors modulate the expression of conditioned fear. Changes in the expression of NR2B and GluR1 indicate that CA3 may modulate the activities of other brain structures. PMID:25446753

  9. Olfactory Sensory Activity Modulates Microglial-Neuronal Interactions during Dopaminergic Cell Loss in the Olfactory Bulb.

    PubMed

    Grier, Bryce D; Belluscio, Leonardo; Cheetham, Claire E J

    2016-01-01

    The mammalian olfactory bulb (OB) displays robust activity-dependent plasticity throughout life. Dopaminergic (DA) neurons in the glomerular layer (GL) of the OB are particularly plastic, with loss of sensory input rapidly reducing tyrosine hydroxylase (TH) expression and dopamine production, followed by a substantial reduction in DA neuron number. Here, we asked whether microglia participate in activity-dependent elimination of DA neurons in the mouse OB. Interestingly, we found a significant reduction in the number of both DA neurons and their synapses in the OB ipsilateral to the occluded naris (occluded OB) within just 7 days of sensory deprivation. Concomitantly, the volume of the occluded OB decreased, resulting in an increase in microglial density. Microglia in the occluded OB also adopted morphologies consistent with activation. Using in vivo 2-photon imaging and histological analysis we then showed that loss of olfactory input markedly altered microglial-neuronal interactions during the time that DA neurons are being eliminated: both microglial process motility and the frequency of wrapping of DA neuron somata by activated microglia increased significantly in the occluded OB. Furthermore, we found microglia in the occluded OB that had completely engulfed components of DA neurons. Together, our data provide evidence that loss of olfactory input modulates microglial-DA neuron interactions in the OB, thereby suggesting an important role for microglia in the activity-dependent elimination of DA neurons and their synapses. PMID:27471450

  10. Olfactory Sensory Activity Modulates Microglial-Neuronal Interactions during Dopaminergic Cell Loss in the Olfactory Bulb

    PubMed Central

    Grier, Bryce D.; Belluscio, Leonardo; Cheetham, Claire E. J.

    2016-01-01

    The mammalian olfactory bulb (OB) displays robust activity-dependent plasticity throughout life. Dopaminergic (DA) neurons in the glomerular layer (GL) of the OB are particularly plastic, with loss of sensory input rapidly reducing tyrosine hydroxylase (TH) expression and dopamine production, followed by a substantial reduction in DA neuron number. Here, we asked whether microglia participate in activity-dependent elimination of DA neurons in the mouse OB. Interestingly, we found a significant reduction in the number of both DA neurons and their synapses in the OB ipsilateral to the occluded naris (occluded OB) within just 7 days of sensory deprivation. Concomitantly, the volume of the occluded OB decreased, resulting in an increase in microglial density. Microglia in the occluded OB also adopted morphologies consistent with activation. Using in vivo 2-photon imaging and histological analysis we then showed that loss of olfactory input markedly altered microglial-neuronal interactions during the time that DA neurons are being eliminated: both microglial process motility and the frequency of wrapping of DA neuron somata by activated microglia increased significantly in the occluded OB. Furthermore, we found microglia in the occluded OB that had completely engulfed components of DA neurons. Together, our data provide evidence that loss of olfactory input modulates microglial-DA neuron interactions in the OB, thereby suggesting an important role for microglia in the activity-dependent elimination of DA neurons and their synapses. PMID:27471450

  11. Addiction pharmacogenetics: a systematic review of the genetic variation of the dopaminergic system.

    PubMed

    Patriquin, Michelle A; Bauer, Isabelle E; Soares, Jair C; Graham, David P; Nielsen, David A

    2015-10-01

    Substance use disorders have significant personal, familial, and societal consequences. Despite the serious consequences of substance use, only a few therapies are effective in treating substance use disorders, thus highlighting a need for improved treatment practices. Substance use treatment response depends on multiple factors such as genetic, biological, and social factors. It is essential that each component is represented in treatment plans. The dopaminergic system plays a critical role in the pharmacotherapy for addictions, and an understanding of the role of variation of genes involved in this system is essential for its success. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement guidelines. A computerized literature search was conducted using PubMed and Scopus (all databases). Articles published up to April 2015 that examined the role of dopaminergic gene variation in the pharmacotherapy of alcohol, opioid, and cocaine use disorders were reviewed. Search terms were dopamine, gene, polymorphism, substance abuse, treatment, and response. Polymorphisms of the DRD2, ANKK1, DAT1, DBH, and DRD4 genes have been found to moderate the effects of pharmacotherapy of alcohol, opioid, and cocaine use disorders. The integration of genetic information with clinical data will inform health professionals of the most efficacious pharmacotherapeutic intervention for substance use disorders. More studies are needed to confirm and extend these findings. PMID:26146874

  12. A novel synthetic activator of Nurr1 induces dopaminergic gene expression and protects against 6-hydroxydopamine neurotoxicity in vitro.

    PubMed

    Hammond, Sean L; Safe, Stephen; Tjalkens, Ronald B

    2015-10-21

    Degeneration of dopaminergic neurons in Parkinson's disease (PD) is associated with decreased expression of the orphan nuclear receptor Nurr1 (NR4A2), which is critical for both homeostasis and development of dopamine (DA) neurons. The synthetic, phytochemical-based compound, 1,1-bis (3'-indolyl)-1-(p-chlorophenyl) methane (C-DIM12) activates Nurr1 in cancer cells and prevents loss of dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD in mice. In the present study, we examined the capacity of C-DIM12 to induce expression of Nurr1-regulated genes in two dopaminergic neuronal cell lines (N2A, N27) and to protect against 6-hydroxydopamine (6-OHDA) neurotoxicity. C-DIM12 induced expression of Nurr1-regulated genes that was abolished by Nurr1 knockdown. C-DIM12 increased expression of transfected human Nurr1, induced Nurr1 protein expression in primary dopaminergic neurons and enhanced neuronal survival from exposure to 6-OHDA. These data indicate that C-DIM12 stimulates neuroprotective expression Nurr1-regulated genes in DA neurons. PMID:26383113

  13. Molecular basis of the dopaminergic system in the cricket Gryllus bimaculatus.

    PubMed

    Watanabe, Takayuki; Sadamoto, Hisayo; Aonuma, Hitoshi

    2013-12-01

    In insects, dopamine modulates various aspects of behavior such as learning and memory, arousal and locomotion, and is also a precursor of melanin. To elucidate the molecular basis of the dopaminergic system in the field cricket Gryllus bimaculatus DeGeer, we identified genes involved in dopamine biosynthesis, signal transduction, and dopamine re-uptake in the cricket. Complementary DNA of two isoforms of tyrosine hydroxylase (TH), which convert tyrosine into L-3,4-dihydroxyphenylalanine, was isolated from the cricket brain cDNA library. In addition, four dopamine receptor genes (Dop1, Dop2, Dop3, and DopEcR) and a high-affinity dopamine transporter gene were identified. The two TH isoforms contained isoform-specific regions in the regulatory ACT domain and showed differential expression patterns in different tissues. In addition, the dopamine receptor genes had a receptor subtype-specific distribution: the Dop1, Dop2, and DopEcR genes were broadly expressed in various tissues at differential expression levels, and the Dop3 gene was restrictedly expressed in neuronal tissues and the testicles. Our findings provide a fundamental basis for understanding the dopaminergic regulation of diverse physiological processes in the cricket. PMID:23539475

  14. Novel FTY720-Based Compounds Stimulate Neurotrophin Expression and Phosphatase Activity in Dopaminergic Cells

    PubMed Central

    2014-01-01

    α-Synuclein is a chaperone-like protein implicated in Parkinson’s disease (PD). Among α-synuclein’s normal functions is an ability to bind to and stimulate the activity of the protein phosphatase 2A (PP2A) catalytic subunit in vitro and in vivo. PP2A activity is impaired in PD and in dementia with Lewy Bodies in brain regions harboring α-synuclein aggregates. Using PP2A as the readout, we measured PP2A activity in response to α-synuclein, ceramides, and FTY720, and then on the basis of those results, we created new FTY720 compounds. We then measured the effects of those compounds in dopaminergic cells. In addition to stimulating PP2A, all three compounds stimulated the expression of brain derived neurotrophic factor and protected MN9D cells against tumor-necrosis-factor-α-associated cell death. FTY720-C2 appears to be more potent while FTY720-Mitoxy targets mitochondria. Importantly, FTY720 is already FDA approved for treating multiple sclerosis and is used clinically worldwide. Our findings suggest that FTY720 and our new FTY720-based compounds have considerable potential for treating synucleinopathies such as PD. PMID:25050165

  15. The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry.

    PubMed

    Hess, Martin E; Hess, Simon; Meyer, Kate D; Verhagen, Linda A W; Koch, Linda; Brönneke, Hella S; Dietrich, Marcelo O; Jordan, Sabine D; Saletore, Yogesh; Elemento, Olivier; Belgardt, Bengt F; Franz, Thomas; Horvath, Tamas L; Rüther, Ulrich; Jaffrey, Samie R; Kloppenburg, Peter; Brüning, Jens C

    2013-08-01

    Dopaminergic (DA) signaling governs the control of complex behaviors, and its deregulation has been implicated in a wide range of diseases. Here we demonstrate that inactivation of the Fto gene, encoding a nucleic acid demethylase, impairs dopamine receptor type 2 (D2R) and type 3 (D3R) (collectively, 'D2-like receptor')-dependent control of neuronal activity and behavioral responses. Conventional and DA neuron-specific Fto knockout mice show attenuated activation of G protein-coupled inwardly-rectifying potassium (GIRK) channel conductance by cocaine and quinpirole. Impaired D2-like receptor-mediated autoinhibition results in attenuated quinpirole-mediated reduction of locomotion and an enhanced sensitivity to the locomotor- and reward-stimulatory actions of cocaine. Analysis of global N(6)-methyladenosine (m(6)A) modification of mRNAs using methylated RNA immunoprecipitation coupled with next-generation sequencing in the midbrain and striatum of Fto-deficient mice revealed increased adenosine methylation in a subset of mRNAs important for neuronal signaling, including many in the DA signaling pathway. Several proteins encoded by these mRNAs had altered expression levels. Collectively, FTO regulates the demethylation of specific mRNAs in vivo, and this activity relates to the control of DA transmission. PMID:23817550

  16. [Behavior and functional state of the dopaminergic brain system in pups of depressive WAG/Rij rats].

    PubMed

    Malyshev, A V; Razumkina, E V; Rogozinskaia, É Ia; Sarkisova, K Iu; Dybynin, V A

    2014-01-01

    In the present work, it has been studied for the first time behavior and functional state of the dopaminergic brain system in pups of "depressive" WAG/Rij rats. Offspring of "depressive" WAG/Rij rats at age of 6-16 days compared with offspring of "normal" (non-depressed) outbred rats of the same age exhibited reduced rate of pshychomotor development, lower body weight, attenuation in integration of coordinated reflexes and vestibular function (greater latency of righting reflex, abnormal negative geotaxis), hyper-reactivity to tactile stimulation, reduced motivation to contact with mother (reduced infant-mother attachment). Differences in a nest seeking response induced by olfactory stimuli (olfactory discrimination test) and in locomotor activity (tests "gait reflex" and "small open field") have not been revealed. Acute injection of the antagonist of D2-like dopamine receptors clebopride 20 min before testing aggravated mother-oriented behavior in 15-days-old pups of both "depressive" and "non-depressive" rats. However this effect was greater in pups of "depressive" WAG/Rij rats compared with pups of "normal" rats that may indicate reduced functional activity of the dopaminergic brain system in offspring of "depressive" rats. It is proposed that reduced attachment behavior in pups of "depressive" WAG/Rij rats might be a consequence of maternal depression and associated with it reduced maternal care. Moreover, reduced attachment behavior in pups of "depressive" rats might be an early precursor (a marker) of depressive-like pathology which become apparent later in life (approximately at age of 3 months). PMID:25723020

  17. The role of purinergic and dopaminergic systems on MK-801-induced antidepressant effects in zebrafish.

    PubMed

    da Silva, Raquel Bohrer; Siebel, Anna Maria; Bonan, Carla Denise

    2015-12-01

    Depression is a serious disease characterized by low mood, anhedonia, loss of interest in daily activities, appetite and sleep disturbances, reduced concentration, and psychomotor agitation. There is a growing interest in NMDA antagonists as a promising target for the development of new antidepressants. Considering that purinergic and dopaminergic systems are involved in depression and anxiety states, we characterized the role of these signaling pathways on MK-801-induced antidepressant effects in zebrafish. Animals treated with MK-801 at the doses of 5, 10, 15, or 20μM during 15, 30, or 60min spent longer time in the top area of aquariums in comparison to control group, indicating an anxiolytic/antidepressant effect induced by this drug. Animals treated with MK-801 spent longer time period at top area until 2 (5μM MK-801) and 4 (20μM MK-801) hours after treatment, returning to basal levels from 24h to 7days after exposure. Repeated MK-801 treatment did not induce cumulative effects, since animals treated daily during 7days had the same behavioral response pattern observed since the first until the 7th day. In order to investigate the effects of adenosine A1 and A2A receptor antagonist and agonist and the influence of modulation of adenosine levels on MK-801 effects, we treated zebrafish with caffeine, DPCPX, CPA, ZM 241385, CGS 21680, AMPCP, EHNA, dipyridamole, and NBTI during 30min before MK-801 exposure. The non-specific adenosine receptor antagonist caffeine (50mg/kg) and the selective A1 receptor antagonist DPCPX (15mg/kg) prevented the behavioral changes induced by MK-801. The non-specific nucleoside transporter (NT) inhibitor dipyridamole (10mg/kg) exacerbated the behavioral changes induced by MK-801. Dopamine receptor antagonists (sulpiride and SCH 23390) did not change the behavioral alterations induced by MK-801. Our findings demonstrated that antidepressant-like effects of MK-801 in zebrafish are mediated through adenosine A1 receptor activation. PMID

  18. Possible dopaminergic stimulation of locus coeruleus alpha1-adrenoceptors involved in behavioral activation.

    PubMed

    Lin, Yan; Quartermain, David; Dunn, Adrian J; Weinshenker, David; Stone, Eric A

    2008-07-01

    alpha(1)-Adrenoceptors of the locus coeruleus (LC) have been implicated in behavioral activation in novel surroundings, but the endogenous agonist that activates these receptors has not been established. In addition to the canonical activation of alpha(1)-receptors by norepinephrine (NE), there is evidence that dopamine (DA) may also activate certain brain alpha(1)-receptors. This study examined the contribution of DA to exploratory activity in a novel cage by determining the effect of infusion of various dopaminergic and adrenergic drugs into the mouse LC. It was found that the D2/D3 agonist, quinpirole, which selectively blocks the release of CNS DA, produced a dose-dependent and virtually complete abolition of exploration and all movement in the novel cage test. The quinpirole-induced inactivity was significantly attenuated by coinfusion of DA but not by the D1 agonist, SKF38390. Furthermore, the DA attenuation of quinpirole inactivity was blocked by coinfusion of the alpha(1)-adrenergic receptor antagonist, terazosin, but not by the D1 receptor antagonist, SCH23390. LC infusions of either quinpirole or terazosin also produced profound inactivity in DA-beta-hydroxylase knockout (Dbh -/-) mice that lack NE, indicating that their behavioral effects were not due to an alteration of the release or action of LC NE. Measurement of endogenous DA, NE, and 5HT and their metabolites in the LC during exposure to the novel cage indicated an increase in the turnover of DA and NE but not 5HT. These results indicate that DA is a candidate as an endogenous agonist for behaviorally activating LC alpha(1)-receptors and may play a role in the activation of this nucleus by novel surroundings. PMID:18435418

  19. Neurogenetic Impairments of Brain Reward Circuitry Links to Reward Deficiency Syndrome (RDS): Potential Nutrigenomic Induced Dopaminergic Activation

    PubMed Central

    Blum, K; Oscar-Berman, M; Giordano, J; Downs, BW; Simpatico, T; Han, D; Femino, John

    2012-01-01

    Work from our laboratory in both in-patient and outpatient facilities utilizing the Comprehensive Analysis of Reported Drugs (CARD)™ found a significant lack of compliance to prescribed treatment medications and a lack of abstinence from drugs of abuse during active recovery. This unpublished, ongoing research provides an impetus to develop accurate genetic diagnosis and holistic approaches that will safely activate brain reward circuitry in the mesolimbic dopamine system. This editorial focuses on the neurogenetics of brain reward systems with particular reference to genes related to dopaminergic function. The terminology “Reward Deficiency Syndrome” (RDS), used to describe behaviors found to have an association with gene-based hypodopaminergic function, is a useful concept to help expand our understanding of Substance Use Disorder (SUD), process addictions, and other obsessive, compulsive and impulsive behaviors. This editorial covers the neurological basis of pleasure and the role of natural and unnatural reward in motivating and reinforcing behaviors. Additionally, it briefly describes the concept of natural dopamine D2 receptor agonist therapy coupled with genetic testing of a panel of reward genes, the Genetic Addiction Risk Score (GARS). It serves as a spring-board for this combination of novel approaches to the prevention and treatment of RDS that was developed from fundamental genomic research. We encourage further required studies. PMID:23264886

  20. Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in the adult rat.

    PubMed

    Pascual, Maria; Boix, Jordi; Felipo, Vicente; Guerri, Consuelo

    2009-02-01

    Adolescence is a developmental period which the risk of drug and alcohol abuse increases. Since mesolimbic dopaminergic system undergoes developmental changes during adolescence, and this system is involved in rewarding effects of drugs of abuse, we addressed the hypothesis that ethanol exposure during juvenile/adolescent period over-activates mesolimbic dopaminergic system inducing adaptations which can trigger long-term enduring behavioural effects of alcohol abuse. We treated juvenile/adolescent or adult rats with ethanol (3 g/kg) for two-consecutive days at 48-h intervals over 14-day period. Here we show that intermittent ethanol treatment during the juvenile/adolescence period alters subsequent ethanol intake. In vivo microdialysis demonstrates that ethanol elicits a similar prolonged dopamine response in the nucleus accumbens of both adolescent and adult animals pre-treated with multiple doses of ethanol, although the basal dopamine levels were higher in ethanol-treated adolescents than in adult-treated animals. Repeated ethanol administration also down-regulates the expression of DRD2 and NMDAR2B phosphorylation in prefrontal cortex of adolescent animals, but not of adult rats. Finally, ethanol treatment during adolescence changes the acetylation of histones H3 and H4 in frontal cortex, nucleus accumbens and striatum, suggesting chromatin remodelling changes. In summary, our findings demonstrate the sensitivity of adolescent brain to ethanol effects on dopaminergic and glutamatergic neurotransmission, and suggest that abnormal plasticity in reward-related processes and epigenetic mechanisms could contribute to the vulnerability of adolescents to alcohol addiction. PMID:19077056

  1. The Role of MAC1 in Diesel Exhaust Particle-induced Microglial Activation and Loss of Dopaminergic Neuron Function

    PubMed Central

    Levesque, Shannon; Taetzsch, Thomas; Lull, Melinda E.; Johnson, Jo Anne; McGraw, Constance; Block, Michelle L.

    2013-01-01

    Increasing reports support that air pollution causes neuroinflammation and is linked to central nervous system (CNS) disease/damage. Diesel exhaust particles (DEP) are a major component of urban air pollution, which has been linked to microglial activation and Parkinson’s disease-like pathology. To begin to address how DEP may exert CNS effects, microglia and neuron-glia cultures were treated with either nanometer-sized DEP (<0.22 µM; 50µg/mL), ultrafine carbon black (ufCB, 50µg/ml), or DEP extracts (eDEP; from 50 µg/ml DEP) and the effect of microglial activation and dopaminergic (DA) neuron function was assessed. All three treatments showed enhanced amoeboid microglia morphology, increased H2O2 production, and decreased DA uptake. Mechanistic inquiry revealed that the scavenger receptor inhibitor fucoidan blocked DEP internalization in microglia, but failed to alter DEP-induced H2O2 production in microglia. However, pretreatment with the MAC1/CD11b inhibitor antibody blocked microglial H2O2 production in response to DEP. MAC1−/− mesencephalic neuron-glia cultures were protected from DEP-induced loss of DA neuron function, as measured by DA uptake. These findings support that DEP may activate microglia through multiple mechanisms, where scavenger receptors regulate internalization of DEP and the MAC1 receptor is mandatory for both DEP-induced microglial H2O2 production and loss of DA neuron function. PMID:23470120

  2. Effects of early and late neonatal bromocriptine treatment on hypothalamic neuropeptides, dopaminergic reward system and behavior of adult rats.

    PubMed

    Carvalho, Janaine C; Lisboa, Patricia C; de Oliveira, Elaine; Peixoto-Silva, Nayara; Pinheiro, Cintia R; Fraga, Mabel C; Claudio-Neto, Sylvio; Franci, Celso R; Manhães, Alex C; Moura, Egberto G

    2016-06-14

    In humans, bromocriptine (BRO) is used as a treatment for many disorders, such as prolactinomas, even during pregnancy and lactation. Previously we demonstrated that maternal BRO treatment at the end of lactation programs offspring for obesity and several endocrine dysfunctions. Here, we studied the long-term effects of direct BRO injection in neonatal Wistar rats on their dopaminergic pathway, anxiety-like behavior and locomotor activity at adulthood. Male pups were either s.c. injected with BRO (0.1μg/once daily) from postnatal day (PN) 1 to 10 or from PN11 to 20. Controls were injected with methanol-saline. Body mass, food intake, neuropeptides, dopamine pathway parameters, anxiety-like behavior and locomotor activity were analyzed. The dopamine pathway was analyzed in the ventral tegmental area (VTA), nucleus accumbens (NAc) and dorsal striatum (DS) at PN180. PN1-10 BRO-treated animals had normal body mass and adiposity but lower food intake and plasma prolactin (PRL). This group had higher POMC in the arcuate nucleus (ARC), higher tyrosine hydroxylase (TH) in the VTA, higher dopa decarboxylase (DDc), higher D2R and μu-opioid receptor in the NAc. Concerning behavior in elevated plus maze (EPM), BRO-treated animals displayed more anxiety-like behaviors. PN11-20 BRO-treated showed normal body mass and adiposity but higher food intake and plasma PRL. This group had lower POMC in the ARC, lower TH in the VTA and lower DAT in the NAc. BRO-treated animals showed less anxiety-like behaviors in the EPM. Thus, neonatal BRO injection, depending on the time of treatment, leads to different long-term dysfunctions in the dopaminergic reward system, food intake behavior and anxiety levels, findings that could be partially due to PRL and POMC changes. PMID:27038750

  3. The Association Between Genetic Variants in the Dopaminergic System and Posttraumatic Stress Disorder

    PubMed Central

    Li, Lizhuo; Bao, Yijun; He, Songbai; Wang, Gang; Guan, Yanlei; Ma, Dexuan; Wang, Pengfei; Huang, Xiaolong; Tao, Shanwei; Zhang, Dewei; Liu, Qiwen; Wang, Yunjie; Yang, Jingyun

    2016-01-01

    Abstract Posttraumatic stress disorder (PTSD) is a complex mental disorder and can severely interfere with the normal life of the affected people. Previous studies have examined the association of PTSD with genetic variants in multiple dopaminergic genes with inconsistent results. To perform a systematic literature search and conduct meta-analysis to examine whether genetic variants in the dopaminergic system is associated with PTSD. PubMed, Cochrane Library, Embase, Google Scholar, and HuGE. The studies included subjects who had been screened for the presence of PTSD; the studies provided data for genetic variants of genes involved in the dopaminergic system; the outcomes of interest included diagnosis status of PTSD; and the studies were case–control studies. Odds ratio was used as a measure of association. We used random-effects model in all the meta-analyses. Between-study heterogeneity was assessed using I2, and publication bias was evaluated using Egger test. Findings from meta-analyses were confirmed using random-effects meta-analyses under the framework of generalized linear model (GLM). A total of 19 studies met the eligibility criteria and were included in our analyses. We found that rs1800497 in DRD2 was significantly associated with PTSD (OR = 1.96, 95% CI: 1.15–3.33; P = 0.014). The 3′-UTR variable number tandem repeat (VNTR) in SLC6A3 also showed significant association with PTSD (OR = 1.62, 95% CI: 1.12–2.35; P = 0.010), but there was no association of rs4680 in COMT with PTSD (P = 0.595). Sample size is limited for some studies; type and severity of traumatic events varied across studies; we could not control for potential confounding factors, such as age at traumatic events and gender; and we could not examine gene–environment interaction due to lack of data. We found that rs1800497 in DRD2 and the VNTR in SLC6A3 showed significant association with PTSD. Future studies controlling for confounding factors, with large

  4. Mesocortical dopaminergic function and human cognition

    SciTech Connect

    Weinberger, D.R.; Berman, K.F.; Chase, T.N.

    1988-01-01

    In summary, we have reviewed rCBF data in humans that suggest that mesoprefrontal dopaminergic activity is involved in human cognition. In patients with Parkinson's disease and possibly in patients with schizophrenia, prefrontal physiological activation during a cognitive task that appears to depend on prefrontal neural systems correlates positively with cognitive performance on the task and with clinical signs of dopaminergic function. It may be possible in the future to examine prefrontal dopamine metabolism directly during prefrontal cognition using positron emission tomography and tracers such as F-18 DOPA. 21 references.

  5. GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol

    PubMed Central

    Herman, Melissa A.; Sidhu, Harpreet; Stouffer, David G.; Kreifeldt, Max; Le, David; Cates-Gatto, Chelsea; Munoz, Michaelanne B.; Roberts, Amanda J.; Parsons, Loren H.; Roberto, Marisa; Wickman, Kevin; Slesinger, Paul A.; Contet, Candice

    2015-01-01

    G protein-gated inwardly rectifying potassium (GIRK) channels are critical regulators of neuronal excitability and can be directly activated by ethanol. Constitutive deletion of the GIRK3 subunit has minimal phenotypic consequences, except in response to drugs of abuse. Here we investigated how the GIRK3 subunit contributes to the cellular and behavioral effects of ethanol, as well as to voluntary ethanol consumption. We found that constitutive deletion of GIRK3 in knockout (KO) mice selectively increased ethanol binge-like drinking, without affecting ethanol metabolism, sensitivity to ethanol intoxication, or continuous-access drinking. Virally mediated expression of GIRK3 in the ventral tegmental area (VTA) reversed the phenotype of GIRK3 KO mice and further decreased the intake of their wild-type counterparts. In addition, GIRK3 KO mice showed a blunted response of the mesolimbic dopaminergic (DA) pathway to ethanol, as assessed by ethanol-induced excitation of VTA neurons and DA release in the nucleus accumbens. These findings support the notion that the subunit composition of VTA GIRK channels is a critical determinant of DA neuron sensitivity to drugs of abuse. Furthermore, our study reveals the behavioral impact of this cellular effect, whereby the level of GIRK3 expression in the VTA tunes ethanol intake under binge-type conditions: the more GIRK3, the less ethanol drinking. PMID:25964320

  6. Dose-dependent on reversible effects of lead on rat dopaminergic system

    SciTech Connect

    Memo, M.; Lucchi, L.; Spano, P.F.; Trabucchi, M.

    1981-02-16

    It has been suggested that hyperactivity and mental retardation, the most serious clinical aspects observed in children during lead intoxication, may occur as consequence of specific alterations of neurotransmitter functions. In our experiments we indicate that the behavioural patterns observed in chronically lead exposed rats may be correlated with an impairment of the dopaminergic system. Performing our study at two different levels of lead exposure, we found a dose-dependent change in dopamine turnover. Moreover, 30 days after the last assumption of lead we observed a complete disappearance of these neurochemical variations. Our findings suggest that lead affects dopamine function in different brain areas in reversible manner, inducing effects which are dose-dependent.

  7. Effect of incubation temperature and androgens on dopaminergic activity in the leopard gecko, Eublepharis macularius.

    PubMed

    Dias, Brian George; Ataya, Ramona Sousan; Rushworth, David; Zhao, Jun; Crews, David

    2007-04-01

    Male leopard geckos that hatch from eggs incubated at a female-biased temperature (Tf) behave differently when compared with males hatching at a temperature which produces a male-biased sex ratio (Tm). We investigated the effect of incubation temperature and androgen implantation on aspects of the dopaminergic system of Tf and Tm males. Our data suggest that more dopamine (DA) is stored in the nucleus accumbens of naive Tf males compared with naïve Tm males when they encounter a receptive female conspecific across a barrier. No difference was measured in the preoptic area and the ventral tegmental area (VTA). This difference in intracellular DA levels in a motivation-related brain nucleus might be correlated with differences in sociosexual behavior observed between the two morphs. There were no differences in tyrosine hydroxylase (TH) expressing cell numbers in the VTA of cholesterol (CH)-implanted naive castrated Tf and Tm males. Only Tf males implanted with testosterone had significantly higher TH immunopositive cell numbers in the VTA compared with CH- and dihydrotestosterone-implanted Tf males. These data indicate that both the embryonic environment as well as the circulating hormonal milieu can modulate neurochemistry, which might in turn be a basis for individual variation in behavior. PMID:17443813

  8. Dopaminergic system and dream recall: An MRI study in Parkinson's disease patients.

    PubMed

    De Gennaro, Luigi; Lanteri, Olimpia; Piras, Fabrizio; Scarpelli, Serena; Assogna, Francesca; Ferrara, Michele; Caltagirone, Carlo; Spalletta, Gianfranco

    2016-03-01

    We investigated the role of the dopamine system [i.e., subcortical-medial prefrontal cortex (mPFC) network] in dreaming, by studying patients with Parkinson's Disease (PD) as a model of altered dopaminergic transmission. Subcortical volumes and cortical thickness were extracted by 3T-MR images of 27 PD patients and 27 age-matched controls, who were asked to fill out a dream diary upon morning awakening for one week. PD patients do not substantially differ from healthy controls with respect to the sleep, dream, and neuroanatomical measures. Multivariate correlational analyses in PD patients show that dopamine agonist dosage is associated to qualitatively impoverished dreams, as expressed by lower bizarreness and lower emotional load values. Visual vividness (VV) of their dream reports positively correlates with volumes of both the amygdalae and with thickness of the left mPFC. Emotional load also positively correlates with hippocampal volume. Beside the replication of our previous finding on the role of subcortical nuclei in dreaming experience of healthy subjects, this represents the first evidence of a specific role of the amygdala-mPFC dopaminergic network system in dream recall. The association in PD patients between higher dopamine agonist dosages and impoverished dream reports, however, and the significant correlations between VV and mesolimbic regions, however, provide an empirical support to the hypothesis that a dopamine network plays a key role in dream generation. The causal relation is however precluded by the intrinsic limitation of assuming the dopamine agonist dosage as a measure of the hypodopaminergic state in PD. Periodicals, Inc. PMID:26704150

  9. An Efficient and Versatile System for Visualization and Genetic Modification of Dopaminergic Neurons in Transgenic Mice

    PubMed Central

    Kramer, Edgar R.

    2015-01-01

    Background & Aims The brain dopaminergic (DA) system is involved in fine tuning many behaviors and several human diseases are associated with pathological alterations of the DA system such as Parkinson’s disease (PD) and drug addiction. Because of its complex network integration, detailed analyses of physiological and pathophysiological conditions are only possible in a whole organism with a sophisticated tool box for visualization and functional modification. Methods & Results Here, we have generated transgenic mice expressing the tetracycline-regulated transactivator (tTA) or the reverse tetracycline-regulated transactivator (rtTA) under control of the tyrosine hydroxylase (TH) promoter, TH-tTA (tet-OFF) and TH-rtTA (tet-ON) mice, to visualize and genetically modify DA neurons. We show their tight regulation and efficient use to overexpress proteins under the control of tet-responsive elements or to delete genes of interest with tet-responsive Cre. In combination with mice encoding tet-responsive luciferase, we visualized the DA system in living mice progressively over time. Conclusion These experiments establish TH-tTA and TH-rtTA mice as a powerful tool to generate and monitor mouse models for DA system diseases. PMID:26291828

  10. Local and Global Resting State Activity in the Noradrenergic and Dopaminergic Pathway Modulated by Reboxetine and Amisulpride in Healthy Subjects

    PubMed Central

    Wiegers, Maike; Walter, Martin; Abler, Birgit; Graf, Heiko

    2016-01-01

    Background: Various psychiatric populations are currently investigated with resting state fMRI, with the aim of individualizing diagnostics and treatment options and improving treatment outcomes. Many of these studies are conducted in large naturalistic samples, providing rich insights regarding disease-related neural alterations, but with the common psychopharmacological medication limiting interpretations of the results. We therefore investigated the effects of common noradrenergic and anti-dopaminergic medications on local and global resting state activity (rs-activity) in healthy volunteers to further the understanding of the respective effects independent from disease-related alterations. Methods: Within a randomized, double-blind, placebo-controlled crossover design, we investigated 19 healthy male subjects by resting state fMRI after the intake of reboxetine (4mg/d), amisulpride (200mg/d), and placebo for 7 days each. Treatment-related differences in local and global rs-activity were measured by the fractional amplitude of low frequency fluctuations (fALFF) and resting state functional connectivity (rs-FC). Results: fALFF revealed alterations of local rs-activity within regions of the core noradrenergic pathway, including the locus coeruleus under reboxetine, correlated with its plasma levels. Moreover, reboxetine led to increased rs-FC between regions within this pathway, i.e. the locus coeruleus, tectum, thalamus, and amygdala. Amisulpride modulated local rs-activity of regions within the dopaminergic pathway, with the altered signal in the putamen correlating with amisulpride plasma levels. Correspondingly, amisulpride increased rs-FC between regions of the dopaminergic pathway comprising the substantia nigra and putamen. Conclusion: Our data provide evidence of how psychopharmacological agents alter local and global rs-activity within the respective neuroanatomical pathways in healthy subjects, which may help with interpreting data in psychiatric

  11. Deficits in coordinated motor behavior and in nigrostriatal dopaminergic system ameliorated and VMAT2 expression up-regulated in aged male rats by administration of testosterone propionate.

    PubMed

    Wang, Li; Kang, Yunxiao; Zhang, Guoliang; Zhang, Yingbo; Cui, Rui; Yan, Wensheng; Tan, Huibing; Li, Shuangcheng; Wu, Baiyila; Cui, Huixian; Shi, Geming

    2016-06-01

    The effects of testosterone propionate (TP) supplements on the coordinated motor behavior and nigrostriatal dopaminergic (NSDA) system were analyzed in aged male rats. The present study showed the coordinated motor behavioral deficits, the reduced activity of NSDA system and the decreased expression of vesicular monoamine transporter 2 (VMAT2) in 24month-old male rats. Long term TP treatment improved the motor coordination dysfunction with aging. Increased tyrosine hydroxylase and dopamine transporter, as well as dopamine and its metabolites were found in the NSDA system of TP-treated 24month-old male rats, indicative of the amelioratory effects of TP supplements on NSDA system of aged male rats. The enhancement of dopaminergic (DAergic) activity of NSDA system by TP supplements might underlie the amelioration of the coordinated motor dysfunction in aged male rats. TP supplements up-regulated VMAT2 expression in NSDA system of aged male rats. Up-regulation of VMAT2 expression in aged male rats following chronic TP treatment might be involved in the maintenance of DAergic function of NSDA system in aged male rats. PMID:26956479

  12. LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors

    PubMed Central

    2012-01-01

    Mutations in the LRRK2 gene are the most common cause of genetic Parkinson’s disease. Although the mechanisms behind the pathogenic effects of LRRK2 mutations are still not clear, data emerging from in vitro and in vivo models suggests roles in regulating neuronal polarity, neurotransmission, membrane and cytoskeletal dynamics and protein degradation. We created mice lacking exon 41 that encodes the activation hinge of the kinase domain of LRRK2. We have performed a comprehensive analysis of these mice up to 20 months of age, including evaluation of dopamine storage, release, uptake and synthesis, behavioral testing, dendritic spine and proliferation/neurogenesis analysis. Our results show that the dopaminergic system was not functionally comprised in LRRK2 knockout mice. However, LRRK2 knockout mice displayed abnormal exploratory activity in the open-field test. Moreover, LRRK2 knockout mice stayed longer than their wild type littermates on the accelerated rod during rotarod testing. Finally, we confirm that loss of LRRK2 caused degeneration in the kidney, accompanied by a progressive enhancement of autophagic activity and accumulation of autofluorescent material, but without evidence of biphasic changes. PMID:22647713

  13. Increased dopaminergic and 5-hydroxytryptaminergic activities in male rat brain following long-term treatment with anabolic androgenic steroids

    PubMed Central

    Thiblin, Ingemar; Finn, Anja; Ross, Svante B; Stenfors, Carina

    1999-01-01

    The effects of treating groups of rats with four different anabolic androgenic steroids (AAS) (testosterone, nandrolone, methandrostenolone, and oxymetholone) on 5-hydroxytryptamine (5-HT) and dopamine (DA) neurones in different brain regions were examined. The AAS was injected six times with 1 week's interval and the rats were sacrificed 2 days after the final injection. 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured. The effect on DA and 5-HT synthesis rate was analysed as the accumulation of 3,4-dihydroxyphenyl-alanine (DOPA) and 5-hydroxytryptophan (5-HTP), respectively, after inhibition of the amino acid decarboxylase with NSD-1015 (3-hydroxy-benzylhydrazine dihydrochloride). Additionally, the monoamine oxidase (MAO) activity was analysed in the hypothalamus. The DOPAC+HVA/DA ratio was increased in the striatum in all treatment groups. However, the synthesis rate of DA was significantly increased only in the methandrostenolone treated group. The 5-HIAA/5-HT ratio was increased in all treatment groups in the hippocampus, in the frontal cortex in the methandrostenolone-treated animals and in the hypothalamus in the testosterone- and oxymetholone-treated rats, while the 5-HT synthesis rate was not affected by the AAS-treatments. The MAO-A activity was increased in the oxymetholone-treated rats while the other treatment groups were unaffected. The MAO-B activity was not changed. The results indicate that relatively high doses of AAS increase dopaminergic and 5-hydroxytryptaminergic metabolism in male rat brain, probably due to enhanced turnover in these monaminergic systems. PMID:10217522

  14. Increased dopaminergic and 5-hydroxytryptaminergic activities in male rat brain following long-term treatment with anabolic androgenic steroids.

    PubMed

    Thiblin, I; Finn, A; Ross, S B; Stenfors, C

    1999-03-01

    1. The effects of treating groups of rats with four different anabolic androgenic steroids (AAS) (testosterone, nandrolone, methandrostenolone, and oxymetholone) on 5-hydroxytryptamine (5-HT) and dopamine (DA) neurones in different brain regions were examined. The AAS was injected six times with 1 week's interval and the rats were sacrificed 2 days after the final injection. 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured. The effect on DA and 5-HT synthesis rate was analysed as the accumulation of 3,4-dihydroxyphenyl-alanine (DOPA) and 5-hydroxytryptophan (5-HTP), respectively, after inhibition of the amino acid decarboxylase with NSD-1015 (3-hydroxy-benzylhydrazine dihydrochloride). Additionally, the monoamine oxidase (MAO) activity was analysed in the hypothalamus. 2. The DOPAC + HVA/DA ratio was increased in the striatum in all treatment groups. However, the synthesis rate of DA was significantly increased only in the methandrostenolone treated group. 3. The 5-HIAA/5-HT ratio was increased in all treatment groups in the hippocampus, in the frontal cortex in the methandrostenolone-treated animals and in the hypothalamus in the testosterone- and oxymetholone-treated rats, while the 5-HT synthesis rate was not affected by the AAS-treatments. 4. The MAO-A activity was increased in the oxymetholone-treated rats while the other treatment groups were unaffected. The MAO-B activity was not changed. 5. The results indicate that relatively high doses of AAS increase dopaminergic and 5-hydroxytryptaminergic metabolism in male rat brain, probably due to enhanced turnover in these monaminergic systems. PMID:10217522

  15. Signaling Pathways Involved in Renal Oxidative Injury: Role of the Vasoactive Peptides and the Renal Dopaminergic System

    PubMed Central

    Rukavina Mikusic, N. L.; Kravetz, M. C.; Kouyoumdzian, N. M.; Della Penna, S. L.; Rosón, M. I.; Fernández, B. E.; Choi, M. R.

    2014-01-01

    The physiological hydroelectrolytic balance and the redox steady state in the kidney are accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Angiotensin II, atrial natriuretic peptide and intrarenal dopamine play a pivotal role in this interactive network. The balance between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide, by one side, and the prooxidant effect of the renin angiotensin system, by the other side, contributes to ensuring the normal function of the kidney. Different pathological scenarios, as nephrotic syndrome and hypertension, where renal sodium excretion is altered, are associated with an impaired interaction between two natriuretic systems as the renal dopaminergic system and atrial natriuretic peptide that may be involved in the pathogenesis of renal diseases. The aim of this review is to update and comment the most recent evidences about the intracellular pathways involved in the relationship between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide and the prooxidant effect of the renin angiotensin system in the pathogenesis of renal inflammation. PMID:25436148

  16. Gdf-15 deficiency does not alter vulnerability of nigrostriatal dopaminergic system in MPTP-intoxicated mice.

    PubMed

    Machado, Venissa; Gilsbach, Ralf; Das, Richa; Schober, Andreas; Bogatyreva, Lioudmila; Hauschke, Dieter; Krieglstein, Kerstin; Unsicker, Klaus; Spittau, Björn

    2016-08-01

    Growth/differentiation factor-15 (Gdf-15) is a member of the transforming growth factor-β (Tgf-β) superfamily and has been shown to be a potent neurotrophic factor for midbrain dopaminergic (DAergic) neurons both in vitro and in vivo. Gdf-15 has also been shown to be involved in inflammatory processes. The aim of this study was to identify the role of endogenous Gdf-15 in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease (PD) by comparing Gdf-15 (+/+) and Gdf-15 (-/-) mice. At 4 days and 14 days post-MPTP administration, both Gdf-15 (+/+) and Gdf-15 (-/-) mice showed a similar decline in DAergic neuron numbers and in striatal dopamine (DA) levels. This was followed by a comparable restorative phase at 90 days and 120 days, indicating that the absence of Gdf-15 does not affect the susceptibility or the recovery capacity of the nigrostriatal system after MPTP administration. The MPTP-induced microglial and astrocytic response was not significantly altered between the two genotypes. However, pro-inflammatory and anti-inflammatory cytokine profiling revealed the differential expression of markers in Gdf-15 (+/+) and Gdf-15 (-/-) mice after MPTP administration. Thus, the MPTP mouse model fails to uncover a major role of endogenous Gdf-15 in the protection of MPTP-lesioned nigrostriatal DAergic neurons, in contrast to its capacity to protect the 6-hydroxydopamine-intoxicated nigrostriatal system. PMID:27115420

  17. Sex-related differences in striatal dopaminergic system after traumatic brain injury.

    PubMed

    Xu, Xiupeng; Cao, Shengwu; Chao, Honglu; Liu, Yinlong; Ji, Jing

    2016-06-01

    Several studies have demonstrated alterations in the dopamine (DA) system after traumatic brain injury (TBI). Additionally, the existence of significant sex-related differences in the dopaminergic system has long been recognized. Accordingly, the purpose of the present study was to investigate whether TBI would differentially alter, in female and male mice, the expression and the function of the striatal vesicular monoamine transporter-2 (VMAT-2), an important DA transporter. After controlled cortical impact (CCI) injury, female mice showed significantly lower striatal DA concentrations and K(+)-evoked DA output. By contrast, no significant sex-related differences were observed in the mRNA and protein levels of striatal dopamine transporter (DAT) and VMAT-2 and the methamphetamine (MA)-evoked DA output. These results demonstrated clear sex-related differences in striatal VMAT-2 function in response to TBI and suggested that female mice may be more sensitive to the TBI-induced inhibition of the VMAT-2 function, as indicated by the greater degree of deficits observed when the VMAT-2 DA-storage function was inhibited by TBI. Moreover, the TBI-induced suppression of locomotion was more pronounced than female mice. Such findings highlight the need for sex-specific considerations when examining differences among brain injury conditions. PMID:27210290

  18. Age-dependent effects of severe traumatic brain injury on cerebral dopaminergic activity in newborn and juvenile pigs.

    PubMed

    Walter, Bernd; Brust, Peter; Füchtner, Frank; Müller, Marco; Hinz, Rainer; Kuwabara, Hiroto; Fritz, Harald; Zwiener, Ulrich; Bauer, Reinhard

    2004-08-01

    There is evidence that the dopaminergic system is sensitive to traumatic brain injury (TBI). However, the age-dependency of this sensitivity has not been studied together with brain oxidative metabolism. We postulate that the acute effects of severe TBI on brain dopamine turnover are age-dependent. Therefore 18F-labelled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with Positron-Emission-Tomography (PET) was used to estimate the activity of the aromatic amino acid decarboxylase (AADC) in the brain of 11 newborn piglets (7-10 days old) and nine juvenile pigs (6-7 weeks old). Six newborn and five juvenile animals were subjected to a severe fluid-percussion (FP) induced TBI. The remaining animals were used as sham operated untreated control groups. Simultaneously, the regional cerebral blood flow (CBF) was measured with colored microspheres and the cerebral metabolic rates of oxygen and glucose were determined. At 1 h after FP-TBI, [18F]FDOPA was infused and PET scanning was performed for 2 h. At 2 h after FP-TBI administration, a second series of measurements of physiological values including CBF and brain oxidative metabolism data had been obtained. Severe FP-TBI elicited a marked increase in the rate constant for fluorodopamine production (k3FDOPA) in all brain regions of newborn piglets studied by between 97% (mesencephalon) and 143% (frontal cortex) (p < 0.05). In contrast, brain hemodynamics and cerebral oxidative metabolism remained unaltered after TBI. Furthermore, the permeability-surface area product of FDOPA (PSFDOPA) was unchanged. In addition, regional blood flow differences between corresponding ipsi- and contralateral brain regions did not occur after TBI. Thus, it is suggested that severe FP-TBI induces an upregulation of AADC activity of newborn piglets that is not related to alterations in brain oxidative metabolism. PMID:15319007

  19. Dopaminergic Modulation of Medial Prefrontal Cortex Deactivation in Parkinson Depression.

    PubMed

    Andersen, Anders H; Smith, Charles D; Slevin, John T; Kryscio, Richard J; Martin, Catherine A; Schmitt, Frederick A; Blonder, Lee X

    2015-01-01

    Parkinson's disease (PD) is associated with emotional abnormalities. Dopaminergic medications ameliorate Parkinsonian motor symptoms, but less is known regarding the impact of dopaminergic agents on affective processing, particularly in depressed PD (dPD) patients. The aim of this study was to examine the effects of dopaminergic pharmacotherapy on brain activation to emotional stimuli in depressed versus nondepressed Parkinson disease (ndPD) patients. Participants included 18 ndPD patients (11 men, 7 women) and 10 dPD patients (7 men, 3 women). Patients viewed photographs of emotional faces during functional MRI. Scans were performed while the patient was taking anti-Parkinson medication and the day after medication had been temporarily discontinued. Results indicate that dopaminergic medications have opposite effects in the prefrontal cortex depending upon depression status. DPD patients show greater deactivation in the ventromedial prefrontal cortex (VMPFC) on dopaminergic medications than off, while ndPD patients show greater deactivation in this region off drugs. The VMPFC is in the default-mode network (DMN). DMN activity is negatively correlated with activity in brain systems used for external visual attention. Thus dopaminergic medications may promote increased attention to external visual stimuli among dPD patients but impede normal suppression of DMN activity during external stimulation among ndPD patients. PMID:26793404

  20. Dopaminergic Modulation of Medial Prefrontal Cortex Deactivation in Parkinson Depression

    PubMed Central

    Andersen, Anders H.; Smith, Charles D.; Slevin, John T.; Kryscio, Richard J.; Martin, Catherine A.; Schmitt, Frederick A.; Blonder, Lee X.

    2015-01-01

    Parkinson's disease (PD) is associated with emotional abnormalities. Dopaminergic medications ameliorate Parkinsonian motor symptoms, but less is known regarding the impact of dopaminergic agents on affective processing, particularly in depressed PD (dPD) patients. The aim of this study was to examine the effects of dopaminergic pharmacotherapy on brain activation to emotional stimuli in depressed versus nondepressed Parkinson disease (ndPD) patients. Participants included 18 ndPD patients (11 men, 7 women) and 10 dPD patients (7 men, 3 women). Patients viewed photographs of emotional faces during functional MRI. Scans were performed while the patient was taking anti-Parkinson medication and the day after medication had been temporarily discontinued. Results indicate that dopaminergic medications have opposite effects in the prefrontal cortex depending upon depression status. DPD patients show greater deactivation in the ventromedial prefrontal cortex (VMPFC) on dopaminergic medications than off, while ndPD patients show greater deactivation in this region off drugs. The VMPFC is in the default-mode network (DMN). DMN activity is negatively correlated with activity in brain systems used for external visual attention. Thus dopaminergic medications may promote increased attention to external visual stimuli among dPD patients but impede normal suppression of DMN activity during external stimulation among ndPD patients. PMID:26793404

  1. Increased Mesohippocampal Dopaminergic Activity and Improved Depression-Like Behaviors in Maternally Separated Rats Following Repeated Fasting/Refeeding Cycles

    PubMed Central

    Jahng, Jeong Won; Yoo, Sang Bae; Kim, Jin Young; Kim, Bom-Taeck; Lee, Jong-Ho

    2012-01-01

    We have previously reported that rats that experienced 3 h of daily maternal separation during the first 2 weeks of birth (MS) showed binge-like eating behaviors with increased activity of the hypothalamic-pituitary-adrenal axis when they were subjected to fasting/refeeding cycles repeatedly. In this study, we have examined the psychoemotional behaviors of MS rats on the fasting/refeeding cycles, together with their brain dopamine levels. Fasting/refeeding cycles normalized the ambulatory activity of MS rats, which was decreased by MS experience. Depression-like behaviors, but not anxiety, by MS experience were improved after fasting/refeeding cycles. Fasting/refeeding cycles did not significantly affect the behavioral scores of nonhandled (NH) control rats. Fasting/refeeding cycles increased dopamine levels not only in the hippocampus but also in the midbrain dopaminergic neurons in MS rats, but not in NH controls. Results demonstrate that fasting/refeeding cycles increase the mesohippocampal dopaminergic activity and improve depression-like behaviors in rats that experienced MS. Together with our previous paper, it is suggested that increased dopamine neurotransmission in the hippocampus may be implicated in the underlying mechanisms by which the fasting/refeeding cycles induce binge-like eating and improve depression-like behaviors in MS rats. PMID:22934157

  2. Molecular Signatures of Natural Selection for Polymorphic Genes of the Human Dopaminergic and Serotonergic Systems: A Review.

    PubMed

    Taub, Daniel R; Page, Joshua

    2016-01-01

    A large body of research has examined the behavioral and mental health consequences of polymorphisms in genes of the dopaminergic and serotonergic systems. Along with this, there has been considerable interest in the possibility that these polymorphisms have developed and/or been maintained due to the action of natural selection. Episodes of natural selection on a gene are expected to leave molecular "footprints" in the DNA sequences of the gene and adjacent genomic regions. Here we review the research literature investigating molecular signals of selection for genes of the dopaminergic and serotonergic systems. The gene SLC6A4, which codes for a serotonin transport protein, was the one gene for which there was consistent support from multiple studies for a selective episode. Positive selection on SLC6A4 appears to have been initiated ∼ 20-25,000 years ago in east Asia and possibly in Europe. There are scattered reports of molecular signals of selection for other neurotransmitter genes, but these have generally failed at replication across studies. In spite of speculation in the literature about selection on these genes, current evidence from population genomic analyses supports selectively neutral processes, such as genetic drift and population dynamics, as the principal drivers of recent evolution in dopaminergic and serotonergic genes other than SLC6A4. PMID:27375535

  3. The role of dopaminergic and serotonergic systems in neurodevelopmental disorders: a focus on epilepsy and seizure susceptibility

    PubMed Central

    Tripathi, Prem Prakash; Bozzi, Yuri

    2015-01-01

    Introduction: The embryonic development of the vertebrate Central Nervous System (CNS) requires the induction of transcription factors regulating the expression of specific subsets of genes in restricted CNS regions. Among these transcription factors, homeobox-containing proteins play a crucial role, and altered expression of these factors can impact the embryonic as well as adult CNS functions. Importantly, the homeobox-containing genes Otx2, Engrailed-1 (En1), and Engrailed-2 (En2) have been described to crucially regulate differentiation of dopaminergic and serotonergic neurons during vertebrate CNS development. Dopaminergic and serotonergic neurons, located in midbrain and hindbrain regions respectively, diffusely innervate several forebrain areas including limbic system, contributing in regulating several physiological functions. Understanding the embryonic development of these neuronal populations is crucial to elucidate their physiological function including brain excitability in the adult brain. New evidence is emerging about the impact of an altered embryonic development of dopamine and serotonin neurons onto seizure susceptibility in the adult life. Methods: In this mini-review, we summarized our kainic acid (KA) induced seizure susceptibility in adult mutant mouse lines with targeted manipulation of Otx2, En1, and En2 genes. Results: Our results demonstrated that altered development of dopamine (DA) neurons does not interfere with KA seizure susceptibility, while increased serotonin (5-hydroxytryptamine, 5-HT) hyperinnervation leads to resistance to KA-induced seizure. Conclusion: We propose that developmental alterations of serotonergic but not dopaminergic circuits play a crucial role in controlling seizure susceptibility in the adult life PMID:26191504

  4. Molecular Signatures of Natural Selection for Polymorphic Genes of the Human Dopaminergic and Serotonergic Systems: A Review

    PubMed Central

    Taub, Daniel R.; Page, Joshua

    2016-01-01

    A large body of research has examined the behavioral and mental health consequences of polymorphisms in genes of the dopaminergic and serotonergic systems. Along with this, there has been considerable interest in the possibility that these polymorphisms have developed and/or been maintained due to the action of natural selection. Episodes of natural selection on a gene are expected to leave molecular “footprints” in the DNA sequences of the gene and adjacent genomic regions. Here we review the research literature investigating molecular signals of selection for genes of the dopaminergic and serotonergic systems. The gene SLC6A4, which codes for a serotonin transport protein, was the one gene for which there was consistent support from multiple studies for a selective episode. Positive selection on SLC6A4 appears to have been initiated ∼ 20–25,000 years ago in east Asia and possibly in Europe. There are scattered reports of molecular signals of selection for other neurotransmitter genes, but these have generally failed at replication across studies. In spite of speculation in the literature about selection on these genes, current evidence from population genomic analyses supports selectively neutral processes, such as genetic drift and population dynamics, as the principal drivers of recent evolution in dopaminergic and serotonergic genes other than SLC6A4. PMID:27375535

  5. Effects of an early experience of reward through maternal contact or its denial on the dopaminergic system of the rat brain.

    PubMed

    Raftogianni, A; Stamatakis, A; Diamantopoulou, A; Kollia, A-M; Stylianopoulou, F

    2014-06-01

    The mesolimbic/mesocortical dopaminergic pathway plays a pivotal role in the reward system. During the neonatal period the mother is the main source of rewarding stimuli. We have developed an experimental model in which rat pups learn a T-maze during the neonatal period (postnatal day (PND) 10-13) using contact with the mother as the reward. One group of animals is allowed contact with the mother (receipt of expected reward, RER) while the other was denied (denial of expected reward, DER). We determined the effects of these two early experiences in the prefrontal cortex (PFC) and the nucleus accumbens (nAc), the levels of dopamine (DA) and its metabolites [3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] by high-performance liquid chromatography and those of D1 and D2 receptors by autoradiographic in vitro binding both on PND 13 and in adulthood. On PND13, 2h after the end of training, the RER experience resulted in higher DA, HVA and D1 receptor levels in the nAc, while the DER in lower DA and its metabolites (DOPAC and HVA) in the PFC. These results could be related to the reward the RER pups received through the contact with their mother. The RER and DER early experience had long-term sex-dependent effects: The RER-induced activation of the dopaminergic system in the nAc was also evident in adult female rats. In contrast, adult DER males, similar to PND13 animals, had reduced dopamine in the PFC. Our results document that early experiences, a key determinant of adult brain function, affect the dopaminergic system which is disturbed in many psychiatric diseases. PMID:24680882

  6. The nigrostriatal dopaminergic system assessed in vivo by positron emission tomography in healthy volunteer subjects and patients with Parkinson's disease

    SciTech Connect

    Leenders, K.L.; Salmon, E.P.; Tyrrell, P.; Perani, D.; Brooks, D.J.; Sager, H.; Jones, T.; Marsden, C.D.; Frackowiak, R.S. )

    1990-12-01

    A group of healthy control subjects and patients with Parkinson's disease were investigated using positron emission tomography and two tracers as indicators of different specific properties of the presynaptic dopaminergic system in caudate nucleus and putamen. The first tracer, 6-L-(18F)-fluorodopa, was used as an analog of levodopa to assess its regional brain uptake, conversion into, and retention as dopamine and further metabolites. The second tracer, (11C)-nomifensine was employed as an indicator of striatal monaminergic reuptake sites that are principally dopaminergic. We have used this tracer to assess dopaminergic nerve terminal density. In patients with Parkinson's disease, striatal uptake of both tracers was decreased, putamen being significantly more affected than caudate. Side-to-side differences of uptake in putamen, but not caudate, correlated with corresponding left-right differences of scored clinical motor performance. Both 6-L(18F)-fluorodopa and (11C)-nomifensine tracer uptake in putamen was decreased on average to 40% of normal values, suggesting that a substantial part of the cellular elements of the dopaminergic nigrostriatal system is still intact in living parkinsonian patients. This is in contrast to the generally extreme depletion of endogenous dopamine in the putamen of patients found at postmortem. Our results lend support to the search for drug treatments that protect against further nigrostriatal cell loss and that could be exhibited as soon as the disease manifests clinically. If successful, a sufficient striatal nerve terminal pool would remain so that the effectiveness of levodopa as a dopamine repletor could persist.

  7. Methamphetamine-Induced Dopamine Transporter Complex Formation and Dopaminergic Deficits: The Role of D2 Receptor Activation

    PubMed Central

    Hadlock, Gregory C.; Chu, Pei-Wen; Walters, Elliot T.; Hanson, Glen R.

    2010-01-01

    Methamphetamine (METH) abuse is a serious public health issue. Of particular concern are findings that repeated high-dose administrations of METH cause persistent dopaminergic deficits in rodents, nonhuman primates, and humans. Previous studies have also revealed that METH treatment causes alterations in the dopamine transporter (DAT), including the formation of higher molecular mass DAT-associated complexes. The current study extends these findings by examining mechanisms underlying DAT complex formation. The association among DAT complex formation and other METH-induced phenomena, including alterations in vesicular monoamine transporter 2 (VMAT2) immunoreactivity, astrocytic activation [as assessed by increased glial fibrillary acidic protein (GFAP) immunoreactivity], and persistent dopaminergic deficits was also explored. Results revealed that METH-induced DAT complex formation and reductions in VMAT2 immunoreactivity precede increases in GFAP immunoreactivity. Furthermore, and as reported previously for DAT complexes, pretreatment with the D2 receptor antagonist eticlopride [S-(−)-3-chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxybenzamide hydrochloride] attenuated the decrease in VMAT2 immunoreactivity as assessed 24 h after METH treatment. DAT complexes distinct from those present 24 h after METH treatment, decreases in VMAT2 immunoreactivity, and increased GFAP immunoreactivity were present 48 to 72 h after METH treatment. Pretreatment with eticlopride attenuated each of these phenomena. Finally, DAT complexes were present 7 days after METH treatment, a time point at which VMAT2 and DAT monomer immunoreactivity were also reduced. Eticlopride pretreatment attenuated each of these phenomena. These findings provide novel insight into not only receptor-mediated mechanisms underlying the effects of METH but also the interaction among factors that probably are associated with the persistent dopaminergic deficits caused by the stimulant. PMID

  8. Lateral habenula as a link between dopaminergic and serotonergic systems contributes to depressive symptoms in Parkinson's disease.

    PubMed

    Luo, Xiao Feng; Zhang, Bei Lin; Li, Ji Cheng; Yang, Ying Ying; Sun, Yan Fei; Zhao, Hua

    2015-01-01

    Degeneration of substantia nigra dopaminergic neurons is a key pathological change of Parkinson's disease (PD), and its motor consequences have been widely recognized. Recently, mood disorders associated with PD have begun to attract a great deal of interest, however, their pathogenesis remains unclear. PD is associated with not only degenerative changes in dopaminergic neurons in the substantia nigra but also changes in serotonergic neurons in the raphe nuclei. The abnormalities in central 5-hydroxytryptamine (5-HT) neurotransmission are thought to play a key role in the pathogenesis of depression. The lateral habenula (LHb) is closely related to the substantia nigra and raphe nuclei, and its hyperactivity is closely related to the pathogenesis of depression. In this study, we screened rats with depressive-like behaviors from PD model animals and found that cytochrome c oxidase activity in the LHb of these rats was twice that seen in the control rats. In the forced swim test, LHb lesions caused a decrease in depressive-like behavior of PD rats as indexed by decreased immobility times and increased climbing times. Additionally, LHb lesions caused an enhance in 5-HT levels in the raphe nuclei. These results suggest that LHb lesions may improve depressive-like behavior in PD rats by increasing 5-HT levels in the raphe nuclei. Thus, LHb contributes to the depressive-like behavior in PD rats via mediating the effects of dopaminergic neurons in the substantia nigra on serotonergic neurons in the raphe nuclei. PMID:25499570

  9. Maternal nicotine exposure during lactation alters food preference, anxiety-like behavior and the brain dopaminergic reward system in the adult rat offspring.

    PubMed

    Pinheiro, C R; Moura, E G; Manhães, A C; Fraga, M C; Claudio-Neto, S; Younes-Rapozo, V; Santos-Silva, A P; Lotufo, B M; Oliveira, E; Lisboa, P C

    2015-10-01

    The mesolimbic reward pathway is activated by drugs of abuse and palatable food, causing a sense of pleasure, which promotes further consumption of these substances. Children whose parents smoke are more vulnerable to present addictive-like behavior to drugs and food.We evaluated the association between maternal nicotine exposure during lactation with changes in feeding, behavior and in the dopaminergic reward system. On postnatal day (PN) 2,Wistar rat dams were implanted with minipumps releasing nicotine (N; 6 mg/kg/day, s.c.) or saline (C) for 14 days. On PN150 and PN160, offspring were divided into 4 groups for a food challenge: N and C that received standard chow(SC); and N and C that could freely self-select (SSD) between high-fat and high-sugar diets (HFD and HSD, respectively). Offspring were tested in the elevated plus maze (EPM) and open field (OF) arena on PN152–153. On PN170, offspring were euthanized for central dopaminergic analysis. SSD animals showed an increased food intake compared to SC ones and a preference for HFD. However, N-SSD animals consumed relatively more HSD than C-SSD ones. Regarding behavior, N animals showed an increase in the time spent in the EPM center and a reduction in relative activity in the OF center. N offspring presented lower dopamine receptor (D2R) and transporter (DAT) contents in the nucleus accumbens, and lower D2R in the arcuate nucleus. Postnatal exposure to nicotine increases preference for sugar and anxiety levels in the adult progeny possibly due to a decrease in dopaminergic action in the nucleus accumbens and arcuate nucleus. PMID:26048299

  10. Age-related changes in the renal dopaminergic system and expression of renal amino acid transporters in WKY and SHR rats.

    PubMed

    Pinto, Vanda; Amaral, João; Silva, Elisabete; Simão, Sónia; Cabral, José Miguel; Afonso, Joana; Serrão, Maria Paula; Gomes, Pedro; Pinho, Maria João; Soares-da-Silva, Patrício

    2011-01-01

    This study examined age-related changes in renal dopaminergic activity and expression of amino acid transporters potentially involved in renal tubular uptake of l-DOPA in Wistar Kyoto (WKY) and spontaneously hypertensive rats. Aging (from 13 to 91 weeks) was accompanied by increases in systolic blood pressure (SBP) in both WKY and SHR. The sum of urinary dopamine and DOPAC and the urinary dopamine/l-DOPA ratio were increased in aged SHR but not in aged WKY. The urinary dopamine/renal delivery of l-DOPA ratio was increased in both rat strains with aging. LAT2 abundance was increased in aged WKY and SHR. The expression of 4F2hc was markedly elevated in aged SHR but not in aged WKY. ASCT2 was upregulated in both aged WKY and SHR. Plasma aldosterone levels and urinary noradrenaline levels were increased in aged WKY and SHR though levels of both entities were more elevated in aged SHR. Activation of the renal dopaminergic system is more pronounced in aged SHR than in aged WKY and is associated with an upregulation of renal cortical ASCT2 in WKY and of LAT2/4F2hc and ASCT2 in SHR. This activation may be the consequence of a counter-regulatory mechanism for stimuli leading to sodium reabsorption. PMID:21699911

  11. EFFECTS OF TRIMETHYLTIN ON DOPAMINERGIC AND SEROTONERGIC FUNCTION IN THE CENTRAL NERVOUS SYSTEM

    EPA Science Inventory

    The effects of trimethyltin (TMT) administration on regional concentrations of dopamine (DA), serotonin (5-HT), and their metabolites were determined. Acute administration of 3 or 7 mg/kg TMT (as the chloride) to adult male Long-Evans rats caused alterations in both dopaminergic ...

  12. Maneb-induced dopaminergic neuronal death is not affected by loss of mitochondrial complex I activity: Results from primary mesencephalic dopaminergic neurons cultured from individual Ndufs4+/+ and Ndufs4-/- mouse embryos

    PubMed Central

    Choi, Won-Seok; Xia, Zhengui

    2014-01-01

    Primary cultures from embryonic mouse ventral mesencephalon are widely used for investigating the mechanisms of dopaminergic neuronal death in Parkinson's disease models. Specifically, single mouse or embryo cultures from littermates can be very useful for comparative studies involving transgenic mice when the neuron cultures are to be prepared before genotyping. However, preparing single mouse embryo culture is technically challenging because of the small number of cells present in the mesencephalon of each embryo (150,000-300,000), of which only 0.5-5% are tyrosine hydroxylase (TH) -positive, dopaminergic neurons. In this study, we optimized the procedure for preparing primary mesencephalic neuron cultures from individual mouse embryos. Mesencephalic neurons that are dissociated delicately, plated on Aclar film coverslips, and incubated in DMEM supplemented with FBS for 5 days and then N2 supplement for 1 day resulted in the best survival of dopaminergic neurons from each embryo. Using this optimized method, we prepared mesencephalic neuron cultures from single Ndufs4+/+ or Ndufs4-/- embryos, and investigated the role of mitochondrial complex I in maneb-induced dopamine neuron death. Our results suggest that maneb toxicity to dopamine neurons is not affected by loss of mitochondrial complex I activity in Ndufs4-/- cultures. PMID:25275677

  13. Salsolinol causing parkinsonism activates endoplasmic reticulum-stress signaling pathways in human dopaminergic SK-N-SH cells.

    PubMed

    Kheradpezhouh, Mohsen; Shavali, Shaik; Ebadi, Manuchair

    2003-01-01

    The endoplasmic reticulum (ER) is a small intracellular organelle to which one-third of cellular proteins are translocated after translation and post-translational modification, folding and the formation of a three- or four-dimensional structure. ER also has a role in the transportation of proteins to other intracellular organelles, the cell surface or the outer space of the cell membrane. Thus, ER is an important intermediate which maintains intracellular homeostasis through complex control systems. Once these control systems are disrupted, serious disturbances occur. Many neurodegenerative diseases including Parkinson's disease involve aggregation and deposition of misfolded proteins such as alpha-synuclein. Endogenously occurring neurotoxins such as Salsolinol and 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) causing Parkinsonism may foster misfolded proteins and bring forth ER stress in dopaminergic neurons. In the present study we examined translational changes fostered by ER stress and mediated by the Parkinsonian endogenous neurotoxins, salsolinol and 1BnTIQ, in dopaminergic cell line. Treatment with salsolinol and 1BnTIQ induced several genes involved in ER stress and unfolded protein response (UPR), such as ER chaperones and GADD153 (CHOP). Immunoblotting confirmed phosphorylation of the key endoplasmic reticulum stress kinase PERK (PKR-like-ER kinase) and eIF2alpha and induction of their downstream targets such as Bip and GADD153. These findings suggest a widespread involvement of ER stress and unfolded protein response in the pathophysiology of Parkinson's disease. PMID:14739562

  14. Transduced PEP-1-PON1 proteins regulate microglial activation and dopaminergic neuronal death in a Parkinson's disease model.

    PubMed

    Kim, Mi Jin; Park, Meeyoung; Kim, Dae Won; Shin, Min Jea; Son, Ora; Jo, Hyo Sang; Yeo, Hyeon Ji; Cho, Su Bin; Park, Jung Hwan; Lee, Chi Hern; Kim, Duk-Soo; Kwon, Oh-Shin; Kim, Joon; Han, Kyu Hyung; Park, Jinseu; Eum, Won Sik; Choi, Soo Young

    2015-09-01

    Parkinson's disease (PD) is an oxidative stress-mediated neurodegenerative disorder caused by selective dopaminergic neuronal death in the midbrain substantia nigra. Paraoxonase 1 (PON1) is a potent inhibitor of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) against oxidation by destroying biologically active phospholipids with potential protective effects against oxidative stress-induced inflammatory disorders. In a previous study, we constructed protein transduction domain (PTD) fusion PEP-1-PON1 protein to transduce PON1 into cells and tissue. In this study, we examined the role of transduced PEP-1-PON1 protein in repressing oxidative stress-mediated inflammatory response in microglial BV2 cells after exposure to lipopolysaccharide (LPS). Moreover, we identified the functions of transduced PEP-1-PON1 proteins which include, mitigating mitochondrial damage, decreasing reactive oxidative species (ROS) production, matrix metalloproteinase-9 (MMP-9) expression and protecting against 1-methyl-4-phenylpyridinium (MPP(+))-induced neurotoxicity in SH-SY5Y cells. Furthermore, transduced PEP-1-PON1 protein reduced MMP-9 expression and protected against dopaminergic neuronal cell death in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice model. Taken together, these results suggest a promising therapeutic application of PEP-1-PON1 proteins against PD and other inflammation and oxidative stress-related neuronal diseases. PMID:26117230

  15. Paradoxical dopaminergic drug effects in extraversion: dose- and time-dependent effects of sulpiride on EEG theta activity

    PubMed Central

    Chavanon, Mira-Lynn; Wacker, Jan; Stemmler, Gerhard

    2013-01-01

    Dopaminergic drugs frequently produce paradoxical effects depending on baseline performance levels, genotype, or personality traits. The present study for the first time aimed to specify the mechanisms underlying such opposite effects using the following recently reported scenario as an example: depending on the personality trait agentic extraversion (agentic facet, aE; i.e., assertiveness, dominance, ambition, positive emotionality) the selective dopamine D2 receptor antagonist sulpiride (200 mg) had opposite effects on resting posterior vs. anterior theta activity in the electroencephalogram (EEG). In order to better describe these opposite pharmaco-EEG effects and to generate hypotheses regarding the underlying mechanisms, we measured the EEG intermittently over 5 h in 80 healthy male volunteers extremely high or low in aE who had received either placebo or one of three doses of sulpiride (50, 200, or 400 mg). The findings suggest a model postulating stronger pre- vs. postsynaptic subreceptor effects in high aE individuals compared to low aE individuals. Future studies may now systematically apply the model to other examples of paradoxical dopaminergic drug effects and examine the molecular basis of individual differences in pre- vs. postsynaptic dopamine D2 subreceptor sensitivities and densities. PMID:23580360

  16. Activation instead of blocking mesolimbic dopaminergic reward circuitry is a preferred modality in the long term treatment of reward deficiency syndrome (RDS): a commentary

    PubMed Central

    Blum, Kenneth; Chen, Amanda Lih Chuan; Chen, Thomas JH; Braverman, Eric R; Reinking, Jeffrey; Blum, Seth H; Cassel, Kimberly; Downs, Bernard W; Waite, Roger L; Williams, Lonna; Prihoda, Thomas J; Kerner, Mallory M; Palomo, Tomas; Comings, David E; Tung, Howard; Rhoades, Patrick; Oscar-Berman, Marlene

    2008-01-01

    Background and hypothesis Based on neurochemical and genetic evidence, we suggest that both prevention and treatment of multiple addictions, such as dependence to alcohol, nicotine and glucose, should involve a biphasic approach. Thus, acute treatment should consist of preferential blocking of postsynaptic Nucleus Accumbens (NAc) dopamine receptors (D1-D5), whereas long term activation of the mesolimbic dopaminergic system should involve activation and/or release of Dopamine (DA) at the NAc site. Failure to do so will result in abnormal mood, behavior and potential suicide ideation. Individuals possessing a paucity of serotonergic and/or dopaminergic receptors, and an increased rate of synaptic DA catabolism due to high catabolic genotype of the COMT gene, are predisposed to self-medicating any substance or behavior that will activate DA release, including alcohol, opiates, psychostimulants, nicotine, gambling, sex, and even excessive internet gaming. Acute utilization of these substances and/or stimulatory behaviors induces a feeling of well being. Unfortunately, sustained and prolonged abuse leads to a toxic" pseudo feeling" of well being resulting in tolerance and disease or discomfort. Thus, a reduced number of DA receptors, due to carrying the DRD2 A1 allelic genotype, results in excessive craving behavior; whereas a normal or sufficient amount of DA receptors results in low craving behavior. In terms of preventing substance abuse, one goal would be to induce a proliferation of DA D2 receptors in genetically prone individuals. While in vivo experiments using a typical D2 receptor agonist induce down regulation, experiments in vitro have shown that constant stimulation of the DA receptor system via a known D2 agonist results in significant proliferation of D2 receptors in spite of genetic antecedents. In essence, D2 receptor stimulation signals negative feedback mechanisms in the mesolimbic system to induce mRNA expression causing proliferation of D2 receptors

  17. When control fails: influence of the prefrontal but not striatal dopaminergic system on behavioural flexibility in a change detection task.

    PubMed

    Schulz, Stefanie; Arning, Larissa; Pinnow, Marlies; Wascher, Edmund; Epplen, Jörg T; Beste, Christian

    2012-02-01

    There is growing interest in understanding the neurobiological foundations of attention. To examine whether attentional processes in a change detection task are modulated by dopamine signalling, we investigated the influence of two polymorphisms, i.e. Val158Met (rs4680) in the catechol-O-methyl transferase (COMT) and a variable number of tandem repeats polymorphism (VNTR, rs28363170) in the dopamine transporter (DAT1). The COMT Met allele, which results in lower enzyme activity and therefore probably enhanced PFC dopamine signalling, was significantly associated with task-performance and modulated executive control: Homozygous Met/Met allele carriers had difficulties when performing a change detection task, particularly showing the greatest difficulties in case cognitive and behavioural flexibility was necessary and the required reaction was not part of the subject's primary task set. Contrary, no difference between the two genotype groups were evident, when an attentional conflict emerged and attentional control was needed for adequate responding. No association with variation in DAT1 was observed. The results indicate a dissociation of the prefrontal and striatal dopamine system for attentional control and behavioural flexibility in a change detection task: While prefrontal dopamine turnover seems to modulate performance, putatively via difficulties in set shifting leading to behavioural inflexibility in COMT Met allele carriers, striatal dopamine turnover seems less important in this regard. With respect to other studies examining mechanisms of attentional functions in different paradigms, the results suggest that behavioural flexibility and attentional control as two executive subprocesses are differentially influenced by genetic polymorphisms within the dopaminergic system. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. PMID:22067551

  18. PET studies of the presynaptic and postsynaptic dopaminergic system in Tourette's syndrome.

    PubMed Central

    Turjanski, N; Sawle, G V; Playford, E D; Weeks, R; Lammerstma, A A; Lees, A J; Brooks, D J

    1994-01-01

    Dysfunction of the dopaminergic pathway has been postulated to underlie the symptomatology of Tourette's syndrome. Presynaptic functional integrity of dopaminergic terminals was assessed with 18F-dopa PET in 10 patients with Tourette's syndrome, three of whom were drug free and seven of whom were on neuroleptic treatment. Dopamine D2 receptor site density was measured with 11C-raclopride PET in a further group of five drug free patients with Tourette's syndrome. Mean caudate and putamen 18F-dopa influx constants were similar in patients with Tourette's syndrome and controls, and there was no difference in striatal 18F-dopa uptake between the treated and untreated Tourette's syndrome groups. Mean caudate and putamen 11C-raclopride binding potentials in patients with Tourette's syndrome were also similar to control values. The findings suggest that striatal metabolism of exogenous levodopa and the density of striatal D2 receptors are both normal in patients with Tourette's syndrome and that Tourette's syndrome does not arise from a primary dysfunction of dopaminergic terminals. Images PMID:7911827

  19. Preclinical assessment of dopaminergic system in rats by MicroPET using three positron-emitting radiopharmaceuticals

    NASA Astrophysics Data System (ADS)

    Lara-Camacho, V. M.; Ávila-García, M. C.; Ávila-Rodríguez, M. A.

    2014-11-01

    Different diseases associated with dysfunction of dopaminergic system such as Parkinson, Alzheimer, and Schizophrenia are being widely studied with positron emission tomography (PET) which is a noninvasive method useful to assess the stage of these illnesses. In our facility we have recently implemented the production of [11C ]-DTBZ, [11C ]-RAC, and [18F ]-FDOPA, which are among the most common PET radiopharmaceuticals used in neurology applications to get information about the dopamine pathways. In this study two healthy rats were imaged with each of those radiotracers in order to confirm selective striatum uptake as a proof of principle before to release them for human use.

  20. Preclinical assessment of dopaminergic system in rats by MicroPET using three positron-emitting radiopharmaceuticals

    SciTech Connect

    Lara-Camacho, V. M. Ávila-García, M. C. Ávila-Rodríguez, M. A.

    2014-11-07

    Different diseases associated with dysfunction of dopaminergic system such as Parkinson, Alzheimer, and Schizophrenia are being widely studied with positron emission tomography (PET) which is a noninvasive method useful to assess the stage of these illnesses. In our facility we have recently implemented the production of [{sup 11}C]-DTBZ, [{sup 11}C]-RAC, and [{sup 18}F]-FDOPA, which are among the most common PET radiopharmaceuticals used in neurology applications to get information about the dopamine pathways. In this study two healthy rats were imaged with each of those radiotracers in order to confirm selective striatum uptake as a proof of principle before to release them for human use.

  1. The ADHD-susceptibility gene lphn3.1 modulates dopaminergic neuron formation and locomotor activity during zebrafish development.

    PubMed

    Lange, M; Norton, W; Coolen, M; Chaminade, M; Merker, S; Proft, F; Schmitt, A; Vernier, P; Lesch, K-P; Bally-Cuif, L

    2012-09-01

    Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, increased impulsivity and emotion dysregulation. Linkage analysis followed by fine-mapping identified variation in the gene coding for Latrophilin 3 (LPHN3), a putative adhesion-G protein-coupled receptor, as a risk factor for ADHD. In order to validate the link between LPHN3 and ADHD, and to understand the function of LPHN3 in the etiology of the disease, we examined its ortholog lphn3.1 during zebrafish development. Loss of lphn3.1 function causes a reduction and misplacement of dopamine-positive neurons in the ventral diencephalon and a hyperactive/impulsive motor phenotype. The behavioral phenotype can be rescued by the ADHD treatment drugs methylphenidate and atomoxetine. Together, our results implicate decreased Lphn3 activity in eliciting ADHD-like behavior, and demonstrate its correlated contribution to the development of the brain dopaminergic circuitry. PMID:22508465

  2. Effect of Early Overfeeding on Palatable Food Preference and Brain Dopaminergic Reward System at Adulthood: Role of Calcium Supplementation.

    PubMed

    Conceição, E P S; Carvalho, J C; Manhães, A C; Guarda, D S; Figueiredo, M S; Quitete, F T; Oliveira, E; Moura, E G; Lisboa, P C

    2016-05-01

    Rats raised in small litters (SL) are obese and hyperphagic. In the present study, we evaluated whether obesity is associated with changes in the mesocorticolimbic dopaminergic reward system in these animals at adulthood. We also assessed the anti-obesity effects of dietary calcium supplementation. To induce early overfeeding, litters were adjusted to three pups on postnatal day (PN)3 (SL group). Control litters were kept with 10 pups each until weaning (NL group). On PN120, SL animals were subdivided into two groups: SL (standard diet) and SL-Ca [SL with calcium supplementation (10 g calcium carbonate/kg rat chow) for 60 days]. On PN175, animals were subjected to a food challenge: animals could choose between a high-fat (HFD) or a high-sugar diet (HSD). Food intake was recorded after 30 min and 12 h. Euthanasia occurred on PN180. SL rats had higher food intake, body mass and central adiposity. Sixty days of dietary calcium supplementation (SL-Ca) prevented these changes. Only SL animals preferred the HFD at 12 h. Both SL groups had lower tyrosine hydroxylase content in the ventral tegmental area, lower dopaminergic transporter content in the nucleus accumbens, and higher type 2 dopamine receptor (D2R) content in the hypothalamic arcuate nucleus (ARC). They also had higher neuropeptide Y (NPY) and lower pro-opiomelanocortin contents in the ARC. Calcium treatment normalised only D2R and NPY contents. Precocious obesity induces long-term effects in the brain dopaminergic system, which can be associated with an increased preference for fat at adulthood. Calcium treatment prevents this last alteration, partially through its actions on ARC D2R and NPY proteins. PMID:26929129

  3. Estradiol and isotype-selective estrogen receptor agonists modulate the mesocortical dopaminergic system in gonadectomized female rats.

    PubMed

    Sárvári, Miklós; Deli, Levente; Kocsis, Pál; Márk, László; Maász, Gábor; Hrabovszky, Erik; Kalló, Imre; Gajári, Dávid; Vastagh, Csaba; Sümegi, Balázs; Tihanyi, Károly; Liposits, Zsolt

    2014-10-01

    The mesocortical dopaminergic pathway projecting from the ventral tegmental area (VTA) to the prefrontal cortex (PFC) contributes to the processing of reward signals. This pathway is regulated by gonadal steroids including estradiol. To address the putative role of estradiol and isotype-selective estrogen receptor (ER) agonists in the regulation of the rodent mesocortical system, we combined fMRI, HPLC-MS and qRT-PCR techniques. In fMRI experiments adult, chronically ovariectomized rats, treated with either vehicle, estradiol, ERα agonist 16α-lactone-estradiol (LE2) or ERβ agonist diarylpropionitrile (DPN), received a single dose of d-amphetamine-sulphate (10mg/kg, i.p.) and BOLD responses were monitored in the VTA and the PFC. Ovariectomized rats showed no significant response to amphetamine. In contrast, the VTA of ER agonist-substituted ovariectomized rats showed robust amphetamine-evoked BOLD increases. The PFC of estradiol-replaced animals was also responsive to amphetamine. Mass spectroscopic analysis of dopamine and its metabolites revealed a two-fold increase in both dopamine and 3,4-dihydroxyphenylacetic acid content of the PFC in estradiol-replaced animals compared to ovariectomized controls. qRT-PCR studies revealed upregulation of dopamine transporter and dopamine receptor in the VTA and PFC, respectively, of ER agonist-treated ovariectomized animals. Collectively, the results indicate that E2 and isotype-selective ER agonists can powerfully modulate the responsiveness of the mesocortical dopaminergic system, increase the expression of key genes related to dopaminergic neurotransmission and augment the dopamine content of the PFC. In a broader sense, the findings support the concept that the manifestation of reward signals in the PFC is dependent on the actual estrogen milieu of the brain. PMID:24976584

  4. Developmental Exposure to a Dopaminergic Toxicant Produces Altered Locomotor Activity in Larval Zebrafish

    EPA Science Inventory

    In an effort to develop a rapid in vivo screen for EPA’s prioritization of toxic chemicals, we are characterizing the locomotor activity of zebrafish (Danio rerio) larvae after developmental exposure to various classes of prototypic drugs that act on the central nervous system. ...

  5. The influence of dopaminergic system in medial prefrontal cortex on ketamine-induced amnesia in passive avoidance task in mice.

    PubMed

    Farahmandfar, Maryam; Bakhtazad, Atefeh; Akbarabadi, Ardeshir; Zarrindast, Mohammad-Reza

    2016-06-15

    Dopaminergic modulations of glutamate receptors are essential for the prefrontal cortical (PFC) behavioral and cognitive functions. In order to understand the effect of dopamine/glutamate interactions on learning and memory, we investigated the effects of intra medial prefrontal cortex (mPFC) injections of dopaminergic agents on ketamine-induced amnesia by using a one-trial passive avoidance task in mice. Pre-training administration of ketamine (5, 10 and 15mg/kg, i.p.) dose-dependently decreased the memory acquisition of a one-trial passive avoidance task. Pre-training intra-mPFC administration of SKF 38393, D1 receptor agonist and quinpirol D2 receptor agonist, alone did not affect memory acquisition. However, amnesia induced by pre-training ketamine (15mg/kg) significantly decreased by pretreatment of SKF 38393 (2 and 4µg/mouse) and quinpirol (0.3, 1 and 3µg/mouse). Pre-training administration of SCH 23390, D1 receptor antagonist (0.75 and 1μg/mouse, intra-mPFC), and sulpiride D2 receptor antagonist (3μg/mouse, intra-mPFC) impaired memory acquisition. In addition, co-pretreatment of different doses of SCH 23390 and sulpiride with lower dose of ketamine (5mg/kg), which did not induce amnesia by itself, caused inhibition of memory formation. It may be concluded that dopaminergic system of medial prefrontal cortex is involved in the ketamine-induced impairment of memory acquisition. PMID:27041647

  6. Post-trial dopaminergic modulation of conditioned catalepsy: A single apomorphine induced increase/decrease in dopaminergic activation immediately following a conditioned catalepsy response can reverse/enhance a haloperidol conditioned and sensitized catalepsy response.

    PubMed

    Oliveira, Lucas Rangel; Dias, Flávia Regina Cruz; Santos, Breno Garone; Silva, Jade Leal Loureiro; Carey, Robert J; Carrera, Marinete Pinheiro

    2016-09-15

    Haloperidol can induce catalepsy and this drug effect can be conditioned as well as sensitized to contextual cues. We used a paired/unpaired Pavlovian conditioning protocol to establish haloperidol catalepsy conditioned and sensitized responses. Groups of rats were given 10 daily catalepsy tests following administration of vehicle (n=24) or haloperidol (1.0mg/kg) either paired (n=18) or unpaired (n=18) to testing. Subsequently, testing for conditioning was conducted and conditioning and sensitization of catalepsy were observed selectively in the paired group. Immediately following a second test for catalepsy conditioning, the groups were subdivided into 4 vehicle groups, 3 unpaired haloperidol groups and 3 paired haloperidol groups and were given one of three post-trial treatments (vehicle, 0.05mg/kg or 2.0mg/kg apomorphine). One day later the conditioned catalepsy test 3 was carried out and on the next day, a haloperidol challenge test was performed. The post-trial apomorphine treatments had major effects on the paired groups upon both conditioning and the haloperidol challenge test. The low dose apomorphine post-trial treatment enhanced both the conditioned and the haloperidol sensitized catalepsy responses. The high dose apomorphine post-trial treatment eliminated conditioned catalepsy and eliminated the initial acute catalepsy response to haloperidol that was induced in the vehicle control groups. These results demonstrate the sensitivity of conditioned drug cues to modification by increases/decreases in activity of the dopamine system in the immediate post-trial interval after a conditioning trial. This demonstration that post-trial dopaminergic drug treatments can modify conditioned drug behavior has broad implications for conditioned drug effects. PMID:27173428

  7. Naringin: a protector of the nigrostriatal dopaminergic projection.

    PubMed

    Jung, Un Ju; Leem, Eunju; Kim, Sang Ryong

    2014-06-01

    Parkinson's disease is the second most common neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons and a biochemical reduction of striatal dopamine levels. Despite the lack of fully understanding of the etiology of Parkinson's disease, accumulating evidences suggest that Parkinson's disease may be caused by the insufficient support of neurotrophic factors, and by microglial activation, resident immune cells in the brain. Naringin, a major flavonone glycoside in grapefruits and citrus fruits, is considered as a protective agent against neurodegenerative diseases because it can induce not only anti-oxidant effects but also neuroprotective effects by the activation of anti-apoptotic pathways and the induction of neurotrophic factors such as brain-derived neurotrophic factor and vascular endothelial growth factor. We have recently reported that naringin has neuroprotective effects in a neurotoxin model of Parkinson's disease. Our observations show that intraperitoneal injection of naringin induces increases in glial cell line-derived neurotrophic factor expression and mammalian target of rapamycin complex 1 activity in dopaminergic neurons of rat brains with anti-inflammatory effects. Moreover, the production of glial cell line-derived neurotrophic factor by naringin treatment contributes to the protection of the nigrostriatal dopaminergic projection in a neurotoxin model of Parkinson's disease. Although the effects of naringin on the nigrostriatal dopaminergic system in human brains are largely unknown, these results suggest that naringin may be a beneficial natural product for the prevention of dopaminergic degeneration in the adult brain. PMID:24963276

  8. Activity in descending dopaminergic neurons represents but is not required for leg movements in the fruit fly Drosophila

    PubMed Central

    Tschida, Katherine; Bhandawat, Vikas

    2015-01-01

    Modulatory descending neurons (DNs) that link the brain to body motor circuits, including dopaminergic DNs (DA-DNs), are thought to contribute to the flexible control of behavior. Dopamine elicits locomotor-like outputs and influences neuronal excitability in isolated body motor circuits over tens of seconds to minutes, but it remains unknown how and over what time scale DA-DN activity relates to movement in behaving animals. To address this question, we identified DA-DNs in the Drosophila brain and developed an electrophysiological preparation to record and manipulate the activity of these cells during behavior. We find that DA-DN spike rates are rapidly modulated during a subset of leg movements and scale with the total speed of ongoing leg movements, whether occurring spontaneously or in response to stimuli. However, activating DA-DNs does not elicit leg movements in intact flies, nor do acute bidirectional manipulations of DA-DN activity affect the probability or speed of leg movements over a time scale of seconds to minutes. Our findings indicate that in the context of intact descending control, changes in DA-DN activity are not sufficient to influence ongoing leg movements and open the door to studies investigating how these cells interact with other descending and local neuromodulatory inputs to influence body motor output. PMID:25742959

  9. Is the treatment with psychostimulants in children and adolescents with attention deficit hyperactivity disorder harmful for the dopaminergic system?

    PubMed

    Gerlach, Manfred; Grünblatt, Edna; Lange, Klaus W

    2013-06-01

    A major concern regarding psychostimulant medication (amphetamine and methylphenidate) in the treatment of children and adolescents with attention deficit/hyperactivity disorder (ADHD) are the potential adverse effects to the developing brain, particularly in regard to dopaminergic brain function. The present review focuses on the pharmacology of these psychostimulants, their mode of action in the human brain and their potential neurotoxic effects to the developing brain in animals, particularly concerning DA brain function. The potential clinical significance of these findings for the treatment of ADHD in children and adolescents is discussed. Studies on sensitization to psychostimulants' rewarding effects, which is a process expected to increase the risk of substance abuse in humans, are not included. The available findings in non-human primates support the notion that the administration of amphetamine and methylphenidate with procedures simulating clinical treatment conditions does not lead to long-term adverse effects in regard to development, neurobiology or behaviour as related to the central dopaminergic system. PMID:23605387

  10. The effect of Schisandra chinensis extracts on depression by noradrenergic, dopaminergic, GABAergic and glutamatergic systems in the forced swim test in mice.

    PubMed

    Yan, Tingxu; Xu, Mengjie; Wu, Bo; Liao, Zhengzheng; Liu, Zhi; Zhao, Xu; Bi, Kaishun; Jia, Ying

    2016-06-15

    Schisandra chinensis (Turcz.) Baill., as a Chinese functional food, has been widely used in neurological disorders including insomnia and Alzheimer's disease. The treatment of classical neuropsychiatric disorder depression is to be developed from Schisandra chinensis. The antidepressant-like effects of the Schisandra chinensis extracts (SCE), and their probable involvement in the serotonergic, noradrenergic, dopaminergic, GABAergic and glutamatergic systems were investigated by the forced swim test (FST). Acute administration of SCE (600 mg kg(-1), i.g.), a combination of SCE (300 mg kg(-1), i.g.) and reboxetine (a noradrenalin reuptake inhibitor, 2.5 mg kg(-1), i.p.) or imipramine (a TCA, 2 mg kg(-1), i.p.) reduced the immobility time in the FST. Pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4, a selective noradrenergic neurotoxin, 50 mg kg(-1), i.p., 4 days), haloperidol (a non-selective D2 receptor antagonist, 0.2 mg kg(-1), i.p.), SCH 23390 (a selective D1 receptor antagonist, 0.03 mg kg(-1), i.p.), bicuculline (a competitive GABA antagonist, 4 mg kg(-1), i.p.) and N-methyl-d-aspartic acid (NMDA, an agonist at the glutamate site, 75 mg kg(-1), i.p.) effectively reversed the antidepressant-like effect of SCE (600 mg kg(-1), i.g.). However, p-chlorophenylalanine (pCPA, an inhibitor of 5-HT synthesis, 100 mg kg(-1), i.p., 4 days,) did not eliminate the reduced immobility time induced by SCE (600 mg kg(-1), i.g.). Moreover, the treatments did not change the locomotor activity. Altogether, these results indicated that SCE produced antidepressant-like activity, which might be mediated by the modification of noradrenergic, dopaminergic, GABAergic and glutamatergic systems. PMID:27225351

  11. Dopaminergic neurotoxicant 6-OHDA induces oxidative damage through proteolytic activation of PKC{delta} in cell culture and animal models of Parkinson's disease

    SciTech Connect

    Latchoumycandane, Calivarathan; Anantharam, Vellareddy; Jin, Huajun; Kanthasamy, Anumantha; Kanthasamy, Arthi

    2011-11-15

    The neurotoxicant 6-hydroxydopamine (6-OHDA) is used to investigate the cellular and molecular mechanisms underlying selective degeneration of dopaminergic neurons in Parkinson's disease (PD). Oxidative stress and caspase activation contribute to the 6-OHDA-induced apoptotic cell death of dopaminergic neurons. In the present study, we sought to systematically characterize the key downstream signaling molecule involved in 6-OHDA-induced dopaminergic degeneration in cell culture and animal models of PD. Treatment of mesencephalic dopaminergic neuronal N27 cells with 6-OHDA (100 {mu}M) for 24 h significantly reduced mitochondrial activity and increased cytosolic cytochrome c, followed by sequential activation of caspase-9 and caspase-3. Co-treatment with the free radical scavenger MnTBAP (10 {mu}M) significantly attenuated 6-OHDA-induced caspase activities. Interestingly, 6-OHDA induced proteolytic cleavage and activation of protein kinase C delta (PKC{delta}) was completely suppressed by treatment with a caspase-3-specific inhibitor, Z-DEVD-FMK (50 {mu}M). Furthermore, expression of caspase-3 cleavage site-resistant mutant PKC{delta}{sup D327A} and kinase dead PKC{delta}{sup K376R} or siRNA-mediated knockdown of PKC{delta} protected against 6-OHDA-induced neuronal cell death, suggesting that caspase-3-dependent PKC{delta} promotes oxidative stress-induced dopaminergic degeneration. Suppression of PKC{delta} expression by siRNA also effectively protected N27 cells from 6-OHDA-induced apoptotic cell death. PKC{delta} cleavage was also observed in the substantia nigra of 6-OHDA-injected C57 black mice but not in control animals. Viral-mediated delivery of PKC{delta}{sup D327A} protein protected against 6-OHDA-induced PKC{delta} activation in mouse substantia nigra. Collectively, these results strongly suggest that proteolytic activation of PKC{delta} is a key downstream event in dopaminergic degeneration, and these results may have important translational value for

  12. Nicotinic Acetylcholine Receptors containing the α6 subunit contribute to ethanol activation of ventral tegmental area dopaminergic neurons

    PubMed Central

    Liu, Liwang; Zhao-Shea, Rubing; McIntosh, J. Michael; Tapper, Andrew R.

    2013-01-01

    Nicotine and alcohol are often co-abused suggesting a common mechanism of action may underlie their reinforcing properties. Both drugs acutely increase activity of ventral tegmental area (VTA) dopaminergic (DAergic) neurons, a phenomenon associated with reward behavior. Recent evidence indicates that nicotinic acetylcholine receptors (nAChRs), ligand-gated cation channels activated by ACh and nicotine, may contribute to ethanol-mediated activation of VTA DAergic neurons although the nAChR subtype(s) involved has not been fully elucidated. Here we show that expression and activation of nAChRs containing the α6 subunit contribute to ethanol-induced activation of VTA DAergic neurons. In wild-type (WT) mouse midbrain sections that contain the VTA, ethanol (50 or 100 mM) significantly increased firing frequency of DAergic neurons. In contrast, ethanol did not significantly increase activity of VTA DAergic neurons in mice that do not express CHRNA6, the gene encoding the α6 nAChR subunit (α6 knock-out (KO) mice). Ethanol-induced activity in WT slices was also reduced by pre-application of the α6 subtype-selective nAChR antagonist, α-conotoxin MII[E11A]. When co-applied, ethanol potentiated the response to ACh in WT DAergic neurons; whereas co-application of ACh and ethanol failed to significantly increase activity of DAergic neurons in α6 KO slices. Finally, pre-application of α-conotoxin MII[E11A] in WT slices reduced ethanol potentiation of ACh responses. Together our data indicate that α6-subunit containing nAChRs may contribute to ethanol activation of VTA DAergic neurons. These receptors are predominantly expressed in DAergic neurons and known to be critical for nicotine reinforcement, providing a potential common therapeutic molecular target to reduce nicotine and alcohol co-abuse. PMID:23811312

  13. The effect of CA1 dopaminergic system in harmaline-induced amnesia.

    PubMed

    Nasehi, M; Ketabchi, M; Khakpai, F; Zarrindast, M-R

    2015-01-29

    In the present study, the effects of bilateral injections of dopaminergic drugs into the hippocampal CA1 regions (intra-CA1) on harmaline-induced amnesia were examined in male mice. A one-trial step-down passive avoidance task was used for the assessment of memory retention in adult male mice. Pre-training intra-peritoneal (i.p.) administration of harmaline (1 mg/kg) induced impairment of memory retention. Moreover, intra-CA1 administration of dopamine D1 receptor antagonist, SCH23390 (0.02 μg/mouse), dopamine D1 receptor agonist, SKF38393 (0.5 μg/mouse), dopamine D2 receptor antagonist, sulpiride (1 μg/mouse) and dopamine D2 receptor agonist, quinpirole (0.25 and 0.5 μg/mouse) suppressed the learning of a single-trial passive avoidance task. Also, pre-training intra-CA1 injection of subthreshold doses of SCH23390 (0.001 μg/mouse) or sulpiride (0.25 μg/mouse) with the administration of harmaline (1 mg/kg, i.p.) reversed impairment of memory formation. However, pre-training intra-CA1 injection of SKF38393 (0.1 μg/mouse) or quinpirole (0.1 μg/mouse) increased pre-training harmaline (0.25 and 0.5 mg/kg, i.p.)-induced retrieval impairment. Moreover, SKF Ca blocker (SKF) (0.01 μg/mouse) decrease the amnesia induced by harmaline (1 mg/kg), while co-administration of SKF (0.01 μg/mouse)/sulpiride (0.25 μg/mouse) or SCH23390 (0.001 μg/mouse)/sulpiride (0.25 μg/mouse) potentiate amnesia caused by harmaline. These findings implicate the involvement of CA1 dopaminergic mechanism in harmaline-induced impairment of memory acquisition. PMID:25446354

  14. Reduced prefrontal dopaminergic activity in valproic acid-treated mouse autism model.

    PubMed

    Hara, Yuta; Takuma, Kazuhiro; Takano, Erika; Katashiba, Keisuke; Taruta, Atsuki; Higashino, Kosuke; Hashimoto, Hitoshi; Ago, Yukio; Matsuda, Toshio

    2015-08-01

    Previous studies suggest that dysfunction of neurotransmitter systems is associated with the pathology of autism in humans and the disease model rodents, but the precise mechanism is not known. Rodent offspring exposed prenatally to VPA shows autism-related behavioral abnormalities. The present study examined the effect of prenatal VPA exposure on brain monoamine neurotransmitter systems in male and female mice. The prenatal VPA exposure did not affect the levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT) and their metabolites in the prefrontal cortex and striatum, while it significantly reduced methamphetamine (METH) (1.0 mg/kg)-induced hyperlocomotion in male offspring. In vivo microdialysis study demonstrated that prenatal VPA exposure attenuated METH-induced increases in extracellular DA levels in the prefrontal cortex, while it did not affect those in extracellular NA and 5-HT levels. Prenatal VPA exposure also decreased METH-induced c-Fos expression in the prefrontal cortex and the mRNA levels of DA D1 and D2 receptors in the prefrontal cortex. These effects of VPA were not observed in the striatum. In contrast to male offspring, prenatal VPA exposure did not affect METH-induced increases in locomotor activity and prefrontal DA levels and the D1 and D2 receptor mRNA levels in the prefrontal cortex in female offspring. These findings suggest that prenatal VPA exposure causes hypofunction of prefrontal DA system in a sex-dependent way. PMID:25907743

  15. Prothrombin kringle-2 induces death of mesencephalic dopaminergic neurons in vivo and in vitro via microglial activation.

    PubMed

    Kim, Sang Ryong; Chung, Eun Sook; Bok, Eugene; Baik, Hyung Hwan; Chung, Young Cheul; Won, So Yoon; Joe, Eunhye; Kim, Tae Hyong; Kim, Soung Soo; Jin, Min Young; Choi, Sang Ho; Jin, Byung Kwan

    2010-05-15

    We have shown that prothrombin kringle-2 (pKr-2), a domain of human prothrombin distinct from thrombin could activate cultured rat brain microglia in vitro. However, little is known whether pKr-2-induced microglial activation could cause neurotoxicity on dopaminergic (DA) neurons in vivo. To address this question, pKr-2 was injected into the rat substantia nigra (SN). Tyrosine hydroxylase (TH) immunohistochemistry experiments demonstrate significant loss of DA neurons seven days after injection of pKr-2. In parallel, pKr-2-activated microglia were detected in the SN with OX-42 and OX-6 immunohistochemistry. Reverse transcription PCR and double-label immunohistochemistry revealed that activated microglia in vivo exhibit early and transient expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and several proinflammatory cytokines. The pKr-2-induced loss of SN DA neurons was partially inhibited by the NOS inhibitor N(G)-nitro-L-arginine methyl ester hydrochloride, and the COX-2 inhibitor DuP-697. Extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were activated in the SN as early as 1 hr after pKr-2 injection, and localized within microglia. Inhibition of these kinases led to attenuation of mRNA expression of iNOS, COX-2 and several proinflammatory cytokines, and rescue of DA neurons in the SN. Intriguingly, following treatment with pKr-2 in vitro, neurotoxicity was detected exclusively in co-cultures of mesencephalic neurons and microglia, but not microglia-free neuron-enriched mesencephalic cultures, indicating that microglia are required for pKr-2 neurotoxicity. Our results strongly suggest that microglia activated by endogenous compound(s), such as pKr-2, are implicated in the DA neuronal cell death in the SN. PMID:20025058

  16. The Association Between Genetic Variants in the Dopaminergic System and Posttraumatic Stress Disorder: A Meta-Analysis.

    PubMed

    Li, Lizhuo; Bao, Yijun; He, Songbai; Wang, Gang; Guan, Yanlei; Ma, Dexuan; Wang, Pengfei; Huang, Xiaolong; Tao, Shanwei; Zhang, Dewei; Liu, Qiwen; Wang, Yunjie; Yang, Jingyun

    2016-03-01

    Posttraumatic stress disorder (PTSD) is a complex mental disorder and can severely interfere with the normal life of the affected people. Previous studies have examined the association of PTSD with genetic variants in multiple dopaminergic genes with inconsistent results. To perform a systematic literature search and conduct meta-analysis to examine whether genetic variants in the dopaminergic system is associated with PTSD. Data Sources: PubMed, Cochrane Library, Embase, Google Scholar, and HuGE. Study eligibility criteria and participants: The studies included subjects who had been screened for the presence of PTSD; the studies provided data for genetic variants of genes involved in the dopaminergic system; the outcomes of interest included diagnosis status of PTSD; and the studies were case-control studies. Study appraisal and synthesis methods: Odds ratio was used as a measure of association. We used random-effects model in all the meta-analyses. Between-study heterogeneity was assessed using I², and publication bias was evaluated using Egger test. Findings from meta-analyses were confirmed using random-effects meta-analyses under the framework of generalized linear model (GLM). A total of 19 studies met the eligibility criteria and were included in our analyses. We found that rs1800497 in DRD2 was significantly associated with PTSD (OR = 1.96, 95% CI: 1.15-3.33; P = 0.014). The 3'-UTR variable number tandem repeat (VNTR) in SLC6A3 also showed significant association with PTSD (OR = 1.62, 95% CI: 1.12-2.35; P = 0.010), but there was no association of rs4680 in COMT with PTSD (P = 0.595). Sample size is limited for some studies; type and severity of traumatic events varied across studies; we could not control for potential confounding factors, such as age at traumatic events and gender; and we could not examine gene-environment interaction due to lack of data. We found that rs1800497 in DRD2 and the VNTR in SLC6A3 showed significant

  17. Psychostimulant-Induced Testicular Toxicity in Mice: Evidence of Cocaine and Caffeine Effects on the Local Dopaminergic System

    PubMed Central

    Matzkin, María E.; Muñiz, Javier A.; Cadet, Jean Lud; Garcia-Rill, Edgar; Urbano, Francisco J.; Vitullo, Alfredo D.; Bisagno, Veronica

    2015-01-01

    Several organ systems can be affected by psychostimulant toxicity. However, there is not sufficient evidence about the impact of psychostimulant intake on testicular physiology and catecholaminergic systems. The aim of the present study was to further explore potential toxic consequences of chronic exposure to cocaine, caffeine, and their combination on testicular physiology. Mice were injected with a 13-day chronic binge regimen of caffeine (3x5mg/kg), cocaine (3×10mg/kg), or combined administration. Mice treated with cocaine alone or combined with caffeine showed reduced volume of the seminiferous tubule associated to a reduction in the number of spermatogonia. Cocaine-only and combined treatments induced increased lipid peroxidation evaluated by TBARS assay and decreased glutathione peroxidase mRNA expression. Importantly, caffeine-cocaine combination potentiated the cocaine-induced germ cell loss, and induced pro-apoptotic BAX protein expression and diminished adenosine receptor A1 mRNA levels. We analyzed markers of dopaminergic function in the testis and detected the presence of tyrosine hydroxylase (TH) in the cytoplasm of androgen-producing Leydig cells, but also in meiotic germs cells within seminiferous tubules. Moreover, using transgenic BAC-Drd1a-tdTomato and D2R-eGFP mice, we report for the first time the presence of dopamine receptors (DRs) D1 and D2 in testicular mouse Leydig cells. Interestingly, the presence of DRD1 was also detected in the spermatogonia nearest the basal lamina of the seminiferous tubules, which did not show TH staining. We observed that psychostimulants induced downregulation of DRs mRNA expression and upregulation of TH protein expression in the testis. These findings suggest a potential role of the local dopaminergic system in psychostimulant-induced testicular pathology. PMID:26560700

  18. Psychostimulant-Induced Testicular Toxicity in Mice: Evidence of Cocaine and Caffeine Effects on the Local Dopaminergic System.

    PubMed

    González, Candela R; González, Betina; Matzkin, María E; Muñiz, Javier A; Cadet, Jean Lud; Garcia-Rill, Edgar; Urbano, Francisco J; Vitullo, Alfredo D; Bisagno, Veronica

    2015-01-01

    Several organ systems can be affected by psychostimulant toxicity. However, there is not sufficient evidence about the impact of psychostimulant intake on testicular physiology and catecholaminergic systems. The aim of the present study was to further explore potential toxic consequences of chronic exposure to cocaine, caffeine, and their combination on testicular physiology. Mice were injected with a 13-day chronic binge regimen of caffeine (3x5mg/kg), cocaine (3×10mg/kg), or combined administration. Mice treated with cocaine alone or combined with caffeine showed reduced volume of the seminiferous tubule associated to a reduction in the number of spermatogonia. Cocaine-only and combined treatments induced increased lipid peroxidation evaluated by TBARS assay and decreased glutathione peroxidase mRNA expression. Importantly, caffeine-cocaine combination potentiated the cocaine-induced germ cell loss, and induced pro-apoptotic BAX protein expression and diminished adenosine receptor A1 mRNA levels. We analyzed markers of dopaminergic function in the testis and detected the presence of tyrosine hydroxylase (TH) in the cytoplasm of androgen-producing Leydig cells, but also in meiotic germs cells within seminiferous tubules. Moreover, using transgenic BAC-Drd1a-tdTomato and D2R-eGFP mice, we report for the first time the presence of dopamine receptors (DRs) D1 and D2 in testicular mouse Leydig cells. Interestingly, the presence of DRD1 was also detected in the spermatogonia nearest the basal lamina of the seminiferous tubules, which did not show TH staining. We observed that psychostimulants induced downregulation of DRs mRNA expression and upregulation of TH protein expression in the testis. These findings suggest a potential role of the local dopaminergic system in psychostimulant-induced testicular pathology. PMID:26560700

  19. Dopaminergic Circuitry Underlying Mating Drive.

    PubMed

    Zhang, Stephen X; Rogulja, Dragana; Crickmore, Michael A

    2016-07-01

    We develop a new system for studying how innate drives are tuned to reflect current physiological needs and capacities, and how they affect sensory-motor processing. We demonstrate the existence of male mating drive in Drosophila, which is transiently and cumulatively reduced as reproductive capacity is depleted by copulations. Dopaminergic activity in the anterior of the superior medial protocerebrum (SMPa) is also transiently and cumulatively reduced in response to matings and serves as a functional neuronal correlate of mating drive. The dopamine signal is transmitted through the D1-like DopR2 receptor to P1 neurons, which also integrate sensory information relevant to the perception of females, and which project to courtship motor centers that initiate and maintain courtship behavior. Mating drive therefore converges with sensory information from the female at the point of transition to motor output, controlling the propensity of a sensory percept to trigger goal-directed behavior. PMID:27292538

  20. Not only serotonergic system, but also dopaminergic system involved in albiflorin against chronic unpredictable mild stress-induced depression-like behavior in rats.

    PubMed

    Song, Jingjing; Hou, Xintong; Hu, Xinyu; Lu, Chengyu; Liu, Chungang; Wang, Juan; Liu, Wei; Teng, Lirong; Wang, Di

    2015-12-01

    Albiflorin (AF), separated from the root of Paeonia lactiflora Pall, possesses neuro-protective and anti-inflammatory activities. Based on previous results, our present research aims to investigate the antidepressant-like activity of AF in chronic unpredictable mild stress (CUMS)-induced rat model of depression. Eight weeks of CUMS process successfully established depression-like rat model, as evidenced by the enhanced immobility time in forced swimming test and the reduced sucrose preference, which were reversed to near normal by AF (20 mg/kg and 40 mg/kg) and fluoxetine (3 mg/kg; positive drug) treated. Compared to non-treated depression-like rats, the increased levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HTAA) in serum and hypothalamus, and the reduced expressions of 5-HT1A receptor and 5-HT2A receptor in hypothalamus were observed after AF and fluoxetine oral administration indicating that AF-mediated antidepressant-like effect may be related to the normalization of serotonergic system. Additionally, four-week AF treated rats significantly showed improvement in the reduced dopamine and noradrenalin concentration in serum and hypothalamus as observed on depression-like rats. Altered levels of tyrosine hydroxylase, dopamine D2 receptor and dopamine transporter in hypothalamus reverted to the normal level after treatment with both AF and fluoxetine. All these data demonstrate that not only serotonergic system, but also dopaminergic system is involved in AF-mediated antidepressant-like effect in CUMS-induced rat model of depression. PMID:26475043

  1. Estradiol Facilitates Functional Integration of iPSC-Derived Dopaminergic Neurons into Striatal Neuronal Circuits via Activation of Integrin α5β1

    PubMed Central

    Nishimura, Kaneyasu; Doi, Daisuke; Samata, Bumpei; Murayama, Shigeo; Tahara, Tsuyoshi; Onoe, Hirotaka; Takahashi, Jun

    2016-01-01

    Summary For cell transplantation therapy for Parkinson's disease (PD) to be realized, the grafted neurons should be integrated into the host neuronal circuit to restore the lost neuronal function. Here, using wheat-germ agglutinin-based transsynaptic tracing, we show that integrin α5 is selectively expressed in striatal neurons that are innervated by midbrain dopaminergic (DA) neurons. In addition, we found that integrin α5β1 was activated by the administration of estradiol-2-benzoate (E2B) in striatal neurons of adult female rats. Importantly, we observed that the systemic administration of E2B into hemi-parkinsonian rat models facilitates the functional integration of grafted DA neurons derived from human induced pluripotent stem cells into the host striatal neuronal circuit via the activation of integrin α5β1. Finally, methamphetamine-induced abnormal rotation was recovered earlier in E2B-administered rats than in rats that received other regimens. Our results suggest that the simultaneous administration of E2B with stem cell-derived DA progenitors can enhance the efficacy of cell transplantation therapy for PD. PMID:26997644

  2. 7,8-dihydroxyflavone protects 6-OHDA and MPTP induced dopaminergic neurons degeneration through activation of TrkB in rodents.

    PubMed

    Luo, Dandan; Shi, Ying; Wang, Jun; Lin, Qing; Sun, Yi; Ye, Keqiang; Yan, Qiao; Zhang, Hai

    2016-05-01

    Brain-derived neurotrophic factor (BDNF) is a notably important neurotrophin which regulates neuronal survival and differentiation in the nervous system. However, its clinical usage is particularly limited. 7,8-dihydroxyflavone (7,8-DHF), which acts as a selective agonist of BDNF receptor TrkB, is reported to possess neuroprotective effects both in vitro and in vivo. Here we explored the potent neuroprotective effects of 7,8-DHF in 6-OHDA induced rat and MPTP induced mouse model of Parkinsonism. The results demonstrated that treatment with 7,8-DHF in drinking water for four weeks (two weeks before 6-OHDA+two weeks after 6-OHDA lesion) significantly improved dopamine-mediated behaviors in 6-OHDA rat model, and prevented the loss of dopaminergic neurons in the substantia nigra (SN). Phospho-Y816-TrkB immunostaining showed that TrkB phosphorylation was significantly elevated in the SN in 7,8-DHF pretreated group, indicating 7,8-DHF activated TrkB and likely contributed to its neuroprotective effects. 7,8-DHF also protected acute MPTP neurotoxicity in mice but did not affect the climbing behavior in pole test. Thus our study indicates the neuroprotective properties of 7,8-DHF through the activation of TrkB, which provides a novel therapeutic treatment for Parkinson's disease. PMID:27019033

  3. Estradiol Facilitates Functional Integration of iPSC-Derived Dopaminergic Neurons into Striatal Neuronal Circuits via Activation of Integrin α5β1.

    PubMed

    Nishimura, Kaneyasu; Doi, Daisuke; Samata, Bumpei; Murayama, Shigeo; Tahara, Tsuyoshi; Onoe, Hirotaka; Takahashi, Jun

    2016-04-12

    For cell transplantation therapy for Parkinson's disease (PD) to be realized, the grafted neurons should be integrated into the host neuronal circuit to restore the lost neuronal function. Here, using wheat-germ agglutinin-based transsynaptic tracing, we show that integrin α5 is selectively expressed in striatal neurons that are innervated by midbrain dopaminergic (DA) neurons. In addition, we found that integrin α5β1 was activated by the administration of estradiol-2-benzoate (E2B) in striatal neurons of adult female rats. Importantly, we observed that the systemic administration of E2B into hemi-parkinsonian rat models facilitates the functional integration of grafted DA neurons derived from human induced pluripotent stem cells into the host striatal neuronal circuit via the activation of integrin α5β1. Finally, methamphetamine-induced abnormal rotation was recovered earlier in E2B-administered rats than in rats that received other regimens. Our results suggest that the simultaneous administration of E2B with stem cell-derived DA progenitors can enhance the efficacy of cell transplantation therapy for PD. PMID:26997644

  4. β2-adrenergic receptor activation prevents rodent dopaminergic neurotoxicity by inhibiting microglia via a novel signaling pathway

    PubMed Central

    Qian, Li; Wu, Hung-ming; Chen, Shih-Heng; Zhang, Dan; Ali, Syed F.; Peterson, Lynda; Wilson, Belinda; Lu, Ru-Band; Hong, Jau-Shyong; Flood, Patrick M

    2013-01-01

    The role of the β2 Adrenergic Receptor (β2AR) in the regulation of chronic neurodegenerative inflammation within the CNS is poorly understood. The purpose of this study was to determine neuroprotective effects of long-acting β2AR agonists such as salmeterol in rodent models of Parkinson’s disease. Results showed salmeterol exerted potent neuroprotection against both LPS and MPTP/MPP+-induced dopaminergic neurotoxicity both in primary neuron-glia cultures (at sub-nanomolar concentrations) and in mice (1–10 μg/kg/day doses). Further studies demonstrated that salmeterol-mediated neuroprotection is not a direct effect on neurons; instead, it is mediated through the inhibition of LPS-induced microglial activation. Salmeterol significantly inhibited LPS-induced production of microglial pro-inflammatory neurotoxic mediators, such as TNFα, superoxide and nitric oxide, as well as the inhibition of TAK1-mediated phosphorylation of MAPK and p65 NF-κB. The anti-inflammatory effects of salmeterol required β2AR expression in microglia, but were not mediated through the conventional GPCR/cAMP pathway. Rather, salmeterol failed to induce microglial cAMP production, could not be reversed by either PKA inhibitors or an EPAC agonist, and was dependent on beta-arrestin2 expression. Together, our results demonstrate that administration of extremely low doses of salmeterol exhibit potent neuroprotective effects by inhibiting microglial cell activation through a β2AR/β-arrestin2-dependent but cAMP/PKA independent pathway. PMID:21335487

  5. Behavioral and electrophysiological effects of endocannabinoid and dopaminergic systems on salient stimuli

    PubMed Central

    Laricchiuta, Daniela; Musella, Alessandra; Rossi, Silvia; Centonze, Diego

    2014-01-01

    Rewarding effects have been related to enhanced dopamine (DA) release in corticolimbic and basal ganglia structures. The DAergic and endocannabinoid interaction in the responses to reward is described. This study investigated the link between endocannabinoid and DAergic transmission in the processes that are related to response to two types of reward, palatable food and novelty. Mice treated with drugs acting on endocannabinoid system (ECS) (URB597, AM251) or DAergic system (haloperidol) were submitted to approach-avoidance conflict tasks with palatable food or novelty. In the same mice, the cannabinoid type-1 (CB1)-mediated GABAergic transmission in medium spiny neurons of the dorsomedial striatum was analyzed. The endocannabinoid potentiation by URB597 magnified approach behavior for reward (food and novelty) and in parallel inhibited dorsostriatal GABAergic neurotransmission. The decreased activity of CB1 receptor by AM251 (alone or with URB597) or of DAergic D2 receptor by haloperidol had inhibitory effects toward the reward and did not permit the inhibition of dorsostriatal GABAergic transmission. When haloperidol was coadministered with URB597, a restoration effect on reward and reward-dependent motor activity was observed, only if the reward was the palatable food. In parallel, the coadministration led to restoring inhibition of CB1-mediated GABAergic transmission. Thus, in the presence of simultaneous ECS activation and inhibition of DAergic system the response to reward appears to be a stimulus-dependent manner. PMID:24904335

  6. Squamosamide derivative FLZ protects dopaminergic neurons against inflammation-mediated neurodegeneration through the inhibition of NADPH oxidase activity

    PubMed Central

    Zhang, Dan; Hu, Xiaoming; Wei, Sung-Jen; Liu, Jie; Gao, Huiming; Qian, Li; Wilson, Belinda; Liu, Gengtao; Hong, Jau-Shyong

    2008-01-01

    Background Inflammation plays an important role in the pathogenesis of Parkinson's disease (PD) through over-activation of microglia, which consequently causes the excessive production of proinflammatory and neurotoxic factors, and impacts surrounding neurons and eventually induces neurodegeneration. Hence, prevention of microglial over-activation has been shown to be a prime target for the development of therapeutic agents for inflammation-mediated neurodegenerative diseases. Methods For in vitro studies, mesencephalic neuron-glia cultures and reconstituted cultures were used to investigate the molecular mechanism by which FLZ, a squamosamide derivative, mediates anti-inflammatory and neuroprotective effects in both lipopolysaccharide-(LPS)- and 1-methyl-4-phenylpyridinium-(MPP+)-mediated models of PD. For in vivo studies, a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-(MPTP-) induced PD mouse model was used. Results FLZ showed potent efficacy in protecting dopaminergic (DA) neurons against LPS-induced neurotoxicity, as shown in rat and mouse primary mesencephalic neuronal-glial cultures by DA uptake and tyrosine hydroxylase (TH) immunohistochemical results. The neuroprotective effect of FLZ was attributed to a reduction in LPS-induced microglial production of proinflammatory factors such as superoxide, tumor necrosis factor-α (TNF-α), nitric oxide (NO) and prostaglandin E2 (PGE2). Mechanistic studies revealed that the anti-inflammatory properties of FLZ were mediated through inhibition of NADPH oxidase (PHOX), the key microglial superoxide-producing enzyme. A critical role for PHOX in FLZ-elicited neuroprotection was further supported by the findings that 1) FLZ's protective effect was reduced in cultures from PHOX-/- mice, and 2) FLZ inhibited LPS-induced translocation of the cytosolic subunit of p47PHOX to the membrane and thus inhibited the activation of PHOX. The neuroprotective effect of FLZ demonstrated in primary neuronal-glial cultures was further

  7. Simvastatin inhibits the activation of p21ras and prevents the loss of dopaminergic neurons in a mouse model of Parkinson's disease

    PubMed Central

    Ghosh, Anamitra; Roy, Avik; Matras, Joanna; Brahmachari, Saurav; Gendelman, Howard E.; Pahan, Kalipada

    2010-01-01

    Parkinson's disease (PD) is second only to Alzheimer's disease as the most common devastating human neurodegenerative disorder. Despite intense investigation, no interdictive therapy is available for PD. We investigated whether simvastatin, an FDA-approved cholesterol-lowering drug, could protect against nigrostriatal degeneration following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication to model PD in mice. First, MPP+ induced the activation of p21ras and NF-κB in mouse microglial cells. Inhibition of MPP+-induced activation of NF-κB by Δp21ras, a dominant-negative mutant of p21ras, supported the involvement of p21ras in MPP+-induced microglial activation of NF-κB. Interestingly, simvastatin attenuated activation of both p21ras and NF-κB in MPP+-stimulated microglial cells. Consistently, we found a very rapid activation of p21ras in vivo in the substantia nigra pars compacta of MPTP-intoxicated mice. However, after oral administration, simvastatin entered into the nigra, reduced nigral activation of p21ras, attenuated nigral activation of NF-κB, inhibited nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. Similarly, pravastatin, another cholesterol-lowering drug, suppressed microglial inflammatory responses and protected dopaminergic neurons in MPTP-intoxicated mice; but at levels less than simvastatin. Furthermore, both the statins administered 2 days after initiation of the disease were still capable of inhibiting the demise of dopaminergic neurons and concomitant loss of neurotransmitters suggesting that statins are capable of slowing down the progression of neuronal loss in the MPTP mouse model. Therefore, we conclude that statins may be of therapeutic benefit for PD patients. PMID:19864567

  8. In actio optophysiological analyses reveal functional diversification of dopaminergic neurons in the nematode C. elegans

    NASA Astrophysics Data System (ADS)

    Tanimoto, Yuki; Zheng, Ying Grace; Fei, Xianfeng; Fujie, Yukako; Hashimoto, Koichi; Kimura, Koutarou D.

    2016-05-01

    Many neuronal groups such as dopamine-releasing (dopaminergic) neurons are functionally divergent, although the details of such divergence are not well understood. Dopamine in the nematode Caenorhabditis elegans modulates various neural functions and is released from four left-right pairs of neurons. The terminal identities of these dopaminergic neurons are regulated by the same genetic program, and previous studies have suggested that they are functionally redundant. In this study, however, we show functional divergence within the dopaminergic neurons of C. elegans. Because dopaminergic neurons of the animals were supposedly activated by mechanical stimulus upon entry into a lawn of their food bacteria, we developed a novel integrated microscope system that can auto-track a freely-moving (in actio) C. elegans to individually monitor and stimulate the neuronal activities of multiple neurons. We found that only head-dorsal pair of dopaminergic neurons (CEPD), but not head-ventral or posterior pairs, were preferentially activated upon food entry. In addition, the optogenetic activation of CEPD neurons alone exhibited effects similar to those observed upon food entry. Thus, our results demonstrated functional divergence in the genetically similar dopaminergic neurons, which may provide a new entry point toward understanding functional diversity of neurons beyond genetic terminal identification.

  9. In actio optophysiological analyses reveal functional diversification of dopaminergic neurons in the nematode C. elegans

    PubMed Central

    Tanimoto, Yuki; Zheng, Ying Grace; Fei, Xianfeng; Fujie, Yukako; Hashimoto, Koichi; Kimura, Koutarou D.

    2016-01-01

    Many neuronal groups such as dopamine-releasing (dopaminergic) neurons are functionally divergent, although the details of such divergence are not well understood. Dopamine in the nematode Caenorhabditis elegans modulates various neural functions and is released from four left-right pairs of neurons. The terminal identities of these dopaminergic neurons are regulated by the same genetic program, and previous studies have suggested that they are functionally redundant. In this study, however, we show functional divergence within the dopaminergic neurons of C. elegans. Because dopaminergic neurons of the animals were supposedly activated by mechanical stimulus upon entry into a lawn of their food bacteria, we developed a novel integrated microscope system that can auto-track a freely-moving (in actio) C. elegans to individually monitor and stimulate the neuronal activities of multiple neurons. We found that only head-dorsal pair of dopaminergic neurons (CEPD), but not head-ventral or posterior pairs, were preferentially activated upon food entry. In addition, the optogenetic activation of CEPD neurons alone exhibited effects similar to those observed upon food entry. Thus, our results demonstrated functional divergence in the genetically similar dopaminergic neurons, which may provide a new entry point toward understanding functional diversity of neurons beyond genetic terminal identification. PMID:27193056

  10. In actio optophysiological analyses reveal functional diversification of dopaminergic neurons in the nematode C. elegans.

    PubMed

    Tanimoto, Yuki; Zheng, Ying Grace; Fei, Xianfeng; Fujie, Yukako; Hashimoto, Koichi; Kimura, Koutarou D

    2016-01-01

    Many neuronal groups such as dopamine-releasing (dopaminergic) neurons are functionally divergent, although the details of such divergence are not well understood. Dopamine in the nematode Caenorhabditis elegans modulates various neural functions and is released from four left-right pairs of neurons. The terminal identities of these dopaminergic neurons are regulated by the same genetic program, and previous studies have suggested that they are functionally redundant. In this study, however, we show functional divergence within the dopaminergic neurons of C. elegans. Because dopaminergic neurons of the animals were supposedly activated by mechanical stimulus upon entry into a lawn of their food bacteria, we developed a novel integrated microscope system that can auto-track a freely-moving (in actio) C. elegans to individually monitor and stimulate the neuronal activities of multiple neurons. We found that only head-dorsal pair of dopaminergic neurons (CEPD), but not head-ventral or posterior pairs, were preferentially activated upon food entry. In addition, the optogenetic activation of CEPD neurons alone exhibited effects similar to those observed upon food entry. Thus, our results demonstrated functional divergence in the genetically similar dopaminergic neurons, which may provide a new entry point toward understanding functional diversity of neurons beyond genetic terminal identification. PMID:27193056

  11. Sound Sequence Discrimination Learning Motivated by Reward Requires Dopaminergic D2 Receptor Activation in the Rat Auditory Cortex

    ERIC Educational Resources Information Center

    Kudoh, Masaharu; Shibuki, Katsuei

    2006-01-01

    We have previously reported that sound sequence discrimination learning requires cholinergic inputs to the auditory cortex (AC) in rats. In that study, reward was used for motivating discrimination behavior in rats. Therefore, dopaminergic inputs mediating reward signals may have an important role in the learning. We tested the possibility in the…

  12. Effects of Tityus serrulatus crude venom on the GABAergic and dopaminergic systems of the rat brain.

    PubMed

    Dorce, V A; Sandoval, M R

    1994-12-01

    This study was designed to investigate the effect of T. serrulatus scorpion venom on dopamine (DA) and gamma amino butyric acid (GABA) concentrations in different regions of the brain. The ratio of homovanillic acid (HVA) to DA, and the glutamic acid decarboxylase (GAD) activity were determined following intravenous or intracerebral venom injections. The increase in the HVA/DA ratio in the striatum after i.v. or intrastriatal injection could indicate an increase in DA turnover. One hour after i.v. injection of the venom GAD activity was shown to be decreased in the striatum and hypothalamus. After 24 hr GAD activity increased in the striatum and decreased in the hypothalamus and brain stem. These results could indicate different effects of the venom on the GABA system in different areas of the brain. After intrastriatal injection of the scorpion venom, the animals showed stereotyped behavior and rotation activity. Following intrahippocampal injection, myoclonus and orofacial automatisms, which constitute pro-convulsive signals, were observed. These behavioral alterations could be, at least in part, related to the GABA and dopamine alterations caused by the venom, since stereotypy, circling behavior and convulsions are dependent on dopamine and/or GABA. PMID:7725331

  13. Diesel Exhaust Activates & Primes Microglia: Air Pollution, Neuroinflammation, & Regulation of Dopaminergic Neurotoxicity

    EPA Science Inventory

    Air pollution is linked to central nervous system (CNS) disease, but the mechanisms responsible are poorly understood. Rats exposed to Diesel Exhaust (DE, 2.0,0.5, and 0 mg/m3) by inhalation over 4 weeks demonstrated elevated levels of whole brain IL-6 protein, nitrated proteins,...

  14. Perfluorooctane sulfonate (PFOS) exposure could modify the dopaminergic system in several limbic brain regions.

    PubMed

    Salgado, R; López-Doval, S; Pereiro, N; Lafuente, A

    2016-01-01

    Perfluorooctane sulfonate (PFOS) is the most representative of a rising class of persistent organic pollutants perfluorochemicals. In the present study, its neurotoxicity was examined using adult male rats orally treated with 0.5; 1.0; 3.0 and 6.0 mg of PFOS/kg/day for 28 days. At the end of the treatment, the dopamine concentration and its metabolism expressed like the ratio 3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine and homovanillic acid (HVA)/dopamine were measured in the amygdala, prefrontal cortex and hippocampus. Gene and protein expression of the dopamine receptors D1 and D2 were also determined in these limbic areas. The obtained results suggest that: (1) PFOS can alter the dopamine system by modifying its neuronal activity and/or its D1 and D2 receptors in the studied brain regions; (2) the dopamine concentration and metabolism seem to be more sensitive against PFOS toxicity in the hippocampus than in the other analyzed brain areas; (3) the inhibited gene and protein expression of the D1 receptors induced by PFOS in the amygdala could be related to several changes in the HPA axis activity, and lastly; (4) the observed alterations on the dopamine system induced by PFOS could be a possible neurotoxicity mechanism of PFOS, leading to many neurological diseases. PMID:26529483

  15. beta2 Adrenergic receptor activation induces microglial NADPH oxidase activation and dopaminergic neurotoxicity through an ERK-dependent/protein kinase A-independent pathway.

    PubMed

    Qian, Li; Hu, Xiaoming; Zhang, Dan; Snyder, Amanda; Wu, Hung-Ming; Li, Yachen; Wilson, Belinda; Lu, Ru-Band; Hong, Jau-Shyong; Flood, Patrick M

    2009-11-15

    Activation of the beta2 adrenergic receptor (beta2AR) on immune cells has been reported to possess anti-inflammatory properties, however, the pro-inflammatory properties of beta2AR activation remain unclear. In this study, using rat primary mesencephalic neuron-glia cultures, we report that salmeterol, a long-acting beta2AR agonist, selectively induces dopaminergic (DA) neurotoxicity through its ability to activate microglia. Salmeterol selectively increased the production of reactive oxygen species (ROS) by NADPH oxidase (PHOX), the major superoxide-producing enzyme in microglia. A key role of PHOX in mediating salmeterol-induced neurotoxicity was demonstrated by the inhibition of DA neurotoxicity in cultures pretreated with diphenylene-iodonium (DPI), an inhibitor of PHOX activity. Mechanistic studies revealed the activation of microglia by salmeterol results in the selective phosphorylation of ERK, a signaling pathway required for the translocation of the PHOX cytosolic subunit p47(phox) to the cell membrane. Furthermore, we found ERK inhibition, but not protein kinase A (PKA) inhibition, significantly abolished salmeterol-induced superoxide production, p47(phox) translocation, and its ability to mediate neurotoxicity. Together, these findings indicate that beta2AR activation induces microglial PHOX activation and DA neurotoxicity through an ERK-dependent/PKA-independent pathway. PMID:19330844

  16. Cellular Localization of Dieldrin and Structure–Activity Relationship of Dieldrin Analogues in Dopaminergic Cells

    PubMed Central

    Allen, Erin M. G.; Florang, Virginia R.; Davenport, Laurie L.; Jinsmaa, Yunden; Doorn, Jonathan A.

    2015-01-01

    The incidence of Parkinson’s disease (PD) correlates with environmental exposure to pesticides, such as the organochlorine insecticide, dieldrin. Previous studies found an increased concentration of the pesticide in the striatal region of the brains of PD patients and also that dieldrin adversely affects cellular processes associated with PD. These processes include mitochondrial function and reactive oxygen species production. However, the mechanism and specific cellular targets responsible for dieldrin-mediated cellular dysfunction and the structural components of dieldrin contributing to its toxicity (toxicophore) have not been fully defined. In order to identify the toxicophore of dieldrin, a structure–activity approach was used, with the toxicity profiles of numerous analogues of dieldrin (including aldrin, endrin, and cis-aldrin diol) assessed in PC6-3 cells. The MTT and lactate dehydrogenase (LDH) assays were used to monitor cell viability and membrane permeability after treatment with each compound. Cellular assays monitoring ROS production and extracellular dopamine metabolite levels were also used. Structure and stereochemistry for dieldrin were found to be very important for toxicity and other end points measured. Small changes in structure for dieldrin (e.g., comparison to the stereoisomer endrin) yielded significant differences in toxicity. Interestingly, the cis-diol metabolite of dieldrin was found to be significantly more toxic than the parent compound. Disruption of dopamine catabolism yielded elevated levels of the neurotoxin, 3,4-dihydroxyphenylacetaldehyde, for many organochlorines. Comparisons of the toxicity profiles for each dieldrin analogue indicated a structure-specific effect important for elucidating the mechanisms of dieldrin neurotoxicity. PMID:23763672

  17. Behavioral Analysis of Dopaminergic Activation in Zebrafish and Rats Reveals Similar Phenotypes.

    PubMed

    Ek, Fredrik; Malo, Marcus; Åberg Andersson, Madelene; Wedding, Christoffer; Kronborg, Joel; Svensson, Peder; Waters, Susanna; Petersson, Per; Olsson, Roger

    2016-05-18

    Zebrafish is emerging as a complement to mammals in behavioral studies; however, there is a lack of comparative studies with rodents and humans to establish the zebrafish as a predictive translational model. Here we present a detailed phenotype evaluation of zebrafish larvae, measuring 300-3000 variables and analyzing them using multivariate analysis to identify the most important ones for further evaluations. The dopamine agonist apomorphine has previously been shown to have a complex U-shaped dose-response relationship in the variable distance traveled. In this study, we focused on breaking down distance traveled into more detailed behavioral phenotypes for both zebrafish and rats and identified in the multivariate analysis low and high dose phenotypes with characteristic behavioral features. Further analysis of single parameters also identified an increased activity at the lowest concentration indicative of a U-shaped dose-response. Apomorphine increased the distance of each swim movement (bout) at both high and low doses, but the underlying behavior of this increase is different; at high dose, both bout duration and frequency increased whereas bout max speed was higher at low dose. Larvae also displayed differences in place preference. The low dose phenotype spent more time in the center, indicative of an anxiolytic effect, while the high-dose phenotype had a wall preference. These dose-dependent effects corroborated findings in a parallel rat study and previous observations in humans. The translational value of pharmacological zebrafish studies was further evaluated by comparing the amino acid sequence of the dopamine receptors (D1-D4), between zebrafish, rats and humans. Humans and zebrafish share 100% of the amino acids in the binding site for D1 and D3 whereas D2 and D4 receptors share 85-95%. Molecular modeling of dopamine D2 and D4 receptors indicated that nonconserved amino acids have limited influence on important ligand-receptor interactions. PMID

  18. T-cell subpopulations express a different pattern of dopaminergic markers in intra- and extra-thymic compartments.

    PubMed

    Mignini, F; Sabbatini, M; Capacchietti, M; Amantini, C; Bianchi, E; Artico, M; Tammaro, A

    2013-01-01

    An involvement of dopamine in regulation of the immune function has been assessed and dopaminergic system has been found widely represented in thymus. Nevertheless detail on the characterization of dopaminergic system in assisting thymocytes development and lymphocytes mature physiology are still lacking. The present study was designed to characterize dopamine plasma membrane transporter (DAT), vesicular dopamine transporters (VMAT)-1 and -2, and dopamine D1-like and D2-like receptors in rat thymocytes, splenocytes and peripheral blood mononuclear cells. Western blot and RT-PCR analyses, performed on these cells, showed an expression of dopamine transporters and receptors during thymocyte development (when of CD4 and CD8 markers are differently expressed). Furthermore FACS analysis, indicates that DAT and dopamine D1-like receptors are expressed at high levels in thymocytes, splenocytes, and peripheral lymphocytes. The percentage of CD4+ CD8+ (double-positive) thymocytes expressing dopaminergic markers was significantly higher compared to the percentage of double-negative ones. The percentage of CD8+ single positive cells expressing dopaminergic markers was significantly higher than that of CD4+ cells. The results suggest that the dopaminergic system plays a role in the thymus microenvironment during T-cell development. The more pronounced expression of dopaminergic markers in CD8+ subsets suggests that dopamine plays a role in development of cytotoxic T-cells. Our findings indicate dopaminergic system to have a role during the maturation and selection of lymphocytes, and support its involvement in the active phases of immune response. PMID:23830396

  19. SPECT brain imaging of the dopaminergic system in Parkinsonism using {sup 123}I and {sup 99m}Tc labeled agents

    SciTech Connect

    Du Yong

    2004-12-01

    SPECT brain imaging of the dopaminergic system using {sup 123}I and {sup 99m}Tc labeled agents, especially the simultaneous imaging of both pre- and postsynaptic neurons, promises to provide accurate diagnosis and differentiation of Parkinsonism. However, there are many degrading factors that affect the quality and quantitative accuracy of the SPECT images. These degrading factors limit the potential clinical applications of brain SPECT imaging. In this work, we studied these degrading factors by developing and validating a Monte Carlo (MC) method that provides accurate SPECT simulation with detailed modeling of the photon interactions inside the collimator detector system. To compensate for the partial volume effect (PVE) in the SPECT images caused by finite spatial resolution, we developed a new PVE compensation method that takes into account the effects of nonlinearity in iterative reconstruction-based compensation for image degrading factors, including attenuation, scatter, and collimator detector response. Compensation using the new method greatly improved the quantitative accuracy of brain SPECT images. We have also developed model-based method that can accurately estimate the downscatter and crosstalk contamination in the {sup 123}I imaging and the simultaneous {sup 123}I/{sup 99m}Tc dual-isotope imaging. Based on the model-based method, two different approaches to model-based downscatter and crosstalk contamination compensation were proposed. Both methods are based on iterative reconstruction and include compensation for other imaging degrading factors. The model-based downscatter and crosstalk compensation method provided greatly improved accuracy of activity estimates with little effect on the precision. Finally, optimization of energy windows for simultaneous {sup 123}I/{sup 99m}Tc acquisition was performed to find the energy windows with the best trade-off between minimizing the crosstalk and maximizing the detection efficiency for simultaneous

  20. β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease.

    PubMed

    Ojha, Shreesh; Javed, Hayate; Azimullah, Sheikh; Haque, M Emdadul

    2016-07-01

    Parkinson disease (PD) is a neurodegenerative disease characterized by progressive dopaminergic neurodegeneration in the substantia nigra pars compacta (SNc) area. The present study was undertaken to evaluate the neuroprotective effect of β-caryophyllene (BCP) against rotenone-induced oxidative stress and neuroinflammation in a rat model of PD. In the present study, BCP was administered once daily for 4 weeks at a dose of 50 mg/kg body weight prior to a rotenone (2.5 mg/kg body weight) challenge to mimic the progressive neurodegenerative nature of PD. Rotenone administration results in oxidative stress as evidenced by decreased activities of superoxide dismutase, catalase, and depletion of glutathione with a concomitant rise in lipid peroxidation product, malondialdehyde. Rotenone also significantly increased pro-inflammatory cytokines in the midbrain region and elevated the inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the striatum. Further, immunohistochemical analysis revealed loss of dopaminergic neurons in the SNc area and enhanced expression of ionized calcium-binding adaptor molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP), indicators of microglia activation, and astrocyte hypertrophy, respectively, as an index of inflammation. However, treatment with BCP rescued dopaminergic neurons and decreased microglia and astrocyte activation evidenced by reduced Iba-1 and GFAP expression. BCP in addition to attenuation of pro-inflammatory cytokines and inflammatory mediators such as COX-2 and iNOS, also restored antioxidant enzymes and inhibited lipid peroxidation as well as glutathione depletion. The findings demonstrate that BCP provides neuroprotection against rotenone-induced PD and the neuroprotective effects can be ascribed to its potent antioxidant and anti-inflammatory activities. PMID:27316720

  1. Genes in the dopaminergic system and delinquent behaviors across the life course: the role of social controls and risks

    PubMed Central

    Boardman, Jason D.; Menard, Scott; Roettger, Michael E.; Knight, Kelly E.; Boutwell, Brian B.; Smolen, Andrew

    2014-01-01

    This paper examines the interaction between social control and social risk mechanisms and genes within the dopaminergic system (DAT1 and DRD2) as related to serious and violent forms of delinquent behavior among adolescents and young adults. We use nine waves of data from the National Youth Survey Family Study to examine the relevance of protective or risky social factors at four social levels including school, neighborhood, friends, and family within the gene-environment interaction framework. We extend previous work in this area by providing a testable typology of gene-environment interactions derived from current theories in this area. We find consistent evidence that the associations between putatively risky genotypes and delinquent behavior are suppressed within protective social environments. We also provide some evidence that supports the differential susceptibility hypothesis for these outcomes. Our findings largely confirm the conclusions of previous work and continue to highlight the critical role of the social environment within candidate gene studies of complex behaviors. PMID:25419014

  2. Genes in the dopaminergic system and delinquent behaviors across the life course: the role of social controls and risks.

    PubMed

    Boardman, Jason D; Menard, Scott; Roettger, Michael E; Knight, Kelly E; Boutwell, Brian B; Smolen, Andrew

    2014-06-01

    This paper examines the interaction between social control and social risk mechanisms and genes within the dopaminergic system (DAT1 and DRD2) as related to serious and violent forms of delinquent behavior among adolescents and young adults. We use nine waves of data from the National Youth Survey Family Study to examine the relevance of protective or risky social factors at four social levels including school, neighborhood, friends, and family within the gene-environment interaction framework. We extend previous work in this area by providing a testable typology of gene-environment interactions derived from current theories in this area. We find consistent evidence that the associations between putatively risky genotypes and delinquent behavior are suppressed within protective social environments. We also provide some evidence that supports the differential susceptibility hypothesis for these outcomes. Our findings largely confirm the conclusions of previous work and continue to highlight the critical role of the social environment within candidate gene studies of complex behaviors. PMID:25419014

  3. Cystamine/cysteamine rescues the dopaminergic system and shows neurorestorative properties in an animal model of Parkinson's disease.

    PubMed

    Cisbani, G; Drouin-Ouellet, J; Gibrat, C; Saint-Pierre, M; Lagacé, M; Badrinarayanan, S; Lavallée-Bourget, M H; Charest, J; Chabrat, A; Boivin, L; Lebel, M; Bousquet, M; Lévesque, M; Cicchetti, F

    2015-10-01

    The neuroprotective properties of cystamine identified in pre-clinical studies have fast-tracked this compound to clinical trials in Huntington's disease, showing tolerability and benefits on motor symptoms. We tested whether cystamine could have such properties in a Parkinson's disease murine model and now provide evidence that it can not only prevent the neurodegenerative process but also can reverse motor impairments created by a 6-hydroxydopamine lesion 3 weeks post-surgery. Importantly, we report that cystamine has neurorestorative properties 5 weeks post-lesion as seen on the number of nigral dopaminergic neurons which is comparable with treatments of cysteamine, the reduced form of cystamine used in the clinic, as well as rasagiline, increasingly prescribed in early parkinsonism. All three compounds induced neurite arborization of the remaining dopaminergic cells which was further confirmed in ex vivo dopaminergic explants derived from Pitx3-GFP mice. The disease-modifying effects displayed by cystamine/cysteamine would encourage clinical testing. PMID:26232588

  4. Cannabinoid Type 2 (CB2) Receptors Activation Protects against Oxidative Stress and Neuroinflammation Associated Dopaminergic Neurodegeneration in Rotenone Model of Parkinson's Disease.

    PubMed

    Javed, Hayate; Azimullah, Sheikh; Haque, M Emdadul; Ojha, Shreesh K

    2016-01-01

    The cannabinoid type two receptors (CB2), an important component of the endocannabinoid system, have recently emerged as neuromodulators and therapeutic targets for neurodegenerative diseases including Parkinson's disease (PD). The downregulation of CB2 receptors has been reported in the brains of PD patients. Therefore, both the activation and the upregulation of the CB2 receptors are believed to protect against the neurodegenerative changes in PD. In the present study, we investigated the CB2 receptor-mediated neuroprotective effect of β-caryophyllene (BCP), a naturally occurring CB2 receptor agonist, in, a clinically relevant, rotenone (ROT)-induced animal model of PD. ROT (2.5 mg/kg BW) was injected intraperitoneally (i.p.) once daily for 4 weeks to induce PD in male Wistar rats. ROT injections induced a significant loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and DA striatal fibers, following activation of glial cells (astrocytes and microglia). ROT also caused oxidative injury evidenced by the loss of antioxidant enzymes and increased nitrite levels, and induction of proinflammatory cytokines: IL-1β, IL-6 and TNF-α, as well as inflammatory mediators: NF-κB, COX-2, and iNOS. However, treatment with BCP attenuated induction of proinflammatory cytokines and inflammatory mediators in ROT-challenged rats. BCP supplementation also prevented depletion of glutathione concomitant to reduced lipid peroxidation and augmentation of antioxidant enzymes: SOD and catalase. The results were further supported by tyrosine hydroxylase immunohistochemistry, which illustrated the rescue of the DA neurons and fibers subsequent to reduced activation of glial cells. Interestingly, BCP supplementation demonstrated the potent therapeutic effects against ROT-induced neurodegeneration, which was evidenced by BCP-mediated CB2 receptor activation and the fact that, prior administration of the CB2 receptor antagonist AM630 diminished the beneficial

  5. Cannabinoid Type 2 (CB2) Receptors Activation Protects against Oxidative Stress and Neuroinflammation Associated Dopaminergic Neurodegeneration in Rotenone Model of Parkinson's Disease

    PubMed Central

    Javed, Hayate; Azimullah, Sheikh; Haque, M. Emdadul; Ojha, Shreesh K.

    2016-01-01

    The cannabinoid type two receptors (CB2), an important component of the endocannabinoid system, have recently emerged as neuromodulators and therapeutic targets for neurodegenerative diseases including Parkinson's disease (PD). The downregulation of CB2 receptors has been reported in the brains of PD patients. Therefore, both the activation and the upregulation of the CB2 receptors are believed to protect against the neurodegenerative changes in PD. In the present study, we investigated the CB2 receptor-mediated neuroprotective effect of β-caryophyllene (BCP), a naturally occurring CB2 receptor agonist, in, a clinically relevant, rotenone (ROT)-induced animal model of PD. ROT (2.5 mg/kg BW) was injected intraperitoneally (i.p.) once daily for 4 weeks to induce PD in male Wistar rats. ROT injections induced a significant loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and DA striatal fibers, following activation of glial cells (astrocytes and microglia). ROT also caused oxidative injury evidenced by the loss of antioxidant enzymes and increased nitrite levels, and induction of proinflammatory cytokines: IL-1β, IL-6 and TNF-α, as well as inflammatory mediators: NF-κB, COX-2, and iNOS. However, treatment with BCP attenuated induction of proinflammatory cytokines and inflammatory mediators in ROT-challenged rats. BCP supplementation also prevented depletion of glutathione concomitant to reduced lipid peroxidation and augmentation of antioxidant enzymes: SOD and catalase. The results were further supported by tyrosine hydroxylase immunohistochemistry, which illustrated the rescue of the DA neurons and fibers subsequent to reduced activation of glial cells. Interestingly, BCP supplementation demonstrated the potent therapeutic effects against ROT-induced neurodegeneration, which was evidenced by BCP-mediated CB2 receptor activation and the fact that, prior administration of the CB2 receptor antagonist AM630 diminished the beneficial

  6. Drugs Targeting the Dopaminergic Nervous System Alter Locomotion in Larval Zebrafish

    EPA Science Inventory

    As part of an effort at the US Environmental Protection Agency to develop a rapid in vivo screen for prioritization of toxic chemicals, we have begun to characterize the locomotor activity of zebrafish (Danio rerio) larvae. This includes assessing the acute effects of drugs that ...

  7. Targeting the-Dopaminergic Nervous System: Altering Behavior in Larval Zebrafish

    EPA Science Inventory

    Zebrafish (Dania rerio) are becoming an important model system in studying the effects of environmental chemicals on behavior. In order to develop a rapid in vivo screen to prioritize toxic chemicals, we have begun assessing the acute locomotor effects of drugs that act on the do...

  8. Neonatal chlorpyrifos exposure induces loss of dopaminergic neurons in young adult rats.

    PubMed

    Zhang, Jie; Dai, Hongmei; Deng, Yuanying; Tian, Jing; Zhang, Chen; Hu, Zhiping; Bing, Guoying; Zhao, Lingling

    2015-10-01

    Increasing epidemiological and toxicological evidence suggests that pesticides and other environmental exposures may be associated with the development of Parkinson's disease (PD). Chlorpyrifos (CPF) is a widely used organophosphorous pesticide with developmental neurotoxicity. Its neurotoxicity, notably on the monoamine system, suggests that exposure of CPF may induce dopaminergic neuronal injury. We investigated whether neonatal exposure to CPF contributes to initiation and progression of dopaminergic neurotoxicity and explored the possible underlying mechanisms. The newborn rats were administrated 5 mg/kg CPF subcutaneously from postnatal day (PND) 11 to PND 14 daily. The effect of CPF on dopaminergic neurons, microglia, astrocyte, nuclear factor-κB (NF-κB) p. 65 and p. 38 mitogen-activated protein kinase (MAPK) signaling pathways was analyzed in the substantia nigra of rats at 12h, 24h, 72 h, 16d and 46 d after exposure. CPF-treated rats exhibited significant reduction of dopaminergic neurons at 16d and 46 d after exposure, and a significant increase in the expression of microglia and astrocytes in the substantia nigra after CPF exposure. Intense activation of NF-κB p. 65 and p. 38 MAPK inflammatory signaling pathways was observed. Our findings indicate that neonatal exposure to CPF may induce long-term dopaminergic neuronal damage in the substantia nigra mediated by the activation of inflammatory response via NF-κB p. 65 and p. 38 MAPK pathways in the nigrostriatal system. PMID:26215101

  9. A new animal model of placebo analgesia: involvement of the dopaminergic system in reward learning

    PubMed Central

    Lee, In-Seon; Lee, Bombi; Park, Hi-Joon; Olausson, Håkan; Enck, Paul; Chae, Younbyoung

    2015-01-01

    We suggest a new placebo analgesia animal model and investigated the role of the dopamine and opioid systems in placebo analgesia. Before and after the conditioning, we conducted a conditioned place preference (CPP) test to measure preferences for the cues (Rooms 1 and 2), and a hot plate test (HPT) to measure the pain responses to high level-pain after the cues. In addition, we quantified the expression of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and c-Fos in the anterior cingulate cortex (ACC) as a response to reward learning and pain response. We found an enhanced preference for the low level-pain paired cue and enhanced TH expression in the VTA of the Placebo and Placebo + Naloxone groups. Haloperidol, a dopamine antagonist, blocked these effects in the Placebo + Haloperidol group. An increased pain threshold to high-heat pain and reduced c-Fos expression in the ACC were observed in the Placebo group only. Haloperidol blocked the place preference effect, and naloxone and haloperidol blocked the placebo analgesia. Cue preference is mediated by reward learning via the dopamine system, whereas the expression of placebo analgesia is mediated by the dopamine and opioid systems. PMID:26602173

  10. A new animal model of placebo analgesia: involvement of the dopaminergic system in reward learning.

    PubMed

    Lee, In-Seon; Lee, Bombi; Park, Hi-Joon; Olausson, Håkan; Enck, Paul; Chae, Younbyoung

    2015-01-01

    We suggest a new placebo analgesia animal model and investigated the role of the dopamine and opioid systems in placebo analgesia. Before and after the conditioning, we conducted a conditioned place preference (CPP) test to measure preferences for the cues (Rooms 1 and 2), and a hot plate test (HPT) to measure the pain responses to high level-pain after the cues. In addition, we quantified the expression of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and c-Fos in the anterior cingulate cortex (ACC) as a response to reward learning and pain response. We found an enhanced preference for the low level-pain paired cue and enhanced TH expression in the VTA of the Placebo and Placebo + Naloxone groups. Haloperidol, a dopamine antagonist, blocked these effects in the Placebo + Haloperidol group. An increased pain threshold to high-heat pain and reduced c-Fos expression in the ACC were observed in the Placebo group only. Haloperidol blocked the place preference effect, and naloxone and haloperidol blocked the placebo analgesia. Cue preference is mediated by reward learning via the dopamine system, whereas the expression of placebo analgesia is mediated by the dopamine and opioid systems. PMID:26602173

  11. Evolutionarily conserved organization of the dopaminergic system in lamprey: SNc/VTA afferent and efferent connectivity and D2 receptor expression.

    PubMed

    Pérez-Fernández, Juan; Stephenson-Jones, Marcus; Suryanarayana, Shreyas M; Robertson, Brita; Grillner, Sten

    2014-12-01

    The dopaminergic system influences motor behavior, signals reward and novelty, and is an essential component of the basal ganglia in all vertebrates including the lamprey, one of the phylogenetically oldest vertebrates. The intrinsic organization and function of the lamprey basal ganglia is highly conserved. For instance, the direct and indirect pathways are modulated through dopamine D1 and D2 receptors in lamprey and in mammals. The nucleus of the tuberculum posterior, a homologue of the substantia nigra pars compacta (SNc)/ventral tegmental area (VTA) is present in lamprey, but only scarce data exist about its connectivity. Likewise, the D2 receptor is expressed in the striatum, but little is known about its localization in other brain areas. We used in situ hybridization and tracer injections, both in combination with tyrosine hydroxylase immunohistochemistry, to characterize the SNc/VTA efferent and afferent connectivity, and to relate its projection pattern with D2 receptor expression in particular. We show that most features of the dopaminergic system are highly conserved. As in mammals, the direct pallial (cortex in mammals) input and the basal ganglia connectivity with the SNc/VTA are present as part of the evaluation system, as well as input from the tectum as the evolutionary basis for salience/novelty detection. Moreover, the SNc/VTA receives sensory information from the olfactory bulbs, optic tectum, octavolateral area, and dorsal column nucleus, and it innervates, apart from the nigrostriatal pathway, several motor-related areas. This suggests that the dopaminergic system also contributes to the control of different motor centers at the brainstem level. PMID:24942187

  12. Disruption in dopaminergic innervation during photoreceptor degeneration.

    PubMed

    Ivanova, Elena; Yee, Christopher W; Sagdullaev, Botir T

    2016-04-15

    Dopaminergic amacrine cells (DACs) release dopamine in response to light-driven synaptic inputs, and are critical to retinal light adaptation. Retinal degeneration (RD) compromises the light responsiveness of the retina and, subsequently, dopamine metabolism is impaired. As RD progresses, retinal neurons exhibit aberrant activity, driven by AII amacrine cells, a primary target of the retinal dopaminergic network. Surprisingly, DACs are an exception to this physiological change; DACs exhibit rhythmic activity in healthy retina, but do not burst in RD. The underlying mechanism of this divergent behavior is not known. It is also unclear whether RD leads to structural changes in DACs, impairing functional regulation of AII amacrine cells. Here we examine the anatomical details of DACs in three mouse models of human RD to determine how changes to the dopaminergic network may underlie physiological changes in RD. By using rd10, rd1, and rd1/C57 mice we were able to dissect the impacts of genetic background and the degenerative process on DAC structure in RD retina. We found that DACs density, soma size, and primary dendrite length are all significantly reduced. Using a novel adeno-associated virus-mediated technique to label AII amacrine cells in mouse retina, we observed diminished dopaminergic contacts to AII amacrine cells in RD mice. This was accompanied by changes to the components responsible for dopamine synthesis and release. Together, these data suggest that structural alterations of the retinal dopaminergic network underlie physiological changes during RD. PMID:26356010

  13. Histamine H3 Receptor Regulates Sensorimotor Gating and Dopaminergic Signaling in the Striatum.

    PubMed

    Kononoff Vanhanen, Jenni; Nuutinen, Saara; Tuominen, Mervi; Panula, Pertti

    2016-05-01

    The brain histamine system has been implicated in regulation of sensorimotor gating deficits and in Gilles de la Tourette syndrome. Histamine also regulates alcohol reward and consumption via H3 receptor (H3R), possibly through an interaction with the brain dopaminergic system. Here, we identified the histaminergic mechanism of sensorimotor gating and the role of histamine H3R in the regulation of dopaminergic signaling. We found that H3R knockout mice displayed impaired prepulse inhibition (PPI), indicating deficiency in sensorimotor gating. Histamine H1 receptor knockout and histidine decarboxylase knockout mice had similar PPI as their controls. Dopaminergic drugs increased PPI of H3R knockout mice to the same level as in control mice, suggesting that changes in dopamine receptors might underlie deficient PPI response when H3R is lacking. Striatal dopamine D1 receptor mRNA level was lower, and D1 and D2 receptor-mediated activation of extracellular signal-regulated kinase 1/2 was absent in the striatum of H3R knockout mice, suggesting that H3R is essential for the dopamine receptor-mediated signaling. In conclusion, these findings demonstrate that H3R is an important regulator of sensorimotor gating, and the lack of H3R significantly modifies striatal dopaminergic signaling. These data support the usefulness of H3R ligands in neuropsychiatric disorders with preattentional deficits and disturbances in dopaminergic signaling. PMID:26945087

  14. [Impact of opiates on dopaminergic neurons].

    PubMed

    Kaufling, Jennifer; Freund-Mercier, Marie-José; Barrot, Michel

    2016-01-01

    Since the work of Johnson and North, it is known that opiates increase the activity of dopaminergic neurons by a GABA neuron-mediated desinhibition. This model should however be updated based on recent advances. Thus, the neuroanatomical location of the GABA neurons responsible for this desinhibition has been recently detailed: they belong to a brain structure in continuity with the posterior part of the ventral tegmental area and discovered this past decade. Other data also highlighted the critical role played by glutamatergic transmission in the opioid regulation of dopaminergic neuron activity. During protracted opiate withdrawal, the inhibitory/excitatory balance exerted on dopaminergic neurons is altered. These results are now leading to propose an original hypothesis for explaining the impact of protracted opiate withdrawal on mood. PMID:27406773

  15. The atypical homeoprotein Pbx1a participates in the axonal pathfinding of mesencephalic dopaminergic neurons

    PubMed Central

    2012-01-01

    Background The pre B-cell leukemia transcription factor 1 (Pbx1) genes belong to the three amino acid loop extension family of homeodomain proteins that form hetero-oligomeric complexes with other homeodomain transcription factors, thereby modulating target specificity, DNA binding affinity and transcriptional activity of their molecular associates. Results Here, we provide evidence that Pbx1 is expressed in mesencephalic dopaminergic neurons from embryonic day 11 into adulthood and determines some of the cellular properties of this neuronal population. In Pbx1-deficient mice, the mesencephalic dopaminergic axons stall during mid-gestation at the border between di- and telencephalon before entering the ganglionic eminence, leading to a loose organization of the axonal bundle and partial misrouting. In Pbx1-deficient dopaminergic neurons, the high affinity netrin-1 receptor, deleted in colon cancer (DCC), is down-regulated. Interestingly, we found several conserved Pbx1 binding sites in the first intron of DCC, suggesting a direct regulation of DCC transcription by Pbx1. Conclusions The expression of Pbx1 in dopaminergic neurons and its regulation of DCC expression make it an important player in defining the axonal guidance of the midbrain dopaminergic neurons, with possible implications for the normal physiology of the nigro-striatal system as well as processes related to the degeneration of neurons during the course of Parkinson’s disease. PMID:22748019

  16. Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1

    PubMed Central

    Valdés, Pamela; Mercado, Gabriela; Vidal, Rene L.; Molina, Claudia; Parsons, Geoffrey; Court, Felipe A.; Martinez, Alexis; Galleguillos, Danny; Armentano, Donna; Schneider, Bernard L.; Hetz, Claudio

    2014-01-01

    Parkinson disease (PD) is characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta (SNpc). Although growing evidence indicates that endoplasmic reticulum (ER) stress is a hallmark of PD, its exact contribution to the disease process is not well understood. Here we report that developmental ablation of X-Box binding protein 1 (XBP1) in the nervous system, a key regulator of the unfolded protein response (UPR), protects dopaminergic neurons against a PD-inducing neurotoxin. This survival effect was associated with a preconditioning condition that resulted from induction of an adaptive ER stress response in dopaminergic neurons of the SNpc, but not in other brain regions. In contrast, silencing XBP1 in adult animals triggered chronic ER stress and dopaminergic neuron degeneration. Supporting this finding, gene therapy to deliver an active form of XBP1 provided neuroprotection and reduced striatal denervation in animals injected with 6-hydroxydopamine. Our results reveal a physiological role of the UPR in the maintenance of protein homeostasis in dopaminergic neurons that may help explain the differential neuronal vulnerability observed in PD. PMID:24753614

  17. Methamphetamine-induced dopaminergic deficits and refractoriness to subsequent treatment.

    PubMed

    Hanson, Jarom E; Birdsall, Elisabeth; Seferian, Kristi S; Crosby, Marcus A; Keefe, Kristen A; Gibb, James W; Hanson, Glen R; Fleckenstein, Annette E

    2009-04-01

    Repeated high-dose methamphetamine administrations can cause persistent dopaminergic deficits. As individuals abusing methamphetamine are often exposed to recurrent high-dose administration, the impact of its repeated exposure merits investigation. Accordingly, rats were pretreated with repeated high-dose injections of methamphetamine, and subsequently "challenged" with the same neurotoxic regimen 7 or 30 days later. Results revealed that the initial methamphetamine treatment caused persistent deficits in striatal dopamine levels, dopamine transporter function, and vesicular monoamine transporter-2 function. The subsequent methamphetamine challenge treatment was without further persistent effects on these parameters, as assessed 7 days after the challenge, regardless of the interval (7 or 30 days) between the initial and challenge drug exposures. Similarly, a methamphetamine challenge treatment administered 7 days after the initial drug treatment was without further acute effect on dopamine transporter or VMAT-2 function, as assessed 1 h later. Thus, this study describes a model of resistance, possibly explained by: 1) the existence of dopaminergic neurons that are a priori refractory to deficits caused by methamphetamine; 2) the existence of dopaminergic neurons made persistently resistant consequent to a neurotoxic methamphetamine exposure; and/or 3) altered activation of post-synaptic basal ganglia systems necessary for the elaboration of methamphetamine-induced dopamine neurotoxicity. PMID:19326567

  18. Potential environmental neurotoxins related to 1-methyl-4-phenylpyridinium: Selective toxicity of 1-methyl-4-(4'-acetamidophenyl)-pyridinium and 1-methyl-4-cyclohexylpyridinium for dopaminergic neurons in culture

    SciTech Connect

    Michel, P.P.; Dandapani, B.K.; Efange, S.M.; Hefti, F. )

    1990-05-01

    Mesencephalic cells in culture were exposed to various compounds which we hypothesized to be selective toxins for dopaminergic neurons. The culture system was previously shown suitable for assessing selective dopaminergic neurotoxicity, since 1-methyl-4-phenyl-pyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium, destroyed dopaminergic neurons without affecting other cells. Some compounds tested were selected to fulfill two criteria believed to underly the selective dopaminergic neurotoxicity of MPP+, i.e., to be a potential substrate for the uptake carrier for dopamine and to possess a strong delocalized positive charge to inhibit the mitochondrial respiratory system. Other compounds were chosen on the basis of clinical or anecdotal evidence linking them to Parkinson's disease. Among the tested compounds two pyridinium analogs, 1-methyl-4-(4'-acetamidophenyl)pyridinium (MACPP+) and 1-methyl-4-cyclohexylpyridinium (MCP+) were found to be selectively toxic toward dopaminergic neurons. Incubation of cultures with both MACPP+ and MCP+ produced a dramatic reduction in the number of tyrosine hydroxylase-positive cells and the uptake of (3H)dopamine without reducing the number of cells visualized by phase-contrast microscopy or the uptake of (3H)aminobutyric acid. Besides MACPP+ and MCP+ none of the tested compounds exhibited any selective dopaminergic neurotoxicity. Together with earlier findings, these data suggest that the structural requirements are rather strict for a chemical to be a selective dopaminergic neurotoxin and make it unlikely that there is a wide spectrum of environmental dopaminergic toxins.

  19. Deferoxamine-mediated up-regulation of HIF-1α prevents dopaminergic neuronal death via the activation of MAPK family proteins in MPTP-treated mice.

    PubMed

    Guo, Chuang; Hao, Li-Juan; Yang, Zhao-Hui; Chai, Rui; Zhang, Shuai; Gu, Yu; Gao, Hui-Ling; Zhong, Man-Li; Wang, Tao; Li, Jia-Yi; Wang, Zhan-You

    2016-06-01

    Accumulating evidence suggests that an abnormal accumulation of iron in the substantia nigra (SN) is one of the defining characteristics of Parkinson's disease (PD). Accordingly, the potential neuroprotection of Fe chelators is widely acknowledged for the treatment of PD. Although desferrioxamine (DFO), an iron chelator widely used in clinical settings, has been reported to improve motor deficits and dopaminergic neuronal survival in animal models of PD, DFO has poor penetration to cross the blood-brain barrier and elicits side effects. We evaluated whether an intranasal administration of DFO improves the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of dopaminergic neurons in the nigrostriatal axis and investigated the molecular mechanisms of intranasal DFO treatment in preventing MPTP-induced neurodegeneration. Treatment with DFO efficiently alleviated behavioral deficits, increased the survival of tyrosine hydroxylase (TH)-positive neurons, and decreased the action of astrocytes in the SN and striatum in an MPTP-induced PD mouse model. Interestingly, we found that DFO up-regulated the expression of HIF-1α protein, TH, vascular endothelial growth factor (VEGF), and growth associated protein 43 (GAP43) and down-regulated the expression of α-synuclein, divalent metal transporter with iron-responsive element (DMT1+IRE), and transferrin receptor (TFR). This was accompanied by a decrease in iron-positive cells in the SN and striatum of the DFO-treated group. We further revealed that DFO treatment significantly inhibited the MPTP-induced phosphorylation of the c-Jun N-terminal kinase (JNK) and differentially enhanced the phosphorylation of extracellular regulated protein kinases (ERK) and mitogen-activated protein kinase (MAPK)/P38 kinase. Additionally, the effects of DFO on increasing the Bcl-2/Bax ratio were further validated in vitro and in vivo. In SH-SY5Y cells, the DFO-mediated up-regulation of HIF-1α occurred via the activation of

  20. Proclivity to self-injurious behavior in MRL-lpr mice: implications for autoimmunity-induced damage in the dopaminergic system.

    PubMed

    Chun, S; McEvilly, R; Foster, J A; Sakic, B

    2008-11-01

    Systemic lupus erythematosus is frequently accompanied by psychiatric manifestations of unknown origin. Although damage of central neurons had been documented, little is known about neurotransmitter systems affected by the autoimmune/inflammatory process. Recent studies on lupus-prone MRL-lpr mice point to imbalanced dopamine function and neurodegeneration in dopamine-rich brain regions. We follow up on anecdotal observations of singly housed mice developing chest wounds. Compulsive grooming and/or skin biting accounted for open lesions, lending itself to the operational term 'self-injurious behavior' (SIB). Low incidence of spontaneous SIB increased significantly after repeated injections of dopamine-2/3 receptor (D2/D3R) agonist quinpirole (QNP). To further probe the dopaminergic circuitry and examine whether SIB is associated with development of lupus-like disease, we compared behavioral responses among cohorts that differed in the immune status. Two-week treatment with QNP (intraperitoneal, 0.5 mg kg(-1) body weight per day) induced SIB in 60% of diseased MRL-lpr mice, and exacerbated their splenomegaly. Although increased grooming and stereotypy were observed in less symptomatic MRL+/+ controls, only one mouse (10%) developed SIB. Similarly, SIB was not seen in young, asymptomatic groups despite dissimilar ambulatory responses to QNP. In situ hybridization revealed treatment-independent upregulation of D2R mRNA in substantia nigra of diseased MRL-lpr mice. The above results suggest that development of systemic autoimmunity alters sensitivity of the dopaminergic system and renders MRL-lpr mice prone to SIB. Although pathogenic factors were not examined, we hypothesize that immune and endocrine mechanisms jointly contribute to early neuronal damage, which underlies behavioral deficiency in the adulthood. PMID:17768421

  1. Behavioural, biochemical and molecular changes induced by chronic crack-cocaine inhalation in mice: The role of dopaminergic and endocannabinoid systems in the prefrontal cortex.

    PubMed

    Areal, Lorena B; Rodrigues, Livia C M; Andrich, Filipe; Moraes, Livia S; Cicilini, Maria A; Mendonça, Josideia B; Pelição, Fabricio S; Nakamura-Palacios, Ester M; Martins-Silva, Cristina; Pires, Rita G W

    2015-09-01

    Crack-cocaine addiction has increasingly become a public health problem worldwide, especially in developing countries. However, no studies have focused on neurobiological mechanisms underlying the severe addiction produced by this drug, which seems to differ from powder cocaine in many aspects. This study investigated behavioural, biochemical and molecular changes in mice inhaling crack-cocaine, focusing on dopaminergic and endocannabinoid systems in the prefrontal cortex. Mice were submitted to two inhalation sessions of crack-cocaine a day (crack-cocaine group) during 11 days, meanwhile the control group had no access to the drug. We found that the crack-cocaine group exhibited hyperlocomotion and a peculiar jumping behaviour ("escape jumping"). Blood collected right after the last inhalation session revealed that the anhydroecgonine methyl ester (AEME), a specific metabolite of cocaine pyrolysis, was much more concentrated than cocaine itself in the crack-cocaine group. Most genes related to the endocannabinoid system, CB1 receptor and cannabinoid degradation enzymes were downregulated after 11-day crack-cocaine exposition. These changes may have decreased dopamine and its metabolites levels, which in turn may be related with the extreme upregulation of dopamine receptors and tyrosine hydroxylase observed in the prefrontal cortex of these animals. Our data suggest that after 11 days of crack-cocaine exposure, neuroadaptive changes towards downregulation of reinforcing mechanisms may have taken place as a result of neurochemical changes observed on dopaminergic and endocannabinoid systems. Successive changes like these have never been described in cocaine hydrochloride models before, probably because AEME is only produced by cocaine pyrolysis and this metabolite may underlie the more aggressive pattern of addiction induced by crack-cocaine. PMID:25940765

  2. Catalpol protects dopaminergic neurons from LPS-induced neurotoxicity in mesencephalic neuron-glia cultures.

    PubMed

    Tian, Yuan-Yuan; An, Li-Jia; Jiang, Lan; Duan, Yan-Long; Chen, Jun; Jiang, Bo

    2006-12-23

    Inflammation plays an important role in the pathogenesis of Parkinson's disease (PD). Microglia, the resident immune cells in the central nervous system, are pivotal in the inflammatory reaction. Activated microglia can induce expression of inducible nitric-oxide synthase (iNOS) and release significant amounts of nitric oxide (NO) and TNF-alpha, which can damage the dopaminergic neurons. Catalpol, an iridoid glycoside, contained richly in the roots of Rehmannia glutinosa, was found to be neuroprotective in gerbils subjected to transient global cerebral ischemia. But the effect of catalpol on inflammation-mediated neurodegeneration has not been examined. In this study, microglia in mesencephalic neuron-glia cultures were activated with lipopolysaccharide (LPS) and the aim of the study was to examine whether catalpol could protect dopaminergic neurons from LPS-induced neurotoxicity. The results showed that catalpol significantly reduced the release of reactive oxygen species (ROS), TNF-alpha and NO after LPS-induced microglial activation. Further, catalpol attenuated LPS-induced the expression of iNOS. As determined by immunocytochemical analysis, pretreatment by catalpol dose-dependently protected dopaminergic neurons against LPS-induced neurotoxicity. These results suggest that catalpol exerts its protective effect on dopaminergic neurons by inhibiting microglial activation and reducing the production of proinflammatory factors. Thus, catalpol may possess therapeutic potential against inflammation-related neurodegenerative diseases. PMID:17049947

  3. Long Withdrawal of Methylphenidate Induces a Differential Response of the Dopaminergic System and Increases Sensitivity to Cocaine in the Prefrontal Cortex of Spontaneously Hypertensive Rats.

    PubMed

    dos Santos Pereira, Maurício; Sathler, Matheus Figueiredo; Valli, Thais da Rosa; Marques, Richard Souza; Ventura, Ana Lucia Marques; Peccinalli, Ney Ronner; Fraga, Mabel Carneiro; Manhães, Alex C; Kubrusly, Regina

    2015-01-01

    Methylphenidate (MPD) is one of the most prescribed drugs for alleviating the symptoms of Attention Deficit/Hyperactivity Disorder (ADHD). However, changes in the molecular mechanisms related to MPD withdrawal and susceptibility to consumption of other psychostimulants in normal individuals or individuals with ADHD phenotype are not completely understood. The aims of the present study were: (i) to characterize the molecular differences in the prefrontal dopaminergic system of SHR and Wistar strains, (ii) to establish the neurochemical consequences of short- (24 hours) and long-term (10 days) MPD withdrawal after a subchronic treatment (30 days) with Ritalin® (Methylphenidate Hydrochloride; 2.5 mg/kg orally), (iii) to investigate the dopaminergic synaptic functionality after a cocaine challenge in adult MPD-withdrawn SHR and Wistar rats. Our results indicate that SHR rats present reduced [3H]-Dopamine uptake and cAMP accumulation in the prefrontal cortex (PFC) and are not responsive to dopaminergic stimuli in when compared to Wistar rats. After a 24-hour withdrawal of MPD, SHR did not present any alterations in [3H]-Dopamine Uptake, [3H]-SCH 23390 binding and cAMP production; nonetheless, after a 10-day MPD withdrawal, the results showed a significant increase of [3H]-Dopamine uptake, of the quantity of [3H]-SCH 23390 binding sites and of cAMP levels in these animals. Finally, SHR that underwent a 10-day MPD withdrawal and were challenged with cocaine (10 mg/kg i.p.) presented reduced [3H]-Dopamine uptake and increased cAMP production. Wistar rats were affected by the 10-day withdrawal of MPD in [3H]-dopamine uptake but not in cAMP accumulation; in addition, cocaine was unable to induce significant modifications in [3H]-dopamine uptake and in cAMP levels after the 10-day withdrawal of MPD. These results indicate a mechanism that could explain the high comorbidity between ADHD adolescent patients under methylphenidate treatment and substance abuse in adult life

  4. Long Withdrawal of Methylphenidate Induces a Differential Response of the Dopaminergic System and Increases Sensitivity to Cocaine in the Prefrontal Cortex of Spontaneously Hypertensive Rats

    PubMed Central

    dos Santos Pereira, Maurício; Sathler, Matheus Figueiredo; Valli, Thais da Rosa; Marques, Richard Souza; Ventura, Ana Lucia Marques; Peccinalli, Ney Ronner; Fraga, Mabel Carneiro; Manhães, Alex C.; Kubrusly, Regina

    2015-01-01

    Methylphenidate (MPD) is one of the most prescribed drugs for alleviating the symptoms of Attention Deficit/Hyperactivity Disorder (ADHD). However, changes in the molecular mechanisms related to MPD withdrawal and susceptibility to consumption of other psychostimulants in normal individuals or individuals with ADHD phenotype are not completely understood. The aims of the present study were: (i) to characterize the molecular differences in the prefrontal dopaminergic system of SHR and Wistar strains, (ii) to establish the neurochemical consequences of short- (24 hours) and long-term (10 days) MPD withdrawal after a subchronic treatment (30 days) with Ritalin® (Methylphenidate Hydrochloride; 2.5 mg/kg orally), (iii) to investigate the dopaminergic synaptic functionality after a cocaine challenge in adult MPD-withdrawn SHR and Wistar rats. Our results indicate that SHR rats present reduced [3H]-Dopamine uptake and cAMP accumulation in the prefrontal cortex (PFC) and are not responsive to dopaminergic stimuli in when compared to Wistar rats. After a 24-hour withdrawal of MPD, SHR did not present any alterations in [3H]-Dopamine Uptake, [3H]-SCH 23390 binding and cAMP production; nonetheless, after a 10-day MPD withdrawal, the results showed a significant increase of [3H]-Dopamine uptake, of the quantity of [3H]-SCH 23390 binding sites and of cAMP levels in these animals. Finally, SHR that underwent a 10-day MPD withdrawal and were challenged with cocaine (10 mg/kg i.p.) presented reduced [3H]-Dopamine uptake and increased cAMP production. Wistar rats were affected by the 10-day withdrawal of MPD in [3H]-dopamine uptake but not in cAMP accumulation; in addition, cocaine was unable to induce significant modifications in [3H]-dopamine uptake and in cAMP levels after the 10-day withdrawal of MPD. These results indicate a mechanism that could explain the high comorbidity between ADHD adolescent patients under methylphenidate treatment and substance abuse in adult life

  5. Contexts for dopamine specification by calcium spike activity in the central nervous system

    PubMed Central

    Velázquez-Ulloa, Norma A.; Spitzer, Nicholas C.; Dulcis, Davide

    2011-01-01

    Calcium-dependent electrical activity plays a significant role in neurotransmitter specification at early stages of development. To test the hypothesis that activity-dependent differentiation depends on molecular context we investigated the development of dopaminergic neurons in the central nervous system of larval Xenopus laevis. We find that different dopaminergic nuclei respond to manipulation of this early electrical activity by ion channel misexpression with different increases and decreases in numbers of dopaminergic neurons. Focusing on the ventral suprachiasmatic nucleus and the spinal cord in order to gain insight into these differences, we identify distinct subpopulations of neurons that express characteristic combinations of GABA and NPY as co-transmitters and Lim1,2 and Nurr1 transcription factors. We demonstrate that the developmental state of neurons identified by their spatial location and expression of these molecular markers is correlated with characteristic spontaneous calcium spike activity. Different subpopulations of dopaminergic neurons respond differently to manipulation of this early electrical activity. Moreover, retinohypothalamic circuit activation of the ventral suprachiasmatic nucleus recruits expression of dopamine selectively in reserve pool neurons that already express GABA and neuropeptide Y. The results are consistent with the hypothesis that spontaneously active neurons expressing GABA are most susceptible to activity-dependent expression of dopamine both in the spinal cord and in the brain. Because loss of dopaminergic neurons plays a role in neurological disorders such as Parkinson’s disease, understanding how subpopulations of neurons become dopaminergic may lead to protocols for differentiation of neurons in vitro to replace those that have been lost in vivo. PMID:21209192

  6. Enhancement of L-3-hydroxybutyryl-CoA dehydrogenase activity and circulating ketone body levels by pantethine. Relevance to dopaminergic injury

    PubMed Central

    2010-01-01

    Background The administration of the ketone bodies hydroxybutyrate and acetoacetate is known to exert a protective effect against metabolic disorders associated with cerebral pathologies. This suggests that the enhancement of their endogenous production might be a rational therapeutic approach. Ketone bodies are generated by fatty acid beta-oxidation, a process involving a mitochondrial oxido-reductase superfamily, with fatty acid-CoA thioesters as substrates. In this report, emphasis is on the penultimate step of the process, i.e. L-3-hydroxybutyryl-CoA dehydrogenase activity. We determined changes in enzyme activity and in circulating ketone body levels in the MPTP mouse model of Parkinson's disease. Since the active moiety of CoA is pantetheine, mice were treated with pantethine, its naturally-occurring form. Pantethine has the advantage of being known as an anti-inflammatory and hypolipidemic agent with very few side effects. Results We found that dehydrogenase activity and circulating ketone body levels were drastically reduced by the neurotoxin MPTP, whereas treatment with pantethine overcame these adverse effects. Pantethine prevented dopaminergic neuron loss and motility disorders. In vivo and in vitro experiments showed that the protection was associated with enhancement of glutathione (GSH) production as well as restoration of respiratory chain complex I activity and mitochondrial ATP levels. Remarkably, pantethine treatment boosted the circulating ketone body levels in MPTP-intoxicated mice, but not in normal animals. Conclusions These finding demonstrate the feasibility of the enhancement of endogenous ketone body production and provide a promising therapeutic approach to Parkinson's disease as well as, conceivably, to other neurodegenerative disorders. PMID:20416081

  7. Recent Advances in Imaging of Dopaminergic Neurons for Evaluation of Neuropsychiatric Disorders

    PubMed Central

    Shen, Lie-Hang; Liao, Mei-Hsiu; Tseng, Yu-Chin

    2012-01-01

    Dopamine is the most intensely studied monoaminergic neurotransmitter. Dopaminergic neurotransmission plays an important role in regulating several aspects of basic brain function, including motor, behavior, motivation, and working memory. To date, there are numerous positron emission tomography (PET) and single photon emission computed tomography (SPECT) radiotracers available for targeting different steps in the process of dopaminergic neurotransmission, which permits us to quantify dopaminergic activity in the living human brain. Degeneration of the nigrostriatal dopamine system causes Parkinson's disease (PD) and related Parkinsonism. Dopamine is the neurotransmitter that has been classically associated with the reinforcing effects of drug abuse. Abnormalities within the dopamine system in the brain are involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Dopamine receptors play an important role in schizophrenia and the effect of neuroleptics is through blockage of dopamine D2 receptors. This review will concentrate on the radiotracers that have been developed for imaging dopaminergic neurons, describe the clinical aspects in the assessment of neuropsychiatric disorders, and suggest future directions in the diagnosis and management of such disorders. PMID:22570524

  8. Effect of non-selective dopaminergic receptor agonist on disrupted maternal behavior in olfactory bulbectomized mice.

    PubMed

    Sato, Atsushi; Nakagawasai, Osamu; Tan-No, Koichi; Onogi, Hiroshi; Niijima, Fukie; Tadano, Takeshi

    2010-07-11

    Olfactory bulbectomy (OBX) animals are considered a putative model of depression that produces behavioral, physiological, and neurochemical alterations resembling clinical depression. Depression is a critical cause of child abuse and neglect, and it has been reported that maternal behavior involves dopaminergic neurons of the mesolimbic pathway. In this study, we investigated the effect of apomorphine, a non-selective dopaminergic receptor agonist, on maternal behavior to examine the influence of activated brain dopaminergic function in OBX mice. In addition, we conducted the sucrose preference test to examine the reward system which has a critical relationship to mesolimbic dopaminergic function and maternal behavior. Maternal behavior was observed on postnatal day (PND) 0 and 4. OBX female mice showed a reduction in sucrose preference 2 weeks post surgery. OBX dams showed maternal behavior deficits on PND 0, and these deficits were ameliorated by administration of apomorphine. These results suggest that maternal behavior deficits in OBX dams may involve brain hypodopaminergic function in the central nervous system induced by OBX. PMID:20219556

  9. Can the chronic administration of the combination of buprenorphine and naloxone block dopaminergic activity causing anti-reward and relapse potential?

    PubMed

    Blum, Kenneth; Chen, Thomas J H; Bailey, John; Bowirrat, Abdalla; Femino, John; Chen, Amanda L C; Simpatico, Thomas; Morse, Siobhan; Giordano, John; Damle, Uma; Kerner, Mallory; Braverman, Eric R; Fornari, Frank; Downs, B William; Rector, Cynthia; Barh, Debmayla; Oscar-Berman, Marlene

    2011-12-01

    Opiate addiction is associated with many adverse health and social harms, fatal overdose, infectious disease transmission, elevated health care costs, public disorder, and crime. Although community-based addiction treatment programs continue to reduce the harms of opiate addiction with narcotic substitution therapy such as methadone maintenance, there remains a need to find a substance that not only blocks opiate-type receptors (mu, delta, etc.) but also provides agonistic activity; hence, the impetus arose for the development of a combination of narcotic antagonism and mu receptor agonist therapy. After three decades of extensive research, the federal Drug Abuse Treatment Act 2000 (DATA) opened a window of opportunity for patients with addiction disorders by providing increased access to options for treatment. DATA allows physicians who complete a brief specialty-training course to become certified to prescribe buprenorphine and buprenorphine/naloxone (Subutex, Suboxone) for treatment of patients with opioid dependence. Clinical studies indicate that buprenorphine maintenance is as effective as methadone maintenance in retaining patients in substance abuse treatment and in reducing illicit opioid use. With that stated, we must consider the long-term benefits or potential toxicity attributed to Subutex or Suboxone. We describe a mechanism whereby chronic blockade of opiate receptors, in spite of only partial opiate agonist action, may ultimately block dopaminergic activity causing anti-reward and relapse potential. While the direct comparison is not as yet available, toxicity to buprenorphine can be found in the scientific literature. In considering our cautionary note in this commentary, we are cognizant that, to date, this is what we have available, and until such a time when the real magic bullet is discovered, we will have to endure. However, more than anything else this commentary should at least encourage the development of thoughtful new strategies to target

  10. Can the chronic administration of the combination of buprenorphine and naloxone block dopaminergic activity causing anti-reward and relapse potential?

    PubMed Central

    Blum, Kenneth; Chen, Thomas JH; Bailey, John; Bowirrat, Abdulla; Femino, John; Chen, Amanda LC; Simpatico, Thomas; Morse, Siobhan; Giordano, John; Damle, Uma; Kerner, Mallory; Braverman, Eric R.; Fornari, Frank; Downs, B.William; Rector, Cynthia; Barh, Debmayla; Oscar-Berman, Marlene

    2013-01-01

    Opiate addiction is associated with many adverse health and social harms, fatal overdose, infectious disease transmission, elevated health care costs, public disorder, and crime. Although community-based addiction treatment programs continue to reduce the harms of opiate addiction with narcotic substitution therapy such as methadone maintenance, there remains a need to find a substance that not only blocks opiate-type receptors (mu, delta, etc.) but also provides agonistic activity; hence the impetus arose for the development of a combination of narcotic antagonism and mu receptor agonist therapy. After three decades of extensive research the federal Drug Abuse Treatment Act 2000 (DATA) opened a window of opportunity for patients with addiction disorders by providing increased access to options for treatment. DATA allows physicians who complete a brief specialty-training course to become certified to prescribe buprenorphine and buprenorphine/naloxone (Subutex, Suboxone) for treatment of patients with opioid dependence. Clinical studies indicate buprenorphine maintenance is as effective as methadone maintenance in retaining patients in substance abuse treatment and in reducing illicit opioid use. With that stated, we must consider the long-term benefits or potential toxicity attributed to Subutex or Suboxone. We describe a mechanism whereby chronic blockade of opiate receptors, in spite of only partial opiate agonist action, may ultimately block dopaminergic activity causing anti-reward and relapse potential. While the direct comparison is not as yet available, toxicity to buprenorphine can be found in the scientific literature. In considering our cautionary note in this commentary, we are cognizant that to date this is what we have available, and until such a time when the real magic bullet is discovered, we will have to endure. However, more than anything else this commentary should at least encourage the development of thoughtful new strategies to target the

  11. Selective alterations in cerebral metabolism within the mesocorticolimbic dopaminergic system produced by acute cocaine administration in rats

    SciTech Connect

    Porrino, L.J.; Domer, F.R.; Crane, A.M.; Sokoloff, L.

    1988-05-01

    The 2-(/sup 14/C)deoxyglucose method was used to examine the effects of acute intravenous administration of cocaine on local cerebral glucose utilization in rats. These effects were correlated with the effects of cocaine on locomotor activity assessed simultaneously in the same animals. At the lowest dose of cocaine, 0.5 mg/kg (1.47 mumol/kg), alterations in glucose utilization were restricted to the medial prefrontal cortex and nucleus accumbens. Metabolic activity at 1.0 mg/kg (2.9 mumol/kg) was altered in these structures, but in the substantia nigra reticulata and lateral habenula as well. The selectivity of cocaine's effects at low doses demonstrates the particular sensitivity of these structures to cocaine's actions in the brain. In contrast, 5.0 mg/kg (14.7 mumol/kg) produced widespread changes in glucose utilization, particularly in the extrapyramidal system. Only this dose significantly increased locomotor activity above levels in vehicle-treated controls. Rates of glucose utilization were positively correlated with locomotor activity in the globus pallidus, substantia nigra reticulata, and subthalamic nucleus, and negatively correlated in the lateral habenula.

  12. Presynaptic and postsynaptic dopaminergic binding densities in the nigrostriatal and mesocortical systems in early Parkinson's disease: a double-tracer positron emission tomography study.

    PubMed

    Ouchi, Y; Kanno, T; Okada, H; Yoshikawa, E; Futatsubashi, M; Nobezawa, S; Torizuka, T; Sakamoto, M

    1999-11-01

    To investigate changes in the relation between presynaptic and postsynaptic dopaminergic functions in vivo in both nigrostriatal and mesocortical systems in Parkinson's disease (PD), 10 drug-naive early PD patients were studied twice using positron emission tomography with [11C]CFT (dopamine transporter probe) followed by [11C]SCH 23390 (D1 receptor probe). Regional binding potentials (k3/k4) of [11C]CFT and [11C]SCH 23390 in the striatum (nigrostriatal system) and the orbitofrontal cortex (mesocortical system) were estimated by compartment analyses. Levels of [11C]CFT k3/k4 in the two projection areas were shown to be significantly lower in PD, whereas [11C]SCH 23390 levels remained unchanged. Regression analysis showed that estimates of CFT k3/k4 were positively correlated with those of SCH 23390 k3/k4 in the striatum in normal control, whereas the two binding estimates were less positively correlated in the caudate and inversely correlated in the putamen in PD. No significant correlation was observed in the orbitofrontal cortex in both groups. These results indicated that dopamine transporters and D1 receptors change in parallel in the normal striatal synapses, but the association becomes asymmetrical because of reduction in presynaptic and relative elevation in postsynaptic markers in PD. Alterations in synaptic parallel regulation in the nigrostriatal system might reflect early pathophysiology in the parkinsonian brain. PMID:10553989

  13. The dopaminergic system in upper limb motor blocks (ULMB) investigated during bimanual coordination in Parkinson's disease (PD).

    PubMed

    Brown, Matt J N; Almeida, Quincy J; Rahimi, Fariborz

    2015-01-01

    Upper limb motor blocks (ULMB) (inability to initiate or sudden discontinue in voluntary movements) have been identified in both unimanual and bimanual tasks in individuals with Parkinson's disease (PD). In particular, ULMB have been observed during rhythmic bimanual coordination when switching between phase patterns which is required (e.g. between in-phase and anti-phase). While sensory-perceptual mechanisms have recently been suggested to be involved in lower limb freezing, there has been no consensus on the mechanism that evokes ULMB or whether motor blocks respond to dopamine replacement like other motor symptoms of PD. The current study investigated the occurrence of ULMB in PD participants without ('off') and with ('on') dopamine replacement using bimanual wrist flexion-extension with external auditory cues. In Experiment 1, coordination was performed in either in-phase (simultaneous flexion and extension) or anti-phase (asymmetrical flexion and extension between the limbs) in one of three sensory conditions: no vision, normal vision or augmented vision. Cycle frequency was increased within each trial across seven cycle frequencies (0.75-2 Hz). In Experiment 2, coordination was initiated in either phase pattern and participants were cued to make an intentional switch between phases in the middle of trials. Trials were performed at one of two cycle frequencies (1 or 2 Hz) and one of two sensory conditions: no vision or normal vision. Healthy age-matched control participants were also investigated in both experiments for the occurrence of motor blocks that were measured using automated detection from a computer algorithm. The results from Experiment 1 indicated that increasing cycle frequency resulted in more ULMB in individuals with PD during continuous coordinated movement, regardless of dopaminergic status, phase pattern or sensory condition. Experiment 2 also confirmed an increased occurrence of ULMB with increased cycle frequency. Furthermore, a large

  14. Dopaminergic Toxin 1-Methyl-4-Phenylpyridinium, Proteins α-Synuclein and Glia Maturation Factor Activate Mast Cells and Release Inflammatory Mediators.

    PubMed

    Kempuraj, Duraisamy; Thangavel, Ramasamy; Yang, Evert; Pattani, Sagar; Zaheer, Smita; Santillan, Donna A; Santillan, Mark K; Zaheer, Asgar

    2015-01-01

    Parkinson's disease (PD) is characterized by the presence of Lewy bodies and degeneration of dopaminergic neurons. 1-methyl-4-phenylpyridinium (MPP+), a metabolite of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and Lewy body component α-synuclein activates glia in PD pathogenesis. Mast cells and glia maturation factor (GMF) are implicated in neuroinflammatory conditions including Multiple Sclerosis. However, the role of mast cells in PD is not yet known. We have analyzed the effect of recombinant GMF, MPP+, α-synuclein and interleukin-33 (IL-33) on mouse bone marrow-derived cultured mast cells (BMMCs), human umbilical cord blood-derived cultured mast cells (hCBMCs) and mouse brain-derived cultured astrocytes by quantifying cytokines/chemokines released using ELISA or by detecting the expression of co-stimulatory molecules CD40 and CD40L by flow cytometry. GMF significantly released chemokine (C-C motif) ligand 2 (CCL2) from BMMCs but its release was reduced in BMMCs from GMF knockout mice. GMF, α-synuclein and MPP+ released IL-1β, β-hexosaminidase from BMMCs, and IL-8 from hCBMCs. GMF released CCL5, and IL-33- induced the expression of GMF from hCBMCs. Novel GMF expression was detected in hCBMCs and BMMCs by immunocytochemistry. GMF released tumor necrosis factor-alpha (TNF-α) from mouse astrocytes, and this release was greater in BMMC- astrocyte coculture than in individual cultures. Flow cytometry results showed increased IL-33 expression by GMF and MPP+, and GMF-induced CD40 expression in astrocytes. Proinflammatory mediator release by GMF, MPP+ and α-synuclein, as well as GMF expression by mast cells indicate a potential therapeutic target for neurodegenerative diseases including PD. PMID:26275153

  15. Maternal separation and early stress cause long-lasting effects on dopaminergic and endocannabinergic systems and alters dendritic morphology in the nucleus accumbens and frontal cortex in rats.

    PubMed

    Romano-López, Antonio; Méndez-Díaz, Mónica; García, Fabio García; Regalado-Santiago, Citlalli; Ruiz-Contreras, Alejandra E; Prospéro-García, Oscar

    2016-08-01

    A considerable amount experimental studies have shown that maternal separation (MS) is associated with adult offspring abnormal behavior and cognition disorder. Accordingly, this experimental procedure has been proposed as a predictor for alcohol and drug dependence based on the neurodevelopmental soon after birth. Endocannabinoid system (eCBs) has been implicated in reward processes, including drug abuse and dependence. MS and associated stress causes changes in the eCBs that seem to facilitate alcohol consumption. In this study, we seek to evaluate potential morphological changes in neurons of the frontal cortex (FCx) and nucleus accumbens (NAcc), in the expression of receptors and enzymes of the endocannabinoid and dopamine systems and in second messengers, such as Akt, in adult rats subjected to MS and early stress (MS + ES; 2 × 180 min daily) vs. nonseparated rats (NMS). Results showed that MS + ES induces higher D2R expression and lower D3R, FAAH, and MAGL expression compared with NMS rats. Alterations in total dendritic length were also detected and were characterized by increases in the NAcc while there were decreases in the FCx. We believe MS + ES-induced changes in the dopaminergic and endocannabinergic systems and in the neuronal microstructure might be contributing to alcohol seeking behavior and, potential vulnerability to other drugs in rats. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 819-831, 2016. PMID:26539755

  16. A scaling approach to find order parameters quantifying the effects of dopaminergic agents on unconditioned motor activity in rats.

    PubMed

    Paulus, M P; Geyer, M A

    1991-01-01

    1. Three experiments were conducted in the Behavioral Pattern Monitor (BPM) to assess the effects of the D1 agonist SKF-38393, the D2 agonist quinpirole, and the interaction of the D2 antagonists haloperidol with amphetamine or cocaine on the amount, the structure, and the unpredictability of micro-events of rat exploratory behavior. 2. SKF-38393 (0.3, 1.0, 3.0, and 10.0 mg/kg) did not change the amount of motor behavior indicated by the temporal scaling exponent alpha, a descriptor of the local degree of acting, during a 60 min exposure in the BPM. However, SKF-38393 (3.0, and 10.0 mg/kg) significantly increased the spatial scaling exponent d, indicating an increased component of local circumscribed movements. 3. Quinpirole (0.03, 0.1, 0.3, and 1.0 mg/kg) produced a biphasic dose response with respect to the amount of motor behavior. Low doses (0.03, 0.1) significantly decreased the local degree of acting, whereas alpha returned to control group levels for higher doses (0.3, 1.0 mg/kg). The change in activity was accompanied by a significant increase of local movements, i.e. d was increased for the lower doses. 4. Haloperidol (15.0 micrograms/kg) reduced a slightly increased d measure for amphetamine (1.0 mg/kg) treated animals and increased a significantly reduced d for cocaine (20.0 mg/kg) treated animals, without affecting the increases of motor activity induced by both treatments. 5. It is concluded that the structure of motor activity provides an important measure of unconditioned motor behavior, which can be affected independently of the typically measured amount of motor activity. PMID:1684875

  17. Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration

    PubMed Central

    Meka, Durga Praveen; Müller-Rischart, Anne Kathrin; Nidadavolu, Prakash; Mohammadi, Behnam; Motori, Elisa; Ponna, Srinivas Kumar; Aboutalebi, Helia; Bassal, Mahmoud; Annamneedi, Anil; Finckh, Barbara; Miesbauer, Margit; Rotermund, Natalie; Lohr, Christian; Tatzelt, Jörg; Winklhofer, Konstanze F.; Kramer, Edgar R.

    2015-01-01

    Parkin and the glial cell line–derived neurotrophic factor (GDNF) receptor RET have both been independently linked to the dopaminergic neuron degeneration that underlies Parkinson’s disease (PD). In the present study, we demonstrate that there is genetic crosstalk between parkin and the receptor tyrosine kinase RET in two different mouse models of PD. Mice lacking both parkin and RET exhibited accelerated dopaminergic cell and axonal loss compared with parkin-deficient animals, which showed none, and RET-deficient mice, in which we found moderate degeneration. Transgenic expression of parkin protected the dopaminergic systems of aged RET-deficient mice. Downregulation of either parkin or RET in neuronal cells impaired mitochondrial function and morphology. Parkin expression restored mitochondrial function in GDNF/RET-deficient cells, while GDNF stimulation rescued mitochondrial defects in parkin-deficient cells. In both cases, improved mitochondrial function was the result of activation of the prosurvival NF-κB pathway, which was mediated by RET through the phosphoinositide-3-kinase (PI3K) pathway. Taken together, these observations indicate that parkin and the RET signaling cascade converge to control mitochondrial integrity and thereby properly maintain substantia nigra pars compacta dopaminergic neurons and their innervation in the striatum. The demonstration of crosstalk between parkin and RET highlights the interplay in the protein network that is altered in PD and suggests potential therapeutic targets and strategies to treat PD. PMID:25822020

  18. An Imperfect Dopaminergic Error Signal Can Drive Temporal-Difference Learning

    PubMed Central

    Potjans, Wiebke; Diesmann, Markus; Morrison, Abigail

    2011-01-01

    An open problem in the field of computational neuroscience is how to link synaptic plasticity to system-level learning. A promising framework in this context is temporal-difference (TD) learning. Experimental evidence that supports the hypothesis that the mammalian brain performs temporal-difference learning includes the resemblance of the phasic activity of the midbrain dopaminergic neurons to the TD error and the discovery that cortico-striatal synaptic plasticity is modulated by dopamine. However, as the phasic dopaminergic signal does not reproduce all the properties of the theoretical TD error, it is unclear whether it is capable of driving behavior adaptation in complex tasks. Here, we present a spiking temporal-difference learning model based on the actor-critic architecture. The model dynamically generates a dopaminergic signal with realistic firing rates and exploits this signal to modulate the plasticity of synapses as a third factor. The predictions of our proposed plasticity dynamics are in good agreement with experimental results with respect to dopamine, pre- and post-synaptic activity. An analytical mapping from the parameters of our proposed plasticity dynamics to those of the classical discrete-time TD algorithm reveals that the biological constraints of the dopaminergic signal entail a modified TD algorithm with self-adapting learning parameters and an adapting offset. We show that the neuronal network is able to learn a task with sparse positive rewards as fast as the corresponding classical discrete-time TD algorithm. However, the performance of the neuronal network is impaired with respect to the traditional algorithm on a task with both positive and negative rewards and breaks down entirely on a task with purely negative rewards. Our model demonstrates that the asymmetry of a realistic dopaminergic signal enables TD learning when learning is driven by positive rewards but not when driven by negative rewards. PMID:21589888

  19. An imperfect dopaminergic error signal can drive temporal-difference learning.

    PubMed

    Potjans, Wiebke; Diesmann, Markus; Morrison, Abigail

    2011-05-01

    An open problem in the field of computational neuroscience is how to link synaptic plasticity to system-level learning. A promising framework in this context is temporal-difference (TD) learning. Experimental evidence that supports the hypothesis that the mammalian brain performs temporal-difference learning includes the resemblance of the phasic activity of the midbrain dopaminergic neurons to the TD error and the discovery that cortico-striatal synaptic plasticity is modulated by dopamine. However, as the phasic dopaminergic signal does not reproduce all the properties of the theoretical TD error, it is unclear whether it is capable of driving behavior adaptation in complex tasks. Here, we present a spiking temporal-difference learning model based on the actor-critic architecture. The model dynamically generates a dopaminergic signal with realistic firing rates and exploits this signal to modulate the plasticity of synapses as a third factor. The predictions of our proposed plasticity dynamics are in good agreement with experimental results with respect to dopamine, pre- and post-synaptic activity. An analytical mapping from the parameters of our proposed plasticity dynamics to those of the classical discrete-time TD algorithm reveals that the biological constraints of the dopaminergic signal entail a modified TD algorithm with self-adapting learning parameters and an adapting offset. We show that the neuronal network is able to learn a task with sparse positive rewards as fast as the corresponding classical discrete-time TD algorithm. However, the performance of the neuronal network is impaired with respect to the traditional algorithm on a task with both positive and negative rewards and breaks down entirely on a task with purely negative rewards. Our model demonstrates that the asymmetry of a realistic dopaminergic signal enables TD learning when learning is driven by positive rewards but not when driven by negative rewards. PMID:21589888

  20. [Psychopathological correlates of dopaminergic dysfunction in alcoholic and schizophrenic patients].

    PubMed

    Heinz, A

    1999-05-01

    It has been suggested that anhedonia, the loss of pleasure, is associated with a dysfunction of the dopaminergic reward system in schizophrenic and alcohol-dependent patients. In a series of neuroendocrinological and brain imaging studies, we examined pre- and postsynaptic mechanisms of dopaminergic neurotransmission in non-human primates and in schizophrenic and alcohol-dependent patients. Among alcoholics, we found indicators of a sensitization of dopaminergic neurotransmission, which was associated with the relapse risk, but not with anhedonia or depression. Schizophrenics with neuroleptic blockade of striatal dopamine D2 receptors displayed psychomotor slowing and reduced motivation, but not anhedonia. Primate studies pointed to the importance of a temporocortical dysfunction in the pathogenesis of phasic dopaminergic dysregulation in the striatum. These observations indicate that a dysfunction of stimulus-dependent dopamine release may be associated with motivational deficits caused by a reduction in incentive salience, but not with anhedonia. PMID:10407835

  1. 7α-Hydroxypregnenolone, a key neuronal modulator of locomotion, stimulates upstream migration by means of the dopaminergic system in salmon

    PubMed Central

    Haraguchi, Shogo; Yamamoto, Yuzo; Suzuki, Yuko; Hyung Chang, Joon; Koyama, Teppei; Sato, Miku; Mita, Masatoshi; Ueda, Hiroshi; Tsutsui, Kazuyoshi

    2015-01-01

    Salmon migrate upstream against an opposing current in their natal river. However, the molecular mechanisms that stimulate upstream migratory behavior are poorly understood. Here, we show that 7α-hydroxypregnenolone (7α-OH PREG), a newly identified neuronal modulator of locomotion, acts as a key factor for upstream migration in salmon. We first identified 7α-OH PREG and cytochrome P450 7α-hydroxylase (P4507α), a steroidogenic enzyme producing 7α-OH PREG, in the salmon brain and then found that 7α-OH PREG synthesis in the brain increases during upstream migration. Subsequently, we demonstrated that 7α-OH PREG increases upstream migratory behavior of salmon. We further found that 7α-OH PREG acts on dopamine neurons in the magnocellular preoptic nucleus during upstream migration. Thus, 7α-OH PREG stimulates upstream migratory behavior through the dopaminergic system in salmon. These findings provide new insights into the molecular mechanisms of fish upstream migration. PMID:26220247

  2. Endogenous dynorphin protects against neurotoxin-elicited nigrostriatal dopaminergic neuron damage and motor deficits in mice

    PubMed Central

    2012-01-01

    Background The striato-nigral projecting pathway contains the highest concentrations of dynorphin in the brain. The functional role of this opioid peptide in the regulation of mesencephalic dopaminergic (DAergic) neurons is not clear. We reported previously that exogenous dynorphin exerts potent neuroprotective effects against inflammation-induced dopaminergic neurodegeneration in vitro. The present study was performed to investigate whether endogenous dynorphin has neuroprotective roles in vivo. Methods 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine (MA), two commonly used neurotoxins in rodent models of Parkinson’s disease, were administered to wild-type (Dyn+/+) and prodynorphin-deficient mice (Dyn−/−). We examined dopaminergic neurotoxicity by using an automated video tracking system, HPLC, immunocytochemistry, and reverse transcription and polymerase chain reaction (RT-PCR). Results Treatment with MPTP resulted in behavioral impairments in both strains. However, these impairments were more pronounced in Dyn-l- than in Dyn+/+. Dyn−/− showed more severe MPTP-induced dopaminergic neuronal loss in the substantia nigra and striatum than Dyn+/+. Similarly, the levels of dopamine and its metabolites in the striatum were depleted to a greater extent in Dyn−/− than in Dyn+/+. Additional mechanistic studies revealed that MPTP treatment caused a higher degree of microglial activation and M1 phenotype differentiation in Dyn−/− than in Dyn+/+. Consistent with these observations, prodynorphin deficiency also exacerbated neurotoxic effects induced by MA, although this effect was less pronounced than that of MPTP. Conclusions The in vivo results presented here extend our previous in vitro findings and further indicate that endogenous dynorphin plays a critical role in protecting dopaminergic neurons through its anti-inflammatory effects. PMID:22695044

  3. Are Striatal Tyrosine Hydroxylase Interneurons Dopaminergic?

    PubMed Central

    Xenias, Harry S.; Ibáñez-Sandoval, Osvaldo; Koós, Tibor

    2015-01-01

    Striatal GABAergic interneurons that express the gene for tyrosine hydroxylase (TH) have been identified previously by several methods. Although generally assumed to be dopaminergic, possibly serving as a compensatory source of dopamine (DA) in Parkinson's disease, this assumption has never been tested directly. In TH–Cre mice whose nigrostriatal pathway had been eliminated unilaterally with 6-hydroxydopamine, we injected a Cre-dependent virus coding for channelrhodopsin-2 and enhanced yellow fluorescent protein unilaterally into the unlesioned midbrain or bilaterally into the striatum. Fast-scan cyclic voltammetry in striatal slices revealed that both optical and electrical stimulation readily elicited DA release in control striata but not from contralateral striata when nigrostriatal neurons were transduced. In contrast, neither optical nor electrical stimulation could elicit striatal DA release in either the control or lesioned striata when the virus was injected directly into the striatum transducing only striatal TH interneurons. This demonstrates that striatal TH interneurons do not release DA. Fluorescence immunocytochemistry in enhanced green fluorescent protein (EGFP)–TH mice revealed colocalization of DA, l-amino acid decarboxylase, the DA transporter, and vesicular monoamine transporter-2 with EGFP in midbrain dopaminergic neurons but not in any of the striatal EGFP–TH interneurons. Optogenetic activation of striatal EGFP–TH interneurons produced strong GABAergic inhibition in all spiny neurons tested. These results indicate that striatal TH interneurons are not dopaminergic but rather are a type of GABAergic interneuron that expresses TH but none of the other enzymes or transporters necessary to operate as dopaminergic neurons and exert widespread GABAergic inhibition onto direct and indirect spiny neurons. PMID:25904808

  4. Dopaminergic neurotoxins require excitotoxic stimulation in organotypic cultures.

    PubMed

    Kress, Geraldine J; Reynolds, Ian J

    2005-12-01

    We have investigated the properties of the dopaminergic neurotoxins 6-hydroxydopamine, 1-methyl-4-phenylpyridinium and rotenone using an organotypic culture that included slices of substantia nigra, striatum and cortex maintained for about 20 days in vitro. At this age, the organotypic culture contains dopaminergic neurons, visualized using tyrosine hydroxylase (TH) immunohistochemistry, that project into the striatal slice and extend up to 1 mm into the cortical slice. Using TH immunohistochemistry to assess survival of dopaminergic neurons, we found that the three dopaminergic toxins alone were not selectively neurotoxic. However, the addition of a low concentration of N-methyl-d-aspartate together with each individual toxin resulted in profound injury to the dopaminergic neurons, reflected by the loss of cell bodies and the fragmentation of processes. The combined toxicity was completely blocked by MK801. To assess the specificity of the injury, we measured the diameter of cell nuclei in the organotypic culture stained with Hoechst 33342 because the nucleus shrinks when neurons are injured. These measurements showed that the combined toxin treatment selectively injured only the TH immunoreactive cells. Thus, in a model culture system where dopaminergic neurons innervate appropriate targets, excitotoxicity appears to be essential for the manifestation of the toxic actions of 6-hydroxydopamine, 1-methyl-4-phenylpyridinium and rotenone. PMID:15996475

  5. Discovery of nigral dopaminergic neurogenesis in adult mice

    PubMed Central

    Morrison, Brad E.

    2016-01-01

    Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra. As a result, intensive efforts have focused upon mechanisms that facilitate the death of mature dopaminergic neurons. Unfortunately, these efforts have been unsuccessful in providing an effective treatment to address neurodegeneration in this disease. Therefore, alternative theories of pathogenesis are being explored. Adult neurogenesis of dopaminergic neurons is an attractive concept that would provide a possible mechanism of neurodegeneration as well as offer an endogenous means to replenish affected neurons. To determine whether dopaminergic neurons experience neurogenesis in adult mice we developed a novel cell lineage tracing model that permitted detection of neurogenesis without many of the issues associated with popular techniques. Remarkably, we discovered that dopaminergic neurons are replenished in adult mice by Nestin+/Sox2- progenitor cells. What's more, the rate of neurogenesis is similar to the rate of dopaminergic neuron loss reported using a chronic, systemic inflammatory response mouse model. This observation may indicate that neuron loss in Parkinson's disease results from inhibition of neurogenesis. PMID:27482200

  6. Naringin treatment induces neuroprotective effects in a mouse model of Parkinson's disease in vivo, but not enough to restore the lesioned dopaminergic system.

    PubMed

    Kim, Heung Deok; Jeong, Kyoung Hoon; Jung, Un Ju; Kim, Sang Ryong

    2016-02-01

    We recently reported that treatment with naringin, a major flavonoid found in grapefruit and citrus fruits, attenuated neurodegeneration in a rat model of Parkinson's disease (PD) in vivo. In order to investigate whether its effects are universally applied to a different model of PD and whether its treatment induces restorative effects on the lesioned nigrostriatal dopaminergic (DA) projection, we observed the effects of pre-treatment or post-treatment with naringin in a mouse model of PD. For neuroprotective effects, 6-hydroxydopamine (6-OHDA) was unilaterally injected into the striatum of mouse brains for a neurotoxin model of PD in the presence or absence of naringin by daily intraperitoneal injection. Our results showed that naringin protected the nigrostriatal DA projection from 6-OHDA-induced neurotoxicity. Moreover, similar to the effects in rat brains, this treatment induced the activation of mammalian target of rapamycin complex 1 (mTORC1), which is well known as an important survival factor for DA neurons, and inhibited microglial activation in the substantia nigra (SN) of mouse brains treated with 6-OHDA. However, there was no significant change of DA phenotypes in the SN and striatum post-treated with naringin compared with 6-OHDA-lesioned mice, despite the treatment being continued for 12 weeks. These results suggest that post-treatment with naringin alone may not be enough to restore the nigrostriatal DA projection in a mouse model of PD. However, our results apparently suggest that naringin is a beneficial natural product to prevent DA degeneration, which is involved in PD. PMID:26878791

  7. Structure of distress call: implication for specificity and activation of dopaminergic system.

    PubMed

    Mariappan, Subramanian; Bogdanowicz, Wieslaw; Raghuram, Hanumanthan; Marimuthu, Ganapathy; Rajan, Koilmani Emmanuvel

    2016-01-01

    We conducted a set of playback experiments aimed at understanding whether distress-call structure in the greater short-nosed fruit bat Cynopterus sphinx is specific in encoding information relating to stress that attracts conspecifics. We tested the specificity by playing their distress call and its modified version at a foraging site for free-ranging bats, as well as under captive conditions involving either a small group or individuals. In a separate playback experiment, bats showed a significantly greater response when the natural call as opposed to a modified call was played back to captive as well as free-ranging bats at the foraging site. Under captive conditions, bats showed less of a response to the playback of distress calls when in a group than when alone. We subsequently found that tyrosine hydroxylase (TH) and its transcription factor-nuclear receptor related factor 1 (Nurr-1); and the dopamine transporter (DAT) and its receptor (D1DR) were elevated significantly in the amygdala of bats both emitting and responding to a distress call, but not in the case of bats responding to the modified call. These results suggest that distress-call structure encodes information on the state of stress that is capable of being conveyed to conspecifics. PMID:26610332

  8. Contribution of dopamine to mitochondrial complex I inhibition and dopaminergic deficits caused by methylenedioxymethamphetamine in mice.

    PubMed

    Barros-Miñones, L; Goñi-Allo, B; Suquia, V; Beitia, G; Aguirre, N; Puerta, E

    2015-06-01

    Methylenedioxymethamphetamine (MDMA) causes a persistent loss of dopaminergic cell bodies in the substantia nigra of mice. Current evidence indicates that MDMA-induced neurotoxicity is mediated by oxidative stress probably due to the inhibition of mitochondrial complex I activity. In this study we investigated the contribution of dopamine (DA) to such effects. For this, we modulated the dopaminergic system of mice at the synthesis, uptake or metabolism levels. Striatal mitochondrial complex I activity was decreased 1 h after MDMA; an effect not observed in the striatum of DA depleted mice or in the hippocampus, a dopamine spare region. The DA precursor, L-dopa, caused a significant reduction of mitochondrial complex I activity by itself and exacerbated the dopaminergic deficits when combined with systemic MDMA. By contrast, no damage was observed when L-dopa was combined with intrastriatal injections of MDMA. On the other hand, dopamine uptake blockade using GBR 12909, inhibited both, the acute inhibition of complex I activity and the long-term dopaminergic toxicity caused by MDMA. Moreover, the inhibition of DA metabolism with the monoamine oxidase (MAO) inhibitor, pargyline, afforded a significant protection against MDMA-induced complex I inhibition and neurotoxicity. Taken together, these findings point to the formation of hydrogen peroxide subsequent to DA metabolism by MAO, rather than a direct DA-mediated mitochondrial complex I inhibition, and the contribution of a peripheral metabolite of MDMA, as the key steps in the chain of biochemical events leading to DA neurotoxicity caused by MDMA in mice. PMID:25666033

  9. Essential Roles of Enteric Neuronal Serotonin in Gastrointestinal Motility and the Development/Survival of Enteric Dopaminergic Neurons

    PubMed Central

    Li, Zhishan; Chalazonitis, Alcmène; Huang, Yung-yu; Mann, J. John; Margolis, Kara Gross; Yang, Qi Melissa; Kim, Dolly O.; Côté, Francine; Mallet, Jacques; Gershon, Michael D.

    2015-01-01

    The gut contains a large 5-HT pool in enterochromaffin (EC) cells and a smaller 5-HT pool in the enteric nervous system (ENS). During development, enteric neurons are generated asynchronously. We tested hypotheses that serotonergic neurons, which arise early, affect development/survival of later-born dopaminergic, GABAergic, nitrergic, and calcitonin gene-related peptide-expressing neurons and are essential for gastrointestinal motility. 5-HT biosynthesis depends on tryptophan hydroxylase 1 (TPH1) in EC cells and on TPH2 in neurons; therefore, mice lacking TPH1 and/or TPH2 distinguish EC-derived from neuronal 5-HT. Deletion of TPH2, but not TPH1, decreased myenteric neuronal density and proportions of dopaminergic and GABAergic neurons but did not affect the extrinsic sympathetic innervation of the gut; intestinal transit slowed in mice lacking TPH2 mice, but gastric emptying accelerated. Isolated enteric crest-derived cells (ENCDCs) expressed the serotonin reuptake transporter (SERT) and 15 subtypes of 5-HT receptor. Addition of 5- HT to cultures of isolated ENCDCs promoted total and dopaminergic neuronal development. Rings of SERT-immunoreactive terminal axons surrounded myenteric dopaminergic neurons and SERT knock-out increased intestinal levels of dopamine metabolites, implying that enteric dopaminergic neurons receive a serotonergic innervation. Observations suggest that constitutive gastrointestinal motility depends more on neuronal than EC cell serotonin; moreover, serotonergic neurons promote development/survival of some classes of late-born enteric neurons, including dopaminergic neurons, which appear to innervate and activate in the adult ENS. PMID:21677183

  10. Increased Fos Expression Among Midbrain Dopaminergic Cell Groups during Birdsong Tutoring

    PubMed Central

    Nordeen, E.J.; Holtzman, D.A.; Nordeen, K.W.

    2009-01-01

    During avian vocal learning, birds memorize conspecific song patterns and then use auditory feedback to match their vocal output to this acquired template. Some models of song learning posit that during tutoring, conspecific visual, social, and/or auditory cues activate neuromodulatory systems that encourage acquisition of the tutor’s song and attach incentive value to that specific acoustic pattern. This hypothesis predicts that stimuli experienced during social tutoring activate cell populations capable of signaling reward. Using immunocytochemistry for the protein product of the immediate early gene c-Fos, we found that brief exposure of juvenile male zebra finches to a live familiar male tutor increased the density of Fos+ cells within two brain regions implicated in reward processing; the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). This activation of Fos appears to involve both dopaminergic and non-dopaminergic VTA/SNc neurons. Intriguingly, a familiar tutor was more effective than a novel tutor in stimulating Fos expression within these regions. In the periaqueductal gray (PAG), a dopamine-enriched cell population that has been implicated in emotional processing, Fos labeling also was increased after tutoring, with a familiar tutor once again being more effective than a novel conspecific. Since several neural regions implicated in song acquisition receive strong dopaminergic projections from these midbrain nuclei, their activation in conjunction with hearing the tutor’s song could help establish sensory representations that later guide motor sequence learning. PMID:19686474

  11. Dopaminergic function and intertemporal choice.

    PubMed

    Joutsa, J; Voon, V; Johansson, J; Niemelä, S; Bergman, J; Kaasinen, V

    2015-01-01

    The discounting of delayed rewards, also known as temporal or delay discounting, is intrinsic to everyday decisions and can be impaired in pathological states such as addiction disorders. Preclinical and human studies suggest a role for dopaminergic function in temporal discounting but this relationship has not yet been verified using molecular imaging of the living human brain. Here, we evaluated dopaminergic function in temporal discounting using positron emission tomography (PET) with two different dopaminergic ligands assessing three populations in whom temporal discounting has been shown to be impaired. First, we show using [11C]raclopride PET that in pathological gamblers, greater temporal discounting correlates with decreased ventral striatal binding potential, convergent with translational findings of lower nucleus accumbens D2/D3 receptor density in high-impulsive rodents. Temporal discounting also correlates with lower ventral striatal dopamine release in response to high-reward magnitude suggesting that dopamine-mediated devaluation of larger delayed rewards may drive choice preferences. Second, we show using [18F]fluorodopa PET that in Parkinson's disease, temporal discounting correlates with greater left caudate dopaminergic terminal function. Finally, in subjects with Parkinson's disease and dopamine medication-induced behavioral addictions, temporal discounting is further correlated with greater dopaminergic terminal function in the anterior putamen. These findings provide insights into the relationship between striatal dopamine function and temporal discounting, and its potential role in pathological disorders and mechanisms underlying treatment interventions. PMID:25562841

  12. Physiological Characterisation of Human iPS-Derived Dopaminergic Neurons

    PubMed Central

    Ribeiro Fernandes, Hugo J.; Vowles, Jane; James, William S.; Cowley, Sally A.; Wade-Martins, Richard

    2014-01-01

    Human induced pluripotent stem cells (hiPSCs) offer the potential to study otherwise inaccessible cell types. Critical to this is the directed differentiation of hiPSCs into functional cell lineages. This is of particular relevance to research into neurological disease, such as Parkinson’s disease (PD), in which midbrain dopaminergic neurons degenerate during disease progression but are unobtainable until post-mortem. Here we report a detailed study into the physiological maturation over time of human dopaminergic neurons in vitro. We first generated and differentiated hiPSC lines into midbrain dopaminergic neurons and performed a comprehensive characterisation to confirm dopaminergic functionality by demonstrating dopamine synthesis, release, and re-uptake. The neuronal cultures include cells positive for both tyrosine hydroxylase (TH) and G protein-activated inward rectifier potassium channel 2 (Kir3.2, henceforth referred to as GIRK2), representative of the A9 population of substantia nigra pars compacta (SNc) neurons vulnerable in PD. We observed for the first time the maturation of the slow autonomous pace-making (<10 Hz) and spontaneous synaptic activity typical of mature SNc dopaminergic neurons using a combination of calcium imaging and electrophysiology. hiPSC-derived neurons exhibited inositol tri-phosphate (IP3) receptor-dependent release of intracellular calcium from the endoplasmic reticulum in neuronal processes as calcium waves propagating from apical and distal dendrites, and in the soma. Finally, neurons were susceptible to the dopamine neuron-specific toxin 1-methyl-4-phenylpyridinium (MPP+) which reduced mitochondrial membrane potential and altered mitochondrial morphology. Mature hiPSC-derived dopaminergic neurons provide a neurophysiologically-defined model of previously inaccessible vulnerable SNc dopaminergic neurons to bridge the gap between clinical PD and animal models. PMID:24586273

  13. Physiological characterisation of human iPS-derived dopaminergic neurons.

    PubMed

    Hartfield, Elizabeth M; Yamasaki-Mann, Michiko; Ribeiro Fernandes, Hugo J; Vowles, Jane; James, William S; Cowley, Sally A; Wade-Martins, Richard

    2014-01-01

    Human induced pluripotent stem cells (hiPSCs) offer the potential to study otherwise inaccessible cell types. Critical to this is the directed differentiation of hiPSCs into functional cell lineages. This is of particular relevance to research into neurological disease, such as Parkinson's disease (PD), in which midbrain dopaminergic neurons degenerate during disease progression but are unobtainable until post-mortem. Here we report a detailed study into the physiological maturation over time of human dopaminergic neurons in vitro. We first generated and differentiated hiPSC lines into midbrain dopaminergic neurons and performed a comprehensive characterisation to confirm dopaminergic functionality by demonstrating dopamine synthesis, release, and re-uptake. The neuronal cultures include cells positive for both tyrosine hydroxylase (TH) and G protein-activated inward rectifier potassium channel 2 (Kir3.2, henceforth referred to as GIRK2), representative of the A9 population of substantia nigra pars compacta (SNc) neurons vulnerable in PD. We observed for the first time the maturation of the slow autonomous pace-making (<10 Hz) and spontaneous synaptic activity typical of mature SNc dopaminergic neurons using a combination of calcium imaging and electrophysiology. hiPSC-derived neurons exhibited inositol tri-phosphate (IP3) receptor-dependent release of intracellular calcium from the endoplasmic reticulum in neuronal processes as calcium waves propagating from apical and distal dendrites, and in the soma. Finally, neurons were susceptible to the dopamine neuron-specific toxin 1-methyl-4-phenylpyridinium (MPP+) which reduced mitochondrial membrane potential and altered mitochondrial morphology. Mature hiPSC-derived dopaminergic neurons provide a neurophysiologically-defined model of previously inaccessible vulnerable SNc dopaminergic neurons to bridge the gap between clinical PD and animal models. PMID:24586273

  14. S6K Promotes Dopaminergic Neuronal Differentiation Through PI3K/Akt/mTOR-Dependent Signaling Pathways in Human Neural Stem Cells.

    PubMed

    Lee, Jeong Eun; Lim, Mi Sun; Park, Jae Hyun; Park, Chang Hwan; Koh, Hyun Chul

    2016-08-01

    It has recently been reported that the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway regulates neuronal differentiation of neural stem cells (NSCs) derived from rats or mice and is essential for the self-renewal of human embryonic stem cells (hESCs). However, the roles of PI3K/Akt/mTOR signaling pathways during proliferation and dopaminergic neuronal differentiation of human neural stem cells (hNSCs) are poorly understood. In this study, we examined the effect of regulation of these intracellular signaling pathways in hNSCs on the potential to maintain proliferation and induce dopaminergic neuronal differentiation. Dopaminergic neuronal differentiation depended on the concentration of insulin in our culture system. Inhibition of PI3K/Akt with LY294002 reduced proliferation and inhibited dopaminergic neuronal differentiation of these cells. We also found that rapamycin, a specific inhibitor of mTOR, significantly reduced neuronal differentiation without affecting proliferation. Inhibition of the Akt/mTOR signaling pathway led to inhibition of p70 ribosomal S6 kinase (S6K) signaling, which reduced dopaminergic neuronal differentiation in hNSCs. Inhibition of S6K by a specific chemical inhibitor, PF-4708671 inhibited dopaminergic neuronal differentiation of hNSCs. As expected, transduction with a dominant negative S6K1 (S6K1-DN) construct impaired dopaminergic neuronal differentiation of hNSCs. Conversely, overexpression of constitutively active S6K1 (S6K1-CA) promoted dopaminergic neuronal differentiation of these cells. In a survival study, 4 weeks after transplantation, no or very few donor cells were viable in striata grafted with S6K1-DN-transduced hNSCs. In contrast, S6K1-CA-transduced hNSCs survived, integrated into striata to generate tubular masses of grafts and differentiated toward TH-positive cells. Taken together, these data demonstrated that insulin promotes dopaminergic neuronal differentiation through a PI

  15. Dopamine and T cells: dopamine receptors and potent effects on T cells, dopamine production in T cells, and abnormalities in the dopaminergic system in T cells in autoimmune, neurological and psychiatric diseases.

    PubMed

    Levite, M

    2016-01-01

    expression and/or responses to dopamine or production of dopamine, (xiii) drugs that affect the dopaminergic system have potent effects on T cells (e.g. dopamine=Intropin, L-dopa, bromocriptine, haloperidol, quinpirole, reserpine, pergolide, ecopipam, pimozide, amantadine, tetrabenazine, nomifensine, butaclamol). Dopamine-induced activation of resting Teffs and suppression of Tregs seem beneficial for health and may also be used for immunotherapy of cancer and infectious diseases. Independently, suppression of DRs in autoimmune and pro-inflammatory T cells, and also in cancerous T cells, may be advantageous. The review is relevant to Immunologists, Neurologists, Neuroimmunologists, Hematologists, Psychiatrists, Psychologists and Pharmacologists. PMID:25728499

  16. Dopaminergic modulation of sucrose acceptance behavior in Drosophila

    PubMed Central

    Marella, Sunanda; Mann, Kevin; Scott, Kristin

    2012-01-01

    For an animal to survive in a constantly changing environment, its behavior must be shaped by the complex milieu of sensory stimuli it detects, its previous experience and its internal state. Although taste behaviors in the fly are relatively simple, with sugars eliciting acceptance behavior and bitter compounds avoidance, these behaviors are also plastic and modified by intrinsic and extrinsic cues such as hunger and sensory stimuli. Here, we show that dopamine modulates a simple taste behavior, proboscis extension to sucrose. Conditional silencing of dopaminergic neurons reduces proboscis extension probability and increased activation of dopaminergic neurons increases extension to sucrose but not to bitter compounds or water. One dopaminergic neuron with extensive branching in the primary taste relay, the subesophageal ganglion, triggers proboscis extension and its activity is altered by satiety state. These studies demonstrate the marked specificity of dopamine signaling and provide a foundation to examine neural mechanisms of feeding modulation in the fly. PMID:22405204

  17. Involvement of dopaminergic and cholinergic systems in social isolation-induced deficits in social affiliation and conditional fear memory in mice.

    PubMed

    Okada, R; Fujiwara, H; Mizuki, D; Araki, R; Yabe, T; Matsumoto, K

    2015-07-23

    , when analyzed 30 min after the administration of the test drugs, tacrine significantly attenuated the SI-induced decrease in p-CaMKII, p-CREB, and Egr-1 in a manner reversible by scopolamine. Our results suggest that SI-induced deficits in social affiliation and conditioned fear memory were mediated by functional alterations to central dopaminergic and cholinergic systems, respectively. PMID:25943484

  18. [Evaluation of central dopaminergic tone in diabetes mellitus].

    PubMed

    Mainini, E; Martinelli, I; Scarsi, G; Mazzi, C

    1991-01-01

    The role of dopaminergic ways in human copulatory activity and the high frequency of impotence in diabetes mellitus are well known. In order to study the involvement of the central dopaminergic tone in diabetic impotence we have evaluated the PRL and TSH response to metoclopramide (MCP 10 mg ev) in 28 diabetic male patients (15 ID including 6 impotent and 13 NID including 5 impotent ) compared with 9 healthy controls. All subjects were investigated for the presence of neuropathy, retinopathy, macroangiopathy, gonadal and thyroid diseases. The PRL response to MCP was greater (p less than 0.05) in impotent patients than in controls at 60' and 90' in ID, and at 30' and 120' in NID. There was no significant difference in TSH increase and in PRL and TSH response areas between the groups considered. In conclusion, the dopaminergic tone is substantially normal in diabetic patients, while some PRL hyperresponsiveness to MCP exists in impotent diabetics. PMID:1815118

  19. Influence of Dopaminergically Mediated Reward on Somatosensory Decision-Making

    PubMed Central

    Pleger, Burkhard; Ruff, Christian C.; Blankenburg, Felix; Klöppel, Stefan; Driver, Jon; Dolan, Raymond J.

    2009-01-01

    Reward-related dopaminergic influences on learning and overt behaviour are well established, but any influence on sensory decision-making is largely unknown. We used functional magnetic resonance imaging (fMRI) while participants judged electric somatosensory stimuli on one hand or other, before being rewarded for correct performance at trial end via a visual signal, at one of four anticipated financial levels. Prior to the procedure, participants received either placebo (saline), a dopamine agonist (levodopa), or an antagonist (haloperidol). Principal findings: higher anticipated reward improved tactile decisions. Visually signalled reward reactivated primary somatosensory cortex for the judged hand, more strongly for higher reward. After receiving a higher reward on one trial, somatosensory activations and decisions were enhanced on the next trial. These behavioural and neural effects were all enhanced by levodopa and attenuated by haloperidol, indicating dopaminergic dependency. Dopaminergic reward-related influences extend even to early somatosensory cortex and sensory decision-making. PMID:19636360

  20. Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism.

    PubMed

    Dodson, Paul D; Dreyer, Jakob K; Jennings, Katie A; Syed, Emilie C J; Wade-Martins, Richard; Cragg, Stephanie J; Bolam, J Paul; Magill, Peter J

    2016-04-12

    Midbrain dopaminergic neurons are essential for appropriate voluntary movement, as epitomized by the cardinal motor impairments arising in Parkinson's disease. Understanding the basis of such motor control requires understanding how the firing of different types of dopaminergic neuron relates to movement and how this activity is deciphered in target structures such as the striatum. By recording and labeling individual neurons in behaving mice, we show that the representation of brief spontaneous movements in the firing of identified midbrain dopaminergic neurons is cell-type selective. Most dopaminergic neurons in the substantia nigra pars compacta (SNc), but not in ventral tegmental area or substantia nigra pars lateralis, consistently represented the onset of spontaneous movements with a pause in their firing. Computational modeling revealed that the movement-related firing of these dopaminergic neurons can manifest as rapid and robust fluctuations in striatal dopamine concentration and receptor activity. The exact nature of the movement-related signaling in the striatum depended on the type of dopaminergic neuron providing inputs, the striatal region innervated, and the type of dopamine receptor expressed by striatal neurons. Importantly, in aged mice harboring a genetic burden relevant for human Parkinson's disease, the precise movement-related firing of SNc dopaminergic neurons and the resultant striatal dopamine signaling were lost. These data show that distinct dopaminergic cell types differentially encode spontaneous movement and elucidate how dysregulation of their firing in early Parkinsonism can impair their effector circuits. PMID:27001837

  1. Olfactory impairment in the rotenone model of Parkinson’s disease is associated with bulbar dopaminergic D2 activity after REM sleep deprivation

    PubMed Central

    Rodrigues, Lais S.; Targa, Adriano D. S.; Noseda, Ana Carolina D.; Aurich, Mariana F.; Da Cunha, Cláudio; Lima, Marcelo M. S.

    2014-01-01

    Olfactory and rapid eye movement (REM) sleep deficits are commonly found in untreated subjects with a recent diagnosis of Parkinson’s disease (PD). Additionally, different studies report declines in olfactory performance during a short period of sleep deprivation. Mechanisms underlying these clinical manifestations are poorly understood, and impairment of dopamine (DA) neurotransmission in the olfactory bulb and the nigrostriatal pathway may have important roles in olfaction and REM sleep disturbances. Therefore, we hypothesized that modulation of the dopaminergic D2 receptors in the olfactory bulb could provide a more comprehensive understanding of the olfactory deficits in PD and REM sleep deprivation (REMSD). We decided to investigate the olfactory, neurochemical, and histological alterations generated through the administration of piribedil (a selective D2 agonist) or raclopride (a selective D2 antagonist) within the glomerular layer of the olfactory bulb, in rats subjected to intranigral rotenone and REMSD. Our findings provide evidence of the occurrence of a negative correlation (r = −0.52, P = 0.04) between the number of periglomerular TH-ir neurons and the bulbar levels of DA in the rotenone, but not sham, groups. A significant positive correlation (r = 0.34, P = 0.03) was observed between nigrostriatal DA levels and olfactory discrimination index (DI) for the sham groups, indicating that increased DA levels in the substantia nigra pars compacta (SNpc) are associated with enhanced olfactory discrimination performance. Also, increased levels in bulbar and striatal DA were induced by piribedil in the rotenone control and rotenone REMSD groups, consistent with reductions in the DI. The present evidence reinforce the idea that DA produced by periglomerular neurons, particularly the bulbar dopaminergic D2 receptors, is an essential participant in olfactory discrimination processes, as the SNpc, and the striatum. PMID:25520618

  2. Mitochondrial complex I inhibition is not required for dopaminergic neuron death induced by rotenone, MPP+, or paraquat

    PubMed Central

    Choi, Won-Seok; Kruse, Shane E.; Palmiter, Richard D.; Xia, Zhengui

    2008-01-01

    Inhibition of mitochondrial complex I is one of the leading hypotheses for dopaminergic neuron death associated with Parkinson's disease (PD). To test this hypothesis genetically, we used a mouse strain lacking functional Ndufs4, a gene encoding a subunit required for complete assembly and function of complex I. Deletion of the Ndufs4 gene abolished complex I activity in midbrain mesencephalic neurons cultured from embryonic day (E) 14 mice, but did not affect the survival of dopaminergic neurons in culture. Although dopaminergic neurons were more sensitive than other neurons in these cultures to cell death induced by rotenone, MPP+, or paraquat treatments, the absence of complex I activity did not protect the dopaminergic neurons, as would be expected if these compounds act by inhibiting complex 1. In fact, the dopaminergic neurons were more sensitive to rotenone. These data suggest that dopaminergic neuron death induced by treatment with rotenone, MPP+, or paraquat is independent of complex I inhibition. PMID:18812510

  3. Dopaminergic Contributions to Vocal Learning

    PubMed Central

    Hoffmann, Lukas A.; Saravanan, Varun; Wood, Alynda N.; He, Li

    2016-01-01

    Although the brain relies on auditory information to calibrate vocal behavior, the neural substrates of vocal learning remain unclear. Here we demonstrate that lesions of the dopaminergic inputs to a basal ganglia nucleus in a songbird species (Bengalese finches, Lonchura striata var. domestica) greatly reduced the magnitude of vocal learning driven by disruptive auditory feedback in a negative reinforcement task. These lesions produced no measureable effects on the quality of vocal performance or the amount of song produced. Our results suggest that dopaminergic inputs to the basal ganglia selectively mediate reinforcement-driven vocal plasticity. In contrast, dopaminergic lesions produced no measurable effects on the birds' ability to restore song acoustics to baseline following the cessation of reinforcement training, suggesting that different forms of vocal plasticity may use different neural mechanisms. SIGNIFICANCE STATEMENT During skill learning, the brain relies on sensory feedback to improve motor performance. However, the neural basis of sensorimotor learning is poorly understood. Here, we investigate the role of the neurotransmitter dopamine in regulating vocal learning in the Bengalese finch, a songbird with an extremely precise singing behavior that can nevertheless be reshaped dramatically by auditory feedback. Our findings show that reduction of dopamine inputs to a region of the songbird basal ganglia greatly impairs vocal learning but has no detectable effect on vocal performance. These results suggest a specific role for dopamine in regulating vocal plasticity. PMID:26888928

  4. Effect of dopaminergic medication on speech dysfluency in Parkinson's disease: a longitudinal study.

    PubMed

    Tykalová, Tereza; Rusz, Jan; Čmejla, Roman; Klempíř, Jiří; Růžičková, Hana; Roth, Jan; Růžička, Evžen

    2015-08-01

    Although speech dysfluencies have been hypothesized to be associated with abnormal function of dopaminergic system, the effects of dopaminergic medication on speech fluency in Parkinson's disease (PD) have not been systematically studied. The aim of the present study was, therefore, to investigate the long-term effect of dopaminergic medication on speech fluency in PD. Fourteen de novo PD patients with no history of developmental stuttering and 14 age- and sex-matched healthy controls (HC) were recruited. PD subjects were examined three times; before the initiation of dopaminergic treatment and twice in following 6 years. The percentage of dysfluent words was calculated from reading passage and monolog. The amount of medication was expressed by cumulative doses of L-dopa equivalent. After 3-6 years of dopaminergic therapy, PD patients exhibited significantly more dysfluent events compared to healthy subjects as well as to their own speech performance before the introduction of dopaminergic therapy (p < 0.05). In addition, we found a strong positive correlation between the increased occurrence of dysfluent words and the total cumulative dose of L-dopa equivalent (r = 0.75, p = 0.002). Our findings indicate an adverse effect of prolonged dopaminergic therapy contributing to the development of stuttering-like dysfluencies in PD. These findings may have important implication in clinical practice, where speech fluency should be taken into account to optimize dopaminergic therapy. PMID:25583417

  5. Correlation between automated writing movements and striatal dopaminergic innervation in patients with Wilson's disease.

    PubMed

    Hermann, Wieland; Eggers, Birk; Barthel, Henryk; Clark, Daniel; Villmann, Thomas; Hesse, Swen; Grahmann, Friedrich; Kühn, Hans-Jürgen; Sabri, Osama; Wagner, Armin

    2002-08-01

    Handwriting defects are an early sign of motor impairment in patients with Wilson's disease. The basal ganglia being the primary site of copper accumulation in the brain suggests a correlation with lesions in the nigrostiatal dopaminergic system. We have analysed and correlated striatal dopaminergic innervation using [(123)I]beta-CIT-SPECT and automated handwriting movements in 37 patients with Wilson's disease. There was a significant correlation of putaminal dopaminergic innervation with fine motor ability (p < 0,05 for NIV [number of inversion in velocity], NIA [number of inversion in acceleration], frequency). These data suggest that loss of dorsolateral striatal dopaminergic innervation has a pathophysiological function for decreased automated motor control in Wilson's disease. Furthermore analysis of automated handwriting movements could be useful for therapy monitoring and evaluation of striatal dopaminergic innervation. PMID:12195459

  6. [Dopaminergic neuroprotection and reconstruction of neural network tiara].

    PubMed

    Kitamura, Yoshihisa

    2010-10-01

    Parkinson's disease (PD) is an age-related neurodegenerative disorder in whose brain massive loss of dopaminergic neurons and formation of Lewy bodies occur in the substantia nigra (SN). L-Dihydroxyphenylamine (L-DOPA) substitution is still considered the gold standard of antiparkinsonian drug therapy. However, there has been little information available on neuroprotective and regenerative therapies. Recently, we have found that pramipexole and talipexole (D(2)/D(3)-dopaminergic agonists) inhibit dopaminergic neurotoxin-induced production of reactive oxygen species and apoptotic cell death. In addition, treatment with these drugs induces enhancement of anti-apoptotic Bcl-2 expression and inhibition of α-synuclein aggregation. Interestingly, recent study suggests that pramipexole treatment delays the progression of early PD symptom. On the other hand, we investigated the transplantation strategy for PD by assessing whether double-transplants of mouse embryonic stem (ES) cell-derived neurons in the striatum (ST) and SN, or subthalamic nucleus (STN), induce functional recovery in rat hemi-parkinsonian model. The study indicates that both the involvement of ST as a place of transplantation and the number of ES cell-derived neurons are essential factors for efficacy on PD animal model. Interestingly, an invertebrate planarian can regenerate complete organs, including a well-organized central nervous system (brain), within about 7 days. The regeneration process of the planarian dopaminergic neural network (tiara) may be divided into five steps: 1) anterior blastema formation, 2) brain rudiment formation, 3) brain pattern formation, 4) the formation of dopaminergic tiara, and 5) functional recovery of dopaminergic motor regulation, with several kinds of genes and molecular cascades acting at each step. PMID:20930477

  7. Is there room for new non-dopaminergic treatments in Parkinson's disease?

    PubMed

    Pilleri, Manuela; Koutsikos, Konstantinos; Antonini, Angelo

    2013-02-01

    The contribution of non-dopaminergic degeneration to disability in Parkinson's disease (PD) is still debated. It has been argued that no additional advance can be expected in the management of PD by the development of new dopaminergic agents and suggested that future research should mainly focus on therapies targeting the non-dopaminergic systems involved in the pathogenesis of levodopa resistant motor and non-motor symptoms. We believe this is only partially true and the achievement of a stable dopaminergic restoration and modulation of the dopaminergic system is still an important, unmet need of current pharmacological therapies in PD. Currently available oral levodopa and dopamine agonist medications provide insufficient benefit, as the therapeutic window progressively narrows and motor fluctuations eventually develop in most patients. Conversely, the application of infusion and surgical therapies is limited by selective indications and possible irreversible adverse events and device-related problems. Research of new, safer and less invasive strategies, able to modulate the dopaminergic circuits, would certainly improve the management of motor complications, and most importantly such treatments would be also beneficial to axial and non-motor symptoms, which are universally regarded as the major cause of PD functional disability. Indeed, gait and balance problems may improve with dopaminergic treatment in most patients and they become unresponsive only at the very late stages of the disease. Moreover, several non-motor disturbances, including cognition and depression are often linked to oscillation of dopamine concentrations, and are frequently relieved by treatments providing continuous dopaminergic delivery. Finally, drug trials testing non-dopaminergic treatments for motor and non-motor symptoms of PD provided so far disappointing results. Despite the impressive advances of PD therapeutic strategy, we think there is still need for safe, non-invasive and easily

  8. Diagnosis and Healing In Veterans Suspected of Suffering from Post-Traumatic Stress Disorder (PTSD) Using Reward Gene Testing and Reward Circuitry Natural Dopaminergic Activation

    PubMed Central

    Blum, Kenneth; Giordano, John; Oscar-Berman, Marlene; Bowirrat, Abdalla; Simpatico, Thomas; Barh, Debmalya

    2012-01-01

    There is a need for understanding and treating post-traumatic stress disorder (PTSD), in soldiers returning to the United States of America after combat. Likewise, it would be beneficial to finding a way to reduce violence committed by soldiers, here and abroad, who are suspected of having post-traumatic stress disorder (PTSD). We hypothesize that even before combat, soldiers with a childhood background of violence (or with a familial susceptibility risk) would benefit from being genotyped for high-risk alleles. Such a process could help to identify candidates who would be less suited for combat than those without high-risk alleles. Of secondary importance is finding safe methods to treat individuals already exposed to combat and known to have PTSD. Since hypodopaminergic function in the brain’s reward circuitry due to gene polymorphisms is known to increase substance use disorder in individuals with PTSD, it might be parsimonious to administer dopaminergic agonists to affect gene expression (mRNA) to overcome this deficiency. PMID:23264885

  9. Active optical zoom system

    DOEpatents

    Wick, David V.

    2005-12-20

    An active optical zoom system changes the magnification (or effective focal length) of an optical imaging system by utilizing two or more active optics in a conventional optical system. The system can create relatively large changes in system magnification with very small changes in the focal lengths of individual active elements by leveraging the optical power of the conventional optical elements (e.g., passive lenses and mirrors) surrounding the active optics. The active optics serve primarily as variable focal-length lenses or mirrors, although adding other aberrations enables increased utility. The active optics can either be LC SLMs, used in a transmissive optical zoom system, or DMs, used in a reflective optical zoom system. By appropriately designing the optical system, the variable focal-length lenses or mirrors can provide the flexibility necessary to change the overall system focal length (i.e., effective focal length), and therefore magnification, that is normally accomplished with mechanical motion in conventional zoom lenses. The active optics can provide additional flexibility by allowing magnification to occur anywhere within the FOV of the system, not just on-axis as in a conventional system.

  10. Subcellular expression and neuroprotective effects of SK channels in human dopaminergic neurons

    PubMed Central

    Dolga, A M; de Andrade, A; Meissner, L; Knaus, H-G; Höllerhage, M; Christophersen, P; Zischka, H; Plesnila, N; Höglinger, G U; Culmsee, C

    2014-01-01

    Small-conductance Ca2+-activated K+ channel activation is an emerging therapeutic approach for treatment of neurological diseases, including stroke, amyotrophic lateral sclerosis and schizophrenia. Our previous studies showed that activation of SK channels exerted neuroprotective effects through inhibition of NMDAR-mediated excitotoxicity. In this study, we tested the therapeutic potential of SK channel activation of NS309 (25 μM) in cultured human postmitotic dopaminergic neurons in vitro conditionally immortalized and differentiated from human fetal mesencephalic cells. Quantitative RT-PCR and western blotting analysis showed that differentiated dopaminergic neurons expressed low levels of SK2 channels and high levels of SK1 and SK3 channels. Further, protein analysis of subcellular fractions revealed expression of SK2 channel subtype in mitochondrial-enriched fraction. Mitochondrial complex I inhibitor rotenone (0.5 μM) disrupted the dendritic network of human dopaminergic neurons and induced neuronal death. SK channel activation reduced mitochondrial membrane potential, while it preserved the dendritic network, cell viability and ATP levels after rotenone challenge. Mitochondrial dysfunction and delayed dopaminergic cell death were prevented by increasing and/or stabilizing SK channel activity. Overall, our findings show that activation of SK channels provides protective effects in human dopaminergic neurons, likely via activation of both membrane and mitochondrial SK channels. Thus, SK channels are promising therapeutic targets for neurodegenerative disorders such as Parkinson's disease, where dopaminergic cell loss is associated with progression of the disease. PMID:24434522