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Sample records for neurotransmitters serotonin dopamine

  1. Synapsins Differentially Control Dopamine and Serotonin Release

    PubMed Central

    Kile, Brian M.; Guillot, Thomas S.; Venton, B. Jill; Wetsel, William C.; Augustine, George J.; Wightman, R. Mark

    2010-01-01

    Synapsins are a family of synaptic vesicle proteins that are important for neurotransmitter release. Here we have used triple knockout (TKO) mice lacking all three synapsin genes to determine the roles of synapsins in the release of two monoamine neurotransmitters, dopamine and serotonin. Serotonin release evoked by electrical stimulation was identical in substantia nigra pars reticulata slices prepared from TKO and wild-type mice. In contrast, release of dopamine in response to electrical stimulation was approximately doubled in striatum of TKO mice, both in vivo and in striatal slices, in comparison to wild-type controls. This was due to loss of synapsin III, because deletion of synapsin III alone was sufficient to increase dopamine release. Deletion of synapsins also increased the sensitivity of dopamine release to extracellular calcium ions. Although cocaine did not affect the release of serotonin from nigral tissue, this drug did enhance dopamine release. Cocaine-induced facilitation of dopamine release was a function of external calcium, an effect that was reduced in TKO mice. We conclude that synapsins play different roles in the control of release of dopamine and serotonin, with release of dopamine being negatively regulated by synapsins, specifically synapsin III, while serotonin release appears to be relatively independent of synapsins. These results provide further support for the concept that synapsin function in presynaptic terminals varies according to the neurotransmitter being released. PMID:20660258

  2. Inhibition potential of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolites on the in vitro monoamine oxidase (MAO)-catalyzed deamination of the neurotransmitters serotonin and dopamine.

    PubMed

    Steuer, Andrea E; Boxler, Martina I; Stock, Lorena; Kraemer, Thomas

    2016-01-22

    Neurotoxicity of 3,4-methylenedioxymethamphetamine (MDMA) is still controversially discussed. Formation of reactive oxygen species e.g. based on elevated dopamine (DA) concentrations and DA quinone formation is discussed among others. Inhibition potential of MDMA metabolites regarding neurotransmitter degradation by catechol-O-methyltransferase and sulfotransferase was described previously. Their influence on monoamine oxidase (MAO) - the major DA degradation pathway-has not yet been studied in humans. Therefore the inhibition potential of MDMA and its metabolites on the deamination of the neurotransmitters DA and serotonin (5-HT) by MAO-A and B using recombinant human enzymes in vitro should be investigated. In initial studies, MDMA and MDA showed relevant inhibition (>30%) toward MAO A for 5-HT and DA. No relevant effects toward MAO B were observed. Further investigation on MAO-A revealed MDMA as a competitive inhibitor of 5-HT and DA deamination with Ki 24.5±7.1 μM and 18.6±4.3 μM respectively and MDA as a mixed-type inhibitor with Ki 7.8±2.6 μM and 8.4±3.2 μM respectively. Although prediction of in vivo relevance needs to be done with care, relevant inhibitory effects at expected plasma concentrations after recreational MDMA consumption seems unlikely based on the obtained data.

  3. Optogenetic Control of Serotonin and Dopamine Release in Drosophila Larvae

    PubMed Central

    2014-01-01

    Optogenetic control of neurotransmitter release is an elegant method to investigate neurobiological mechanisms with millisecond precision and cell type-specific resolution. Channelrhodopsin-2 (ChR2) can be expressed in specific neurons, and blue light used to activate those neurons. Previously, in Drosophila, neurotransmitter release and uptake have been studied after continuous optical illumination. In this study, we investigated the effects of pulsed optical stimulation trains on serotonin or dopamine release in larval ventral nerve cords. In larvae with ChR2 expressed in serotonergic neurons, low-frequency stimulations produced a distinct, steady-state response while high-frequency patterns were peak shaped. Evoked serotonin release increased with increasing stimulation frequency and then plateaued. The steady-state response and the frequency dependence disappeared after administering the uptake inhibitor fluoxetine, indicating that uptake plays a significant role in regulating the extracellular serotonin concentration. Pulsed stimulations were also used to evoke dopamine release in flies expressing ChR2 in dopaminergic neurons and similar frequency dependence was observed. Release due to pulsed optical stimulations was modeled to determine the uptake kinetics. For serotonin, Vmax was 0.54 ± 0.07 μM/s and Km was 0.61 ± 0.04 μM; and for dopamine, Vmax was 0.12 ± 0.03 μM/s and Km was 0.45 ± 0.13 μM. The amount of serotonin released per stimulation pulse was 4.4 ± 1.0 nM, and the amount of dopamine was 1.6 ± 0.3 nM. Thus, pulsed optical stimulations can be used to mimic neuronal firing patterns and will allow Drosophila to be used as a model system for studying mechanisms underlying neurotransmission. PMID:24849718

  4. Neurotransmitter alterations in PTSD: catecholamines and serotonin.

    PubMed

    Southwick, S M; Paige, S; Morgan, C A; Bremner, J D; Krystal, J H; Charney, D S

    1999-10-01

    In this chapter we review trauma-related studies involving epinephrine (E), norepinephrine (NE), and serotonin (5-HT). Central catecholamine neurons seem to play a critical role in level of alertness, vigilance, orienting, selective attention, memory, fear conditioning, and cardiovascular responses to life-threatening stimuli. Evidence of catecholamine dysregulation in post-traumatic stress disorder (PTSD) includes exaggerated increases in heart rate and blood pressure when exposed to visual and auditory reminders of trauma, elevated 24-hour urine catecholamine excretion, decreased platelet alpha-2 adrenergic receptor number, exaggerated behavioral, cardiovascular, and biochemical responses to IY yohimbine, decreased cortical brain metabolism secondary to IV yohimbine, and clinical efficacy of adrenergic blocking agents. Serotonin seems to play numerous roles in the central nervous system, including regulation of sleep, aggression, appetite, cardiovascular and respiratory activity, motor output, anxiety, mood, neuroendocrine secretion, and analgesia. Evidence of serotonergic dysregulation in PTSD includes frequent symptoms of aggression, impulsivity, depression and suicidality, decreased platelet paroxetine binding, blunted prolactin response to fenfluramine, exaggerated reactivity to m-chloro-phenyl-piperazine, and clinical efficacy of serotonin reuptake inhibitors. It has been suggested that alterations in NE, E, and 5-HT may have relevance for symptoms commonly seen in survivors with PTSD, including hypervigilance, exaggerated startle, irritability, impulsivity, aggression, intrusive memories, depressed mood, and suicidality.

  5. A calcium-channel homologue required for adaptation to dopamine and serotonin in Caenorhabditis elegans

    NASA Astrophysics Data System (ADS)

    Schafer, William R.; Kenyon, Cynthia J.

    1995-05-01

    PROCESSING and storage of information by the nervous system requires the ability to modulate the response of excitable cells to neurotransmitter. A simple process of this type, known as adaptation or desensitization, occurs when prolonged stimulation triggers processes that attenuate the response to neurotransmitter. Here we report that the Caenorhabditis elegans gene unc-2 is required for adaptation to two neurotransmitters, dopamine and serotonin. A loss-of-function mutation in unc-2 resulted in failure to adapt either to paralysis by dopamine or to stimulation of egg laying by serotonin. In addition, unc-2 mutants displayed behaviours similar to those induced by serotonin treatment. We found that unc-2 encodes a homologue of a voltage-sensitive calcium-channel α-1 subunit. Expression of unc-2 occurs in two types of neurons implicated in the control of egg laying, a behaviour regulated by serotonin. Unc-2 appears to be required in modulatory neurons to downregulate the response of the egg-laying muscles to serotonin. We propose that adaptation to serotonin occurs through activation of an Unc-2-dependent calcium influx, which modulates the post-synaptic response to serotonin, perhaps by inhibiting the release of a potentiating neuropeptide.

  6. Antihistamine effect on synaptosomal uptake of serotonin, norepinephrine and dopamine

    NASA Technical Reports Server (NTRS)

    Brown, P. A.; Vernikos, J.

    1980-01-01

    A study on the effects of five H1 and H2 antihistamines on the synaptosomal uptake of serotonin (5HT), norepinephrine (NE), and dopamine (DA) is presented. Brain homogenates from female rats were incubated in Krebs-Ringer phosphate buffer solution in the presence of one of three radioactive neurotransmitters, and one of the five antihistamines. Low concentrations of pyrilamine competitively inhibited 5HT uptake, had little effect on NE uptake, and no effect on DA uptake. Promethazine, diphenhydramine, metiamide, and cimetidine had no effect on 5HT or DA uptake at the same concentration. Diphenhydramine had a small inhibitory effect on NE uptake. It is concluded that pyrilamine is a selective and potent competitive inhibitor of 5HT uptake at concentrations between .05 and .5 micromolars.

  7. Serotonin-S2 and dopamine-D2 receptors are the same size in membranes

    SciTech Connect

    Brann, M.R.

    1985-12-31

    Target size analysis was used to compare the sizes of serotonin-S2 and dopamine-D2 receptors in rat brain membranes. The sizes of these receptors were standardized by comparison with the muscarinic receptor, a receptor of known size. The number of serotonin-S2 receptors labeled with (3H)ketanserin or (3H)spiperone in frontal cortex decreased as an exponential function of radiation dose, and receptor affinity was not affected. The number of dopamine-D2 receptors labeled with (3H)spiperone in striatum also decreased as an exponential function of radiation dose, and D2 and S2 receptors were equally sensitive to radiation. In both striatum and frontal cortex, the number of muscarinic receptors labeled with (3H)QNB decreased as an exponential function of radiation dose, and were much less sensitive to radiation than S2 and D2 receptors. These data indicate that in rat brain membranes, S2 and D2 receptors are of similar size, and both molecules are much larger than the muscarinic receptor.

  8. The role of serotonin and neurotransmitters during craniofacial development.

    PubMed

    Moiseiwitsch, J R

    2000-01-01

    Several neurotransmitters, in particular serotonin (5-HT), have demonstrated multiple functions during early development and mid-gestational craniofacial morphogenesis. Early studies indicated that 5-HT is present in the oocyte, where it appears to function as a regulator of cell cleavage. Later, it has a significant role during gastrulation, during which there are significant areas of 5-HT uptake in the primitive streak. Subsequently, in association with neurulation, 5-HT uptake is seen in the floor plate of the developing neural tube. During neural crest formation and branchial arch formation, 5-HT has been demonstrated to facilitate cell migration and stimulate cell differentiation. During morphogenesis of the craniofacial structures, 5-HT stimulates dental development and may aid in cusp formation. All of the most commonly prescribed antidepressant drugs inhibit serotonin uptake, yet they do not appear to cause major craniofacial malformations in vivo. Given the wide spectrum of effects that 5-HT has during development, it is difficult to understand why these anti-depressants are not major teratogens. Redundancy within the system may allow receptor and uptake pathways to function normally even with lower than normal levels of circulating serotonin. Serotonin-binding proteins, that are expressed in most craniofacial regions at critical times during craniofacial development, may have a buffering capacity that maintains adequate 5-HT tissue concentrations over a wide range of 5-HT serum concentrations. Dental development appears to be particularly sensitive to even small fluctuations in concentrations of 5-HT. Therefore, it may be that children of patients who have received selective serotonergic re-uptake inhibitors (such as Prozac and Zoloft) or the less selective tricyclic anti-depressant drugs (such as Elavil) would be at a higher risk for developmental dental defects such as anodontia and hypodontia. In this review, the evidence supporting a role for 5-HT

  9. The neurotransmitter dopamine modulates vascular permeability in the endothelium

    PubMed Central

    Bhattacharya, Resham; Sinha, Sutapa; Yang, Su-Ping; Patra, Chittaranjan; Dutta, Shamit; Wang, Enfeng; Mukhopadhyay, Debabrata

    2008-01-01

    Background Vascular permeability factor/Vascular endothelial growth factor (VPF/VEGF), a multifunctional cytokine, is a potent inducer of vascular permeability, an important early step in angiogenesis. It is known that the neurotransmitter dopamine can inhibit VPF/VEGF mediated angiogenesis, in particular microvascular permeability, but the effectors of this action remain unclear. Results Here, we define the signaling pathway modulated by dopamine that inhibits VPF/VEGF induced vascular permeability in endothelial cells. Signals from VPF/VEGF lead to changes in the phosphorylation of tight junction protein zonula occludens (ZO-1) and adherens junction proteins like VE-cadherin and associated catenins, thus weakening endothelial cell-cell adhesion and increasing vascular permeability. We found VEGF receptor-2 (VEGFR-2) to be part of a multi-protein complex involving ZO-1, VE-cadherin and β-catenin. VPF/VEGF induced phosphorylations of VE-cadherin, β-catenin and ZO-1 were inhibited by dopamine treatment. Association of occludin with ZO-1 and ZO-1 with VE-cadherin were significantly inhibited by dopamine in VEGF treated cells. Furthermore, we identified Src as an important target for dopamine-mediated inhibition of VPF/VEGF induced permeability. Conclusion Taken together, our results provide molecular insights of dopamine function in the vascular endothelium and suggest a central role of Src in regulating key molecules that control vascular permeability. PMID:18662404

  10. The Design, Synthesis and Structure-Activity Relationship of Mixed Serotonin, Norepinephrine and Dopamine Uptake Inhibitors

    NASA Astrophysics Data System (ADS)

    Chen, Zhengming; Yang, Ji; Skolnick, Phil

    The evolution of antidepressants over the past four decades has involved the replacement of drugs with a multiplicity of effects (e.g., TCAs) by those with selective actions (i.e., SSRIs). This strategy was employed to reduce the adverse effects of TCAs, largely by eliminating interactions with certain neurotransmitters or receptors. Although these more selective compounds may be better tolerated by patients, selective drugs, specifically SSRIs, are not superior to older drugs in treating depressed patients as measured by response and remission rates. It may be an advantage to increase synaptic levels of both serotonin and norepinephrine, as in the case of dual uptake inhibitors like duloxetine and venlafaxine. An important recent development has been the emergence of the triple-uptake inhibitors (TUIs/SNDRIs), which inhibit the uptake of the three neurotransmitters most closely linked to depression: serotonin, norepinephrine, and dopamine. Preclinical studies and clinical trials indicate that a drug inhibiting the reuptake of all three of these neurotransmitters could produce more rapid onset of action and greater efficacy than traditional antidepressants. This review will detail the medicinal chemistry involved in the design, synthesis and discovery of mixed serotonin, norepinephrine and dopamine transporter uptake inhibitors.

  11. Impaired Brain Dopamine and Serotonin Release and Uptake in Wistar Rats Following Treatment with Carboplatin.

    PubMed

    Kaplan, Sam V; Limbocker, Ryan A; Gehringer, Rachel C; Divis, Jenny L; Osterhaus, Gregory L; Newby, Maxwell D; Sofis, Michael J; Jarmolowicz, David P; Newman, Brooke D; Mathews, Tiffany A; Johnson, Michael A

    2016-06-15

    Chemotherapy-induced cognitive impairment, known also as "chemobrain", is a medical complication of cancer treatment that is characterized by a general decline in cognition affecting visual and verbal memory, attention, complex problem solving skills, and motor function. It is estimated that one-third of patients who undergo chemotherapy treatment will experience cognitive impairment. Alterations in the release and uptake of dopamine and serotonin, central nervous system neurotransmitters that play important roles in cognition, could potentially contribute to impaired intellectual performance in those impacted by chemobrain. To investigate how chemotherapy treatment affects these systems, fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes was used to measure dopamine and serotonin release and uptake in coronal brain slices containing the striatum and dorsal raphe nucleus, respectively. Measurements were taken from rats treated weekly with selected doses of carboplatin and from control rats treated with saline. Modeling the stimulated dopamine release plots revealed an impairment of dopamine release per stimulus pulse (80% of saline control at 5 mg/kg and 58% at 20 mg/kg) after 4 weeks of carboplatin treatment. Moreover, Vmax, the maximum uptake rate of dopamine, was also decreased (55% of saline control at 5 mg/kg and 57% at 20 mg/kg). Nevertheless, overall dopamine content, measured in striatal brain lysates by high performance liquid chromatography, and reserve pool dopamine, measured by FSCV after pharmacological manipulation, did not significantly change, suggesting that chemotherapy treatment selectively impairs the dopamine release and uptake processes. Similarly, serotonin release upon electrical stimulation was impaired (45% of saline control at 20 mg/kg). Measurements of spatial learning discrimination were taken throughout the treatment period and carboplatin was found to alter cognition. These studies support the need for additional

  12. Impaired Brain Dopamine and Serotonin Release and Uptake in Wistar Rats Following Treatment with Carboplatin

    PubMed Central

    2016-01-01

    Chemotherapy-induced cognitive impairment, known also as “chemobrain”, is a medical complication of cancer treatment that is characterized by a general decline in cognition affecting visual and verbal memory, attention, complex problem solving skills, and motor function. It is estimated that one-third of patients who undergo chemotherapy treatment will experience cognitive impairment. Alterations in the release and uptake of dopamine and serotonin, central nervous system neurotransmitters that play important roles in cognition, could potentially contribute to impaired intellectual performance in those impacted by chemobrain. To investigate how chemotherapy treatment affects these systems, fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes was used to measure dopamine and serotonin release and uptake in coronal brain slices containing the striatum and dorsal raphe nucleus, respectively. Measurements were taken from rats treated weekly with selected doses of carboplatin and from control rats treated with saline. Modeling the stimulated dopamine release plots revealed an impairment of dopamine release per stimulus pulse (80% of saline control at 5 mg/kg and 58% at 20 mg/kg) after 4 weeks of carboplatin treatment. Moreover, Vmax, the maximum uptake rate of dopamine, was also decreased (55% of saline control at 5 mg/kg and 57% at 20 mg/kg). Nevertheless, overall dopamine content, measured in striatal brain lysates by high performance liquid chromatography, and reserve pool dopamine, measured by FSCV after pharmacological manipulation, did not significantly change, suggesting that chemotherapy treatment selectively impairs the dopamine release and uptake processes. Similarly, serotonin release upon electrical stimulation was impaired (45% of saline control at 20 mg/kg). Measurements of spatial learning discrimination were taken throughout the treatment period and carboplatin was found to alter cognition. These studies support the need for additional

  13. Modulation for emergent networks: serotonin and dopamine.

    PubMed

    Weng, Juyang; Paslaski, Stephen; Daly, James; VanDam, Courtland; Brown, Jacob

    2013-05-01

    In autonomous learning, value-sensitive experiences can improve the efficiency of learning. A learning network needs be motivated so that the limited computational resources and the limited lifetime are devoted to events that are of high value for the agent to compete in its environment. The neuromodulatory system of the brain is mainly responsible for developing such a motivation system. Although reinforcement learning has been extensively studied, many existing models are symbolic whose internal nodes or modules have preset meanings. Neural networks have been used to automatically generate internal emergent representations. However, modeling an emergent motivational system for neural networks is still a great challenge. By emergent, we mean that the internal representations emerge autonomously through interactions with the external environments. This work proposes a generic emergent modulatory system for emergent networks, which includes two subsystems - the serotonin system and the dopamine system. The former signals a large class of stimuli that are intrinsically aversive (e.g., stress or pain). The latter signals a large class of stimuli that are intrinsically appetitive (e.g., pleasure or sweet). We experimented with this motivational system for two settings. The first is a visual recognition setting to investigate how such a system can learn through interactions with a teacher, who does not directly give answers, but only punishments and rewards. The second is a setting for wandering in the presence of a friend and a foe.

  14. Mapping neurotransmitter networks with PET: an example on serotonin and opioid systems.

    PubMed

    Tuominen, Lauri; Nummenmaa, Lauri; Keltikangas-Järvinen, Liisa; Raitakari, Olli; Hietala, Jarmo

    2014-05-01

    All functions of the human brain are consequences of altered activity of specific neural pathways and neurotransmitter systems. Although the knowledge of "system level" connectivity in the brain is increasing rapidly, we lack "molecular level" information on brain networks and connectivity patterns. We introduce novel voxel-based positron emission tomography (PET) methods for studying internal neurotransmitter network structure and intercorrelations of different neurotransmitter systems in the human brain. We chose serotonin transporter and μ-opioid receptor for this analysis because of their functional interaction at the cellular level and similar regional distribution in the brain. Twenty-one healthy subjects underwent two consecutive PET scans using [(11)C]MADAM, a serotonin transporter tracer, and [(11)C]carfentanil, a μ-opioid receptor tracer. First, voxel-by-voxel "intracorrelations" (hub and seed analyses) were used to study the internal structure of opioid and serotonin systems. Second, voxel-level opioid-serotonin intercorrelations (between neurotransmitters) were computed. Regional μ-opioid receptor binding potentials were uniformly correlated throughout the brain. However, our analyses revealed nonuniformity in the serotonin transporter intracorrelations and identified a highly connected local network (midbrain-striatum-thalamus-amygdala). Regionally specific intercorrelations between the opioid and serotonin tracers were found in anteromedial thalamus, amygdala, anterior cingulate cortex, dorsolateral prefrontal cortex, and left parietal cortex, i.e., in areas relevant for several neuropsychiatric disorders, especially affective disorders. This methodology enables in vivo mapping of connectivity patterns within and between neurotransmitter systems. Quantification of functional neurotransmitter balances may be a useful approach in etiological studies of neuropsychiatric disorders and also in drug development as a biomarker-based rationale for targeted

  15. Brain dopamine-serotonin vesicular transport disease presenting as a severe infantile hypotonic parkinsonian disorder.

    PubMed

    Jacobsen, Jessie C; Wilson, Callum; Cunningham, Vicki; Glamuzina, Emma; Prosser, Debra O; Love, Donald R; Burgess, Trent; Taylor, Juliet; Swan, Brendan; Hill, Rosamund; Robertson, Stephen P; Snell, Russell G; Lehnert, Klaus

    2016-03-01

    Two male siblings from a consanguineous union presented in early infancy with marked truncal hypotonia, a general paucity of movement, extrapyramidal signs and cognitive delay. By mid-childhood they had made little developmental progress and remained severely hypotonic and bradykinetic. They developed epilepsy and had problems with autonomic dysfunction and oculogyric crises. They had a number of orthopaedic problems secondary to their hypotonia. Cerebrospinal fluid (CSF) neurotransmitters were initially normal, apart from mildly elevated 5-hydroxyindolacetic acid, and the children did not respond favourably to a trial of levodopa-carbidopa. The youngest died from respiratory complications at 10 years of age. Repeat CSF neurotransmitters in the older sibling at eight years of age showed slightly low homovanillic acid and 5-hydroxyindoleacetic acid levels. Whole-exome sequencing revealed a novel mutation homozygous in both children in the monoamine transporter gene SLC18A2 (p.Pro237His), resulting in brain dopamine-serotonin vesicular transport disease. This is the second family to be described with a mutation in this gene. Treatment with the dopamine agonist pramipexole in the surviving child resulted in mild improvements in alertness, communication, and eye movements. This case supports the identification of the causal mutation in the original case, expands the clinical phenotype of brain dopamine-serotonin vesicular transport disease and confirms that pramipexole treatment may lead to symptomatic improvement in affected individuals.

  16. Alterations of dopamine and serotonin transmission in schizophrenia.

    PubMed

    Remington, Gary

    2008-01-01

    The present chapter outlines current thinking regarding serotonin and dopamine in schizophrenia. Each has individually been linked to theories regarding the illness' pathophysiology although the focus here is on their interactive role, a model that has driven drug development in the field for the last 10-15 years. With clozapine as a prototype, a new class of 'atypical' antipsychotics entered the clinical market, hinged predominantly on the notion that these agents were superior to conventional antipsychotics through their ratio of serotonin 5-HT(2)/dopamine D(2) binding. This model has since been challenged both clinically and theoretically, but interest in serotonin-dopamine interactions remains high in the face of a broader conceptualization of schizophrenia's symptom domains, in combination with a shift in the perceived role of dopamine vis-à-vis these different clinical features. At present, there is particular interest in the 5-HT(1A), 5-HT(2C), 5-HT(6) and 5-HT(7) receptors as the search for improved pharmacological treatments for schizophrenia continues.

  17. Morphology of salivary gland and distribution of dopamine and serotonin on red palm weevil (RPW), Rhynchophorus ferrugineus (Coleoptera: Curculionidae)

    NASA Astrophysics Data System (ADS)

    Hidayah, A. S. Nurul; Wahida, O. Nurul; Shafinaz, M. N. Norefrina; Idris, A. G.

    2013-11-01

    The Red Palm Weevil (RPW), Rhynchophorus ferrugineus (Olivier, 1790) is insect pest to plants of the family Palmaceae. No study has been reported on the digestive mechanism of Red Palm Weevil (RPW). Salivary glands are responsible in the feeding regulation of insect while serotonin and dopamine play a significant role in the regulation of this gland. It is great to see the morphology of the salivary gland and how dopamine and serotonin possibly play their role in this gland. Two variation of RPW, striped and spotted RPW were chosen. The morphology of the gland of both RPW variants examined by using light microscopy was found to be a tubular type. Immunohistochemical analysis conducted showed that serotonin and dopamine in both variations did not innervate the glands suggesting they are not act as neurotransmitter. However, it can be detected on few areas within the glands. This suggests that serotonin and dopamine may act as a hormone because there is no evidence on the nerve fibers. The role of these biogenic amines in the salivary gland of RPW needs further investigation. Hopefully the data would help in understanding the mechanism of salivary glands control by biogenic amines in RPW specifically and insects with sucking mouthpart generally.

  18. Neurotransmitters

    NASA Video Gallery

    Our nerve cells (neurons) communicate with each other using little chemical messengers called neurotransmitters. These neurotransmitters are transferred from one neuron to the next within a space c...

  19. Altered Dopamine and Serotonin Metabolism in Motorically Asymptomatic R6/2 Mice

    PubMed Central

    Mochel, Fanny; Durant, Brandon; Durr, Alexandra; Schiffmann, Raphael

    2011-01-01

    The pattern of cerebral dopamine (DA) abnormalities in Huntington disease (HD) is complex, as reflected by the variable clinical benefit of both DA antagonists and agonists in treating HD symptoms. In addition, little is known about serotonin metabolism despite the early occurrence of anxiety and depression in HD. Post-mortem enzymatic changes are likely to interfere with the in vivo profile of biogenic amines. Hence, in order to reliably characterize the regional and chronological profile of brain neurotransmitters in a HD mouse model, we used a microwave fixation system that preserves in vivo concentrations of dopaminergic and serotoninergic amines. DA was decreased in the striatum of R6/2 mice at 8 and 12 weeks of age while DA metabolites, 3-methoxytyramine and homovanillic acid, were already significantly reduced in 4-week-old motorically asymptomatic R6/2 mice. In the striatum, hippocampus and frontal cortex of 4, 8 and 12-week-old R6/2 mice, serotonin and its metabolite 5-hydroxyindoleacetic acid were significantly decreased in association with a decreased turnover of serotonin. In addition, automated high-resolution behavioural analyses displayed stress-like behaviours such as jumping and grooming and altered spatial learning in R6/2 mice at age 4 and 6 weeks respectively. Therefore, we describe the earliest alterations of DA and serotonin metabolism in a HD murine model. Our findings likely underpin the neuropsychological symptoms at time of disease onset in HD. PMID:21483838

  20. Opponency Revisited: Competition and Cooperation Between Dopamine and Serotonin

    PubMed Central

    Boureau, Y-Lan; Dayan, Peter

    2011-01-01

    Affective valence lies on a spectrum ranging from punishment to reward. The coding of such spectra in the brain almost always involves opponency between pairs of systems or structures. There is ample evidence for the role of dopamine in the appetitive half of this spectrum, but little agreement about the existence, nature, or role of putative aversive opponents such as serotonin. In this review, we consider the structure of opponency in terms of previous biases about the nature of the decision problems that animals face, the conflicts that may thus arise between Pavlovian and instrumental responses, and an additional spectrum joining invigoration to inhibition. We use this analysis to shed light on aspects of the role of serotonin and its interactions with dopamine. PMID:20881948

  1. Involvement of central noradrenaline, serotonin and dopamine system in the antidepressant activity of fruits of Solanum torvum (Solanaceae).

    PubMed

    Momin, Rehan; Mohan, Mahalaxmi

    2012-01-01

    The methanolic extract (ME) of Solanum torvum seeds and its ethyl acetate fraction (EAF) were investigated for their antidepressant activity using behavioral (forced swim test, FST and tail suspension test, TST) and biochemical (monoamine oxidase, MAO reduced activity) tests. ME (10, 30 and 100 mg kg(-1)) and EAF (10 and 30 mg kg(-1)) dose dependently inhibited the immobility period, increased noradrenaline, serotonin and dopamine levels and inhibited the MAO enzymes in FST and TST using mice. Furthermore, we have observed antagonism between the threshold dose of ME (30 and 100 mg kg(-1)) and EAF (10 and 30 mg kg(-1)) with antagonists on behaviour mediated by neurotransmitters noradrenaline, serotonin and dopamine. MAO-A inhibition was more prominent as compared to MAO-B inhibition. The study provides evidence for antidepressant actions of S. torvum.

  2. Deep brain stimulation of the nucleus accumbens shell increases impulsive behavior and tissue levels of dopamine and serotonin.

    PubMed

    Sesia, Thibaut; Bulthuis, Vincent; Tan, Sonny; Lim, Lee Wei; Vlamings, Rinske; Blokland, Arjan; Steinbusch, Harry W M; Sharp, Trevor; Visser-Vandewalle, Veerle; Temel, Yasin

    2010-10-01

    The nucleus accumbens (NAc) is gaining interest as a target for deep brain stimulation (DBS) in refractory neuropsychiatric disorders with impulsivity as core symptom. The nucleus accumbens is composed of two subterritories, core and shell, which have different anatomical connections. In animal models, it has been shown that DBS of the NAc changes impulsive action. Here, we tested the hypothesis that a change in impulsive action by DBS of the NAc is associated with changes in dopamine levels. Rats received stimulating electrodes either in the NAc core or shell, and underwent behavioral testing in a reaction time task. In addition, in a second experiment, the effect of DBS of the NAc core and shell on extracellular dopamine and serotonin levels was assessed in the NAc and medial prefrontal cortex. Control subjects received sham surgery. We have found that DBS of the NAc shell stimulation induced more impulsive action but less perseverative checking. These effects were associated with increased levels of dopamine and serotonin in the NAc, but not in the medial prefrontal cortex. DBS of the NAc core had no effect on impulsive action, but decreased perseverative responses indicative of a better impulse control. In these subjects, no effects were found on neurotransmitter levels. Our data point out that DBS of the NAc shell has negative effects on impulsive action which is accompanied by increases of dopamine and serotonin levels in the NAc, whereas DBS of the NAc core has beneficial behavioral effects.

  3. Serotonin and Dopamine: Unifying Affective, Activational, and Decision Functions

    PubMed Central

    Cools, Roshan; Nakamura, Kae; Daw, Nathaniel D

    2011-01-01

    Serotonin, like dopamine (DA), has long been implicated in adaptive behavior, including decision making and reinforcement learning. However, although the two neuromodulators are tightly related and have a similar degree of functional importance, compared with DA, we have a much less specific understanding about the mechanisms by which serotonin affects behavior. Here, we draw on recent work on computational models of dopaminergic function to suggest a framework by which many of the seemingly diverse functions associated with both DA and serotonin—comprising both affective and activational ones, as well as a number of other functions not overtly related to either—can be seen as consequences of a single root mechanism. PMID:20736991

  4. Duck cerebellum participates in regulation of food intake via the neurotransmitters serotonin and neuropeptide Y.

    PubMed

    Liu, Hua Z; Li, Xin Y; Tong, Jing J; Qiu, Zheng Y; Zhan, Han C; Sha, Jun N; Peng, Ke M

    2008-10-01

    Two important neurotransmitters, serotonin (5-hydroxytryptamine, 5-HT) and neuropeptide Y (NPY), have been confirmed to be involved in food intake regulation. To clarify whether the cerebellum participates in modulation of food intake through these two neurotransmitters, we investigated the distribution and expression levels of 5-HT and NPY in cerebellum of the duck. Our results showed that 5-HT and NPY were distributed only at the Purkinje cell layer of the duck cerebellum. Moreover, the expression level of 5-HT in fasted (4 h) and tryptophan (100-200 mg/kg)-treated ducks was significantly higher than that in control animals (P<0.01), whereas the expression of NPY was significantly decreased (P<0.01). Therefore, our results indicated that inhibitory regulation of food intake respectively increased and decreased cerebellar 5-HT and NPY in the duck.

  5. Relationship between dopamine deficit and the expression of depressive behavior resulted from alteration of serotonin system.

    PubMed

    Lee, Minkyung; Ryu, Young Hoon; Cho, Won Gil; Kang, Yeo Wool; Lee, Soo Jin; Jeon, Tae Joo; Lyoo, Chul Hyoung; Kim, Chul Hoon; Kim, Dong Goo; Lee, Kyochul; Choi, Tae Hyun; Choi, Jae Yong

    2015-09-01

    Depression frequently accompanies in Parkinson's disease (PD). Previous research suggested that dopamine (DA) and serotonin systems are closely linked with depression in PD. However, comprehensive studies about the relationship between these two neurotransmitter systems are limited. Therefore, the purpose of this study is to evaluate the effect of dopaminergic destruction on the serotonin system. The interconnection between motor and depression was also examined. Two PET scans were performed in the 6-hydroxydopamine (6-OHDA) lesioned and sham operated rats: [(18) F]FP-CIT for DA transporters and [(18) F]Mefway for serotonin 1A (5-HT(1A)) receptors. Here, 6-OHDA is a neurotoxin for dopaminergic neurons. Behavioral tests were used to evaluate the severity of symptoms: rotational number for motor impairment and immobility time, acquired from the forced swim test for depression. Region-of-interests were drawn in the striatum and cerebellum for the DA system and hippocampus and cerebellum for the 5-HT system. The cerebellum was chosen as a reference region. Nondisplaceable binding potential in the striatum and hippocampus were compared between 6-OHDA and sham groups. As a result, the degree of DA depletion was negatively correlated with rotational behavior (R(2)  = 0.79, P = 0.003). In 6-OHDA lesioned rats, binding values for 5-HT(1A) receptors was 22% lower than the sham operated group. This decrement of 5-HT(1A) receptor binding was also correlated with the severity of depression (R(2)  = 0.81, P = 0.006). Taken together, this research demonstrated that the destruction of dopaminergic system causes the reduction of the serotonergic system resulting in the expression of depressive behavior. The degree of dopaminergic dysfunction was positively correlated with the impairment of the serotonin system. Severity of motor symptoms was also closely related to depressive behavior.

  6. Temperature dependence of electrical properties of mixture of exogenous neurotransmitters dopamine and epinephrine

    NASA Astrophysics Data System (ADS)

    Patki, Mugdha; Patil, Vidya

    2016-05-01

    Neurotransmitters are chemical messengers that support the communication between the neurons. In vitro study of exogenous neurotransmitters Dopamine and Epinephrine and their mixture, carried out to learn about their electrical properties being dielectric constant and conductivity amongst others. Dielectric constant and conductivity of the selected neurotransmitters are found to increase with temperature. As a result, the time constant of the system increases with temperature. This change leads to increase in the time taken by the synapse to transport the action potential. The correlation between physical properties of exogenous neurotransmitters and psychological and physiological behaviour of human being may be understood with the help of current study. The response time of Epinephrine is in microseconds whereas response time of Dopamine is in milliseconds. The response time for both the neurotransmitters and their mixture is found to be increasing with temperature indicating the symptoms such as depression, apathy, chronic fatigue and low physical energy with no desire to exercise the body, which are observed during the fever.

  7. Effect of selective serotonin reuptake inhibitors on expression of 5-HT1AR and neurotransmitters in rats with vascular dementia.

    PubMed

    Guo, K; Yin, G; Zi, X H; Zhu, H X; Pan, Q

    2016-12-02

    5-hydroxytryptamine receptor 1A (5-HT1AR) is closely associated with cognitive functions. Selective serotonin reuptake inhibitors (SSRIs) can protect individuals from brain damage following ischemia/hypoxia. To investigate the function of SSRIs in vascular dementia (VD), we established a rat model of VD, and observed the effect of SSRIs on the expression of 5-HT1AR mRNA and neurotransmitters. Male SD rats (6 months) were randomly assigned into sham, model, and SSRI groups (N = 30). VD was achieved by permanent ligation of the bilateral common carotid artery. Escitalopram, a highly selective 5-HT reabsorption inhibitor, was ip injected into the rats for three consecutive weeks. The Morris water-maze was used to test learning and memory. H&E staining for neuronal injury was conducted on cortical and hippocampal tissues. HPLC was used to determine the levels of dopamine (DA), 5-HT, and norepinephrine (NE). RT-PCR was used to determine expression of 5-HT1AR mRNA. As compared to control rats, model animals demonstrated elongated escape latency, lower platform crossing times, and significant injuries to hippocampal CA1 neurons. This was accompanied by reductions in DA, 5-HT, and NE levels in hippocampal tissues, as well as reduced cortical 5-HT and decreased 5-HT1AR mRNA expression (P < 0.05). Escitalopram treatments reduced escape latency, elevated platform crossing times, improved CA1 neuronal damage, increased DA and 5-HT levels in hippocampal and cortical neurons, as well as elevated expression of 5-HT1AR mRNA (P < 0.05). Therefore, SSRIs may improve cognitive dysfunction of VD rats, possibly by stimulating expression of neurotransmitters and protecting neurons.

  8. Dispensable, Redundant, Complementary, and Cooperative Roles of Dopamine, Octopamine, and Serotonin in Drosophila melanogaster

    PubMed Central

    Chen, Audrey; Ng, Fanny; Lebestky, Tim; Grygoruk, Anna; Djapri, Christine; Lawal, Hakeem O.; Zaveri, Harshul A.; Mehanzel, Filmon; Najibi, Rod; Seidman, Gabriel; Murphy, Niall P.; Kelly, Rachel L.; Ackerson, Larry C.; Maidment, Nigel T.; Jackson, F. Rob; Krantz, David E.

    2013-01-01

    To investigate the regulation of Drosophila melanogaster behavior by biogenic amines, we have exploited the broad requirement of the vesicular monoamine transporter (VMAT) for the vesicular storage and exocytotic release of all monoamine neurotransmitters. We used the Drosophila VMAT (dVMAT) null mutant to globally ablate exocytotic amine release and then restored DVMAT activity in either individual or multiple aminergic systems, using transgenic rescue techniques. We find that larval survival, larval locomotion, and female fertility rely predominantly on octopaminergic circuits with little apparent input from the vesicular release of serotonin or dopamine. In contrast, male courtship and fertility can be rescued by expressing DVMAT in octopaminergic or dopaminergic neurons, suggesting potentially redundant circuits. Rescue of major aspects of adult locomotion and startle behavior required octopamine, but a complementary role was observed for serotonin. Interestingly, adult circadian behavior could not be rescued by expression of DVMAT in a single subtype of aminergic neurons, but required at least two systems, suggesting the possibility of unexpected cooperative interactions. Further experiments using this model will help determine how multiple aminergic systems may contribute to the regulation of other behaviors. Our data also highlight potential differences between behaviors regulated by standard exocytotic release and those regulated by other mechanisms. PMID:23086220

  9. Quantitation of dopamine, serotonin and adenosine content in a tissue punch from a brain slice using capillary electrophoresis with fast-scan cyclic voltammetry detection.

    PubMed

    Fang, Huaifang; Pajski, Megan L; Ross, Ashley E; Venton, B Jill

    2013-01-01

    Methods to determine neurochemical concentrations in small samples of tissue are needed to map interactions among neurotransmitters. In particular, correlating physiological measurements of neurotransmitter release and the tissue content in a small region would be valuable. HPLC is the standard method for tissue content analysis but it requires microliter samples and the detector often varies by the class of compound being quantified; thus detecting molecules from different classes can be difficult. In this paper, we develop capillary electrophoresis with fast-scan cyclic voltammetry detection (CE-FSCV) for analysis of dopamine, serotonin, and adenosine content in tissue punches from rat brain slices. Using field-amplified sample stacking, the limit of detection was 5 nM for dopamine, 10 nM for serotonin, and 50 nM for adenosine. Neurotransmitters could be measured from a tissue punch as small as 7 µg (7 nL) of tissue, three orders of magnitude smaller than a typical HPLC sample. Tissue content analysis of punches in successive slices through the striatum revealed higher dopamine but lower adenosine content in the anterior striatum. Stimulated dopamine release was measured in a brain slice, then a tissue punch collected from the recording region. Dopamine content and release had a correlation coefficient of 0.71, which indicates much of the variance in stimulated release is due to variance in tissue content. CE-FSCV should facilitate measurements of tissue content in nanoliter samples, leading to a better understanding of how diseases or drugs affect dopamine, serotonin, and adenosine content.

  10. Miniaturized and Wireless Optical Neurotransmitter Sensor for Real-Time Monitoring of Dopamine in the Brain

    PubMed Central

    Kim, Min H.; Yoon, Hargsoon; Choi, Sang H.; Zhao, Fei; Kim, Jongsung; Song, Kyo D.; Lee, Uhn

    2016-01-01

    Real-time monitoring of extracellular neurotransmitter concentration offers great benefits for diagnosis and treatment of neurological disorders and diseases. This paper presents the study design and results of a miniaturized and wireless optical neurotransmitter sensor (MWONS) for real-time monitoring of brain dopamine concentration. MWONS is based on fluorescent sensing principles and comprises a microspectrometer unit, a microcontroller for data acquisition, and a Bluetooth wireless network for real-time monitoring. MWONS has a custom-designed application software that controls the operation parameters for excitation light sources, data acquisition, and signal processing. MWONS successfully demonstrated a measurement capability with a limit of detection down to a 100 nanomole dopamine concentration, and high selectivity to ascorbic acid (90:1) and uric acid (36:1). PMID:27834927

  11. Interaction Between Brain Histamine and Serotonin, Norepinephrine, and Dopamine Systems: In Vivo Microdialysis and Electrophysiology Study.

    PubMed

    Flik, Gunnar; Folgering, Joost H A; Cremers, Thomas I H F; Westerink, Ben H C; Dremencov, Eliyahu

    2015-06-01

    Brain monoamines (serotonin, norepinephrine, dopamine, and histamine) play an important role in emotions, cognition, and pathophysiology and treatment of mental disorders. The interactions between serotonin, norepinephrine, and dopamine were studied in numerous works; however, histamine system received less attention. The aim of this study was to investigate the interactions between histamine and other monoamines, using in vivo microdialysis and electrophysiology. It was found that the inverse agonist of histamine-3 receptors, thioperamide, increased the firing activity of dopamine neurons in the ventral tegmental area. Selective agonist of histamine-3 receptors, immepip, reversed thiperamide-induced stimulation of firing activity of dopamine neurons. The firing rates of serotonin and norpeinephrine neurons were not attenuated by immepip or thioperamide. Thioperamide robustly and significantly increased extracellular concentrations of serotonin, norepinephrine, and dopamine in the rat prefrontal cortex and slightly increased norepinephrine and dopamine levels in the tuberomammillary nucleus of the hypothalamus. It can be concluded that histamine stimulates serotonin, norepinephrine, and dopamine transmission in the brain. Modulation of firing of dopamine neurons is a key element in functional interactions between histamine and other monoamines. Antagonists of histamine-3 receptors, because of their potential ability to stimulate monoamine neurotransmission, might be beneficial in the treatment of mental disorders.

  12. GABA, glutamate, dopamine and serotonin transporters expression on forgetting.

    PubMed

    Tellez, Ruth; Gómez-Viquez, Leticia; Liy-Salmeron, Gustavo; Meneses, Alfredo

    2012-07-01

    Notwithstanding several neurotransmission systems are frequently related to memory formation; forgetting process and neurotransmission systems or their transporters; the role of γ-aminobutyric acid (GAT1), glutamate (EACC1), dopamine (DAT) and serotonin (SERT) is poorly understood. Hence, in this paper western-blot analysis was used to evaluate expression of GAT1, EAAC1, DAT and SERT during forgetting in trained and untrained rats treated with the selective serotonin transporter inhibitor fluoxetine, the amnesic drug d-methamphetamine (METH) and fluoxetine plus METH. Transporters expression was determined in the hippocampus (HIP), prefrontal cortex (PFC) and striatum (STR). Results indicated that forgetting of Pavlovian/instrumental autoshaping was associated to up-regulation of GAT1 (PFC and HIP) and DAT (PFC) while SERT (HIP) was down-regulated; no-changes were observed in striatum. Methamphetamine administration did not affect forgetting at 216 h post-training but up-regulated hippocampal DAT and EACC, prefrontal cortex DAT and striatal GAT1 or EACC1. Fluoxetine alone prevented forgetting, which was associated to striatal GAT1 and hippocampal DAT up-regulation, but prefrontal cortex GAT1 down-regulation. Fluoxetine plus METH administration was also able to prevent forgetting, which was associated to hippocampal DAT, prefrontal cortex SERT and striatal GAT1, DAT or SERT up-regulation, but prefrontal cortex GAT1 down-regulation. Together these data show that forgetting provokes primarily hippocampal and prefrontal cortex transporters changes; forgetting represent a behavioral process hardly modifiable and its prevention could causes different transporters expression patterns.

  13. Fluorescent false neurotransmitter reveals functionally silent dopamine vesicle clusters in the striatum

    PubMed Central

    Pereira, Daniela B.; Schmitz, Yvonne; Mészáros, József; Merchant, Paolomi; Hu, Gang; Li, Shu; Henke, Adam; Lizardi-Ortiz, José E.; Karpowicz, Richard J.; Morgenstern, Travis J.; Sonders, Mark S.; Kanter, Ellen; Rodriguez, Pamela C.; Mosharov, Eugene V.; Sames, Dalibor; Sulzer, David

    2016-01-01

    Neurotransmission at dopaminergic synapses has been studied with techniques that provide high temporal resolution but cannot resolve individual synapses. To elucidate the spatial dynamics and heterogeneity of individual dopamine boutons, we developed fluorescent false neurotransmitter 200 (FFN200), a vesicular monoamine transporter 2 (VMAT2) substrate that is the first probe to selectively trace monoamine exocytosis in both neuronal cell culture and brain tissue. By monitoring electrically-evoked Ca2+ transients with GCaMP3 and FFN200 release simultaneously, we find that only a small fraction of dopamine boutons that exhibit Ca2+ influx engage in exocytosis, a result confirmed with activity-dependent loading of the endocytic probe FM 1-43. Thus, only a low fraction of striatal dopamine axonal sites with uptake-competent VMAT2 vesicles are capable of transmitter release. This is consistent with the presence of functionally “silent” dopamine vesicle clusters and represents a first report suggestive of presynaptically silent neuromodulatory synapses. PMID:26900925

  14. The role of dopamine and serotonin in conditioned food aversion learning in the honeybee

    PubMed Central

    2011-01-01

    For most animals, eating entails the risk of being poisoned. Learning how to identify foods with toxins is an important mechanism that reduces the risk of poisoning. While conditioned food aversions have been studied in vertebrates for over 50 years, the neural circuits underlying this form of learning have been difficult to elucidate because of their complexity. Insects, such as fruit flies and honeybees, are important models for the study of the neural mechanisms of learning and memory, but conditioned food aversions have not yet been reported from either species. My collaborators and I recently established that the honeybee has the ability to learn to avoid odors associated with toxins in food using two independent neural pathways. In these experiments, we found that honeybees can learn to associate scents with toxins that they can pre-ingestively detect using their proboscis. This form of learning is primarily mediated by the neurotransmitter, dopamine. We also found a second mechanism: bees can learn to avoid odors associated with the malaise caused by ingesting toxins. This form of learning is mediated by serotonin. Our data are the first to show that two different mechanisms account for conditioned food aversions in insects. PMID:21980568

  15. Variations of dopamine, serotonin, and amino acid concentrations in Noda epileptic rat (NER) retina.

    PubMed

    Chanut, Evelyne; Labarthe, Benoît; Lacroix, Brigitte; Noda, Atsuhi; Gasdeblay, Sylvie; Bondier, Jean-Robert; Versaux-Botteri, Claudine

    2006-01-27

    Noda epileptic rats (NER) exhibit frequent spontaneous tonic-clonic convulsions which represent a valuable model of human epilepsy. If implication of brain neurotransmitters was largely reported, little is known about retina. However, it has been reported that human epilepsy syndrome varies not only with the location of seizure foci but also according to rhythmic patterns, for which retina has a major role in the transmission of external light-dark cycle information. The purpose of this work was to evaluate dopamine (DA), DA metabolites, serotonin (5-HT), and amino acid [glutamate, aspartate, glycine, gamma aminobutyric acid (GABA), and taurine] level variations in retina from NER, at two different nycthemeral periods (11 a.m. and 11 p.m.) and at different ages (2, 6, and 12 months). In NER, retinal dopaminergic function was decreased as soon as 2 months, whereas GABA levels were increased, even if no differences among the different ages could be distinguished. These variations were associated to a slight increase in 5-HT. Other amino acids tested were not affected by epilepsy, whereas taurine decreased with aging in NER as well as in control rats. Retinal 5-HT occurs principally as a precursor of melatonin (MEL). A triangular interaction may be hypothesized: MEL could decrease DA synthesis or release by enhancing GABA activity. Taken together, these results suggest that the retinal physiology is affected by the epileptic status and that information transmitted from retina to the brain should be affected by epilepsy in NER.

  16. The role of dopamine and serotonin in conditioned food aversion learning in the honeybee.

    PubMed

    Wright, Geraldine A

    2011-05-01

    For most animals, eating entails the risk of being poisoned. Learning how to identify foods with toxins is an important mechanism that reduces the risk of poisoning. While conditioned food aversions have been studied in vertebrates for over 50 years, the neural circuits underlying this form of learning have been difficult to elucidate because of their complexity. Insects, such as fruit flies and honeybees, are important models for the study of the neural mechanisms of learning and memory, but conditioned food aversions have not yet been reported from either species. My collaborators and I recently established that the honeybee has the ability to learn to avoid odors associated with toxins in food using two independent neural pathways. In these experiments, we found that honeybees can learn to associate scents with toxins that they can pre-ingestively detect using their proboscis. This form of learning is primarily mediated by the neurotransmitter, dopamine. We also found a second mechanism: bees can learn to avoid odors associated with the malaise caused by ingesting toxins. This form of learning is mediated by serotonin. Our data are the first to show that two different mechanisms account for conditioned food aversions in insects.

  17. Electrochemical Analysis of Neurotransmitters

    NASA Astrophysics Data System (ADS)

    Bucher, Elizabeth S.; Wightman, R. Mark

    2015-07-01

    Chemical signaling through the release of neurotransmitters into the extracellular space is the primary means of communication between neurons. More than four decades ago, Ralph Adams and his colleagues realized the utility of electrochemical methods for the study of easily oxidizable neurotransmitters, such as dopamine, norepinephrine, and serotonin and their metabolites. Today, electrochemical techniques are frequently coupled to microelectrodes to enable spatially resolved recordings of rapid neurotransmitter dynamics in a variety of biological preparations spanning from single cells to the intact brain of behaving animals. In this review, we provide a basic overview of the principles underlying constant-potential amperometry and fast-scan cyclic voltammetry, the most commonly employed electrochemical techniques, and the general application of these methods to the study of neurotransmission. We thereafter discuss several recent developments in sensor design and experimental methodology that are challenging the current limitations defining the application of electrochemical methods to neurotransmitter measurements.

  18. Electrochemical Analysis of Neurotransmitters

    PubMed Central

    Bucher, Elizabeth S.; Wightman, R. Mark

    2016-01-01

    Chemical signaling through the release of neurotransmitters into the extracellular space is the primary means of communication between neurons. More than four decades ago, Ralph Adams and his colleagues realized the utility of electrochemical methods for the study of easily oxidizable neurotransmitters, such as dopamine, norepinephrine, and serotonin and their metabolites. Today, electrochemical techniques are frequently coupled to microelectrodes to enable spatially resolved recordings of rapid neurotransmitter dynamics in a variety of biological preparations spanning from single cells to the intact brain of behaving animals. In this review, we provide a basic overview of the principles underlying constant-potential amperometry and fast-scan cyclic voltammetry, the most commonly employed electrochemical techniques, and the general application of these methods to the study of neurotransmission. We thereafter discuss several recent developments in sensor design and experimental methodology that are challenging the current limitations defining the application of electrochemical methods to neurotransmitter measurements. PMID:25939038

  19. Electrochemical Analysis of Neurotransmitters.

    PubMed

    Bucher, Elizabeth S; Wightman, R Mark

    2015-01-01

    Chemical signaling through the release of neurotransmitters into the extracellular space is the primary means of communication between neurons. More than four decades ago, Ralph Adams and his colleagues realized the utility of electrochemical methods for the study of easily oxidizable neurotransmitters, such as dopamine, norepinephrine, and serotonin and their metabolites. Today, electrochemical techniques are frequently coupled to microelectrodes to enable spatially resolved recordings of rapid neurotransmitter dynamics in a variety of biological preparations spanning from single cells to the intact brain of behaving animals. In this review, we provide a basic overview of the principles underlying constant-potential amperometry and fast-scan cyclic voltammetry, the most commonly employed electrochemical techniques, and the general application of these methods to the study of neurotransmission. We thereafter discuss several recent developments in sensor design and experimental methodology that are challenging the current limitations defining the application of electrochemical methods to neurotransmitter measurements.

  20. The antipsychotic aripiprazole induces antinociceptive effects: Possible role of peripheral dopamine D2 and serotonin 5-HT1A receptors.

    PubMed

    Almeida-Santos, Ana F; Ferreira, Renata C M; Duarte, Igor D; Aguiar, Daniele C; Romero, Thiago R L; Moreira, Fabricio A

    2015-10-15

    Aripiprazole is an antipsychotic that acts by multiple mechanisms, including partial agonism at dopamine D2 and serotonin 5-HT1A receptors. Since these neurotransmitters also modulate pain and analgesia, we tested the hypothesis that systemic or local administration of aripiprazole induces antinociceptive responses. Systemic aripiprazole (0.1-10 mg/kg; i.p.) injection in mice inhibited formalin-induced paw licking and PGE2-induced hyperalgesia in the paw pressure test. This effect was mimicked by intra-plantar administration (12.5-100 µg/paw) in the ipsi, but not contralateral, paw. The peripheral action of aripiprazole (100 µg/paw) was reversed by haloperidol (0.1-10 µg/paw), suggesting the activation of dopamine receptors as a possible mechanism. Accordingly, quinpirole (25-100 µg/paw), a full agonist at D2/D3 receptors, also reduced nociceptive responses.. In line with the partial agoniztic activity of aripiprazole, low dose of this compound inhibited the effect of quinpirole (both at 25 µg/paw). Finally, peripheral administration of NAN-190 (0.1-10 μg/paw), a 5-HT1A antagonist, also prevented aripiprazole-induced antinociception. In conclusion, systemic or local administration of aripiprazole induces antinociceptive effects. Similar to its antipsychotic activity, the possible peripheral mechanism involves dopamine D2 and serotoninergic 5-HT1A receptors. Aripiprazole and other dopaminergic modulators should be further investigated as new treatments for certain types of pain.

  1. [The Effect of memantine on spinal alpha-motoneurons and on the content of dopamine, noradrenaline and serotonin in the striatum and lumbar spinal cord].

    PubMed

    Sontag, K H; Wand, P; Schwarz, M; Wesemann, W; Osborne, N N

    1982-01-01

    In the present paper the pharmacological effect of 1,3-dimethyl-5-aminoadamantane (DMAA, D-145, memantine, Memantine was investigated on the reflex activity of spinal alpha-motoneurones of the cat and on spontaneous hyperactivity of alpha-motoneurones of spastic Han-Wist rats. The activity of both systems is reduced by the drug. Furthermore the content of dopamine, noradrenaline, and serotonin of striatum and lumbar spinal cord of normals and mutants is dose dependently decreased. It is assumed that memantine depresses the activation of central nervous membranes and reduces repetitive discharges of axons and in addition acts by release of neurotransmitters.

  2. Dopamine and Serotonin Modulate Human GABAρ1 Receptors Expressed in Xenopus laevis Oocytes

    PubMed Central

    2011-01-01

    GABAρ1 receptors are highly expressed in bipolar neurons of the retina and to a lesser extent in several areas of the central nervous system (CNS), and dopamine and serotonin are also involved in the modulation of retinal neural transmission. Whether these biogenic amines have a direct effect on ionotropic GABA receptors was not known. Here, we report that GABAρ1 receptors, expressed in X. laevis oocytes, were negatively modulated by dopamine and serotonin and less so by octopamine and tyramine. Interestingly, these molecules did not have effects on GABAA receptors. 5-Carboxamido-tryptamine and apomorphine did not exert evident effects on any of the receptors. Schild plot analyses of the inhibitory actions of dopamine and serotonin on currents elicited by GABA showed slopes of 2.7 ± 0.3 and 6.1 ± 1.8, respectively, indicating a noncompetitive mechanism of inhibition. The inhibition of GABAρ1 currents was independent of the membrane potential and was insensitive to picrotoxin, a GABA receptor channel blocker and to the GABAρ-specific antagonist (1,2,5,6-tetrahydropyridine-4-yl)methyl phosphinic acid (TPMPA). Dopamine and serotonin changed the sensitivity of GABAρ1 receptors to the inhibitory actions of Zn2+. In contrast, La3+ potentiated the amplitude of the GABA currents generated during negative modulation by dopamine (EC50 146 μM) and serotonin (EC50 196 μM). The functional role of the direct modulation of GABAρ receptors by dopamine and serotonin remains to be elucidated; however, it may represent an important modulatory pathway in the retina, where GABAρ receptors are highly expressed and where these biogenic amines are abundant. PMID:22860179

  3. Impact of grafted serotonin and dopamine neurons on development of L-DOPA-induced dyskinesias in parkinsonian rats is determined by the extent of dopamine neuron degeneration.

    PubMed

    Carlsson, Thomas; Carta, Manolo; Muñoz, Ana; Mattsson, Bengt; Winkler, Christian; Kirik, Deniz; Björklund, Anders

    2009-02-01

    Previous studies have shown that serotonin neurons play an important role in the induction and maintenance of L-DOPA-induced dyskinesia in animals with lesion of the nigrostriatal dopamine system. Patients with Parkinson's disease that receive transplants of foetal ventral mesencephalic tissue, the graft cell preparation is likely to contain, in addition to dopamine neurons, serotonin neurons that will vary in number depending on the landmarks used for dissection. Here, we have studied the impact of grafted serotonin neurons--alone or mixed with dopamine neurons--on the development of L-DOPA-induced dyskinesia in rats with a partial 6-hydroxydopamine lesion of the host nigrostriatal projection. In these rats, which showed only low-level dyskinesia at the time of transplantation, serotonin grafts induced a worsening in the severity of dyskinesia that developed during continued L-DOPA treatment, while the dopamine-rich graft had the opposite, dampening effect. The detrimental effect seen in animals with serotonin neuron grafts was dramatically increased when the residual dopamine innervation in the striatum was removed by a second 6-hydroxydopamine lesion. Interestingly, rats with grafts that contained a mixture of dopamine and serotonin neurons (in approximately 2:1) showed a marked reduction in L-DOPA-induced dyskinesia over time, and the appearance of severe dyskinesia induced by the removal of the residual dopamine innervation, seen in the animals with transplants of serotonin neurons alone, was blocked. FosB expression in the striatal projection neurons, which is associated with dyskinesias, was also normalized by the dopamine-rich grafts, but not by the serotonin neuron grafts. These data indicate that as long as a sufficient portion, some 10-20%, of the dopamine innervation still remains, the increased host serotonin innervation generated by the grafted serotonin neurons will have limited effect on the development or severity of L-DOPA-induced dyskinesias. At

  4. Environment- and activity-dependent dopamine neurotransmitter plasticity in the adult substantia nigra.

    PubMed

    Aumann, Tim D

    2016-04-01

    The ability of neurons to change the amount or type of neurotransmitter they use, or 'neurotransmitter plasticity', is an emerging new form of adult brain plasticity. For example, it has recently been shown that neurons in the adult rat hypothalamus up- or down-regulate dopamine (DA) neurotransmission in response to the amount of light the animal receives (photoperiod), and that this in turn affects anxiety- and depressive-like behaviors (Dulcis et al., 2013). In this Chapter I consolidate recent evidence from my laboratory suggesting neurons in the adult mouse substantia nigra pars compacta (SNc) also undergo DA neurotransmitter plasticity in response to persistent changes in their electrical activity, including that driven by the mouse's environment or behavior. Specifically, we have shown that the amounts of tyrosine hydroxylase (TH, the rate-limiting enzyme in DA synthesis) gene promoter activity, TH mRNA and TH protein in SNc neurons increases or decreases after ∼20h of altered electrical activity. Also, infusion of ion-channel agonists or antagonists into the midbrain for 2 weeks results in ∼10% (∼500 neurons) more or fewer TH immunoreactive (TH+) SNc neurons, with no change in the total number of SNc neurons (TH+ and TH-). Targeting ion-channels mediating cell-autonomous pacemaker activity in, or synaptic input and afferent pathways to, SNc neurons are equally effective in this regard. In addition, exposing mice to different environments (sex pairing or environment enrichment) for 1-2 weeks induces ∼10% more or fewer TH+ SNc (and ventral tegmental area or VTA) neurons and this is abolished by concurrent blockade of synaptic transmission in midbrain. Although further research is required to establish SNc (and VTA) DA neurotransmitter plasticity, and to determine whether it alters brain function and behavior, it is an exciting prospect because: (1) It may play important roles in movement, motor learning, reward, motivation, memory and cognition; and (2

  5. Conjugated Polymer Nanoparticles for Fluorescence Imaging and Sensing of Neurotransmitter Dopamine in Living Cells and the Brains of Zebrafish Larvae.

    PubMed

    Qian, Cheng-Gen; Zhu, Sha; Feng, Pei-Jian; Chen, Yu-Lei; Yu, Ji-Cheng; Tang, Xin; Liu, Yun; Shen, Qun-Dong

    2015-08-26

    Nanoscale materials are now attracting a great deal of attention for biomedical applications. Conjugated polymer nanoparticles have remarkable photophysical properties that make them highly advantageous for biological fluorescence imaging. We report on conjugated polymer nanoparticles with phenylboronic acid tags on the surface for fluorescence detection of neurotransmitter dopamine in both living PC12 cells and brain of zebrafish larvae. The selective enrichment of dopamine and fluorescence signal amplification characteristics of the nanoparticles show rapid and high-sensitive probing such neurotransmitter with the detection limit of 38.8 nM, and minimum interference from other endogenous molecules. It demonstrates the potential of nanomaterials as a multifunctional nanoplatform for targeting, diagnosis, and therapy of dopamine-relative disease.

  6. Early Antipsychotic Treatment in Juvenile Rats Elicits Long-Term Alterations to the Dopamine Neurotransmitter System.

    PubMed

    De Santis, Michael; Lian, Jiamei; Huang, Xu-Feng; Deng, Chao

    2016-11-22

    Prescription of antipsychotic drugs (APDs) to children has substantially increased in recent years. Whilst current investigations into potential long-term effects have uncovered some alterations to adult behaviours, further investigations into potential changes to neurotransmitter systems are required. The current study investigated potential long-term changes to the adult dopamine (DA) system following aripiprazole, olanzapine and risperidone treatment in female and male juvenile rats. Levels of tyrosine hydroxylase (TH), phosphorylated-TH (p-TH), dopamine active transporter (DAT), and D₁ and D₂ receptors were measured via Western blot and/or receptor autoradiography. Aripiprazole decreased TH and D₁ receptor levels in the ventral tegmental area (VTA) and p-TH levels in the prefrontal cortex (PFC) of females, whilst TH levels decreased in the PFC of males. Olanzapine decreased PFC p-TH levels and increased D₂ receptor expression in the PFC and nucleus accumbens (NAc) in females only. Additionally, risperidone treatment increased D₁ receptor levels in the hippocampus of females, whilst, in males, p-TH levels increased in the PFC and hippocampus, D₁ receptor expression decreased in the NAc, and DAT levels decreased in the caudate putamen (CPu), and elevated in the VTA. These results suggest that early treatment with various APDs can cause different long-term alterations in the adult brain, across both treatment groups and genders.

  7. Early Antipsychotic Treatment in Juvenile Rats Elicits Long-Term Alterations to the Dopamine Neurotransmitter System

    PubMed Central

    De Santis, Michael; Lian, Jiamei; Huang, Xu-Feng; Deng, Chao

    2016-01-01

    Prescription of antipsychotic drugs (APDs) to children has substantially increased in recent years. Whilst current investigations into potential long-term effects have uncovered some alterations to adult behaviours, further investigations into potential changes to neurotransmitter systems are required. The current study investigated potential long-term changes to the adult dopamine (DA) system following aripiprazole, olanzapine and risperidone treatment in female and male juvenile rats. Levels of tyrosine hydroxylase (TH), phosphorylated-TH (p-TH), dopamine active transporter (DAT), and D1 and D2 receptors were measured via Western blot and/or receptor autoradiography. Aripiprazole decreased TH and D1 receptor levels in the ventral tegmental area (VTA) and p-TH levels in the prefrontal cortex (PFC) of females, whilst TH levels decreased in the PFC of males. Olanzapine decreased PFC p-TH levels and increased D2 receptor expression in the PFC and nucleus accumbens (NAc) in females only. Additionally, risperidone treatment increased D1 receptor levels in the hippocampus of females, whilst, in males, p-TH levels increased in the PFC and hippocampus, D1 receptor expression decreased in the NAc, and DAT levels decreased in the caudate putamen (CPu), and elevated in the VTA. These results suggest that early treatment with various APDs can cause different long-term alterations in the adult brain, across both treatment groups and genders. PMID:27879654

  8. Dissociable roles of dopamine and serotonin transporter function in a rat model of negative urgency.

    PubMed

    Yates, Justin R; Darna, Mahesh; Gipson, Cassandra D; Dwoskin, Linda P; Bardo, Michael T

    2015-09-15

    Negative urgency is a facet of impulsivity that reflects mood-based rash action and is associated with various maladaptive behaviors in humans. However, the underlying neural mechanisms of negative urgency are not fully understood. Several brain regions within the mesocorticolimbic pathway, as well as the neurotransmitters dopamine (DA) and serotonin (5-HT), have been implicated in impulsivity. Extracellular DA and 5-HT concentrations are regulated by DA transporters (DAT) and 5-HT transporters (SERT); thus, these transporters may be important molecular mechanisms underlying individual differences in negative urgency. The current study employed a reward omission task to model negative urgency in rats. During reward trials, a cue light signaled the non-contingent delivery of one sucrose pellet; immediately following the non-contingent reward, rats responded on a lever to earn sucrose pellets (operant phase). Omission trials were similar to reward trials, except that non-contingent sucrose was omitted following the cue light prior to the operant phase. As expected, contingent responding was higher following omission of expected reward than following delivery of expected reward, thus reflecting negative urgency. Upon completion of behavioral training, Vmax and Km were obtained from kinetic analysis of [(3)H]DA and [(3)H]5-HT uptake using synaptosomes prepared from nucleus accumbens (NAc), dorsal striatum (Str), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC) isolated from individual rats. Vmax for DAT in NAc and for SERT in OFC were positively correlated with negative urgency scores. The current findings suggest that mood-based impulsivity (negative urgency) is associated with enhanced DAT function in NAc and SERT function in OFC.

  9. Dissociable Roles of Dopamine and Serotonin Transporter Function in a Rat Model of Negative Urgency

    PubMed Central

    Yates, Justin R.; Darna, Mahesh; Gipson, Cassandra D.; Dwoskin, Linda P.; Bardo, Michael T.

    2015-01-01

    Negative urgency is a facet of impulsivity that reflects mood-based rash action and is associated with various maladaptive behaviors in humans. However, the underlying neural mechanisms of negative urgency are not fully understood. Several brain regions within the mesocorticolimbic pathway, as well as the neurotransmitters dopamine (DA) and serotonin (5-HT), have been implicated in impulsivity. Extracellular DA and 5-HT concentrations are regulated by DA transporters (DAT) and 5-HT transporters (SERT); thus, these transporters may be important molecular mechanisms underlying individual differences in negative urgency. The current study employed a reward omission task to model negative urgency in rats. During reward trials, a cue light signaled the non-contingent delivery of one sucrose pellet; immediately following the non-contingent reward, rats responded on a lever to earn sucrose pellets (operant phase). Omission trials were similar to reward trials, except that non-contingent sucrose was omitted following the cue light prior to the operant phase. As expected, contingent responding was higher following omission of expected reward than following delivery of expected reward, thus reflecting negative urgency. Upon completion of behavioral training, Vmax and Km were obtained from kinetic analysis of [3H]DA and [3H]5-HT uptake using synaptosomes prepared from nucleus accumbens (NAc), dorsal striatum (Str), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC) isolated from individual rats. Vmax for DAT in NAc and for SERT in OFC were positively correlated with negative urgency scores. The current findings suggest that mood-based impulsivity (negative urgency) is associated with enhanced DAT function in NAc and SERT function in OFC. PMID:26005123

  10. Silibinin attenuates cognitive deficits and decreases of dopamine and serotonin induced by repeated methamphetamine treatment.

    PubMed

    Lu, Ping; Mamiya, Takayoshi; Lu, Lingling; Mouri, Akihiro; Niwa, Minae; Kim, Hyoung-Chun; Zou, Li-Bo; Nagai, Taku; Yamada, Kiyofumi; Ikejima, Takashi; Nabeshima, Toshitaka

    2010-03-05

    Cognitive deficits are a core feature of patients with methamphetamine (METH) abuse. It has been reported that repeated METH treatment impairs long-term recognition memory in the novel object recognition test (NORT) in mice. Recent studies indicate that silibinin, a flavonoid derived from the herb milk thistle, has potent neuroprotective effects in cell cultures and several animal models of neurological diseases. However, its effect on the cognitive deficit induced by METH remains unclear. In the present study, we attempt to clarify the effect of silibinin on impairments of recognition memory caused by METH in mice. Mice were co-administered silibinin with METH for 7 days and then cognitive function was assessed by NORT after 7-day withdrawal. Tissue levels of dopamine and serotonin as well as their metabolites in the prefrontal cortex and hippocampus were measured 1 day after NORT. Silibinin dose-dependently ameliorated the impairment of recognition memory caused by METH treatment in mice. Silibinin significantly attenuated the decreases in the dopamine content of the prefrontal cortex and serotonin content of the hippocampus caused by METH treatment. We also found a correlation between the recognition values and dopamine and serotonin contents of the prefrontal cortex and hippocampus. The effect of silibinin on cognitive impairment may be associated with an amelioration of decreases in dopamine and serotonin levels in the prefrontal cortex and hippocampus, respectively. These results suggest that silibinin may be useful as a pharmacological tool to investigate the mechanisms of METH-induced cognitive impairments.

  11. Structure-Guided Directed Evolution of Highly Selective P450-based Magnetic Resonance Imaging Sensors for Dopamine and Serotonin

    PubMed Central

    Brustad, Eric M.; Lelyveld, Victor S.; Snow, Christopher D.; Crook, Nathan; Jung, Sang Taek; Martinez, Francisco M.; Scholl, Timothy J.; Jasanoff, Alan; Arnold, Frances H.

    2012-01-01

    New tools that allow dynamic visualization of molecular neural events are important for studying the basis of brain activity and disease. Sensors that permit ligand-sensitive magnetic resonance imaging (MRI) are useful reagents due to the non-invasive nature and good temporal and spatial resolution of MR methods. Paramagnetic metalloproteins can be effective MRI sensors due to the selectivity imparted by the protein active site and the ability to tune protein properties using techniques such as directed evolution. Here we show that structure-guided directed evolution of the active site of the cytochrome P450 BM3 heme domain (BM3h) produces highly selective MRI probes with sub-micromolar affinities for small molecules. We report a new, high affinity dopamine sensor as well as the first MRI reporter for serotonin, with which we demonstrate quantification of neurotransmitter release in vitro. We also present a detailed structural analysis of evolved BM3h lineages to systematically dissect the molecular basis of neurotransmitter binding affinity, selectivity, and enhanced MRI contrast activity in these engineered proteins. PMID:22659321

  12. Graft-induced dyskinesias in Parkinson's disease: High striatal serotonin/dopamine transporter ratio.

    PubMed

    Politis, Marios; Oertel, Wolfgang H; Wu, Kit; Quinn, Niall P; Pogarell, Oliver; Brooks, David J; Bjorklund, Anders; Lindvall, Olle; Piccini, Paola

    2011-09-01

    Graft-induced dyskinesias are a serious complication after neural transplantation in Parkinson's disease. One patient with Parkinson's disease, treated with fetal grafts 14 years ago and deep brain stimulation 6 years ago, showed marked improvement of motor symptoms but continued to suffer from OFF-medication graft-induced dyskinesias. The patient received a series of clinical and imaging assessments. Positron emission tomography and single-photon emission computed tomography 14 years posttransplantation revealed an elevated serotonin/dopamine transporter ratio in the grafted striatum compatible with serotonergic hyperinnervation. Inhibition of serotonin neuron activity by systemic administration of a 5-HT(1A) agonist suppressed graft-induced dyskinesias. Our data provide further evidence that serotonergic neurons mediate graft-induced dyskinesias in Parkinson's disease. Achieving a normal striatal serotonin/dopamine transporter ratio following transplantation of fetal tissue or stem cells should be necessary to avoid the development of graft-induced dyskinesias.

  13. The roles of dopamine and serotonin in decision making: evidence from pharmacological experiments in humans.

    PubMed

    Rogers, Robert D

    2011-01-01

    Neurophysiological experiments in primates, alongside neuropsychological and functional magnetic resonance investigations in humans, have significantly enhanced our understanding of the neural architecture of decision making. In this review, I consider the more limited database of experiments that have investigated how dopamine and serotonin activity influences the choices of human adults. These include those experiments that have involved the administration of drugs to healthy controls, experiments that have tested genotypic influences upon dopamine and serotonin function, and, finally, some of those experiments that have examined the effects of drugs on the decision making of clinical samples. Pharmacological experiments in humans are few in number and face considerable methodological challenges in terms of drug specificity, uncertainties about pre- vs post-synaptic modes of action, and interactions with baseline cognitive performance. However, the available data are broadly consistent with current computational models of dopamine function in decision making and highlight the dissociable roles of dopamine receptor systems in the learning about outcomes that underpins value-based decision making. Moreover, genotypic influences on (interacting) prefrontal and striatal dopamine activity are associated with changes in choice behavior that might be relevant to understanding exploratory behaviors and vulnerability to addictive disorders. Manipulations of serotonin in laboratory tests of decision making in human participants have provided less consistent results, but the information gathered to date indicates a role for serotonin in learning about bad decision outcomes, non-normative aspects of risk-seeking behavior, and social choices involving affiliation and notions of fairness. Finally, I suggest that the role played by serotonin in the regulation of cognitive biases, and representation of context in learning, point toward a role in the cortically mediated cognitive

  14. Activation, internalization, and recycling of the serotonin 2A receptor by dopamine

    PubMed Central

    Bhattacharyya, Samarjit; Raote, Ishier; Bhattacharya, Aditi; Miledi, Ricardo; Panicker, Mitradas M.

    2006-01-01

    Serotonergic and dopaminergic systems, and their functional interactions, have been implicated in the pathophysiology of various CNS disorders. Here, we use recombinant serotonin (5-HT) 2A (5-HT2A) receptors to further investigate direct interactions between dopamine and 5-HT receptors. Previous studies in Xenopus oocytes showed that dopamine, although not the cognate ligand for the 5-HT2A receptor, acts as a partial-efficacy agonist. At micromolar concentrations, dopamine also acts as a partial-efficacy agonist on 5-HT2A receptors in HEK293 cells. Like 5-HT, dopamine also induces receptor-internalization in these cells, although at significantly higher concentrations than 5-HT. Interestingly, if the receptors are first sensitized or “primed” by subthreshold concentrations of 5-HT, then dopamine-induced internalization occurs at concentrations ≈10-fold lower than when dopamine is used alone. Furthermore, unlike 5-HT-mediated internalization, dopamine-mediated receptor internalization, alone, or after sensitization by 5-HT, does not depend on PKC. Dopamine-internalized receptors recycle to the surface at rates similar to those of 5-HT-internalized receptors. Our results suggest a previously uncharacterized role for dopamine in the direct activation and internalization of 5-HT2A receptors that may have clinical relevance to the function of serotonergic systems in anxiety, depression, and schizophrenia and also to the treatment of these disorders. PMID:17005723

  15. Gustatory plasticity in C. elegans involves integration of negative cues and NaCl taste mediated by serotonin, dopamine, and glutamate.

    PubMed

    Hukema, Renate K; Rademakers, Suzanne; Jansen, Gert

    2008-11-01

    While naïve Caenorhabditis elegans individuals are attracted to 0.1-200 mM NaCl, they become strongly repelled by these NaCl concentrations after prolonged exposure to 100 mM NaCl. We call this behavior gustatory plasticity. Here, we show that C. elegans displays avoidance of low NaCl concentrations only when pre-exposure to NaCl is combined with a negative stimulus, e.g., a repellent, or in the absence of food. By testing serotonin and/or dopamine signaling mutants and rescue by exogenously supplying these neurotransmitters, we found that serotonin and dopamine play a role during the plasticity response, while serotonin is also required during development. In addition, we also show that glutamate plays an important role in the response to NaCl, both in chemoattraction to NaCl and in gustatory plasticity. Thus, C. elegans can associate NaCl with negative stimuli using dopaminergic, serotonergic, and glutamatergic neurotransmission. Finally, we show that prolonged starvation enhances gustatory plasticity and can induce avoidance of NaCl in most gustatory plasticity mutants tested. Only mutation of the glutamate-gated Cl(-) channel gene avr-15 affected starvation-enhanced gustatory plasticity. These results suggest that starvation induces avoidance of NaCl largely independent of the normal gustatory plasticity mechanism.

  16. Ca2+ channel blockade prevents lysergic acid diethylamide-induced changes in dopamine and serotonin metabolism.

    PubMed

    Antkiewicz-Michaluk, L; Románska, I; Vetulani, J

    1997-07-30

    To investigate the effect of a single and multiple administration of lysergic acid diethylamide (LSD) on cerebral metabolism of dopamine and serotonin, male Wistar rats were treated with low and high doses (0.1 and 2.0 mg/kg i.p.) of LSD and the levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 3-methoxytyramine, serotonin and 5-hydroxyindoleacetic acid were assayed by HPLC in the nucleus accumbens, striatum and frontal cortex. Some rats received nifedipine, 5 mg/kg i.p., before each injection of LSD to assess the effect of a Ca2+ channel blockade. High-dose LSD treatment (8 x 2 mg/kg per day) caused a strong stimulation of dopamine metabolism in the nucleus accumbens and striatum, and serotonin metabolism in the nucleus accumbens: the changes were observed 24 (but not 1 h) after the last dose. The changes induced by the low-dose treatment (8 x 0.1 mg/kg per day) had a different pattern, suggesting the release of dopamine from vesicles to cytoplasm. Co-administration of nifedipine completely prevented the LSD-induced biochemical changes. The results suggest that Ca2+ channel blocking agents may prevent development of some behavioral consequences of chronically used LSD.

  17. Dopamine and γ-aminobutyric acid are colocalized in restricted groups of neurons in the sea lamprey brain: insights into the early evolution of neurotransmitter colocalization in vertebrates

    PubMed Central

    Barreiro-Iglesias, Antón; Villar-Cerviño, Verona; Anadón, Ramón; Rodicio, María Celina

    2009-01-01

    Since its discovery, the possible corelease of classic neurotransmitters from neurons has received much attention. Colocalization of monoamines and amino acidergic neurotransmitters [mainly glutamate and dopamine (DA) or serotonin] in mammalian neurons has been reported. However, few studies have dealt with the colocalization of DA and γ-aminobutyric acid (GABA) in neurons. With the aim of providing some insight into the colocalization of neurotransmitters during early vertebrate phylogeny, we studied GABA expression in dopaminergic neurons in the sea lamprey brain by using double-immunofluorescence methods with anti-DA and anti-GABA antibodies. Different degrees of colocalization of DA and GABA were observed in different dopaminergic brain nuclei. A high degree of colocalization (GABA in at least 25% of DA-immunoreactive neurons) was observed in populations of the caudal rhombencephalon, ventral isthmus, postoptic commissure nucleus, preoptic nucleus and in granule-like cells of the olfactory bulb. A new DA-immunoreactive striatal population that showed colocalization with GABA in about a quarter of its neurons was observed. In the periventricular hypothalamus, colocalization was observed in only a few cells, despite the abundance of DA- and GABA-immunoreactive neurons, and no double-labelled cells were observed in the paratubercular nucleus. The frequent colocalization of DA and GABA reveals that the dopaminergic populations of lampreys are more complex than previously reported. Double-labelled fibres or terminals were observed in different brain regions, suggesting possible corelease of DA and GABA by these lamprey neurons. The present results suggest that colocalization of DA and GABA in neurons appeared early in vertebrate evolution. PMID:19840024

  18. Alterations in dopamine and serotonin uptake systems in the striatum of the weaver mutant mouse.

    PubMed

    Stotz, E H; Palacios, J M; Landwehrmeyer, B; Norton, J; Ghetti, B; Simon, J R; Triarhou, L C

    1994-01-01

    In the striatum of the homozygous weaver mutant mouse (wv/wv), dopamine content, uptake and tyrosine hydroxylase activity are decreased compared to wild-type (+/+) mice. In mice heterozygous for the weaver gene (wv/+), these dopaminergic parameters exhibit only minor reductions compared to +/+ mice. The wv/wv striatum has recently been shown to have an increase in serotonin content. In the present study, the serotonin uptake system of the weaver striatum was investigated. Synaptosomal uptake of [3H] serotonin was determined in the dorsal portion of wv/wv and +/+ striatum, and serotonin uptake sites were examined by the binding of [3H] citalopram in the striatum of wv/wv, wv/+ and +/+ mice. The dopamine uptake system was also investigated in all three genotypes via the binding of [3H] mazindol. Synaptosomal uptake of [3H] serotonin was increased by 79% in the dorsal portion of the wv/wv striatum compared to that seen in the +/+ striatum. The binding of [3H] citalopram was increased by 62% in the dorsolateral and by 111% in the dorsomedial portions of the wv/wv striatum compared to +/+. [3H] Citalopram binding in the wv/+ striatum was also higher than +/+, but this increase did not reach statistical significance. Within the wv/wv striatum, [3H] mazindol binding was almost completely absent (88-89% reduction) in the dorsal portion and severely reduced in the other striatal areas. These data support the notion that the dorsal portion of the wv/wv striatum, which has the severest reduction in dopamine uptake, is hyperinnervated by serotonin fibers.

  19. 5×5 CMOS capacitive sensor array for detection of the neurotransmitter dopamine.

    PubMed

    Lu, Michael S-C; Chen, Yi-Chung; Huang, Po-Chiun

    2010-11-15

    This work presents miniaturized CMOS (complementary metal oxide semiconductor) capacitive sensors for detection of the neurotransmitter dopamine (DA) down to the sub-fM range. Sensing resolution is significantly enhanced by monolithic sensor integration to reduce the parasitic effect and the use of sub-μm interdigitated microelectrodes as the sensing interface. The 5 × 5 sensor array contains five designs of different electrode sizes and each design has five sensors. The positive charges produced from protonation of boronate and amino group after immobilization of 4-carboxyphenylboronic acid (CPBA) result in an increase of the electrode-analyte capacitance. Then the negative charges produced after binding of CPBA and DA molecules decrease the electrode-analyte capacitance. Signal transduction is achieved through a CMOS readout circuit whose output frequency is inversely proportional to the capacitance. Experimental results showed the ratios of average percentage capacitance changes of the experiment groups over those of the control groups were all larger than one for the five designs at DA concentration of 0.1 fM. Selectivity against the non-analyte species, such as tyramine, has also been demonstrated.

  20. Enhanced serotonin and mesolimbic dopamine transmissions in a rat model of neuropathic pain.

    PubMed

    Sagheddu, Claudia; Aroni, Sonia; De Felice, Marta; Lecca, Salvatore; Luchicchi, Antonio; Melis, Miriam; Muntoni, Anna Lisa; Romano, Rosaria; Palazzo, Enza; Guida, Francesca; Maione, Sabatino; Pistis, Marco

    2015-10-01

    In humans, affective consequences of neuropathic pain, ranging from depression to anxiety and anhedonia, severely impair quality of life and are a major disease burden, often requiring specific medications. Depressive- and anxiety-like behaviors have also been observed in animal models of peripheral nerve injury. Dysfunctions in central nervous system monoamine transmission have been hypothesized to underlie depressive and anxiety disorders in neuropathic pain. To assess whether these neurons display early changes in their activity that in the long-term might lead to chronicization, maladaptive plasticity and affective consequences, we carried out in vivo extracellular single unit recordings from serotonin neurons in the dorsal raphe nucleus (DRN) and from dopamine neurons in ventral tegmental area (VTA) in the spared nerve injury (SNI) model of neuropathic pain in rats. Extracellular dopamine levels and the expression of dopamine D1, D2 receptors and tyrosine hydroxylase (TH) were measured in the nucleus accumbens. We report that, two weeks following peripheral nerve injury, discharge rate of serotonin DRN neurons and burst firing of VTA dopamine cells are enhanced, when compared with sham-operated animals. We also observed higher extracellular dopamine levels and reduced expression of D2, but not D1, receptors and TH in the nucleus accumbens. Our study confirms that peripheral neuropathy induces changes in the serotonin and dopamine systems that might be the early result of chronic maladaptation to persistent pain. The allostatic activation of these neural systems, which mirrors that already described as a consequence of stress, might lead to depression and anxiety previously observed in neuropathic animals but also an attempt to cope positively with the negative experience.

  1. Serotonin and Dopamine Transporter Binding in Children with Autism Determined by SPECT

    ERIC Educational Resources Information Center

    Makkonen, Ismo; Riikonen, Raili; Kokki, Hannu; Airaksinen, Mauno M.; Kuikka, Jyrki T.

    2008-01-01

    Disturbances in the serotonergic system have been recognized in autism. To investigate the association between serotonin and dopamine transporters and autism, we studied 15 children (14 males, one female; mean age 8y 8mo [SD 3y 10mo]) with autism and 10 non-autistic comparison children (five males, five females; mean age 9y 10mo [SD 2y 8mo]) using…

  2. [Preliminary research on multi-neurotransmitters' change regulation in 120 depression patients' brains].

    PubMed

    Chi, Ming; Qing, Xue-Mei; Pan, Yan-Shu; Xu, Feng-Quan; Liu, Chao; Zhang, Cheng; Xu, Zhen-Hua

    2014-04-01

    In view of the effective traditional Chinese medicine (TCM) in the treatment of clinical depression, the mechanism is not clear, this study attempts to research the cause of depression in a complex situation to lay the foundation for the next step of TCM curative effect evaluation. Based on the brain wave of 120 depression patients and 40 ordinary person, the change regulation of acetylcholine, dopamine, norepinephrine, depression neurotransmitters and excited neurotransmitters in the whole and various encephalic regions' multi-neurotransmitters of depression patients-serotonin are analysed by search of encephalo-telex (SET) system, which lays the foundation for the diagnosis of depression. The result showed that: contrased with the normal person group, the mean value of the six neurotransmitters in depression patients group are: (1) in the whole encephalic region of depression patients group the dopamine fall (P < 0.05), and in the double centralregions, right temporal region and right parietal region distinct fall (P < 0.01); (2) in the right temporal region of depression patients group the serotonin rise (P < 0.05); (3) in the right central region, left parietal region of depression patients group the acetylcholine fall (P < 0.05), left rear temporal region fall obviously (P < 0.01). The correlation research between antagonizing pairs of neurotransmitters and neurotransmitters: (1) the three antagonizing pairs of neurotransmitters-serotonin and dopamine, acetylcholine and norepinephrine, depression neurotransmitters and excited neurotransmitters, in ordinary person group and depression patients group are characterizeed by middle or strong negative correlation. Serotonin and dopamine, which are characterized by weak negative correlation in the right rear temporal region of ordinary person group, are characterized by strong negative correlation in the other encephalic regions and the whole encephalic (ordinary person group except the right rear temporal region

  3. Blocking serotonin but not dopamine reuptake alters neural processing during perceptual decision making

    PubMed Central

    Costa, Vincent D.; Kakalios, Laura; Averbeck, Bruno B.

    2016-01-01

    Dopamine and serotonin have opponent interactions on aspects of impulsivity. Therefore we wanted to test the hypothesis that dopamine and serotonin would have opposing effects on speed-accuracy trade-offs in a perceptual decision making task. Unlike other behavioral measures of impulsivity, perceptual decision making allows us to determine whether decreasing premature responses, often interpreted as decreased impulsivity, corresponds to increased behavioral performance. We administered GBR-12909 (a dopamine transporter blocker), escitalopram (a serotonin transporter blocker) or saline in separate sessions to three rhesus macaques. We found that animals had slower reaction times on escitalopram than on GBR-12909 or saline. However, they were also least accurate on escitalopram. Animals were faster, although non-significantly, on GBR than saline and had equivalent accuracy. Administration of GBR-12909 did cause animals to be faster in error trials than correct trials. Therefore, from the point of view of reaction times the animals were less impulsive on escitalopram. However, the decreased accuracy shows that they were not able to make use of the slower response time to make more accurate decisions. Therefore, impulsivity was reduced on escitalopram, but at the expense of information processing rate in the perceptual inference task. PMID:27513807

  4. Effect of dopamine and serotonin receptor antagonists on fencamfamine-induced abolition of latent inhibition.

    PubMed

    de Aguiar, Cilene Rejane Ramos Alves; de Aguiar, Marlison José Lima; DeLucia, Roberto; Silva, Maria Teresa Araujo

    2013-01-05

    The purpose of this investigation was to verify the role of dopamine and serotonin receptors in the effect of fencamfamine (FCF) on latent inhibition. FCF is a psychomotor stimulant with an indirect dopaminergic action. Latent inhibition is a model of attention. Latent inhibition is blocked by dopaminergic agents and facilitated by dopamine receptor agonists. FCF has been shown to abolish latent inhibition. The serotonergic system may also participate in the neurochemical mediation of latent inhibition. The selective dopamine D(1) receptor antagonist SCH 23390 (7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol), D(2) receptor antagonists pimozide (PIM) and methoclopramide (METH), and serotonin 5-HT(2A/C) receptor antagonist ritanserin (RIT) were used in the present study. Latent inhibition was evaluated using a conditioned emotional response procedure. Male Wistar rats that were water-restricted were subjected to a three-phase procedure: preexposure to a tone, tone-shock conditioning, and a test of the effect of the tone on licking frequency. All of the drugs were administered before the preexposure and conditioning phases. The results showed that FCF abolished latent inhibition, and this effect was clearly antagonized by PIM and METH and moderately attenuated by SCH 23390. At the doses used in the present study, RIT pretreatment did not affect latent inhibition and did not eliminate the effect of FCF, suggesting that the FCF-induced abolition of latent inhibition is not mediated by serotonin 5-HT(2A/C) receptors. These results suggest that the effect of FCF on latent inhibition is predominantly related to dopamine D(2) receptors and that dopamine D(2) receptors participate in attention processes.

  5. Impact of dopamine versus serotonin cell transplantation for the development of graft-induced dyskinesia in a rat Parkinson model.

    PubMed

    García, Joanna; Carlsson, Thomas; Döbrössy, Máté; Nikkhah, Guido; Winkler, Christian

    2012-08-27

    Graft-induced dyskinesia (GID), covering a range of dystonic and choreiform involuntary movements, has been observed in some patients with Parkinson's disease (PD) after intracerebral cell transplantation. These dyskinesias have been severe in a number of patients and represent one of the main obstacles for further development of the cell therapy in PD. Serotonin neurons, included into the dopaminergic cell suspension due to the nature of the dissection process, have been suggested as a key factor for the development of GID, since the administration of the serotonin (5-HT)(1A)-receptor agonist buspirone reduced dyskinesia in transplanted PD patients. In the present study, we characterized GID in the rat PD model after transplantation of dopaminergic grafts containing different amounts of serotonin neurons. The severity of GID was significantly correlated with the amount of grafted dopamine and serotonin neurons, but the r-values were low. However, neither the innervation density of dopamine and serotonin fibers in the grafted striatum nor the dopamine-to-serotonin cell ratio correlated significantly with the severity of GID. The results extend prior knowledge of the role of dopaminergic grafts in the development of GID and show that, in the animal model, serotonin neurons within the graft suspension might be involved, but given sufficient dopamine cells, their impact on GID may be minor.

  6. Analysis of microdialysate monoamines, including noradrenaline, dopamine and serotonin, using capillary ultra-high performance liquid chromatography and electrochemical detection.

    PubMed

    Ferry, Barbara; Gifu, Elena-Patricia; Sandu, Ioana; Denoroy, Luc; Parrot, Sandrine

    2014-03-01

    Electrochemical methods are very often used to detect catecholamine and indolamine neurotransmitters separated by conventional reverse-phase high performance liquid chromatography (HPLC). The present paper presents the development of a chromatographic method to detect monoamines present in low-volume brain dialysis samples using a capillary column filled with sub-2μm particles. Several parameters (repeatability, linearity, accuracy, limit of detection) for this new ultrahigh performance liquid chromatography (UHPLC) method with electrochemical detection were examined after optimization of the analytical conditions. Noradrenaline, adrenaline, serotonin, dopamine and its metabolite 3-methoxytyramine were separated in 1μL of injected sample volume; they were detected above concentrations of 0.5-1nmol/L, with 2.1-9.5% accuracy and intra-assay repeatability equal to or less than 6%. The final method was applied to very low volume dialysates from rat brain containing monoamine traces. The study demonstrates that capillary UHPLC with electrochemical detection is suitable for monitoring dialysate monoamines collected at high sampling rate.

  7. Wireless Instantaneous Neurotransmitter Concentration System–based amperometric detection of dopamine, adenosine, and glutamate for intraoperative neurochemical monitoring

    PubMed Central

    Agnesi, Filippo; Tye, Susannah J.; Bledsoe, Jonathan M.; Griessenauer, Christoph J.; Kimble, Christopher J.; Sieck, Gary C.; Bennet, Kevin E.; Garris, Paul A.; Blaha, Charles D.; Lee, Kendall H.

    2009-01-01

    Object In a companion study, the authors describe the development of a new instrument named the Wireless Instantaneous Neurotransmitter Concentration System (WINCS), which couples digital telemetry with fast-scan cyclic voltammetry (FSCV) to measure extracellular concentrations of dopamine. In the present study, the authors describe the extended capability of the WINCS to use fixed potential amperometry (FPA) to measure extracellular concentrations of dopamine, as well as glutamate and adenosine. Compared with other electrochemical techniques such as FSCV or high-speed chronoamperometry, FPA offers superior temporal resolution and, in combination with enzyme-linked biosensors, the potential to monitor nonelectroactive analytes in real time. Methods The WINCS design incorporated a transimpedance amplifier with associated analog circuitry for FPA; a microprocessor; a Bluetooth transceiver; and a single, battery-powered, multilayer, printed circuit board. The WINCS was tested with 3 distinct recording electrodes: 1) a carbon-fiber microelectrode (CFM) to measure dopamine; 2) a glutamate oxidase enzyme-linked electrode to measure glutamate; and 3) a multiple enzyme-linked electrode (adenosine deaminase, nucleoside phosphorylase, and xanthine oxidase) to measure adenosine. Proof-of-principle analyses included noise assessments and in vitro and in vivo measurements that were compared with similar analyses by using a commercial hardwired electrochemical system (EA161 Picostat, eDAQ; Pty Ltd). In urethane-anesthetized rats, dopamine release was monitored in the striatum following deep brain stimulation (DBS) of ascending dopaminergic fibers in the medial forebrain bundle (MFB). In separate rat experiments, DBS-evoked adenosine release was monitored in the ventrolateral thalamus. To test the WINCS in an operating room setting resembling human neurosurgery, cortical glutamate release in response to motor cortex stimulation (MCS) was monitored using a large-mammal animal

  8. Computational modeling of extracellular dopamine kinetics suggests low probability of neurotransmitter release.

    PubMed

    Rooney, Katherine E; Wallace, Lane J

    2015-11-01

    Dopamine in the striatum signals the saliency of current environmental input and is involved in learned formation of appropriate responses. The regular baseline-firing rate of dopaminergic neurons suggests that baseline dopamine is essential for proper brain function. The first goal of the study was to estimate the likelihood of full exocytotic dopamine release associated with each firing event under baseline conditions. A computer model of extracellular space associated with a single varicosity was developed using the program MCell to estimate kinetics of extracellular dopamine. Because the literature provides multiple kinetic values for dopamine uptake depending on the system tested, simulations were run using different kinetic parameters. With all sets of kinetic parameters evaluated, at most, 25% of a single vesicle per varicosity would need to be released per firing event to maintain a 5-10 nM extracellular dopamine concentration, the level reported by multiple microdialysis experiments. The second goal was to estimate the fraction of total amount of stored dopamine released during a highly stimulated condition. This was done using the same model system to simulate published measurements of extracellular dopamine following electrical stimulation of striatal slices in vitro. The results suggest the amount of dopamine release induced by a single electrical stimulation may be as large as the contents of two vesicles per varicosity. We conclude that dopamine release probability at any particular varicosity is low. This suggests that factors capable of increasing release probability could have a powerful effect on sculpting dopamine signals.

  9. Structural and vibrational investigations of a neurotransmitter molecule: Serotonin (5-hydroxy tryptamine)

    NASA Astrophysics Data System (ADS)

    Jha, Omkant; Yadav, R. A.

    2016-11-01

    Structural and vibrational studies have been carried out for the most stable conformer of serotonin (5-HT) at the DFT/B3LYP/6-311++G** level using the Gaussian 09 software. In light of the computed vibrational parameters the observed IR and Raman frequencies have been analyzed. To help assign the vibrational fundamentals the GAR2PED software has been used to compute PEDs. Several of the fundamentals are drastically changed in going from indole to serotonin. The two NH bonds of the NH2 group are slightly different possibly due to bonding of the two H atoms of the NH2 group with different atoms. The rocking and wagging modes of the NH2 groups show mixing with the other modes while the remaining four modes are pure group modes. The Kekule phenyl ring stretching mode is found to remain almost unchanged. The HOMO-LUMO energy gap supports to pharmacological active property of the serotonin molecule. The HOMO and LUMO study suggests the existence of charge transfer within the molecule. The NBO analysis has been carried out to gather information regarding the proper and improper hydrogen bonds.

  10. In vivo assessment of dopamine D-2 and serotonin S-2 receptors measured by C-11 N-methylspiperone (NMSP) in manic-depressive illness

    SciTech Connect

    Wong, D.F.; Pearlson, G.; Wagner, H.N. Jr.; Dannals, R.F.; Suneja, S.; Bjorgvinsson, E.; Links, J.M.; Ravert, H.T.; Wilson, A.A.; Schaerf, F.

    1985-05-01

    The hypothesis has been suggested that either the dopaminergic or serotonergic neurotransmitter systems may be involved in manic-depressive illness (MD). The authors have studied 16 subjects with C-11 NMSP PET imaging. Two had never received neuroleptics; 4 were drug free for 1 month at the time of scanning; of these 3 were acutely manic; the rest were on stable lithium treatment. The dopamine and serotonin binding was estimated by the 43 min. caudate/cerebellum (Ca/Cb) and frontal/cerebellum (FC/Cb) ratios, respectively. No statistically significant difference was detected when compared to 44 age and sex matched controls. Based upon the variance in the normal data and the average age of the patient group studied, the probability of detecting a difference of >30% between patients and normals is >0.8. Hence, identification of receptor abnormalities if present will be improved with increased sample size of both normals and patients.

  11. Role of melatonin, serotonin 2B, and serotonin 2C receptors in modulating the firing activity of rat dopamine neurons.

    PubMed

    Chenu, Franck; Shim, Stacey; El Mansari, Mostafa; Blier, Pierre

    2014-02-01

    Melatonin has been widely used for the management of insomnia, but is devoid of antidepressant effect in the clinic. In contrast, agomelatine which is a potent melatonin receptor agonist is an effective antidepressant. It is, however, a potent serotonin 2B (5-HT(2B)) and serotonin 2C (5-HT(2C)) receptor antagonist as well. The present study was aimed at investigating the in vivo effects of repeated administration of melatonin (40 mg/kg/day), the 5-HT(2C) receptor antagonist SB 242084 (0.5 mg/kg/day), the selective 5-HT(2B) receptor antagonist LY 266097 (0.6 mg/kg/day) and their combination on ventral tegmental area (VTA) dopamine (DA), locus coeruleus (LC) norepinephrine (NE), and dorsal raphe nucleus (DRN) serotonin (5-HT) firing activity. Administration of melatonin twice daily increased the number of spontaneously active DA neurons but left the firing of NE neurons unaltered. Long-term administration of melatonin and SB 242084, by themselves, had no effect on the firing rate and burst parameters of 5-HT and DA neurons. Their combination, however, enhanced only the number of spontaneously active DA neurons, while leaving the firing of 5-HT neurons unchanged. The addition of LY 266097, which by itself is devoid of effect, to the previous regimen increased for DA neurons the number of bursts per minute and the percentage of spikes occurring in bursts. In conclusion, the combination of melatonin receptor activation as well as 5-HT(2C) receptor blockade resulted in a disinhibition of DA neurons. When 5-HT(2B) receptors were also blocked, the firing and the bursting activity of DA neurons were both enhanced, thus reproducing the effect of agomelatine.

  12. The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters.

    PubMed

    Bulling, Simon; Schicker, Klaus; Zhang, Yuan-Wei; Steinkellner, Thomas; Stockner, Thomas; Gruber, Christian W; Boehm, Stefan; Freissmuth, Michael; Rudnick, Gary; Sitte, Harald H; Sandtner, Walter

    2012-05-25

    Ibogaine, a hallucinogenic alkaloid proposed as a treatment for opiate withdrawal, has been shown to inhibit serotonin transporter (SERT) noncompetitively, in contrast to all other known inhibitors, which are competitive with substrate. Ibogaine binding to SERT increases accessibility in the permeation pathway connecting the substrate-binding site with the cytoplasm. Because of the structural similarity between ibogaine and serotonin, it had been suggested that ibogaine binds to the substrate site of SERT. The results presented here show that ibogaine binds to a distinct site, accessible from the cell exterior, to inhibit both serotonin transport and serotonin-induced ionic currents. Ibogaine noncompetitively inhibited transport by both SERT and the homologous dopamine transporter (DAT). Ibogaine blocked substrate-induced currents also in DAT and increased accessibility of the DAT cytoplasmic permeation pathway. When present on the cell exterior, ibogaine inhibited SERT substrate-induced currents, but not when it was introduced into the cytoplasm through the patch electrode. Similar to noncompetitive transport inhibition, the current block was not reversed by increasing substrate concentration. The kinetics of inhibitor binding and dissociation, as determined by their effect on SERT currents, indicated that ibogaine does not inhibit by forming a long-lived complex with SERT, but rather binds directly to the transporter in an inward-open conformation. A kinetic model for transport describing the noncompetitive action of ibogaine and the competitive action of cocaine accounts well for the results of the present study.

  13. The Mechanistic Basis for Noncompetitive Ibogaine Inhibition of Serotonin and Dopamine Transporters*

    PubMed Central

    Bulling, Simon; Schicker, Klaus; Zhang, Yuan-Wei; Steinkellner, Thomas; Stockner, Thomas; Gruber, Christian W.; Boehm, Stefan; Freissmuth, Michael; Rudnick, Gary; Sitte, Harald H.; Sandtner, Walter

    2012-01-01

    Ibogaine, a hallucinogenic alkaloid proposed as a treatment for opiate withdrawal, has been shown to inhibit serotonin transporter (SERT) noncompetitively, in contrast to all other known inhibitors, which are competitive with substrate. Ibogaine binding to SERT increases accessibility in the permeation pathway connecting the substrate-binding site with the cytoplasm. Because of the structural similarity between ibogaine and serotonin, it had been suggested that ibogaine binds to the substrate site of SERT. The results presented here show that ibogaine binds to a distinct site, accessible from the cell exterior, to inhibit both serotonin transport and serotonin-induced ionic currents. Ibogaine noncompetitively inhibited transport by both SERT and the homologous dopamine transporter (DAT). Ibogaine blocked substrate-induced currents also in DAT and increased accessibility of the DAT cytoplasmic permeation pathway. When present on the cell exterior, ibogaine inhibited SERT substrate-induced currents, but not when it was introduced into the cytoplasm through the patch electrode. Similar to noncompetitive transport inhibition, the current block was not reversed by increasing substrate concentration. The kinetics of inhibitor binding and dissociation, as determined by their effect on SERT currents, indicated that ibogaine does not inhibit by forming a long-lived complex with SERT, but rather binds directly to the transporter in an inward-open conformation. A kinetic model for transport describing the noncompetitive action of ibogaine and the competitive action of cocaine accounts well for the results of the present study. PMID:22451652

  14. In vivo binding of /sup 3/H-N-methylspiperone to dopamine and serotonin receptors

    SciTech Connect

    Frost, J.J.; Smith, A.C.; Kuhar, M.J.; Dannals, R.F.; Wagner, H.N. Jr.

    1987-03-09

    /sup 3/H-N-methylspiperone (/sup 3/H-NMSP) was used to label dopamine-2 and serotonin-2 in vivo in the mouse. The striatum/cerebellum binding ratio reached a maximum of 80 eight hours after intravenous administration of /sup 3/H-NMSP. The frontal cortex/cerebellum ratio was 5 one hour after injection. The binding of /sup 3/H-NMSP was saturable in the frontal cortex and cerebellum between doses of 10 and 1000 ..mu..g/kg. Between 0.01 and 10 ..mu..g/kg the ratio total/nonspecific binding increased from 14 to 21. Inhibition of /sup 3/H-NMSP binding in the frontal cortex and striatum by ketanserin, a selective serotonin-2 antagonist, demonstrated that 20% of the total binding in the striatum was to serotonin-2 rectors and 91% of the total binding in the frontal cortex was to serotonin-2 receptors. Compared to /sup 3/H-spiperone, /sup 3/H-NMSP 1) results in a much higher specific/nonspecific binding ratio in the striatum and frontal cortex and 2) displays more than a two-fold higher brain uptake. 18 references, 4 figures.

  15. Mimicking maternal smoking and pharmacotherapy of preterm labor: interactions of fetal nicotine and dexamethasone on serotonin and dopamine synaptic function in adolescence and adulthood.

    PubMed

    Slotkin, Theodore A; Seidler, Frederic J

    2010-04-29

    Fetal coexposure to nicotine and dexamethasone is common: maternal smoking increases the incidence of preterm delivery and glucocorticoids are the consensus treatment for prematurity. We gave pregnant rats 3mg/kg/day of nicotine throughout gestation, a regimen that reproduces smokers' plasma levels, and then on gestational days 17, 18 and 19, we administered 0.2mg/kg of dexamethasone. We evaluated developmental indices for serotonin (5HT) and dopamine synaptic function throughout adolescence, young adulthood and later adulthood, assessing the brain regions possessing major 5HT and dopamine projections and cell bodies. Males displayed persistent upregulation of 5HT(1A) and 5HT(2) receptors and the 5HT transporter, with a distinct hierarchy of effects: nicotinedopamine pathways as evidenced by increased neurotransmitter turnover. Superimposed on these overall effects, there were significant differences in temporal and regional relationships among the different treatments, often involving effects that emerged later in life, after a period of apparent normality. This indicates that nicotine and dexamethasone do not simply produce an initial neuronal injury that persists throughout the lifespan but rather, they alter the developmental trajectory of synaptic function. The fact that the combined treatment produced greater effects for many parameters points to potentially worse neurobehavioral outcomes after pharmacotherapy of preterm labor in the offspring of smokers.

  16. Dissociable Effects of Serotonin and Dopamine on the Valuation of Harm in Moral Decision Making

    PubMed Central

    Crockett, Molly J.; Siegel, Jenifer Z.; Kurth-Nelson, Zeb; Ousdal, Olga T.; Story, Giles; Frieband, Carolyn; Grosse-Rueskamp, Johanna M.; Dayan, Peter; Dolan, Raymond J.

    2015-01-01

    Summary An aversion to harming others is a core component of human morality and is disturbed in antisocial behavior [1–4]. Deficient harm aversion may underlie instrumental and reactive aggression, which both feature in psychopathy [5]. Past work has highlighted monoaminergic influences on aggression [6–11], but a mechanistic account of how monoamines regulate antisocial motives remains elusive. We previously observed that most people show a greater aversion to inflicting pain on others than themselves [12]. Here, we investigated whether this hyperaltruistic disposition is susceptible to monoaminergic control. We observed dissociable effects of the serotonin reuptake inhibitor citalopram and the dopamine precursor levodopa on decisions to inflict pain on oneself and others for financial gain. Computational models of choice behavior showed that citalopram increased harm aversion for both self and others, while levodopa reduced hyperaltruism. The effects of citalopram were stronger than those of levodopa. Crucially, neither drug influenced the physical perception of pain or other components of choice such as motor impulsivity or loss aversion [13, 14], suggesting a direct and specific influence of serotonin and dopamine on the valuation of harm. We also found evidence for dose dependency of these effects. Finally, the drugs had dissociable effects on response times, with citalopram enhancing behavioral inhibition and levodopa reducing slowing related to being responsible for another’s fate. These distinct roles of serotonin and dopamine in modulating moral behavior have implications for potential treatments of social dysfunction that is a common feature as well as a risk factor for many psychiatric disorders. PMID:26144968

  17. Novel synergistic treatment of ethanol withdrawal seizures in rats with dopamine and serotonin agonists.

    PubMed

    Mirovsky, Y; Yu, Y L; Wagner, G C; Sekowski, A; Goldberg, M; Fisher, H

    1995-02-01

    A recent observation in this laboratory of a simultaneous increase in striatal dopamine and a decrease in serotonin in ethanol-dependent rats during ethanol withdrawal prompted studies with combined dopaminergic + serotoninergic agonists to stop withdrawal seizures. Amphetamine (2 mg/kg) + fenfluramine (8 mg/kg) given jointly, but not separately, prevented ethanol withdrawal seizures as effectively as benzodiazepines (chlordiazepoxide), the current drugs of choice. The combination of amphetamine and fenfluramine, unlike chlordiazepoxide, significantly reduced intake of ethanol during and immediately following ethanol withdrawal.

  18. Recognition Properties and Competitive Assays of a Dual Dopamine/Serotonin Selective Molecularly Imprinted Polymer

    PubMed Central

    Suedee, Roongnapa; Seechamnanturakit, Vatcharee; Suksuwan, Acharee; Canyuk, Bhutorn

    2008-01-01

    A molecularly imprinted polymer (MIP) with dual dopamine/serotonin-like binding sites (DS-MIP) was synthesized for use as a receptor model of study the drug-interaction of biological mixed receptors at a molecular level. The polymer material was produced using methacrylic acid (MAA) and acrylamide (ACM) as functional monomers, N,N′-methylene bisacrylamide (MBAA) as cross-linker, methanol/water mixture (4:1, v/v) as porogen and a mixture of dopamine (D) and serotonin (S) as templates. The prepared DS-MIP exhibited the greatest rebinding of the template(s) in aqueous methanol solution with decreased recognition in acetonitrile, water and methanol solvent. The binding affinity and binding capacity of DS-MIP with S were found to be higher than those of DS-MIP with D. The selectivity profiles of DS-MIP suggest that the D binding site of DS-MIP has sufficient integrity to discriminate between species of non-optimal functional group orientation, whilst the S binding site of DS-MIP is less selective toward species having structural features and functional group orientations different from S. The ligand binding activities of a series of ergot derivatives (ergocryptine, ergocornine, ergocristine, ergonovine, agroclavine, pergolide and terguride) have been studied with the DS-MIP using a competitive ligand binding assay protocol. The binding affinities of DS-MIP were demonstrated in the micro- or submicro-molar range for a series of ergot derivatives, whereas the binding affinities were considerably greater to natural receptors derived from the rat hypothalamus. The DS-MIP afforded the same pattern of differentiation as the natural receptors, i.e. affinity for the clavines > lysergic acid derivatives > ergopeptines. The results suggest that the discrimination for the ergot derivatives by the dopamine and serotonin sites of DS-MIP is due to the structural features and functional orientation of the phenylethylamine and indolylethylamine entities at the binding sites, and the

  19. Inhibition of neuronal mitochondrial complex I or lysosomal glucocerebrosidase is associated with increased dopamine and serotonin turnover.

    PubMed

    de la Fuente, Carmen; Burke, Derek; Eaton, Simon; Heales, Simon J

    2017-02-24

    Parkinson's disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic and serotoninergic signalling. A number of pathogenic mechanisms have been implicated including loss of mitochondrial function at the level of complex I, and lysosomal metabolism at the level of lysosomal glucocerebrosidase (GBA1). In order to investigate further the potential involvement of complex I and GBA1 in PD, we assessed the impact of loss of respective enzyme activities upon dopamine and serotonin turnover. Using SH-SY5Y cells, complex I deficiency was modelled by using rotenone whilst GBA1 deficiency was modelled by the use of conduritol B epoxide (CBE). Dopamine, its principal metabolites, and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the extracellular medium were quantified by HPLC. Inhibition of complex I significantly increased extracellular concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-HIAA. Comparable results were observed with CBE. These results suggest increased monoamine oxidase activity and provide evidence for involvement of impaired complex I or GBA1 activity in the dopamine/serotonin deficiency seen in PD. Use of extracellular media may also permit relatively rapid assessment of dopamine/serotonin metabolism and permit screening of novel therapeutic agents.

  20. Dopamine and serotonin genetic risk scores predicting substance and nicotine use in attention deficit/hyperactivity disorder.

    PubMed

    Groenman, Annabeth P; Greven, Corina U; van Donkelaar, Marjolein M J; Schellekens, Arnt; van Hulzen, Kimm J E; Rommelse, Nanda; Hartman, Catharina A; Hoekstra, Pieter J; Luman, Marjolein; Franke, Barbara; Faraone, Stephen V; Oosterlaan, Jaap; Buitelaar, Jan K

    2016-07-01

    Individuals with attention deficit/hyperactivity disorder (ADHD) are at increased risk of developing substance use disorders (SUDs) and nicotine dependence. The co-occurrence of ADHD and SUDs/nicotine dependence may in part be mediated by shared genetic liability. Several neurobiological pathways have been implicated in both ADHD and SUDs, including dopamine and serotonin pathways. We hypothesized that variations in dopamine and serotonin neurotransmission genes were involved in the genetic liability to develop SUDs/nicotine dependence in ADHD. The current study included participants with ADHD (n = 280) who were originally part of the Dutch International Multicenter ADHD Genetics study. Participants were aged 5-15 years and attending outpatient clinics at enrollment in the study. Diagnoses of ADHD, SUDs, nicotine dependence, age of first nicotine and substance use, and alcohol use severity were based on semi-structured interviews and questionnaires. Genetic risk scores were created for both serotonergic and dopaminergic risk genes previously shown to be associated with ADHD and SUDs and/or nicotine dependence. The serotonin genetic risk score significantly predicted alcohol use severity. No significant serotonin × dopamine risk score or effect of stimulant medication was found. The current study adds to the literature by providing insight into genetic underpinnings of the co-morbidity of ADHD and SUDs. While the focus of the literature so far has been mostly on dopamine, our study suggests that serotonin may also play a role in the relationship between these disorders.

  1. The serotonin-dopamine interaction measured with positron emission tomography (PET) and C-11 raclopride in normal human subjects

    SciTech Connect

    Smith, G.S.; Dewey, S.L.; Logan, J.

    1994-05-01

    Our previous studies have shown that the interaction between serotonin and dopamine can be measured with C-11 raclopride and PET in the baboon brain. A series of studies was undertaken to extend dim findings to the normal human brain. PET studies were conducted in male control subjects (n=8) using the CTI 931 tomograph. Two C-11 raclopride scans were performed, prior to and 180 minutes following administration of the selective serotonin releasing agent, fenfluramine (60mg/PO). The neuroendocrine response to fenfluramine challenge is commonly used in psychiatric research as an index of serotonin activity. The C-11 raclopride data were analyzed with the distribution volume method. For the group of subjects, an increase was observed in the striatum to cerebellum ratio (specific to non-specific binding ratio), in excess of the test-retest variability of the ligand. Variability in response was observed across subjects. These results are consistent with our previous findings in the baboon that citalopram administration increased C-11 raclopride binding, consistent with a decrease in endogenous dopamine. In vivo microdialysis studies in freely moving rats confirmed that citalopram produces a time-dependent decrease in extracellular dopamine levels, consistent with the PET results. In vivo PET studies of the serotonin-dopamine interaction are relevant to the evaluation of etiologic and therapeutic mechanisms in schizophrenia and affective disorder.

  2. Dopamine and serotonin levels following prenatal viral infection in mouse--implications for psychiatric disorders such as schizophrenia and autism.

    PubMed

    Winter, Christine; Reutiman, Teri J; Folsom, Timothy D; Sohr, Reinhard; Wolf, Rainer J; Juckel, Georg; Fatemi, S Hossein

    2008-10-01

    Prenatal viral infection has been associated with neurodevelopmental disorders such as schizophrenia and autism. It has previously been demonstrated that viral infection causes deleterious effects on brain structure and function in mouse offspring following late first trimester (E9) and middle-late second trimester (E18) administration of influenza virus. Neurochemical analysis following infection on E18 using this model has revealed significantly altered levels of serotonin, 5-hydroxyindoleacetic acid, and taurine, but not dopamine. In order to monitor these different patterns of monoamine expression in exposed offspring in more detail and to see if there are changes in the dopamine system at another time point, pregnant C57BL6J mice were infected with a sublethal dose of human influenza virus or sham-infected using vehicle solution on E16. Male offspring of the infected mice were collected at P0, P14, and P56, their brains removed and cerebellum dissected and flash frozen. Dopamine and serotonin levels were then measured using HPLC-ED technique. When compared to controls, there was a significant decrease in serotonin levels in the cerebella of offspring of virally exposed mice at P14. No differences in levels of dopamine were observed in exposed and control mice, although there was a significant decrease in dopamine at P14 and P56 when compared to P0. The present study shows that the serotonergic system is disrupted following prenatal viral infection, potentially modelling disruptions that occur in patients with schizophrenia and autism.

  3. Evidence for Noncanonical Neurotransmitter Activation: Norepinephrine as a Dopamine D2-Like Receptor Agonist.

    PubMed

    Sánchez-Soto, Marta; Bonifazi, Alessandro; Cai, Ning Sheng; Ellenberger, Michael P; Newman, Amy Hauck; Ferré, Sergi; Yano, Hideaki

    2016-04-01

    The Gαi/o-coupled dopamine D2-like receptor family comprises three subtypes: the D2 receptor (D2R), with short and long isoform variants (D2SR and D2LR), D3 receptor (D3R), and D4 receptor (D4R), with several polymorphic variants. The common overlap of norepinephrine innervation and D2-like receptor expression patterns prompts the question of a possible noncanonical action by norepinephrine. In fact, previous studies have suggested that norepinephrine can functionally interact with D4R. To our knowledge, significant interactions between norepinephrine and D2R or D3R receptors have not been demonstrated. By using radioligand binding and bioluminescent resonance energy transfer (BRET) assays in transfected cells, the present study attempted a careful comparison between dopamine and norepinephrine in their possible activation of all D2-like receptors, including the two D2R isoforms and the most common D4R polymorphic variants. Functional BRET assays included activation of G proteins with all Gαi/o subunits, adenylyl cyclase inhibition, and β arrestin recruitment. Norepinephrine acted as a potent agonist for all D2-like receptor subtypes, with the general rank order of potency of D3R > D4R ≥ D2SR ≥ D2L. However, for both dopamine and norepinephrine, differences depended on the Gαi/o protein subunit involved. The most striking differences were observed with Gαi2, where the rank order of potencies for both dopamine and norepinephrine were D4R > D2SR = D2LR > D3R. Furthermore the results do not support the existence of differences in the ability of dopamine and norepinephrine to activate different human D4R variants. The potency of norepinephrine for adrenergic α2A receptor was only about 20-fold higher compared with D3R and D4R across the three functional assays.

  4. Evidence for Noncanonical Neurotransmitter Activation: Norepinephrine as a Dopamine D2-Like Receptor Agonist

    PubMed Central

    Sánchez-Soto, Marta; Bonifazi, Alessandro; Cai, Ning Sheng; Ellenberger, Michael P.; Newman, Amy Hauck

    2016-01-01

    The Gαi/o-coupled dopamine D2-like receptor family comprises three subtypes: the D2 receptor (D2R), with short and long isoform variants (D2SR and D2LR), D3 receptor (D3R), and D4 receptor (D4R), with several polymorphic variants. The common overlap of norepinephrine innervation and D2-like receptor expression patterns prompts the question of a possible noncanonical action by norepinephrine. In fact, previous studies have suggested that norepinephrine can functionally interact with D4R. To our knowledge, significant interactions between norepinephrine and D2R or D3R receptors have not been demonstrated. By using radioligand binding and bioluminescent resonance energy transfer (BRET) assays in transfected cells, the present study attempted a careful comparison between dopamine and norepinephrine in their possible activation of all D2-like receptors, including the two D2R isoforms and the most common D4R polymorphic variants. Functional BRET assays included activation of G proteins with all Gαi/o subunits, adenylyl cyclase inhibition, and β arrestin recruitment. Norepinephrine acted as a potent agonist for all D2-like receptor subtypes, with the general rank order of potency of D3R > D4R ≥ D2SR ≥ D2L. However, for both dopamine and norepinephrine, differences depended on the Gαi/o protein subunit involved. The most striking differences were observed with Gαi2, where the rank order of potencies for both dopamine and norepinephrine were D4R > D2SR = D2LR >> D3R. Furthermore the results do not support the existence of differences in the ability of dopamine and norepinephrine to activate different human D4R variants. The potency of norepinephrine for adrenergic α2A receptor was only about 20-fold higher compared with D3R and D4R across the three functional assays. PMID:26843180

  5. Studies on striatal neurotoxicity caused by the 3,4-methylenedioxymethamphetamine/ malonate combination: implications for serotonin/dopamine interactions.

    PubMed

    Goñi-Allo, Beatriz; Ramos, Mar'a; Herv'as, Isabel; Lasheras, Berta; Aguirre, Norberto

    2006-03-01

    The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) produces long-term toxicity to serotonin (5-HT) neurones in rats, which is exacerbated when combined with the mitochondrial inhibitor malonate. Moreover, MDMA, which does not produce dopamine depletion in the rat, potentiates malonate-induced striatal dopamine toxicity. Because the malonate/MDMA combination acutely causes a synergistic increase of 5-HT and dopamine release, in this study we sought to determine whether pharmacological blockade of MDMA- and/or malonate-induced dopamine release prevents neurotoxicity. Fluoxetine, given 30 min prior to the malonate/MDMA combination, afforded complete protection against 5-HT depletion and reversed MDMA-induced exacerbation of dopamine toxicity found in the malonate/MDMA treated rats. Protection afforded by fluoxetine was not related to changes in MDMA-induced hyperthermia. Similarly, potentiation of malonate-induced dopamine toxicity caused by MDMA was not observed in p-chlorophenylalanine-5-HT depleted rats. Finally, the dopamine transporter inhibitor GBR 12909 completely prevented dopamine neurotoxicity caused by the malonate/MDMA combination and reversed the exacerbating toxic effects of malonate on MDMA-induced 5-HT depletion without significantly altering the hyperthermic response. Overall, these results suggest that the synergic release of dopamine caused by the malonate/MDMA combination plays an important role in the long-term toxic effects. A possible mechanism of neurotoxicity and protection is proposed.

  6. A rapid and simple method for the determination of 3,4-dihydroxyphenylacetic acid, norepinephrine, dopamine, and serotonin in mouse brain homogenate by HPLC with fluorimetric detection.

    PubMed

    De Benedetto, Giuseppe Egidio; Fico, Daniela; Pennetta, Antonio; Malitesta, Cosimino; Nicolardi, Giuseppe; Lofrumento, Dario Domenico; De Nuccio, Francesco; La Pesa, Velia

    2014-09-01

    A fast and simple isocratic high-performance liquid chromatography method for the determination of 3,4-dihydroxyphenylacetic acid (DOPAC), norepinephrine (NE), dopamine (DA), and serotonin (5-HT) in homogenate samples of mouse striatum employing the direct fluorescence of the neurotransmitters is described. The method has been optimized and validated. The analytes were separated in 15min on a reversed-phase column (C18) with acetate buffer (pH 4.0, 12mM)-methanol (86:14, v/v) as mobile phase; the flow rate was 1ml/min. The fluorescence measurements were carried out at 320nm with excitation at 279nm. The calibration curve for DA was linear up to about 2.5μg/ml, with a coefficient of determination (r(2)) of 0.9995 with a lower limit of quantification of 0.031μg/ml. Since the procedure does not involve sample pre-purification or derivatisation, the recovery ranged from 97% to 102% and relative standard deviation (RSD) was better than 2.9%, the use of the internal standard is not mandatory, further simplifying the method. Similar performance was obtained for the other analytes. As a result, thanks to its simplicity, rapidity and adequate working range, the method can be used for the determination of 3,4-dihydroxyphenylacetic acid, dopamine, norepinephrine and serotonin in animal tissues. An experimental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson-like disease has been used to demonstrate the method is fit-for-purpose.

  7. Caenorhabditis elegans selects distinct crawling and swimming gaits via dopamine and serotonin.

    PubMed

    Vidal-Gadea, Andrés; Topper, Stephen; Young, Layla; Crisp, Ashley; Kressin, Leah; Elbel, Erin; Maples, Thomas; Brauner, Martin; Erbguth, Karen; Axelrod, Abram; Gottschalk, Alexander; Siegel, Dionicio; Pierce-Shimomura, Jonathan T

    2011-10-18

    Many animals, including humans, select alternate forms of motion (gaits) to move efficiently in different environments. However, it is unclear whether primitive animals, such as nematodes, also use this strategy. We used a multifaceted approach to study how the nematode Caenorhabditis elegans freely moves into and out of water. We demonstrate that C. elegans uses biogenic amines to switch between distinct crawling and swimming gaits. Dopamine is necessary and sufficient to initiate and maintain crawling after swimming. Serotonin is necessary and sufficient to transition from crawling to swimming and to inhibit a set of crawl-specific behaviors. Further study of locomotory switching in C. elegans and its dependence on biogenic amines may provide insight into how gait transitions are performed in other animals.

  8. Molecular mechanisms of cocaine reward: Combined dopamine and serotonin transporter knockouts eliminate cocaine place preference

    PubMed Central

    Sora, Ichiro; Hall, F. Scott; Andrews, Anne M.; Itokawa, Masanari; Li, Xiao-Fei; Wei, Hong-Bing; Wichems, Christine; Lesch, Klaus-Peter; Murphy, Dennis L.; Uhl, George R.

    2001-01-01

    Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET). Cocaine reward/reinforcement has been linked to actions at DAT or to blockade of SERT. However, knockouts of neither DAT, SERT, or NET reduce cocaine reward/reinforcement, leaving substantial uncertainty about cocaine's molecular mechanisms for reward. Conceivably, the molecular bases of cocaine reward might display sufficient redundancy that either DAT or SERT might be able to mediate cocaine reward in the other's absence. To test this hypothesis, we examined double knockout mice with deletions of one or both copies of both the DAT and SERT genes. These mice display viability, weight gain, histologic features, neurochemical parameters, and baseline behavioral features that allow tests of cocaine influences. Mice with even a single wild-type DAT gene copy and no SERT copies retain cocaine reward/reinforcement, as measured by conditioned place-preference testing. However, mice with no DAT and either no or one SERT gene copy display no preference for places where they have previously received cocaine. The serotonin dependence of cocaine reward in DAT knockout mice is thus confirmed by the elimination of cocaine place preference in DAT/SERT double knockout mice. These results provide insights into the brain molecular targets necessary for cocaine reward in knockout mice that develop in their absence and suggest novel strategies for anticocaine medication development. PMID:11320258

  9. Serotonin and Dopamine Play Complementary Roles in Gambling to Recover Losses

    PubMed Central

    Campbell-Meiklejohn, Daniel; Wakeley, Judi; Herbert, Vanessa; Cook, Jennifer; Scollo, Paolo; Ray, Manaan Kar; Selvaraj, Sudhakar; Passingham, Richard E; Cowen, Phillip; Rogers, Robert D

    2011-01-01

    Continued gambling to recover losses—‘loss chasing'—is a prominent feature of social and pathological gambling. However, little is known about the neuromodulators that influence this behavior. In three separate experiments, we investigated the role of serotonin activity, D2/D3 receptor activity, and beta-adrenoceptor activity on the loss chasing of age and IQ-matched healthy adults randomized to treatment or an appropriate control/placebo. In Experiment 1, participants consumed amino-acid drinks that did or did not contain the serotonin precursor, tryptophan. In Experiment 2, participants received a single 176 μg dose of the D2/D3 receptor agonist, pramipexole, or placebo. In Experiment 3, participants received a single 80 mg dose of the beta-adrenoceptor blocker, propranolol, or placebo. Following treatment, participants completed a computerized loss-chasing game. Mood and heart rate were measured at baseline and following treatment. Tryptophan depletion significantly reduced the number of decisions made to chase losses, and the number of consecutive decisions to chase, in the absence of marked changes in mood. By contrast, pramipexole significantly increased the value of losses chased and diminished the value of losses surrendered. Propranolol markedly reduced heart rate, but produced no significant changes in loss-chasing behavior. Loss chasing can be thought of as an aversively motivated escape behavior controlled, in part, by the marginal value of continued gambling relative to the value of already accumulated losses. Serotonin and dopamine appear to play dissociable roles in the tendency of individuals to gamble to recover, or to seek to ‘escape' from, previous losses. Serotonergic activity seems to promote the availability of loss chasing as a behavioral option, whereas D2/D3 receptor activity produces complex changes in the value of losses judged worth chasing. Sympathetic arousal, at least as mediated by beta-adrenoceptors, does not play a

  10. GABA, glutamate, dopamine and serotonin transporters expression on memory formation and amnesia.

    PubMed

    Tellez, Ruth; Gómez-Víquez, Leticia; Meneses, Alfredo

    2012-02-01

    Notwithstanding several neurotransmission systems are frequently related to memory formation, amnesia and/or therapeutic targets for memory alterations, the role of transporters γ-aminobutyric acid (GABA, GAT1), glutamate (neuronal glutamate transporter excitatory amino acid carrier; EACC1), dopamine (DAT) and serotonin (SERT) is poorly understood. Hence, in this paper Western-blot analysis was used to evaluate expression changes on them during memory formation in trained and untrained rats treated with the selective serotonin transporter inhibitor fluoxetine, the amnesic drug d-methamphetamine (METH) and fluoxetine plus METH. Transporters expression was evaluated in the hippocampus, prefrontal cortex and striatum. Data indicated that in addition of memory performance other behavioral parameters (e.g., explorative behavior, food-intake, etc.) that memory formation was recorded. Thus, memory formation in a Pavlovian/instrumental autoshaping was associated to up-regulation of prefrontal cortex GAT1 and EAAC1, striatal SERT, DAT and EACC1; while, hippocampal EACC1, GAT1 and SERT were down-regulated. METH impaired short (STM) and long-term memory (LTM), at 24 or 48h. The METH-induced amnesia down-regulated SERT, DAT, EACC1 and GAT1 in hippocampus and the GAT1 in striatum; no-changes were observed in prefrontal cortex. Post-training administration of fluoxetine improved LTM (48h), which was associated to DAT, GAT1 (prefrontal cortex) up-regulation, but GAT1 (striatum) and SERT (hippocampus) down-regulation. Fluoxetine plus METH administration was able to prevent amnesia, which was associated to DAT, EACC1 and GAT1 (prefrontal cortex), SERT and DAT (hippocampus) and EACC1 or DAT (striatal) up-regulation. Together these data show that memory formation, amnesia and anti-amnesic effects are associated to specific patters of transporters expression.

  11. Effect of champagne compared to still white wine on peripheral neurotransmitter concentrations.

    PubMed

    Boyer, Jean-Christophe; Bancel, Etiennette; Perray, Pascale Fabbro; Pouderoux, Philippe; Balmes, Jean-Louis; Bali, Jean-Pierre

    2004-09-01

    To evaluate how the peripheral release of neurotransmitters such as serotonin, dopamine, cholecystokinin, and beta-endorphin is involved in drinking behavior, blood concentrations of these neurotransmitters were followed in 40 healthy young volunteers during the first hour after ingestion of a moderate dose of some common alcoholic beverages (champagne, still white wine) as compared to water. Concerning serotonin levels, two groups of subjects are statistically distinct: one with low basal serotonin levels (< 620 nmol/L) which responded with an increase in serotonin (52% in 10 minutes), and a second group with higher basal serotonin levels (> 620 nmol/L) which responded with a decrease ( 190% in 60 minutes). Variations in serotonin concentrations appear to depend upon the alcoholic content of the beverage. A rapid increase in plasma dopamine concentrations after consumption of champagne seems to be due to the nonalcoholic content of the beverage. Cholecystokinin values were not significantly different between the three beverages: the observed increase can be explained by a moderate gastric distention. Beta-endorphin levels didn't change significantly after drinking. In conclusion, some significant blood variations of serotonin and dopamine appeared even after moderately dose of champagne or still white wine. These changes might be partially responsible for the different drinking behavior.

  12. Depressive-like behaviors alterations induced by intranigral MPTP, 6-OHDA, LPS and rotenone models of Parkinson's disease are predominantly associated with serotonin and dopamine.

    PubMed

    Santiago, Ronise M; Barbieiro, Janaína; Lima, Marcelo M S; Dombrowski, Patrícia A; Andreatini, Roberto; Vital, Maria A B F

    2010-08-16

    Depression is a frequently encountered non-motor feature of Parkinson's disease (PD) and it can have a significant impact on patient's quality of life. Considering the differential pathophysiology of depression in PD, it prompts the idea that a degenerated nigrostriatal system plays a role in depressive-like behaviors, whilst animal models of PD are employed. Therefore, we addressed the question of whether dopamine (DA) depletion, promoted by the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), lipopolysaccharide (LPS) and rotenone are able to induce depressive-like behaviors and neurotransmitters alterations similarly that encountered in PD. To test this rationale, we performed intranigral injections of each neurotoxin, followed by motor behavior, depressive-like behaviors, histological and neurochemical tests. After the motor recovery period, MPTP, 6-OHDA and rotenone were able to produce anhedonia and behavioral despair. These altered behavioral responses were accompanied by reductions of striatal DA, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) restricted to the 6-OHDA group. Additionally, decreases on the hippocampal serotonin (5-HT) content were detected for the MPTP, 6-OHDA and rotenone groups. Notably, strong correlations were detected among the groups when 5-HT and DA were correlated with swimming (r=+0.97; P=0.001) and immobility (r=-0.90; P=0.012), respectively. Our data indicate that MPTP, 6-OHDA and rotenone, but not LPS were able to produce depressive-like behaviors accompanied primarily by hippocampal 5-HT reductions. Moreover, DA and 5-HT strongly correlated with "emotional" impairments suggesting an important participation of these neurotransmitters in anhedonia and behavioral despair after nigral lesions promoted by the neurotoxins.

  13. The effects of serotonin, dopamine, gonadotropin-releasing hormones, and corazonin, on the androgenic gland of the giant freshwater prawn, Macrobrachium rosenbergii.

    PubMed

    Siangcham, Tanapan; Tinikul, Yotsawan; Poljaroen, Jaruwan; Sroyraya, Morakot; Changklungmoa, Narin; Phoungpetchara, Ittipon; Kankuan, Wilairat; Sumpownon, Chanudporn; Wanichanon, Chaitip; Hanna, Peter J; Sobhon, Prasert

    2013-11-01

    Neurotransmitters and neurohormones are agents that control gonad maturation in decapod crustaceans. Of these, serotonin (5-HT) and dopamine (DA) are neurotransmitters with known antagonist roles in female reproduction, whilst gonadotropin-releasing hormones (GnRHs) and corazonin (Crz) are neurohormones that exercise both positive and negative controls in some invertebrates. However, the effects of these agents on the androgenic gland (AG), which controls testicular maturation and male sex development in decapods, via insulin-like androgenic gland hormone (IAG), are unknown. Therefore, we set out to assay the effects of 5-HT, DA, l-GnRH-III, oct-GnRH and Crz, on the AG of small male Macrobrachium rosenbergii (Mr), using histological studies, a BrdU proliferative cell assay, immunofluorescence of Mr-IAG, and ELISA of Mr-IAG. The results showed stimulatory effects by 5-HT and l-GnRH-III through significant increases in AG size, proliferation of AG cells, and Mr-IAG production (P<0.05). In contrast, DA and Crz caused inhibitory effects on the AG through significant decreases in AG size, proliferation of AG cells, and Mr-IAG production (P<0.05). Moreover, the prawns treated with Crz died before day 16 of the experimental period. We propose that 5-HT and certain GnRHs can be now used to stimulate reproduction in male M. rosenbergii, as they induce increases in AG and testicular size, IAG production, and spermatogenesis. The mechanisms by which these occur are part of our on-going research.

  14. A Comparison of the Subsecond Dynamics of Neurotransmission of Dopamine and Serotonin

    PubMed Central

    2013-01-01

    The neuromodulators dopamine (DA) and serotonin (5-hydroxytryptamine; 5-HT) are similar in a number of ways. Both monoamines can act by volume transmission at metabotropic receptors to modulate synaptic transmission in brain circuits. Presynaptic regulation of 5-HT and DA is governed by parallel processes, and behaviorally, both exert control over emotional processing. However, differences are also apparent: more than twice as many 5-HT receptor subtypes mediate postsynaptic effects than DA receptors and different presynaptic regulation is also emerging. Monoamines are amenable to real-time electrochemical detection using fast scan cyclic voltammetry (FSCV), which allows resolution of the subsecond dynamics of release and reuptake in response to a single action potential. This approach has greatly enriched understanding of DA transmission and has facilitated an integrated view of how DA mediates behavioral control. However, technical challenges are associated with FSCV measurement of 5-HT and understanding of 5-HT transmission at subsecond resolution has not advanced at the same rate. As a result, how the actions of 5-HT at the level of the synapse translate into behavior is poorly understood. Recent technical advances may aid the study of 5-HT in real-time. It is timely, therefore, to compare and contrast what is currently understood of the subsecond characteristics of transmission for DA and 5-HT. In doing so, a number of areas are highlighted as being worthy of exploration for 5-HT. PMID:23627553

  15. In vivo brain microdialysis studies on the striatal dopamine and serotonin release in zitter mutant rats.

    PubMed

    Yoshimoto, Kanji; Nishimura, Akira; Hattori, Hiroyuki; Joyce, Jeffery N; Yoshida, Toshihide; Hioki, Chizuko; Kogure, Akinori; Ueda, Shuichi

    2006-07-01

    In the present study, using in vivo brain microdialysis, we investigated the basal extracellular dopamine (DA) and serotonin (5-HT) release in the caudal striatum (cSTR) of young (4-6 months old) and aged (10-12 months old) zitter mutant rats. The basal extracellular levels of DA release in both young and aged zitter rats were significantly lower than that of age-matched Sprague-Dawley (SD) rats, whereas only aged zitter rats showed a significant difference in the basal 5-HT release. Dopaminergic neurons were more vulnerable than serotonergic neurons in the cSTR of zitter mutant rats during aging. Perfusion of 60 mM potassium (K+) enhanced the extracellular levels of cSTR DA in the young zitter rats and the extracellular levels of both DA and 5-HT in the cSTR of the aged zitter rats. The firing rate of K+-stimulated monoamine release in the cSTR was significantly higher in the zitter rats than in the age-matched SD rats. These findings suggest that there are innate quantitative differences in the releasable pool and the availability of monoamines in the cSTR of zitter mutant rats.

  16. Serotonin 5-HT2 Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

    PubMed Central

    Cunningham, Kathryn A.

    2015-01-01

    Cocaine exhibits prominent abuse liability, and chronic abuse can result in cocaine use disorder with significant morbidity. Major advances have been made in delineating neurobiological mechanisms of cocaine abuse; however, effective medications to treat cocaine use disorder remain to be discovered. The present review will focus on the role of serotonin (5-HT; 5-hydroxytryptamine) neurotransmission in the neuropharmacology of cocaine and related abused stimulants. Extensive research suggests that the primary contribution of 5-HT to cocaine addiction is a consequence of interactions with dopamine (DA) neurotransmission. The literature on the neurobiological and behavioral effects of cocaine is well developed, so the focus of the review will be on cocaine with inferences made about other monoamine uptake inhibitors and releasers based on mechanistic considerations. 5-HT receptors are widely expressed throughout the brain, and several different 5-HT receptor subtypes have been implicated in mediating the effects of endogenous 5-HT on DA. However, the 5-HT2A and 5-HT2C receptors in particular have been implicated as likely candidates for mediating the influence of 5-HT in cocaine abuse as well as to traits (e.g., impulsivity) that contribute to the development of cocaine use disorder and relapse in humans. Lastly, new approaches are proposed to guide targeted development of serotonergic ligands for the treatment of cocaine use disorder. PMID:25505168

  17. Inhibition of the Aplysia sensory neuron calcium current with dopamine and serotonin.

    PubMed

    Dunn, Tyler W; Sossin, Wayne S

    2013-11-01

    The inhibition of Aplysia pleural mechanosensory neuron synapses by dopamine and serotonin through activation of endogenous dopaminergic and expressed 5-HT1Apl(a)/b receptors, respectively, involves a reduction in action potential-associated calcium influx. We show that the inhibition of synaptic efficacy is downstream of the readily releasable pool, suggesting that inhibition is at the level of calcium secretion coupling, likely a result of the changes in the calcium current. Indeed, the inhibitory responses directly reduce a CaV2-like calcium current in isolated sensory neurons. The inhibition of the calcium current is voltage independent as it is not affected by a strong depolarizing prepulse, consistent with other invertebrate CaV2 calcium currents. Similar to voltage-independent inhibition of vertebrate nociceptors, inhibition was blocked with Src tyrosine kinase inhibitors. The data suggest a conserved mechanism by which G protein-coupled receptor activation can inhibit the CaV2 calcium current in nociceptive neurons.

  18. [The action of 1-aminoadamantane. Comparative studies with isolated nerve endings and thrombocytes on the release of serotonin and dopamine].

    PubMed

    Haacke, U; Sturm, G; Süwer, V; Wesemann, W; Wildenhahn, G

    1977-07-01

    Nerve endings isolated from rat brain accumulate exogenous serotonin and dopamine. Both biogenic amines are released from nerve endings as well by means of electrical stimulation with rectangular pulses of alternating polarity as by incubation with 5 X 10(-4) to 5 X 10(-5) M solutions of the adamantane derivatives 1-aminoadamantane hydrochloride (D 1) and 1-amino-3,5-dimethyladamantane hydrochloride (memantine, D 145). The electrically stimulated liberation is small but is significantly increased after simultaneous incubation of the nerve endings with subthreshold concentrations of 1-aminoadamantanes (5X10(-6) to 5X10(-5) M). The reuptake of released serotonin is noncompetitively inhibited by 1-aminoadamantanes. Also in blood platelets frequently used as model cells of the nerve endings the serotonin uptake is inhibited by small concentrations of D 145, 10(-5) to 2X10(-4) M. High concentrations of D 145- greater than 2X10(-3) M, induce the "release-reaction", the simultaneous liberation of serotonin, ATP, and ADP. In the concentration range of 2X10(-4) to 2X10(-3) M D 145 only serotonin is set free.

  19. Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: prominent effects of dopamine transporter deletions.

    PubMed

    Perona, Maria T G; Waters, Shonna; Hall, Frank Scott; Sora, Ichiro; Lesch, Klaus-Peter; Murphy, Dennis L; Caron, Marc; Uhl, George R

    2008-09-01

    Antidepressant drugs produce therapeutic actions and many of their side effects via blockade of the plasma membrane transporters for serotonin (SERT/SLC6A2), norepinephrine (NET/SLC6A1), and dopamine (DAT/SLC6A3). Many antidepressants block several of these transporters; some are more selective. Mouse gene knockouts of these transporters provide interesting models for possible effects of chronic antidepressant treatments. To examine the role of monoamine transporters in models of depression DAT, NET, and SERT knockout (KO) mice and wild-type littermates were studied in the forced swim test (FST), the tail suspension test, and for sucrose consumption. To dissociate general activity from potential antidepressant effects three types of behavior were assessed in the FST: immobility, climbing, and swimming. In confirmation of earlier reports, both DAT KO and NET KO mice exhibited less immobility than wild-type littermates whereas SERT KO mice did not. Effects of DAT deletion were not simply because of hyperactivity, as decreased immobility was observed in DAT+/- mice that were not hyperactive as well as in DAT-/- mice that displayed profound hyperactivity. Climbing was increased, whereas swimming was almost eliminated in DAT-/- mice, and a modest but similar effect was seen in NET KO mice, which showed a modest decrease in locomotor activity. Combined increases in climbing and decreases in immobility are characteristic of FST results in antidepressant animal models, whereas selective effects on swimming are associated with the effects of stimulant drugs. Therefore, an effect on climbing is thought to more specifically reflect antidepressant effects, as has been observed in several other proposed animal models of reduced depressive phenotypes. A similar profile was observed in the tail suspension test, where DAT, NET, and SERT knockouts were all found to reduce immobility, but much greater effects were observed in DAT KO mice. However, to further determine whether

  20. A Nonoxidative Electrochemical Sensor Based on a Self-Doped Polyaniline/Carbon Nanotube Composite for Sensitive and Selective Detection of the Neurotransmitter Dopamine: A Review

    PubMed Central

    Ali, Shah R.; Parajuli, Rishi R.; Balogun, Yetunde; Ma, Yufeng; He, Huixin

    2008-01-01

    interferences toward in vivo and in vitro detection of the neurotransmitter dopamine. PMID:27873994

  1. Antipsychotic drugs disrupt normal development in Caenorhabditis elegans via additional mechanisms besides dopamine and serotonin receptors

    PubMed Central

    Donohoe, Dallas R.; Aamodt, Eric J.; Osborn, Elizabeth; Dwyer, Donard S.

    2006-01-01

    Antipsychotic drugs may produce adverse effects during development in humans and rodents. However, the extent of these effects has not been systematically characterized nor have molecular mechanisms been identified. Consequently, we sought to evaluate the effects of an extensive panel of antipsychotic drugs in a model organism, C. elegans, whose development is well characterized, and which offers the possibility of identifying novel molecular targets. For these studies, animals were grown from hatching in the presence of vehicle (control) or antipsychotic drugs over a range of concentrations (20–160 μM) and growth was analyzed by measuring head-to-tail length at various intervals. First-generation antipsychotics (e.g., fluphenazine) generally slowed growth and maturation more than second-generation drugs such as quetiapine, and olanzapine. This is consistent with in vitro effects on human neuronal cell lines. Clozapine, a second-generation drug, produced similar growth deficits as haloperidol. Converging lines of evidence, including the failure to rescue growth with high concentrations of agonists, suggested that the drug-induced delay in development was not mediated by the major neurotransmitter receptors recognized by the antipsychotic drugs. Moreover, in serotonin-deficient tph-1 mutants, the drugs dramatically slowed development and led to larval arrest (including dauer formation), and neuronal abnormalities. Evaluation of alternative targets of the antipsychotics revealed a potential role for calmodulin and underscored the significance of Ca2+-calmodulin signaling in development. These findings suggest that antipsychotic drugs may interfere with normal developmental processes, and provide a tool for investigating the key signaling pathways involved. PMID:16962336

  2. Effect of psilocin on extracellular dopamine and serotonin levels in the mesoaccumbens and mesocortical pathway in awake rats.

    PubMed

    Sakashita, Yuichi; Abe, Kenji; Katagiri, Nobuyuki; Kambe, Toshie; Saitoh, Toshiaki; Utsunomiya, Iku; Horiguchi, Yoshie; Taguchi, Kyoji

    2015-01-01

    Psilocin (3-[2-(dimethylamino)ethyl]-1H-indol-4-ol) is a hallucinogenic component of the Mexican mushroom Psilocybe mexicana and a skeletal serotonin (5-HT) analogue. Psilocin is the active metabolite of psilocybin (3-[2-(dimethylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate). In the present study, we examined the effects of systemically administered psilocin on extracellular dopamine and 5-HT concentrations in the ventral tegmental area (VTA), nucleus accumbens, and medial prefrontal cortex of the dopaminergic pathway in awake rats using in vivo microdialysis. Intraperitoneal administration of psilocin (5, 10 mg/kg) significantly increased extracellular dopamine levels in the nucleus accumbens. Psilocin did not affect the extracellular 5-HT level in the nucleus accumbens. Conversely, systemic administration of psilocin (10 mg/kg) significantly increased extracellular 5-HT levels in the medial prefrontal cortex of rats, but dopamine was decreased in this region. However, neither extracellular dopamine nor 5-HT levels in the VTA were altered by administration of psilocin. Behaviorally, psilocin significantly increased the number of head twitches. Thus, psilocin affects the dopaminergic system in the nucleus accumbens. In the serotonergic system, psilocin contribute to a crucial effect in the medial prefrontal cortex. The present data suggest that psilocin increased both the extracellular dopamine and 5-HT concentrations in the mesoaccumbens and/or mesocortical pathway.

  3. Serotonin and Dopamine Gene Variation and Theory of Mind Decoding Accuracy in Major Depression: A Preliminary Investigation

    PubMed Central

    Zahavi, Arielle Y.; Sabbagh, Mark A.; Washburn, Dustin; Mazurka, Raegan; Bagby, R. Michael; Strauss, John; Kennedy, James L.; Ravindran, Arun; Harkness, Kate L.

    2016-01-01

    Theory of mind–the ability to decode and reason about others’ mental states–is a universal human skill and forms the basis of social cognition. Theory of mind accuracy is impaired in clinical conditions evidencing social impairment, including major depressive disorder. The current study is a preliminary investigation of the association of polymorphisms of the serotonin transporter (SLC6A4), dopamine transporter (DAT1), dopamine receptor D4 (DRD4), and catechol-O-methyl transferase (COMT) genes with theory of mind decoding in a sample of adults with major depression. Ninety-six young adults (38 depressed, 58 non-depressed) completed the ‘Reading the Mind in the Eyes task’ and a non-mentalistic control task. Genetic associations were only found for the depressed group. Specifically, superior accuracy in decoding mental states of a positive valence was seen in those homozygous for the long allele of the serotonin transporter gene, 9-allele carriers of DAT1, and long-allele carriers of DRD4. In contrast, superior accuracy in decoding mental states of a negative valence was seen in short-allele carriers of the serotonin transporter gene and 10/10 homozygotes of DAT1. Results are discussed in terms of their implications for integrating social cognitive and neurobiological models of etiology in major depression. PMID:26974654

  4. Voltammetric characterization of the effect of monoamine uptake inhibitors and releasers on dopamine and serotonin uptake in mouse caudate-putamen and substantia nigra slices

    PubMed Central

    John, Carrie E.; Jones, Sara R.

    2007-01-01

    Summary Fast scan cyclic voltammetry is an electrochemical technique used to measure dynamics of transporter-mediated monoamine uptake in real time and provides a tool to evaluate the detailed effects of monoamine uptake inhibitors and releasers on dopamine and serotonin transporter function. We measured the effects of cocaine, methylphenidate, 2β-propanoyl–3β-(4tolyl) tropane (PTT), fluoxetine, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), phentermine and fenfluramine on dopamine and serotonin uptake following electrically stimulated release in mouse caudate-putamen and substantia nigra pars reticulata slices. We determined rank orders of uptake inhibition effects based on two variables; increases in apparent Km for dopamine and serotonin uptake and inhibition constant (Ki) values. For example, the rank order of uptake inhibition based on apparent Km values at the dopamine transporter was amphetamine ≥ PTT ≥ methylphenidate ≫ methamphetamine = phentermine = MDMA > cocaine ≫ fluoxetine = fenfluramine, and at the serotonin transporter was fluoxetine = methamphetamine = fenfluramine = MDMA > amphetamine = cocaine = PTT ≥ methylphenidate > phentermine. Additionally, changes in electrically stimulated release were documented. This is the first study using voltammetry to measure the effects of a wide range of monoamine uptake inhibitors and releasers on dopamine and serotonin uptake in mouse brain slices. These studies also highlight methodological considerations for comparison of effects between heterogeneous brain regions. PMID:17459426

  5. Brexpiprazole for the Treatment of Schizophrenia: A Review of this Novel Serotonin-Dopamine Activity Modulator.

    PubMed

    McEvoy, Joseph; Citrome, Leslie

    2016-01-01

    Brexpiprazole is an antipsychotic medication and received approval by the U.S. Food and Drug Administration for the treatment of schizophrenia in July 2015. Brexpiprazole acts as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A and at adrenergic alpha1B and alpha2C receptors. Compared with aripiprazole, brexpiprazole is more potent at 5-HT1A receptors and displays less intrinsic activity at D2 receptors. The recommended dose range of brexpiprazole for the treatment of schizophrenia is 2-4 mg/day; the recommended titration schedule is to start with 1 mg/day and increase to 2 mg/day on Day 5 to Day 7, then to 4 mg/day on Day 8. Two positive, 6-week, Phase 3 randomized controlled trials in acute schizophrenia demonstrated superiority of brexpiprazole over placebo. Pooled responder rates were 46% for brexpiprazole 2-4 mg/day vs. 31% for placebo, resulting in a number needed to treat (NNT) of 7. In a 52-week, randomized withdrawal study, significantly fewer patients relapsed in the brexpiprazole group compared with placebo (13.5% vs. 38.5%), resulting in an NNT of 4. The most commonly encountered adverse event (incidence ≥4% and at least twice the rate of placebo) is increased weight. Short-term weight gain appears modest (approximately 10% of patients receiving brexpiprazole 1-4 mg/day gained ≥7% body weight from baseline, compared with 4% for those randomized to placebo, resulting in a number needed to harm [NNH] of 17); however, more outliers with an increase of ≥7% of body weight were evident in open-label, 52-week safety studies. Effects on glucose and lipids were small. Rates of akathisia as an adverse event were 5.5% for the pooled doses of brexpiprazole 1-4 mg/day vs. 4.6% for placebo, yielding an NNH of 112. Minimal effects on prolactin were observed, and no clinically relevant effects on the ECG QTc interval were evident. Brexpiprazole is also approved as an adjunct medication for the treatment of

  6. Neurotransmitters and neuromodulators controlling the anterior byssus retractor muscle of Mytilus edulis.

    PubMed

    Muneoka, Y; Fujisawa, Y; Matsuura, M; Ikeda, T

    1991-01-01

    1. The anterior byssus retractor muscle (ABRM) of Mytilus edulis is innervated by at least two kinds of nerves, excitatory and relaxing nerves. The principal neurotransmitters released from these nerves have been shown to be acetylcholine and serotonin, respectively. 2. Some other monoamines, such as dopamine and octopamine, and various peptides, such as FMRFamide-related peptides, Mytilus inhibitory peptides, SCP-related peptides and a catch-relaxing peptide, may also be involved in the regulation of the muscle as neurotransmitters or neuromodulators. 3. The ABRM seems to be typical of invertebrate muscles controlled by multiple neurotransmitters and neuromodulators.

  7. A Bacoside containing Bacopa monnieri extract reduces both morphine hyperactivity plus the elevated striatal dopamine and serotonin turnover.

    PubMed

    Rauf, Khalid; Subhan, Fazal; Sewell, Robert D E

    2012-05-01

    Bacopa monnieri (BM) has been used in Ayurvedic medicine as a nootropic, anxiolytic, antiepileptic and antidepressant. An n-butanol extract of the plant (nBt-ext BM) was analysed and found to contain Bacoside A (Bacoside A3, Bacopaside II and Bacopasaponin C). The effects of the BM extract were then studied on morphine-induced hyperactivity as well as dopamine and serotonin turnover in the striatum since these parameters have a role in opioid sensitivity and dependence. Mice were pretreated with saline or nBt-ext BM (5, 10 and 15 mg/kg, orally), 60 min before morphine administration and locomotor activity was subsequently recorded. Immediately after testing, striatal tissues were analysed for dopamine (DA), serotonin (5HT) and their metabolites using HPLC coupled with electrochemical detection. The results indicated that nBt-ext BM significantly (p < 0.001) decreased locomotor activity in both the saline and morphine treated groups. Additionally, nBt-ext BM significantly lowered morphine-induced dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-H1AA) upsurges in the striatum but failed to affect DA, 5-HT and their metabolites in the saline treated group. These findings suggest that nBt-ext BM has an antidopaminergic/serotonergic effect and may have potential beneficial effects in the treatment of morphine dependence.

  8. Blocking effect of serotonin on inhibitory dopamine receptor activity of Aplysia ganglion cells.

    PubMed

    Shozushima, M

    1984-01-01

    The abdominal ganglion of Aplysia includes neurons with a characteristic dopamine (DA) receptor, the activation of which induces a marked hyperpolarization with a specific increase in the permeability of the membrane to K+. The DA receptor of this type is called the "HK-type." A 2-min exposure to 1 microM serotonin (5-HT) had little effect on the resting membranes with the receptor of HK-type, but significantly depressed the responses to 10 microM DA. The depressing effect of 5-HT on this type of response was completely reversible after a 15-min washing with normal artificial Aplysia blood. Lineweaver-Burke type plotting of the DA-induced responses showed a systematic shift of the straight lines when the concentration of 5-HT was increased; the slope of the line became steeper but the intercept on the ordinate remained unchanged. The dose-inhibition curves, in which relative responses to a given [DA] were plotted against log [5-HT], showed a parallel shift toward the right when the concentration of DA increased. These findings suggest that 5-HT competes with DA for common binding sites at the DA receptor of HK-type, and that the blockade is not due to the interaction of 5-HT with K+-channels in the receptor membrane. The effect of other indole derivatives suggests that the DA receptor of HK-type includes anionic and cationic sites to which the NH2 group and 5-HO group of 5-HT could specifically bind, thus exhibiting competitive blockade.

  9. Comodulation of dopamine and serotonin on prefrontal cortical rhythms: a theoretical study

    PubMed Central

    Wang, Da-Hui; Wong-Lin, KongFatt

    2013-01-01

    The prefrontal cortex (PFC) is implicated to play an important role in cognitive control. Abnormal PFC activities and rhythms have been observed in some neurological and neuropsychiatric disorders, and evidences suggest influences from the neuromodulators dopamine (DA) and serotonin (5-HT). Despite the high level of interest in these brain systems, the combined effects of DA and 5-HT modulation on PFC dynamics remain unknown. In this work, we build a mathematical model that incorporates available experimental findings to systematically study the comodulation of DA and 5-HT on the network behavior, focusing on beta and gamma band oscillations. Single neuronal model shows pyramidal cells with 5-HT1A and 2A receptors can be non-monotonically modulated by 5-HT. Two-population excitatory-inhibitory type network consisting of pyramidal cells with D1 receptors can provide rich repertoires of oscillatory behavior. In particular, 5-HT and DA can modulate the amplitude and frequency of the oscillations, which can emerge or cease, depending on receptor types. Certain receptor combinations are conducive for the robustness of the oscillatory regime, or the existence of multiple discrete oscillatory regimes. In a multi-population heterogeneous model that takes into account possible combination of receptors, we demonstrate that robust network oscillations require high DA concentration. We also show that selective D1 receptor antagonists (agonists) tend to suppress (enhance) network oscillations, increase the frequency from beta toward gamma band, while selective 5-HT1A antagonists (agonists) act in opposite ways. Selective D2 or 5-HT2A receptor antagonists (agonists) can lead to decrease (increase) in oscillation amplitude, but only 5-HT2A antagonists (agonists) can increase (decrease) the frequency. These results are comparable to some pharmacological effects. Our work illustrates the complex mechanisms of DA and 5-HT when operating simultaneously through multiple receptors

  10. Serotonin and dopamine striatal innervation in Parkinson's disease and Huntington's chorea.

    PubMed

    Bédard, Catherine; Wallman, Marie-Josée; Pourcher, Emmanuelle; Gould, Peter V; Parent, André; Parent, Martin

    2011-09-01

    In contrast to our vast knowledge of the dopamine (DA) system, much less is known about the involvement of serotonin (5-HT) in neurodegenerative diseases affecting the basal ganglia. Therefore, we designed a study that aimed at characterizing the status of the striatal DA and 5-HT systems in patients who suffered from either Parkinson's (PD) or Huntington's disease (HD), compared to age-matched controls. Antibodies against tyrosine hydroxylase (TH) and 5-HT transporter (SERT) were used as markers of DA and 5-HT axonal profiles, respectively. The density and pattern of TH+ and SERT + innervation were determined by optical density measurements as well as by direct stereological estimates of labeled axon varicosities. The results reveal a significant decrease in TH immunoreactivity and TH + axon terminals throughout the striatum in both PD and HD, whereas the intensity of SERT immunostaining and the density of SERT + axon varicosities were found to be slightly increased in the striatum of PD and HD patients compared to controls. These findings reveal that the nigrostriatal DA system is significantly impaired in both PD and HD compared to the striatal 5-HT innervation, which is slightly increased in these two conditions. The striatal 5-HT augmentation observed in PD might be the result of a neural mechanism designed to compensate for DA denervation, whereas the marked atrophy of the striatum might explain the increase in the 5-HT innervation noted in HD. These findings underline the importance of the complex interplay between DA and 5-HT striatal afferents in the elaboration of appropriate motor behaviour.

  11. Daidzin and its antidipsotropic analogs inhibit serotonin and dopamine metabolism in isolated mitochondria.

    PubMed

    Keung, W M; Vallee, B L

    1998-03-03

    Daidzin, a major active principle of an ancient Chinese herbal treatment (Radix puerariae) for alcohol abuse, selectively suppresses ethanol intake in all rodent models tested. It also inhibits mitochondrial aldehyde dehydrogenase (ALDH-2). Studies on ethanol intake suppression and ALDH-2 inhibition by structural analogs of daidzin established a link between these two activities and suggested that daidzin may suppress ethanol intake by inhibiting ALDH-2. ALDH-2 is a principal enzyme involved in serotonin (5-HT) and dopamine (DA) metabolism. Thus, daidzin may act by inhibiting 5-HT and DA metabolism. To evaluate this possibility, we have studied the effect of daidzin and its analogs on 5-HT and DA metabolism in isolated hamster and rat liver mitochondria. Daidzin potently inhibits the formation of 5-hydroxyindole-3-acetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC) from their respective amines in isolated mitochondria. Inhibition is concentration-dependent and is accompanied by a concomitant accumulation of 5-hydroxyindole-3-acetaldehyde and 3, 4-dihydroxyphenylacetaldehyde. Daidzin analogs that suppress hamster ethanol intake also inhibit 5-HIAA and DOPAC formation. Comparing their effects on mitochondria-catalyzed 5-HIAA or DOPAC formation and hamster ethanol intake reveals a positive correlation-the stronger the inhibition on 5-HIAA or DOPAC formation, the greater the ethanol intake suppression. Daidzin and its active analogs, at concentrations that significantly inhibit 5-HIAA formation, have little or no effect on mitochondria-catalyzed 5-HT depletion. It appears that the antidipsotropic action of daidzin is not mediated by 5-HT (or DA) but rather by its reactive intermediates 5-hydroxyindole-3-acetaldehyde and, presumably, 3, 4-dihydroxyphenylacetaldehyde as well, which accumulates in the presence of daidzin.

  12. Lack of evidence for reduced prefrontal cortical serotonin and dopamine efflux after acute tryptophan depletion

    PubMed Central

    Meerkerk, Dorie (T). J.; Lieben, Cindy K. J.; Blokland, Arjan; Feenstra, Matthijs G. P.

    2007-01-01

    Rationale Acute tryptophan depletion (ATD) is a widely used method to study the role of serotonin (5-HT) in affect and cognition. ATD results in a strong but transient decrease in plasma tryptophan and central 5-HT synthesis and availability. Although its use is widespread, the evidence that the numerous functional effects of ATD are caused by actual changes in 5-HT neuronal release is not very strong. Thus far, decreases in 5-HT efflux (thought to reflect synaptic release) were only reported after chronic tryptophan depletion or when ATD was combined with blockade of 5-HT reuptake. Objective With the current experiment, we aimed to study the validity of the method of ATD by measuring the extent to which it reduces the efflux of 5-HT (and dopamine) in the prefrontal cortex in the absence of reuptake blockage. Materials and methods We simultaneously measured in freely moving animals plasma tryptophan via a catheter in the jugular vein and 5-HT and DA efflux in the medial prefrontal cortex through microdialysis after ATD treatment. Results ATD reduced plasma tryptophan to less than 30% of control, without affecting 5-HT or DA efflux in the prefrontal cortex, indicating that even strong reductions of plasma tryptophan do not necessarily result in decreases in central 5-HT efflux. Conclusion The present experiment showed that reductions in plasma tryptophan, similar to values associated with behavioural effects, do not necessarily reduce 5-HT efflux and suggest that the cognitive and behavioural effects of ATD may not be (exclusively) due to alterations in 5-HT release. PMID:17713760

  13. Calcitriol protects against the dopamine- and serotonin-depleting effects of neurotoxic doses of methamphetamine.

    PubMed

    Cass, Wayne A; Smith, Michael P; Peters, Laura E

    2006-08-01

    Repeated methamphetamine (METH) administration to animals can result in long-lasting decreases in brain dopamine (DA) and serotonin (5-HT) content. Calcitriol, the active metabolite of vitamin D, has potent effects on brain cells, both in vitro and in vivo, including the ability to upregulate trophic factors and protect against various lesions. The present experiments were designed to examine the ability of calcitriol to protect against METH-induced reductions in striatal and nucleus accumbens levels of DA and 5-HT. Male Fischer-344 rats were administered vehicle or calcitriol (1 microg/kg, s.c.) once a day for eight consecutive days. After the seventh day of treatment the animals were given METH (5 mg/kg, s.c.) or saline four times in 1 day at 2-h intervals. Seven days later the striata and accumbens were harvested from the animals for high-performance liquid chromatography (HPLC) analysis of monoamines and metabolites. In animals treated with vehicle and METH, there were significant reductions in DA, 5-HT, and their metabolites in both the striatum and accumbens. In animals treated with calcitriol and METH, the magnitude of the METH-induced reductions in DA, 5-HT, and metabolites was substantially and significantly attenuated. The calcitriol treatments did not reduce the hyperthermia associated with multiple injections of METH, indicating that the neuroprotective effects of calcitriol are not due to the prevention of increases in body temperature. These results suggest that calcitriol can provide significant protection against the DA- and 5-HT-depleting effects of neurotoxic doses of METH.

  14. Positive and negative feedback learning and associated dopamine and serotonin transporter binding after methamphetamine

    PubMed Central

    Stolyarova, Alexandra; O’Dell, Steve J.; Marshall, John F.; Izquierdo, Alicia

    2014-01-01

    Learning from mistakes and prospectively adjusting behavior in response to reward feedback is an important facet of performance monitoring. Dopamine (DA) pathways play an important role in feedback learning and a growing literature has also emerged on the importance of serotonin (5HT) in reward learning, particularly during punishment or reward omission (negative feedback). Cognitive impairments resulting from psychostimulant exposure may arise from altered patterns in feedback learning, which in turn may be modulated by DA and 5HT transmission. We analyzed long-term, off-drug changes in learning from positive and negative feedback and associated striatal DA transporter (DAT) and frontocortical 5HT transporter (SERT) binding in rats pretreated with methamphetamine (mAMPH). Specifically, we assessed the reversal phase of pairwise visual discrimination learning in rats receiving single dose- (mAMPHsingle) vs. escalating-dose exposure (mAMPHescal). Using fine-grained trial-by-trial analyses, we found increased sensitivity to and reliance on positive feedback in mAMPH-pretreated animals, with the mAMPHsingle group showing more pronounced use of this type of feedback. In contrast, overall negative feedback sensitivity was not altered following any mAMPH treatment. In addition to validating the enduring effects of mAMPH on early reversal learning, we found more consecutive error commissions before the first correct response in mAMPH-pretreated rats. This behavioral rigidity was negatively correlated with subregional frontocortical SERT whereas positive feedback sensitivity negatively correlated with striatal DAT binding. These results provide new evidence for the overlapping, yet dissociable roles of DA and 5HT systems in overcoming perseveration and in learning new reward rules. PMID:24959862

  15. Activation of transcription factor genes in striatum by cocaine: role of both serotonin and dopamine systems.

    PubMed

    Bhat, R V; Baraban, J M

    1993-10-01

    Acute administration of cocaine increases expression of the transcription factor genes c-fos and zif268 in the striatum. This response is thought to be mediated via D1 dopamine (DA) receptors, as it is blocked by the selective D1 receptor antagonist SCH 23390. However, the directly acting D1 receptor agonists, apomorphine and SKF 38393, do not mimic cocaine's activation of these genes raising the possibility that D1 receptor activation is necessary, but not sufficient, to trigger transcription factor expression. Because cocaine blocks uptake of norepinephrine (NE) and serotonin (5-HT), as well as DA, we examined whether cocaine's ability to inhibit NE and 5-HT uptake may contribute to its induction of c-fos and zif268 expression in striatum. In examining the effects of selective monoamine uptake inhibitors, we observed that fluoxetine or citalopram, selective inhibitors of 5-HT uptake, potentiated the ability of mazindol, a DA and NE uptake inhibitor, to induce zif268 and c-fos expression, even though these 5-HT uptake inhibitors had no effect when administered alone. In contrast, the selective NE uptake inhibitor, desipramine, administered alone, or in combination with fluoxetine, did not increase expression of zif268 or c-fos. Furthermore, selective denervation of 5-HT projections by p-chloroamphetamine treatment attenuated the increase in zif268 and c-fos expression induced by cocaine in the striatum. In contrast, selective lesions of NE projections with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride failed to block cocaine's activation of these genes in the striatum. Taken together, these findings indicate that cocaine's ability to induce striatal expression of c-fos and zif268 is mediated by its effects on both the 5-HT and DA systems.

  16. Positive and negative feedback learning and associated dopamine and serotonin transporter binding after methamphetamine.

    PubMed

    Stolyarova, Alexandra; O'Dell, Steve J; Marshall, John F; Izquierdo, Alicia

    2014-09-01

    Learning from mistakes and prospectively adjusting behavior in response to reward feedback is an important facet of performance monitoring. Dopamine (DA) pathways play an important role in feedback learning and a growing literature has also emerged on the importance of serotonin (5HT) in reward learning, particularly during punishment or reward omission (negative feedback). Cognitive impairments resulting from psychostimulant exposure may arise from altered patterns in feedback learning, which in turn may be modulated by DA and 5HT transmission. We analyzed long-term, off-drug changes in learning from positive and negative feedback and associated striatal DA transporter (DAT) and frontocortical 5HT transporter (SERT) binding in rats pretreated with methamphetamine (mAMPH). Specifically, we assessed the reversal phase of pairwise visual discrimination learning in rats receiving single dose- (mAMPHsingle) vs. escalating-dose exposure (mAMPHescal). Using fine-grained trial-by-trial analyses, we found increased sensitivity to and reliance on positive feedback in mAMPH-pretreated animals, with the mAMPHsingle group showing more pronounced use of this type of feedback. In contrast, overall negative feedback sensitivity was not altered following any mAMPH treatment. In addition to validating the enduring effects of mAMPH on early reversal learning, we found more consecutive error commissions before the first correct response in mAMPH-pretreated rats. This behavioral rigidity was negatively correlated with subregional frontocortical SERT whereas positive feedback sensitivity negatively correlated with striatal DAT binding. These results provide new evidence for the overlapping, yet dissociable roles of DA and 5HT systems in overcoming perseveration and in learning new reward rules.

  17. Structure-activity studies of 3'-4'-dichloro-meperidine analogues at dopamine and serotonin transporters.

    PubMed

    Rhoden, Jill B; Bouvet, Maud; Izenwasser, Sari; Wade, Dean; Lomenzo, Stacey A; Trudell, Mark L

    2005-10-01

    The structure-activity relationships of 3',4'-dichloro-meperidine were investigated at dopamine (DAT) and serotonin transporters (SERT). Large ester substituents and lipophilic groups at the 4-position favored molecular recognition at the SERT. The benzyl ester of 3',4'-dichloro-meperidine exhibited high potency and high selectivity for the SERT (DAT/SERT=760). Chemical modification of the ester group and N-substitution generally led to compounds with decreased DAT affinity. Only small esters and alkyl groups were tolerated at the 4-position of the meperidine ring system by the DAT. Overall, the meperidine analogues were generally more selective for the SERT than for the DAT.

  18. Neurotransmitters: The Critical Modulators Regulating Gut-Brain Axis.

    PubMed

    Mittal, Rahul; Debs, Luca H; Patel, Amit P; Nguyen, Desiree; Patel, Kunal; O'Connor, Gregory; Grati, M'hamed; Mittal, Jeenu; Yan, Denise; Eshraghi, Adrien A; Deo, Sapna K; Daunert, Sylvia; Liu, Xue Zhong

    2016-08-11

    Neurotransmitters including catecholamines and serotonin play a crucial role in maintaining homeostasis in the human body. Studies on these neurotransmitters mainly revolved around their role in the "fight or flight" response, transmitting signals across a chemical synapse and modulating blood flow throughout the body. However, recent research has demonstrated that neurotransmitters can play a significant role in the gastrointestinal (GI) physiology. Norepinephrine (NE), epinephrine (E), dopamine (DA), and serotonin have recently been a topic of interest because of their roles in the gut physiology and their potential roles in gastrointestinal and central nervous system pathophysiology. These neurotransmitters are able to regulate and control not only blood flow, but also affect gut motility, nutrient absorption, gastrointestinal innate immune system, and the microbiome. Furthermore, in pathological states such as inflammatory bowel disease (IBD) and Parkinson's disease, the levels of these neurotransmitters are dysregulated, therefore causing a variety of gastrointestinal symptoms. Research in this field has shown that exogenous manipulation of catecholamine serum concentrations can help in decreasing symptomology and/or disease progression. In this review article, we discuss the current state-of-the-art research and literature regarding the role of neurotransmitters in regulation of normal gastrointestinal physiology, their impact on several disease processes, and novel work focused on the use of exogenous hormones and/or psychotropic medications to improve disease symptomology. This article is protected by copyright. All rights reserved.

  19. Cloning of the cocaine-sensitive bovine dopamine transporter

    SciTech Connect

    Usdin, T.B.; Chen, C.; Brownstein, M.J.; Hoffman, B.J. ); Mezey, E. )

    1991-12-15

    A cDNA encoding the dopamine transporter from bovine brain substantia nigra was identified on the basis of its structural homology to other, recently cloned, neurotransmitter transporters. The sequence of the 693-amino acid protein is quite similar to those of the rat {gamma}-aminobutyric acid, human norepinephrine, and rat serotonin transporters. Dopamine transporter mRNA was detected by in situ hybridization in the substantia nigra but not in the locus coeruleus, raphe, caudate, or other brain areas. ({sup 3}H)Dopamine accumulation in tissue culture cells transfected with the cDNA was inhibited by amphetamine, cocaine, and specific inhibitors of dopamine transports, including GBR12909.

  20. Impact of Serotonin 2C Receptor Null Mutation on Physiology and Behavior Associated with Nigrostriatal Dopamine Pathway Function

    PubMed Central

    Abdallah, Luna; Bonasera, Stephen J.; Hopf, F. Woodward; O’Dell, Laura; Giorgetti, Marco; Jongsma, Minke; Carra, Scott; Pierucci, Massimo; Di Giovanni, Giuseppe; Esposito, Ennio; Parsons, Loren H.; Bonci, Antonello; Tecott, Laurence H.

    2011-01-01

    The impact of serotonergic neurotransmission on brain dopaminergic pathways has substantial relevance to many neuropsychiatric disorders. A particularly prominent role has been ascribed to the inhibitory effects of serotonin 2C receptor (5-HT2CR) activation on physiology and behavior mediated by the mesolimbic dopaminergic pathway, particularly in the terminal region of the nucleus accumbens. The influence of this receptor subtype on functions mediated by the nigrostriatal dopaminergic pathway is less clear. Here we report that a null mutation eliminating expression of 5-HT2CRs produces marked alterations in the activity and functional output of this pathway. 5-HT2CR mutant mice displayed increased activity of substantia nigra pars compacta (SNc) dopaminergic neurons, elevated baseline extracellular dopamine concentrations in the dorsal striatum (DSt), alterations in grooming behavior, and enhanced sensitivity to the stereotypic behavioral effects of D-amphetamine and GBR 12909. These psychostimulant responses occurred in the absence of phenotypic differences in drug-induced extracellular dopamine concentration, suggesting a phenotypic alteration in behavioral responses to released dopamine. This was further suggested by enhanced behavioral responses of mutant mice to the D1 receptor agonist SKF 81297. Differences in DSt D1 or D2 receptor expression were not found, nor were differences in medium spiny neuron firing patterns or intrinsic membrane properties following dopamine stimulation. We conclude that 5-HT2CRs regulate nigrostriatal dopaminergic activity and function both at SNc dopaminergic neurons and at a locus downstream of the DSt. PMID:19553455

  1. Clozapine and cocaine effects on dopamine and serotonin release in nucleus accumbens during psychostimulant behavior and withdrawal.

    PubMed

    Broderick, Patricia A; Hope, Omotola; Okonji, Catherine; Rahni, David N; Zhou, Yueping

    2004-01-01

    There is an increasing awareness that a psychosis, similar to that of schizophrenic psychosis, can be derived from cocaine addiction. Thus, the prototypical atypical antipsychotic medication, clozapine, a 5-HT(2)/DA(2) antagonist, was studied for its effects on cocaine-induced dopamine (DA) and serotonin (5-HT) release in nucleus accumbens (NAcc) of behaving male Sprague-Dawley laboratory rats with In Vivo Microvoltammetry, while animals' locomotor (forward ambulations), an A(10) behavior, was monitored at the same time with infrared photobeams. Release mechanisms for monoamines were determined by using a depolarization blocker, gamma-butyrolactone (gammaBL). BRODERICK PROBE microelectrodes selectively detected release of DA and 5-HT within seconds and sequentially in A(10) nerve terminals, NAcc. Acute and subacute studies were performed for each treatment group. Acute studies are defined as single injection of drug(s) after a stable baseline of each monoamine and locomotor behavior has been achieved. Subacute studies are defined as 24-h follow-up studies on each monoamine and locomotor behavior, in the same animal at which time, no further drug was administered. Results showed that (1) acute administration of cocaine (10 mg/kg ip) (n=5) significantly increased both DA and 5-HT release above baseline (P<.001) while locomotion was also significantly increased above baseline (P<.001). In subacute studies, DA release decreased significantly below baseline (P<.001) and significant decreases in 5-HT release occurred at the 15-min mark and at each time point during the second part of the hour (P<.05); the maximum decrease in 5-HT was 40% below baseline. Locomotor behavior, on the other hand, increased significantly above baseline (P<.05). (2) Acute administration of clozapine/cocaine (20 and 10 mg/kg ip, respectively; n=6) produced a significant block of the cocaine-induced increase in DA (P<.001) and 5-HT release (P<.001). Cocaine-induced locomotion was blocked

  2. Role of prenatal undernutrition in the expression of serotonin, dopamine and leptin receptors in adult mice: implications of food intake.

    PubMed

    Manuel-Apolinar, Leticia; Rocha, Luisa; Damasio, Leticia; Tesoro-Cruz, Emiliano; Zarate, Arturo

    2014-02-01

    Perturbations in the levels of serotonin expression have a significant impact on behavior and have been implicated in the pathogenesis of several neuropsychiatric disorders including anxiety, mood and appetite. Fetal programming is a risk factor for the development of metabolic diseases during adulthood. Moreover, previous studies have shown that serotonin (5‑HT), dopamine and leptin are important in energy balance. In the present study, the impact of maternal malnutrition‑induced prenatal undernutrition (UN) was investigated in mice and the expression of 5‑HT1A, dopamine (D)1, D2 and Ob‑Rb receptors was analyzed in the hypothalamus during adulthood. The UN group showed a low birth weight compared with the control group. With regard to receptor expression, 5‑HT1A in the UN group was increased in the hypothalamus and D1 was reduced, whereas D2 showed an increase from postnatal day (P)14 in the arcuate nucleus. Ob‑Rb receptor expression was increased in the hypothalamus at P14 and P90. These observations indicated that maternal caloric restriction programs a postnatal body weight gain in offspring with an increased food intake in early postnatal life which continues into adulthood. In addition, UN in mice was found to be affected by Ob‑Rb, 5‑HT1A and D1/2 receptor expression, indicating that these observations may be associated with hyperphagia and obesity.

  3. Dopamine and serotonin receptors measured in vivo in Huntington's Disease with C-11 n-methylspiperone PET imaging

    SciTech Connect

    Wong, D.F.; Links, J.M.; Wanger, H.N. Jr.; Folstein, S.E.; Suneja, S.; Dannals, R.F.; Ravert, H.T.; Wilson, A.A.; Tune, L.E.; Pearlson, G.

    1985-05-01

    Thirteen patients with the clinical diagnosis of Huntington's Disease (HD) and nine persons at risk to develop the disease were studied by positron emission tomography (PET) after administration of /sup 11/C-n-methylspiperone (NMSP), a tracer with a high affinity for D2 dopamine and, to a lesser degree, for S2 serotonin receptors. All subjects had an X-ray CT scan for positioning and to assess caudate size. Dopamine and serotonin receptor binding (D2 and S2) were estimated by the caudate/cerebellum activity ratio at 43 min. post injection (CA/CB), and frontal cortex/cerebellum (FR/CB), respectively. CA/CB's of HD pts. were lower than age and sex matched controls. However, when corrected by recovery coefficients (RC) for our PET using CT dimensions of the caudate, CA/CB's were higher than normal. The relative total number of D2 receptors (estimated by CA/CB x CT caudate volume) was lower than the controls without or with RC correction.

  4. Role of prenatal undernutrition in the expression of serotonin, dopamine and leptin receptors in adult mice: Implications of food intake

    PubMed Central

    MANUEL-APOLINAR, LETICIA; ROCHA, LUISA; DAMASIO, LETICIA; TESORO-CRUZ, EMILIANO; ZARATE, ARTURO

    2014-01-01

    Perturbations in the levels of serotonin expression have a significant impact on behavior and have been implicated in the pathogenesis of several neuropsychiatric disorders including anxiety, mood and appetite. Fetal programming is a risk factor for the development of metabolic diseases during adulthood. Moreover, previous studies have shown that serotonin (5-HT), dopamine and leptin are important in energy balance. In the present study, the impact of maternal malnutrition-induced prenatal undernutrition (UN) was investigated in mice and the expression of 5-HT1A, dopamine (D)1, D2 and Ob-Rb receptors was analyzed in the hypothalamus during adulthood. The UN group showed a low birth weight compared with the control group. With regard to receptor expression, 5-HT1A in the UN group was increased in the hypothalamus and D1 was reduced, whereas D2 showed an increase from postnatal day (P)14 in the arcuate nucleus. Ob-Rb receptor expression was increased in the hypothalamus at P14 and P90. These observations indicated that maternal caloric restriction programs a postnatal body weight gain in offspring with an increased food intake in early postnatal life which continues into adulthood. In addition, UN in mice was found to be affected by Ob-Rb, 5-HT1A and D1/2 receptor expression, indicating that these observations may be associated with hyperphagia and obesity. PMID:24337628

  5. Neurotransmitters, psychotropic drugs and microglia: clinical implications for psychiatry.

    PubMed

    Kato, T A; Yamauchi, Y; Horikawa, H; Monji, A; Mizoguchi, Y; Seki, Y; Hayakawa, K; Utsumi, H; Kanba, S

    2013-01-01

    Psychiatric disorders have long and dominantly been regarded to be induced by disturbances of neuronal networks including synapses and neurotransmitters. Thus, the effects of psychotropic drugs such as antipsychotics and antidepressants have been understood to modulate synaptic regulation via receptors and transporters of neurotransmitters such as dopamine and serotonin. Recently, microglia, immunological/inflammatory cells in the brain, have been indicated to have positive links to psychiatric disorders. Positron emission tomography (PET) imaging and postmortem studies have revealed microglial activation in the brain of neuropsychiatric disorders such as schizophrenia, depression and autism. Animal models of neuropsychiatric disorders have revealed the underlying microglial pathologies. In addition, various psychotropic drugs have been suggested to have direct effects on microglia. Until now, the relationship between microglia, neurotransmitters and psychiatric disorders has not been well understood. Therefore, in this review, at first, we summarize recent findings of interaction between microglia and neurotransmitters such as dopamine, serotonin, norepinephrine, acetylcholine and glutamate. Next, we introduce up-to-date knowledge of the effects of psychotropic drugs such as antipsychotics, antidepressants and antiepileptics on microglial modulation. Finally, we propose the possibility that modulating microglia may be a key target in the treatment of various psychiatric disorders. Further investigations and clinical trials should be conducted to clarify this perspective, using animal in vivo studies and imaging studies with human subjects.

  6. Separate serotonin and dopamine receptors modulate the duration of post-tetanic potentiation at an Aplysia synapse without affecting other aspects of synaptic transmission.

    PubMed

    Newlin, S A; Schlapfer, W T; Barondes, S H

    1980-01-06

    We have studied the effect of the biogenic amines, serotonin and dopamine, on post-tetanic potentiation (PTP) at an identified synapse in the abdominal ganglion of Aplysia californica. We found that: (1) 10(-7) M perfused serotonin doubles the rate constant of decay of PTP. The effect is specific in that neither the size of the non-potentiated (isolated) EPSP nor the amplitude of PTP is affected. As reported previously, higher doses of serotonin will also increase the amplitude of PTP and decrease the size of the isolated EPSP; (2) 5 X 10(-7) M dopamine in the perfusate increases the rate constant of decay of PTP by about 50%. The effect is also specific in that neither PTP amplitude nor the size of the isolated EPSP is affected; (3) SQ10,631, a serotonin antagonist, blocks the effect of perfused serotonin on PTP decay rate. It does not antagonize the dopamine effect. SQ10,631 also slows the endogenous decay of PTP in some preparations which exhibit an unusually fast PTP decay rate, suggesting a naturally occurring source of serotonin within the ganglion capable of affecting the rate constant of PTP decay; (4) (+)-butaclamol, a dopamine antagonist, blocks the effect of dopamine on the rate constant of PTP decay, whereas (-)-butaclamol has little effect. Butaclamol does not block the effect of serotonin on the rate constant of PTP decay; (5) phosphodiesterase inhibitors potentiate the effect of serotonin on the rate constant of PTP decay, and cyclic AMP analogues mimic the effect of the biogenic amines, suggesting that the aminergic modulation of the rate of decay of PTP is coupled with activation of adenylate cyclase and accumulation of cyclic AMP; and (6) the evidence presented is consistent with the hypothesis that serotonin and dopamine are capable of specifically modifying the rate of change in the efficacy of transmitter release which underlies PTP. It also suggests that the two biogenic amines operate separately and in parallel via presynaptic receptor

  7. High dose sapropterin dihydrochloride therapy improves monoamine neurotransmitter turnover in murine phenylketonuria (PKU).

    PubMed

    Winn, Shelley R; Scherer, Tanja; Thöny, Beat; Harding, Cary O

    2016-01-01

    Central nervous system (CNS) deficiencies of the monoamine neurotransmitters, dopamine and serotonin, have been implicated in the pathophysiology of neuropsychiatric dysfunction in phenylketonuria (PKU). Increased brain phenylalanine concentration likely competitively inhibits the activities of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), the rate limiting steps in dopamine and serotonin synthesis respectively. Tetrahydrobiopterin (BH4) is a required cofactor for TH and TPH activity. Our hypothesis was that treatment of hyperphenylalaninemic Pah(enu2/enu2) mice, a model of human PKU, with sapropterin dihydrochloride, a synthetic form of BH4, would stimulate TH and TPH activities leading to improved dopamine and serotonin synthesis despite persistently elevated brain phenylalanine. Sapropterin (20, 40, or 100mg/kg body weight in 1% ascorbic acid) was administered daily for 4 days by oral gavage to Pah(enu2/enu2) mice followed by measurement of brain biopterin, phenylalanine, tyrosine, tryptophan and monoamine neurotransmitter content. A significant increase in brain biopterin content was detected only in mice that had received the highest sapropterin dose, 100mg/kg. Blood and brain phenylalanine concentrations were unchanged by sapropterin therapy. Sapropterin therapy also did not alter the absolute amounts of dopamine and serotonin in brain but was associated with increased homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), dopamine and serotonin metabolites respectively, in both wild type and Pah(enu2/enu2) mice. Oral sapropterin therapy likely does not directly affect central nervous system monoamine synthesis in either wild type or hyperphenylalaninemic mice but may stimulate synaptic neurotransmitter release and subsequent metabolism.

  8. Effects of Acute Tryptophan Depletion on Brain Serotonin Function and Concentrations of Dopamine and Norepinephrine in C57BL/6J and BALB/cJ Mice

    PubMed Central

    Biskup, Caroline Sarah; Sánchez, Cristina L.; Arrant, Andrew; Van Swearingen, Amanda E. D.; Kuhn, Cynthia; Zepf, Florian Daniel

    2012-01-01

    Acute tryptophan depletion (ATD) is a method of lowering brain serotonin (5-HT). Administration of large neutral amino acids (LNAA) limits the transport of endogenous tryptophan (TRP) across the blood brain barrier by competition with other LNAAs and subsequently decreases serotonergic neurotransmission. A recent discussion on the specificity and efficacy of the ATD paradigm for inhibition of central nervous 5-HT has arisen. Moreover, side effects such as vomiting and nausea after intake of amino acids (AA) still limit its use. ATD Moja-De is a revised mixture of AAs which is less nauseating than conventional protocols. It has been used in preliminary clinical studies but its effects on central 5-HT mechanisms and other neurotransmitter systems have not been validated in an animal model. We tested ATD Moja-De (TRP−) in two strains of mice: C57BL/6J, and BALB/cJ, which are reported to have impaired 5-HT synthesis and a more anxious phenotype relative to other strains of mice. ATD Moja-De lowered brain TRP, significantly decreased 5-HT synthesis as indexed by 5-HTP levels after decarboxlyase inhibition, and lowered 5-HT and 5-HIAA in both strains of mice, however more so in C57BL/6J than in BALB/cJ. Dopamine and its metabolites as well as norepinephrine were not affected. A balanced (TRP+) control mixture did not raise 5-HT or 5-HIAA. The present findings suggest that ATD Moja-De effectively and specifically suppresses central serotonergic function. These results also demonstrate a strain- specific effect of ATD Moja-De on anxiety-like behavior. PMID:22629305

  9. Serotonin and GABA are colocalized in restricted groups of neurons in the larval sea lamprey brain: insights into the early evolution of neurotransmitter colocalization in vertebrates

    PubMed Central

    Barreiro-Iglesias, Antón; Cornide-Petronio, María Eugenia; Anadón, Ramón; Rodicio, María Celina

    2009-01-01

    Colocalization of the classic neurotransmitters serotonin (5-HT) and γ-aminobutyric acid (GABA) (or the enzyme that synthesizes the latter, glutamate decarboxylase) has been reported in a few neurons of the rat raphe magnus-obscurus nuclei. However, there are no data on the presence of neurochemically similar neurons in the brain of non-mammalian vertebrates. Lampreys are the oldest extant vertebrates and may provide important data on the phylogeny of neurochemical systems. The colocalization of 5-HT and GABA in neurons of the sea lamprey brain was studied using antibodies directed against 5-HT and GABA and confocal microscopy. Colocalization of the neurotransmitters was observed in the diencephalon and the isthmus. In the diencephalon, about 87% of the serotonergic cells of the rostral tier of the dorsal thalamus (close to the zona limitans) exhibited GABA immunoreactivity. In addition, occasional cells double-labelled for GABA and 5-HT were observed in the hypothalamic tuberal nucleus and the pretectum. Of the three serotonergic isthmic subgroups already recognized in the sea lamprey isthmus (dorsal, medial and ventral), such double-labelled cells were only observed in the ventral subgroup (about 61% of the serotonergic cells in the ventral subgroup exhibited GABA immunoreactivity). An equivalence between these lamprey isthmic cells and the serotonergic/GABAergic raphe cells of mammals is suggested. Present findings suggest that serotonergic/GABAergic neurons are more extensive in lampreys than in the rat and probably appeared before the separation of agnathans and gnathostomes. Cotransmission by release of 5-HT and GABA by the here-described lamprey brain neurons is proposed. PMID:19552725

  10. Polyethylenimine Carbon Nanotube Fiber Electrodes for Enhanced Detection of Neurotransmitters

    PubMed Central

    2015-01-01

    Carbon nanotube (CNT)-based microelectrodes have been investigated as alternatives to carbon-fiber microelectrodes for the detection of neurotransmitters because they are sensitive, exhibit fast electron transfer kinetics, and are more resistant to surface fouling. Wet spinning CNTs into fibers using a coagulating polymer produces a thin, uniform fiber that can be fabricated into an electrode. CNT fibers formed in poly(vinyl alcohol) (PVA) have been used as microelectrodes to detect dopamine, serotonin, and hydrogen peroxide. In this study, we characterize microelectrodes with CNT fibers made in polyethylenimine (PEI), which have much higher conductivity than PVA-CNT fibers. PEI-CNT fibers have lower overpotentials and higher sensitivities than PVA-CNT fiber microelectrodes, with a limit of detection of 5 nM for dopamine. The currents for dopamine were adsorption controlled at PEI-CNT fiber microelectrodes, independent of scan repetition frequency, and stable for over 10 h. PEI-CNT fiber microelectrodes were resistant to surface fouling by serotonin and the metabolite interferant 5-hydroxyindoleacetic acid (5-HIAA). No change in sensitivity was observed for detection of serotonin after 30 flow injection experiments or after 2 h in 5-HIAA for PEI-CNT electrodes. The antifouling properties were maintained in brain slices when serotonin was exogenously applied multiple times or after bathing the slice in 5-HIAA. Thus, PEI-CNT fiber electrodes could be useful for the in vivo monitoring of neurochemicals. PMID:25117550

  11. Serotonin-dopamine antagonism ameliorates impairments of spontaneous alternation and locomotor hyperactivity induced by repeated electroconvulsive seizures in rats.

    PubMed

    Hidaka, Noriaki; Suemaru, Katsuya; Araki, Hiroaki

    2010-08-01

    We have shown that seven consecutive administrations of electroconvulsive shock (ECS) produce impairment of spontaneous alternation behavior in a Y-maze test and a locomotor hyperactivity in an open-field test even 24h after the last administration in rats. To clarify the mechanisms of the behavioral impairments, we investigated the effect of drugs acting on dopaminergic and serotonergic nervous systems. The dopamine-2 (D(2)) receptor antagonists haloperidol and sulpiride abolished locomotor hyperactivity, but did not show effects on the impairment of spontaneous alternation behavior. The serotonin-2 (5-HT(2)) receptor antagonist ketanserin suppressed the impairment of spontaneous alternation behavior without affecting locomotor hyperactivity. The 5-HT(2) and D(2) receptor antagonist risperidone significantly ameliorated both behavioral impairments. These results suggest that 5-HT(2) receptors and D(2) receptors are associated with repeated ECS-induced impairment of spontaneous alternation behavior and locomotor hyperactivity, respectively.

  12. A carbon nanofiber based biosensor for simultaneous detection of dopamine and serotonin in the presence of ascorbic acid.

    PubMed

    Rand, Emily; Periyakaruppan, Adaikkappan; Tanaka, Zuki; Zhang, David A; Marsh, Michael P; Andrews, Russell J; Lee, Kendall H; Chen, Bin; Meyyappan, M; Koehne, Jessica E

    2013-04-15

    A biosensor based on an array of vertically aligned carbon nanofibers (CNFs) grown by plasma enhanced chemical vapor deposition is found to be effective for the simultaneous detection of dopamine (DA) and serotonin (5-HT) in the presence of excess ascorbic acid (AA). The CNF electrode outperforms the conventional glassy carbon electrode (GCE) for both selectivity and sensitivity. Using differential pulse voltammetry (DPV), three distinct peaks are seen for the CNF electrode at 0.13 V, 0.45 V, and 0.70 V for the ternary mixture of AA, DA, and 5-HT. In contrast, the analytes are indistinguishable in a mixture using a GCE. For the CNF electrode, the detection limits are 50 nM for DA and 250 nM for 5-HT.

  13. The role of endogenous serotonin in methamphetamine-induced neurotoxicity to dopamine nerve endings of the striatum.

    PubMed

    Thomas, David M; Angoa Pérez, Mariana; Francescutti-Verbeem, Dina M; Shah, Mrudang M; Kuhn, Donald M

    2010-11-01

    Methamphetamine (METH) is a neurotoxic drug of abuse that damages the dopamine (DA) neuronal system in a highly delimited manner. The brain structure most affected by METH is the striatum where long-term DA depletion and microglial activation are maximal. Endogenous DA has been implicated as a critical participant in METH-induced neurotoxicity, most likely as a substrate for non-enzymatic oxidation by METH-generated reactive oxygen species. The striatum is also extensively innervated by serotonin (5HT) nerve endings and this neurochemical system is modified by METH in much the same manner as seen in DA nerve endings (i.e., increased release of 5HT, loss of function in tryptophan hydroxylase and the serotonin transporter, long-term depletion of 5HT stores). 5HT can also be modified by reactive oxygen species to form highly reactive species that damage neurons but its role in METH neurotoxicity has not been assessed. Increases in 5HT levels with 5-hydroxytryptophan do not change METH-induced neurotoxicity to the DA nerve endings as revealed by reductions in DA, tyrosine hydroxylase and dopamine transporter levels. Partial reductions in 5HT with p-chlorophenylalanine are without effect on METH toxicity, despite the fact that p-chlorophenylalanine largely prevents METH-induced hyperthermia. Mice lacking the gene for brain tryptophan hydroxylase 2 are devoid of brain 5HT and respond to METH in the same manner as wild-type controls, despite showing enhanced drug-induced hyperthermia. Taken together, the present results indicate that endogenous 5HT does not appear to play a role in METH-induced damage to DA nerve endings of the striatum.

  14. Association study of 37 genes related to serotonin and dopamine neurotransmission and neurotrophic factors in cocaine dependence.

    PubMed

    Fernàndez-Castillo, N; Roncero, C; Grau-Lopez, L; Barral, C; Prat, G; Rodriguez-Cintas, L; Sánchez-Mora, C; Gratacòs, M; Ramos-Quiroga, J A; Casas, M; Ribasés, M; Cormand, B

    2013-02-01

    Cocaine dependence is a neuropsychiatric disorder in which both environmental and genetic factors are involved. Several processes, that include reward and neuroadaptations, mediate the transition from use to dependence. In this regard, dopamine and serotonin neurotransmission systems are clearly involved in reward and other cocaine-related effects, whereas neurotrophic factors may be responsible for neuroadaptations associated with cocaine dependence. We examined the contribution to cocaine dependence of 37 genes related to the dopaminergic and serotoninergic systems, neurotrophic factors and their receptors through a case-control association study with 319 single nucleotide polymorphisms selected according to genetic coverage criteria in 432 cocaine-dependent patients and 482 sex-matched unrelated controls. Single marker analyses provided evidence for association of the serotonin receptor HTR2A with cocaine dependence [rs6561333; nominal P-value adjusted for age = 1.9e-04, odds ratio = 1.72 (1.29-2.30)]. When patients were subdivided according to the presence or absence of psychotic symptoms, we confirmed the association between cocaine dependence and HTR2A in both subgroups of patients. Our data show additional evidence for the involvement of the serotoninergic system in the genetic susceptibility to cocaine dependence.

  15. Pharmacological and Behavioral Characterization of D-473, an Orally Active Triple Reuptake Inhibitor Targeting Dopamine, Serotonin and Norepinephrine Transporters

    PubMed Central

    Dutta, Aloke K.; Santra, Soumava; Sharma, Horrick; Voshavar, Chandrashekhar; Xu, Liping; Mabrouk, Omar; Antonio, Tamara; Reith, Maarten E. A.

    2014-01-01

    Major depressive disorder (MDD) is a debilitating disease affecting a wide cross section of people around the world. The current therapy for depression is less than adequate and there is a considerable unmet need for more efficacious treatment. Dopamine has been shown to play a significant role in depression including production of anhedonia which has been one of the untreated symptoms in MDD. It has been hypothesized that drugs acting at all three monoamine transporters including dopamine transporter should provide more efficacious antidepressants activity. This has led to the development of triple reuptake inhibitor D-473 which is a novel pyran based molecule and interacts with all three monoamine transporters. The monoamine uptake inhibition activity in the cloned human transporters expressed in HEK-293 cells (70.4, 9.18 and 39.7 for DAT, SERT and NET, respectively) indicates a serotonin preferring triple reuptake inhibition profile for this drug. The drug D-473 exhibited good brain penetration and produced efficacious activity in rat forced swim test under oral administration. The optimal efficacy dose did not produce any locomotor activation. Microdialysis experiment demonstrated that systemic administration of D-473 elevated extracellular level of the three monoamines DA, 5-HT, and NE efficaciously in the dorsal lateral striatum (DLS) and the medial prefrontal cortex (mPFC) area, indicating in vivo blockade of all three monoamine transporters by D-473. Thus, the current biological data from D-473 indicate potent antidepressant activity of the molecule. PMID:25427177

  16. Photo-renewable electroanalytical sensor for neurotransmitters detection in body fluid mimics.

    PubMed

    Pifferi, Valentina; Soliveri, Guido; Panzarasa, Guido; Cappelletti, Giuseppe; Meroni, Daniela; Falciola, Luigi

    2016-10-01

    A composite electrode with a sandwich structure combining the properties of silver nanoparticles and a titania photoactive layer was used for the electroanalytical detection, by differential pulse voltammetry, of three neurotransmitters: dopamine, norepinephrine, and serotonin. The three analytes were determined at low detection limits (around 0.03 μM) also in the presence of conventional interferents, such as uric and ascorbic acids. The fouling of the electrode surface was overcome by irradiating the device with UVA light, restoring the initial sensor sensitivity. Dopamine, norepinephrine, and serotonin were determined also in simulated biological matrices: liquor (artificially reproduced cerebrospinal fluid) and serum. Moreover, the contemporaneous detection of dopamine and norepinephrine in simulated human urine solutions was also demonstrated, representing the first step towards clinical applications of the proposed methodology. Graphical abstract The photo-renewable electroanalytical sensor.

  17. Detection and Monitoring of Neurotransmitters - a Spectroscopic Analysis

    NASA Astrophysics Data System (ADS)

    Manciu, Felicia; Lee, Kendall; Durrer, William; Bennet, Kevin

    2012-10-01

    In this work we demonstrate the capability of confocal Raman mapping spectroscopy for simultaneously and locally detecting important compounds in neuroscience such as dopamine, serotonin, and adenosine. The Raman results show shifting of the characteristic vibrations of the compounds, observations consistent with previous spectroscopic studies. Although some vibrations are common in these neurotransmitters, Raman mapping was achieved by detecting non-overlapping characteristic spectral signatures of the compounds, as follows: for dopamine the vibration attributed to C-O stretching, for serotonin the indole ring stretching vibration, and for adenosine the adenine ring vibrations. Without damage, dyeing, or preferential sample preparation, confocal Raman mapping provided positive detection of each neurotransmitter, allowing association of the high-resolution spectra with specific micro-scale image regions. Such information is particularly important for complex, heterogeneous samples, where modification of the chemical or physical composition can influence the neurotransmission processes. We also report an estimated dopamine diffusion coefficient two orders of magnitude smaller than that calculated by the flow-injection method.

  18. Radiotracers for PET and SPECT studies of neurotransmitter systems

    SciTech Connect

    Fowler, J.S.

    1991-01-01

    The study of neurotransmitter systems is one of the major thrusts in emission tomography today. The current generation of Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) radiotracers examines neurotransmitter properties from a number of different perspectives including their pre and post synaptic sites and the activity of the enzymes which regulate their concentration. Although the dopamine system has been the most extensively investigated, other neurotransmitter systems including the acetylcholine muscarine, serotonin, benzodiazepine, opiate, NMDA and others are also under intensive development. Enzymes involved in the synthesis and regulation of neurotransmitter concentration, for example monoamine oxidase and amino acid decarboxylase has also been probed in vivo. Medical applications range from the study of normal function and the characterization of neurotransmitter activity in neurological and psychiatric diseases and in heart disease and cancer to the study of the binding of therapeutic drugs and substances of abuse. This chapter will provide an overview of the current generation of radiotracers for PET and SPECT studies of neurotransmitter systems including radiotracer design, synthesis localization mechanisms and applications in emission tomography. 60 refs., 1 tab.

  19. Association of dopamine- and serotonin-related genes with canine aggression.

    PubMed

    Våge, J; Wade, C; Biagi, T; Fatjó, J; Amat, M; Lindblad-Toh, K; Lingaas, F

    2010-06-01

    Human-directed canine aggression was studied using 50 aggressive and 81 non-aggressive dogs. We examined 62 single nucleotide polymorphisms (SNPs) occurring in or in the close vicinity of 16 neurotransmitter-related genes. Allelic associations with aggression were identified for DRD1, HTR1D, HTR2C and SLC6A1. Risk or protective haplotypes for aggressive behaviour based on 2-5 SNPs were identified. The frequency of aggressive dogs varied significantly between the haplotypes within loci and the odds ratios of aggression in dogs with risk haplotypes compared with protective haplotypes varied from 4.4 (HTR2C) to 9.0 (SLC6A1). A risk haplotype across the neurotransmitter receptor gene HTR1D harboured a non-synonymous SNP with a potential effect on protein function. We identified no haplotypes in complete association with the recorded phenotypes, supporting a complex inheritance of aggression.

  20. Associations between Dopamine and Serotonin Genes and Job Satisfaction: Preliminary Evidence from the Add Health Study

    ERIC Educational Resources Information Center

    Song, Zhaoli; Li, Wendong; Arvey, Richard D.

    2011-01-01

    Previous behavioral genetic studies have found that job satisfaction is partially heritable. We went a step further to examine particular genetic markers that may be associated with job satisfaction. Using an oversample from the National Adolescent Longitudinal Study (Add Health Study), we found 2 genetic markers, dopamine receptor gene DRD4 VNTR…

  1. Neurotransmitters in the Gas Phase: La-Mb Studies

    NASA Astrophysics Data System (ADS)

    Cabezas, C.; Mata, S.; López, J. C.; Alonso, J. L.

    2011-06-01

    LA-MB-FTMW spectroscopy combines laser ablation with Fourier transform microwave spectroscopy in supersonic jets overcoming the problems of thermal decomposition associated with conventional heating methods. We present here the results on LA-MB-FTMW studies of some neurotransmitters. Six conformers of dopamine, four of adrenaline, five of noradrenaline and three conformers of serotonin have been characterized in the gas phase. The rotational and nuclear quadrupole coupling constants extracted from the analysis of the rotational spectrum are directly compared with those predicted by ab initio methods to achieve the conclusive identification of different conformers and the experimental characterization of the intramolecular forces at play which control conformational preferences.

  2. Pharmacogenetic study of antipsychotic induced acute extrapyramidal symptoms in a first episode psychosis cohort: role of dopamine, serotonin and glutamate candidate genes.

    PubMed

    Mas, S; Gassó, P; Lafuente, A; Bioque, M; Lobo, A; Gonzàlez-Pinto, A; Olmeda, M S; Corripio, I; Llerena, A; Cabrera, B; Saiz-Ruiz, J; Bernardo, M

    2016-10-01

    This study investigated whether the risk of presenting antipsychotic (AP)-induced extrapyramidal symptoms (EPS) could be related to single-nucleotide polymorphisms (SNPs) in a naturalistic cohort of first episode psychosis (FEP) patients. Two hundred and two SNPs in 31 candidate genes (involved in dopamine, serotonin and glutamate pathways) were analyzed in the present study. One hundred and thirteen FEP patients (43 presenting EPS and 70 non-presenting EPS) treated with high-potency AP (amisulpride, paliperidone, risperidone and ziprasidone) were included in the analysis. The statistical analysis was adjusted by age, gender, AP dosage, AP combinations and concomitant treatments as covariates. Four SNPs in different genes (DRD2, SLC18A2, HTR2A and GRIK3) contributed significantly to the risk of EPS after correction for multiple testing (P<1 × 10(-4)). These findings support the involvement of dopamine, serotonin and glutamate pathways in AP-induced EPS.

  3. Identification and developmental expression of the enzymes responsible for dopamine, histamine, octopamine and serotonin biosynthesis in the copepod crustacean Calanus finmarchicus.

    PubMed

    Christie, Andrew E; Fontanilla, Tiana M; Roncalli, Vittoria; Cieslak, Matthew C; Lenz, Petra H

    2014-01-01

    Neurochemicals are likely to play key roles in physiological/behavioral control in the copepod crustacean Calanus finmarchicus, the biomass dominant zooplankton for much of the North Atlantic Ocean. Previously, a de novo assembled transcriptome consisting of 206,041 unique sequences was used to characterize the peptidergic signaling systems of Calanus. Here, this assembly was mined for transcripts encoding enzymes involved in amine biosynthesis. Using known Drosophila melanogaster proteins as templates, transcripts encoding putative Calanus homologs of tryptophan-phenylalanine hydroxylase (dopamine, octopamine and serotonin biosynthesis), tyrosine hydroxylase (dopamine biosynthesis), DOPA decarboxylase (dopamine and serotonin biosynthesis), histidine decarboxylase (histamine biosynthesis), tyrosine decarboxylase (octopamine biosynthesis), tyramine β-hydroxylase (octopamine biosynthesis) and tryptophan hydroxylase (serotonin biosynthesis) were identified. Reverse BLAST and domain analyses show that the proteins deduced from these transcripts possess sequence homology to and the structural hallmarks of their respective enzyme families. Developmental profiling revealed a remarkably consistent pattern of expression for all transcripts, with the highest levels of expression typically seen in the early nauplius and early copepodite. These expression patterns suggest roles for amines during development, particularly in the metamorphic transitions from embryo to nauplius and from nauplius to copepodite. Taken collectively, the data presented here lay a strong foundation for future gene-based studies of aminergic signaling in this and other copepod species, in particular assessment of the roles they may play in developmental control.

  4. Identification and developmental expression of the enzymes responsible for dopamine, histamine, octopamine and serotonin biosynthesis in the copepod crustacean Calanus finmarchicus

    PubMed Central

    Christie, Andrew E.; Fontanilla, Tiana M.; Roncalli, Vittoria; Cieslak, Matthew C.; Lenz, Petra H.

    2013-01-01

    Neurochemicals are likely to play key roles in physiological/behavioral control in the copepod crustacean Calanus finmarchicus, the biomass dominant zooplankton for much of the North Atlantic Ocean. Previously, a de novo assembled transcriptome consisting of 206,041 unique sequences was used to characterize the peptidergic signaling systems of Calanus. Here, this assembly was mined for transcripts encoding enzymes involved in amine biosynthesis. Using known Drosophila melanogaster proteins as templates, transcripts encoding putative Calanus homologs of tryptophan-phenylalanine hydroxylase (dopamine, octopamine and serotonin biosynthesis), tyrosine hydroxylase (dopamine biosynthesis), DOPA decarboxylase (dopamine and serotonin biosynthesis), histidine decarboxylase (histamine biosynthesis), tyrosine decarboxylase (octopamine biosynthesis), tyramine β-hydroxylase (octopamine biosynthesis) and tryptophan hydroxylase (serotonin biosynthesis) were identified. Reverse BLAST and domain analyses show that the proteins deduced from these transcripts possess sequence homology to and the structural hallmarks of their respective enzyme families. Developmental profiling revealed a remarkably consistent pattern of expression for all transcripts, with the highest levels of expression typically seen in the early nauplius and early copepodite. These expression patterns suggest roles for amines during development, particularly in the metamorphic transitions from embryo to nauplius and from nauplius to copepodite. Taken collectively, the data presented here lay a strong foundation for future gene-based studies of aminergic signaling in this and other copepod species, in particular assessment of the roles they may play in developmental control. PMID:24148657

  5. Carbon fiber nanoelectrodes applied to microchip electrophoresis amperometric detection of neurotransmitter dopamine in rat pheochromocytoma (PC12) cells.

    PubMed

    Cheng, Han; Huang, Wei-Hua; Chen, Rong-Sheng; Wang, Zong-Li; Cheng, Jie-Ke

    2007-05-01

    Microelectrodes have been adopted in electrochemical detection for CE or microchip CE in recent years. In this paper, the use of nanoelectrodes (with tip diameter of 100-300 nm) as the electrochemical detector in microchip CE is firstly reported. The experimental results indicated that both the sensitivity and resolution of microchip CE with the carbon fiber nanoelectrode (CFNE) amperometric detection have been improved markedly comparing with the traditional microelectrodes. The detection limit of dopamine (S/N = 3) is 5.9x10(-8) M, which is one or two orders of magnitude lower than that reported so far, and the resolution of dopamine (DA) and isoprenaline (IP) has also improved from 0.6 (using 7 mum carbon fiber microelectrodes, CFME) to 1.0. We assembled a novel and easily operated microchip CE system with end-column amperometric detection, which allows the convenient and fast replacement of the passivated electrodes. Under the optimized condition, the RSDs of peak height and migration time are 1.47 and 0.31%, respectively (n = 40), indicating that the system displays excellent reproducibility. The nanoelectrode-based microchip CE system has been successfully applied to the determination of DA in cultured rat pheochromocytoma (PC12) cells, and the average content of DA in an individual PC12 cell is 0.54 +/- 0.07 fmol, which is in good agreement with that reported in the literature.

  6. Effects of AT1 receptor antagonism on kainate-induced seizures and concomitant changes in hippocampal extracellular noradrenaline, serotonin, and dopamine levels in Wistar-Kyoto and spontaneously hypertensive rats.

    PubMed

    Tchekalarova, Jana; Loyens, Ellen; Smolders, Ilse

    2015-05-01

    In the management of epilepsy, AT1 receptor antagonists have been suggested as an additional treatment strategy. A hyperactive brain angiotensin (Ang) II system and upregulated AT1 receptors are implicated in the cerebrovascular alterations in a genetic form of hypertension. Uncontrolled hypertension could also, in turn, be a risk factor for a seizure threshold decrease and development of epileptogenesis. The present study aimed to assess the effects of the selective AT1 receptor antagonist ZD7155 on kainic acid (KA)-induced status epilepticus (SE) development and accompanying changes in the hippocampal extracellular (EC) neurotransmitter levels of noradrenaline (NAD), serotonin (5-HT), and dopamine (DA) in spontaneously hypertensive rats (SHRs) and their parent strain Wistar-Kyoto (WKY) rats, since monoamines are well-known neurotransmitters involved in mechanisms of both epilepsy and hypertension. Status epilepticus was evoked in freely moving rats by a repetitive intraperitoneal (i.p.) administration of KA in subconvulsant doses. In the treatment group, ZD7155 (5mg/kg i.p.) was coadministered with the first KA injection. Spontaneously hypertensive rats exhibited higher susceptibility to SE than WKY rats, but the AT1 receptor antagonist did not alter the development of SE in SHRs or in WKY rats. In vivo microdialysis demonstrated significant KA-induced increases of the hippocampal NAD and DA levels in SHRs and of NAD, 5-HT, and DA in WKY rats. Although SHRs developed more severe seizures while receiving a lower dose of KA compared to WKY rats, AT1 receptor antagonism completely prevented all KA-induced increases of hippocampal monoamine levels in both rat strains without affecting seizure development per se. These results suggest a lack of direct relationship between KA-induced seizure susceptibility and adaptive changes of hippocampal NAD, 5-HT, and DA levels in the effects of ZD7155 in WKY rats and SHRs.

  7. Ionotropic and metabotropic activation of a neuronal chloride channel by serotonin and dopamine in the leech Hirudo medicinalis

    PubMed Central

    Ali, Declan W; Catarsi, Stefano; Drapeau, Pierre

    1998-01-01

    Cl− channels on the pressure-sensitive (P) neuron in the leech are directly activated by synaptic release of serotonin (5-HT) and are indirectly stimulated by the cAMP second messenger pathway, suggesting an unusual dual regulation of the channels. We have investigated the mode of action of 5-HT and dopamine (DA) on a Cl− channel in adult P cells in culture by recording from cell-attached patches.5-HT increased Cl− channel activity only when included in the recording pipette and not when applied in the bath.Pipette or, more effectively, bath application of DA led to an increase in Cl− channel activity. This effect was blocked by the potent and specific dopaminergic (DA1) receptor blocker, SCH-23390.The stimulation by DA, but not by 5-HT, was also blocked by the cAMP-dependent protein kinase A (PKA) inhibitor Rp-cAMP and was mimicked by the membrane-permeant cAMP analogue dibutyryl cAMP (db-cAMP).Our results show that 5-HT directly gates a Cl− channel that is also activated by DA via the cAMP pathway. This study demonstrates that a ligand-gated channel can be independently operated by another transmitter acting via a second messenger pathway. PMID:9547394

  8. Essential Roles of Dopamine and Serotonin in Tooth Repair: Functional Interplay Between Odontogenic Stem Cells and Platelets.

    PubMed

    Baudry, Anne; Alleaume-Butaux, Aurélie; Dimitrova-Nakov, Sasha; Goldberg, Michel; Schneider, Benoît; Launay, Jean-Marie; Kellermann, Odile

    2015-08-01

    Characterizing stem cell intrinsic functions is an ongoing challenge for cell therapies. Here, we report that two independent A4 and H8 stem cell lines isolated from mouse molar pulp display the overall functions of bioaminergic cells. Both clones produce neurotrophins and synthesize, catabolize, store, and transport serotonin (5-hydroxytryptamine [5-HT]) and dopamine (DA). They express 5-HT1D,2B,7 and D1,3 autoreceptors, which render pulpal stem cells competent to respond to circulating 5-HT and DA. We show that injury-activated platelets are the source of systemic 5-HT and DA necessary for dental repair since natural dentin reparation is impaired in two rat models with monoamine storage-deficient blood platelets. Moreover, selective inhibition of either D1, D3, 5-HT2B, or 5-HT7 receptor within the pulp of wild-type rat molars after lesion alters the reparative process. Altogether our data argue that 5-HT and DA coreleased by pulp injury-activated platelets are critical for stem cell-mediated dental repair through 5-HT and DA receptor signalings.

  9. In vivo assessment of dopamine and serotonin receptors measured by C-11 n-methylspiperone (NMSP) in patients with schizophrenia

    SciTech Connect

    Wong, D.F.; Tune, L.E.; Wagner, H.N. Jr.; Suneja, S.; Bjorvinsson, E.; Pearlson, G.; Dannals, R.F.; Ravert, H.T.; Wilson, A.A.; Links, J.M.

    1985-05-01

    The authors carried out PET imaging with C-11 NMSP in 13 pts. diagnosed as chronic schizophrenic by (DSM 3) criteria. They had no detectable serum neuroleptics by radioassay at the time of the scan. No pt. had received a neuroleptic for at least 1 week before study, with an avg. abstinence of 7 mo. One had never been on neuroleptics. During the time of scanning, 8/13 had delusions and hallucinations. There was no statistically significant difference from 44 age and sex matched control subjects for the 43 min. Caudate/cerebellar ratio, or the Frontal/Cerebellar ratio, both measures of relative dopamine D2, and serotonin S2 binding. These preliminary studies suggest that these drug free pts. show no large differences in the receptor levels compared to normal data. Differences from in vitro data could be due to: differences in duration of illness (the avg. 10.3) yrs.; difference in age (our pts. vg. 32.7 are much younger than those dying with schizophrenia); drug induced effects at death or persistent neuroleptic effect in our pts.; or difference in method.

  10. From linked open data to molecular interaction: studying selectivity trends for ligands of the human serotonin and dopamine transporter.

    PubMed

    Zdrazil, Barbara; Hellsberg, Eva; Viereck, Michael; Ecker, Gerhard F

    2016-09-14

    Retrieval of congeneric and consistent SAR data sets for protein targets of interest is still a laborious task to do if no appropriate in-house data set is available. However, combining integrated open data sources (such as the Open PHACTS Discovery Platform) with workflow tools now offers the possibility of querying across multiple domains and tailoring the search to the given research question. Starting from two phylogenetically related protein targets of interest (the human serotonin and dopamine transporters), the whole chemical compound space was explored by implementing a scaffold-based clustering of compounds possessing biological measurements for both targets. In addition, potential hERG blocking liabilities were included. The workflow allowed studying the selectivity trends of scaffold series, identifying potentially harmful compound series, and performing SAR, docking studies and molecular dynamics (MD) simulations for a consistent data set of 56 cathinones. This delivered useful insights into driving determinants for hDAT selectivity over hSERT. With respect to the scaffold-based analyses it should be noted that the cathinone data set could be retrieved only when Murcko scaffold analyses were combined with similarity searches such as a common substructure search.

  11. MPA-capped CdTe quantum dots exposure causes neurotoxic effects in nematode Caenorhabditis elegans by affecting the transporters and receptors of glutamate, serotonin and dopamine at the genetic level, or by increasing ROS, or both

    NASA Astrophysics Data System (ADS)

    Wu, Tianshu; He, Keyu; Zhan, Qinglin; Ang, Shengjun; Ying, Jiali; Zhang, Shihan; Zhang, Ting; Xue, Yuying; Tang, Meng

    2015-12-01

    As quantum dots (QDs) are widely used in biomedical applications, the number of studies focusing on their biological properties is increasing. While several studies have attempted to evaluate the toxicity of QDs towards neural cells, the in vivo toxic effects on the nervous system and the molecular mechanisms are unclear. The aim of the present study was to investigate the neurotoxic effects and the underlying mechanisms of water-soluble cadmium telluride (CdTe) QDs capped with 3-mercaptopropionic acid (MPA) in Caenorhabditis elegans (C. elegans). Our results showed that exposure to MPA-capped CdTe QDs induced behavioral defects, including alterations to body bending, head thrashing, pharyngeal pumping and defecation intervals, as well as impaired learning and memory behavior plasticity, based on chemotaxis or thermotaxis, in a dose-, time- and size-dependent manner. Further investigations suggested that MPA-capped CdTe QDs exposure inhibited the transporters and receptors of glutamate, serotonin and dopamine in C. elegans at the genetic level within 24 h, while opposite results were observed after 72 h. Additionally, excessive reactive oxygen species (ROS) generation was observed in the CdTe QD-treated worms, which confirmed the common nanotoxicity mechanism of oxidative stress damage, and might overcome the increased gene expression of neurotransmitter transporters and receptors in C. elegans induced by long-term QD exposure, resulting in more severe behavioral impairments.

  12. Acute effects of tianeptine on circulating neurotransmitters and cardiovascular parameters.

    PubMed

    Lechin, Fuad; van der Dijs, Bertha; Hernández, Gerardo; Orozco, Beatriz; Rodríguez, Simon; Baez, Scarlet

    2006-03-01

    Tianeptine is a serotonin-uptake enhancer drug whose antidepressant effectiveness is based on its ability to reduce rather than increase serotonin availability at the synaptic cleft. This paradoxical neuropharmacological mechanism has raised doubt among neuropharmacologists and psychiatrists as to the role of tianeptine as a trusty-reliable antidepressant drug. This controversial issue led us to investigate the acute effects of a single, oral dose (12.5 mg) of this drug on circulating neurotransmitters and cardiovascular parameters in 50 healthy subjects. The drug provoked a striking and significant reduction of plasma noradrenaline (NA) and plasma serotonin (f-5-HT) while it increased plasma dopamine (DA) and platelet serotonin (p-5-HT) concentrations within the 4-h study period. No adrenaline (Ad) changes were registered. The NA/Ad ratio and the f-5-HT/p-5-HT ratio showed significant reduction throughout the test. Finally, although diastolic blood pressure (DBP) showed significant decrease, neither systolic blood pressure (SBP) nor heart rate (HR) showed significant change. These findings are consistent with the postulation that tianeptine reduces both neural sympathetic activity and parasympathetic activity without affecting adrenal sympathetic activity, enabling us to discuss the possible mechanisms involved in the antidepressant effects of tianeptine. The well-known fact that major depressed patients always show raised NA plus lower than normal p-5-HT levels, both disorders which are normalized by tianeptine, gives neurochemical support to the clinical improvement triggered by the drug in these patients. Summarizing, the results presented in this study demonstrate that tianeptine triggers significant reduction of circulating noradrenaline and plasma serotonin while increasing circulating dopamine and platelet serotonin. Other possible neuropharmacological effects are also discussed.

  13. Serotonin- and Dopamine-Related Gene Expression in db/db Mice Islets and in MIN6 β-Cells Treated with Palmitate and Oleate

    PubMed Central

    Cataldo, L. R.; Olmos, P.; Galgani, J. E.; Valenzuela, R.; Aranda, E.; Cortés, V. A.; Santos, J. L.

    2016-01-01

    High circulating nonesterified fatty acids (NEFAs) concentration, often reported in diabetes, leads to impaired glucose-stimulated insulin secretion (GSIS) through not yet well-defined mechanisms. Serotonin and dopamine might contribute to NEFA-dependent β-cell dysfunction, since extracellular signal of these monoamines decreases GSIS. Moreover, palmitate-treated β-cells may enhance the expression of the serotonin receptor Htr2c, affecting insulin secretion. Additionally, the expression of monoamine-oxidase type B (Maob) seems to be lower in islets from humans and mice with diabetes compared to nondiabetic islets, which may lead to increased monoamine concentrations. We assessed the expression of serotonin- and dopamine-related genes in islets from db/db and wild-type (WT) mice. In addition, the effect of palmitate and oleate on the expression of such genes, 5HT content, and GSIS in MIN6 β-cell was determined. Lower Maob expression was found in islets from db/db versus WT mice and in MIN6 β-cells in response to palmitate and oleate treatment compared to vehicle. Reduced 5HT content and impaired GSIS in response to palmitate (−25%; p < 0.0001) and oleate (−43%; p < 0.0001) were detected in MIN6 β-cells. In conclusion, known defects of GSIS in islets from db/db mice and MIN6 β-cells treated with NEFAs are accompanied by reduced Maob expression and reduced 5HT content. PMID:27366756

  14. Early toxic effect of 6-hydroxydopamine on extracellular concentrations of neurotransmitters in the rat striatum: an in vivo microdialysis study.

    PubMed

    Tobón-Velasco, Julio César; Silva-Adaya, Daniela; Carmona-Aparicio, Liliana; García, Esperanza; Galván-Arzate, Sonia; Santamaría, Abel

    2010-12-01

    The early effects of 6-OHDA as a Parkinsonian model in rodents are relevant since pharmacological and toxicological points of view, as they can explain the acute and chronic deleterious events occurring in the striatum. In this study, we focused our attention on the neurochemical and motor dysfunction produced after a pulse infusion of 6-OHDA, paying special attention to the capacity of this molecule to induce neurotransmitter release and behavioural alterations. Extracellular levels of dopamine, serotonin, norepinephrine, glutamate, glutamine, aspartate, glycine and GABA were all assessed in striatal dialysates in freely moving rats immediately after exposed to a single pulse of 6-OHDA in dorsal striatum, and major behavioural markers of motor alterations were simultaneously explored. Enhanced release of dopamine, serotonin and norepinephrine was found immediately after 6-OHDA pulse. Delayed glutamate and glycine release were detected and a biphasic effect on GABA was observed. Mostly serotonin and dopamine outflow, followed by glutamate, correlated with wet dog shakes and other behavioural qualitative alterations. Early dopamine release, accompanied by other neurotransmitters, can generate an excitatory environment affecting the striatal neurons with immediate consequences for behavioural performance. In turn, these changes might be accounting for later features of toxicity described in this model.

  15. Orquestic regulation of neurotransmitters on reward-seeking behavior

    PubMed Central

    2014-01-01

    The ventral tegmental area is strongly associated with the reward system. Dopamine is released in areas such as the nucleus accumbens and prefrontal cortex as a result of rewarding experiences such as food, sex, and neutral stimuli that become associated with them. Electrical stimulation of the ventral tegmental area or its output pathways can itself serve as a potent reward. Different drugs that increase dopamine levels are intrinsically rewarding. Although the dopaminergic system represent the cornerstone of the reward system, other neurotransmitters such as endogenous opioids, glutamate, γ-Aminobutyric acid, acetylcholine, serotonin, adenosine, endocannabinoids, orexins, galanin and histamine all affect this mesolimbic dopaminergic system. Consequently, genetic variations of neurotransmission are thought influence reward processing that in turn may affect distinctive social behavior and susceptibility to addiction. Here, we discuss current evidence on the orquestic regulation of different neurotranmitters on reward-seeking behavior and its potential effect on drug addiction. PMID:25061480

  16. Serotonin levels in the dorsal raphe nuclei of both chipmunks and mice are enhanced by long photoperiod, but brain dopamine level response to photoperiod is species-specific.

    PubMed

    Goda, Ryosei; Otsuka, Tsuyoshi; Iwamoto, Ayaka; Kawai, Misato; Shibata, Satomi; Furuse, Mitsuhiro; Yasuo, Shinobu

    2015-04-23

    Seasonal affective disorder (SAD) is a subtype of major depressive or bipolar disorders associated with the shortened photoperiod in winter. This depressive disorder is integrally tied to the seasonal regulation of the brain's serotonergic system. Recently, we found that C57BL/6J mice subjected to a forced-swim test exhibited immobility, a photoperiod-dependent depression-associated behavior, and suppression of brain serotonin levels. However, mice are nocturnal animals, and it is unclear whether the brain serotonergic system responds similarly to photoperiod in nocturnal and diurnal species. This study compared the responses of brain serotonergic and dopaminergic systems to photoperiod in diurnal chipmunks and nocturnal C57BL/6J mice. In both species, serotonin levels in the dorsal raphe nuclei were higher under long-day conditions than short-day conditions, suggesting a similarity in the photoperiod responses of the serotonergic systems. However, photoperiod affected dopamine levels in various brain regions differently in the two species. Some chipmunk brain regions exhibited stronger photoperiod-induced changes in dopamine levels than those of C57BL/6J mice, and the direction of the changes in the hypothalamus was opposite. In conclusion, photoperiod may regulate the brain serotonergic system through similar mechanisms, regardless of whether the animals are diurnal or nocturnal, but photoperiod-dependent regulation of brain dopamine is species-specific.

  17. Analysis of neurotransmitter tissue content of Drosophila melanogaster in different life stages.

    PubMed

    Denno, Madelaine E; Privman, Eve; Venton, B Jill

    2015-01-21

    Drosophila melanogaster is a widely used model organism for studying neurological diseases with similar neurotransmission to mammals. While both larva and adult Drosophila have central nervous systems, not much is known about how neurotransmitter tissue content changes through development. In this study, we quantified tyramine, serotonin, octopamine, and dopamine in larval, pupal, and adult fly brains using capillary electrophoresis coupled to fast-scan cyclic voltammetry. Tyramine and octopamine content varied between life stages, with almost no octopamine being present in the pupa, while tyramine levels in the pupa were very high. Adult females had significantly higher dopamine content than males, but no other neurotransmitters were dependent on sex in the adult. Understanding the tissue content of different life stages will be beneficial for future work comparing the effects of diseases on tissue content throughout development.

  18. Central serotonin(2B) receptor blockade inhibits cocaine-induced hyperlocomotion independently of changes of subcortical dopamine outflow.

    PubMed

    Devroye, Céline; Cathala, Adeline; Di Marco, Barbara; Caraci, Filippo; Drago, Filippo; Piazza, Pier Vincenzo; Spampinato, Umberto

    2015-10-01

    The central serotonin2B receptor (5-HT2BR) is currently considered as an interesting pharmacological target for improved treatment of drug addiction. In the present study, we assessed the effect of two selective 5-HT2BR antagonists, RS 127445 and LY 266097, on cocaine-induced hyperlocomotion and dopamine (DA) outflow in the nucleus accumbens (NAc) and the dorsal striatum of freely moving rats. The peripheral administration of RS 127445 (0.16 mg/kg, i.p.) or LY 266097 (0.63 mg/kg, i.p.) significantly reduced basal DA outflow in the NAc shell, but had no effect on cocaine (10 mg/kg, i.p.)-induced DA outflow in this brain region. Also, RS 127445 failed to modify both basal and cocaine-induced DA outflow in the NAc core and the dorsal striatum. Conversely, both 5-HT2BR antagonists reduced cocaine-induced hyperlocomotion. Furthermore, RS 127445 as well as the DA-R antagonist haloperidol (0.1 mg/kg, i.p.) reduced significantly the late-onset hyperlocomotion induced by the DA-R agonist quinpirole (0.5 mg/kg, s.c.). Altogether, these results demonstrate that 5-HT2BR blockade inhibits cocaine-induced hyperlocomotion independently of changes of subcortical DA outflow. This interaction takes place downstream to DA neurons and could involve an action at the level of dorsostriatal and/or NAc DA transmission, in keeping with the importance of these brain regions in the behavioural responses of cocaine. Overall, this study affords additional knowledge into the regulatory control exerted by the 5-HT2BR on ascending DA pathways, and provides additional support to the proposed role of 5-HT2BRs as a new pharmacological target in drug addiction.

  19. [123I]beta-CIT SPECT demonstrates decreased brain dopamine and serotonin transporter levels in untreated parkinsonian patients.

    PubMed

    Haapaniemi, T H; Ahonen, A; Torniainen, P; Sotaniemi, K A; Myllylä, V V

    2001-01-01

    Striatal dopamine transporters (DATs) and serotonin transporters (SERTs) were evaluated in untreated patients with Parkinson's disease (PD) and controls using single-photon emission computed tomography (SPECT) with 2beta-carboxymethoxy-3beta-(4-iodophenyl)tropane ([123I]beta-CIT). The striatal DAT specific to non-displaceable uptake ratios of 29, and the SERT uptake measurements of 27, PD patients were compared with those of 21 and 16 controls, respectively. The results were correlated with Unified Parkinson's Disease Rating Scale (UPDRS) scores, the Hoehn & Yahr stage, age, duration of the disease, and the major PD signs. The specific DAT binding in the caudate, the putamen and the caudate/putamen ratio were measured. In all of the PD patients the striatal uptake values were bilaterally reduced, being 36.9% (P < 0.001) lower than those of the controls. In the hemiparkinsonian patients the reduction was greater on the side contralateral to the initial symptoms (33.3% vs. 27.8%) and the uptake ratios indicated a more pronounced deficit in the putamen (39.1%) than in the caudate (27.9%). The DAT uptake correlated with the UPDRS total score and activities of daily living (ADL) and motor subscores, the Hoehn & Yahr stage, and rigidity score. PD patients had significantly higher caudate to putamen ratios than the controls. In the PD patients the SERT values were lower in the thalamic and frontal regions. The SERT uptake ratio of the frontal area correlated with the UPDRS subscore I. [123I]beta-CIT SPECT provides a useful method for confirming the clinical diagnosis of PD with correlation to disease severity. Additionally, this technique allows the simultaneous measurement of SERT uptake and shows that PD patients, interestingly, seem to have decreased SERT availability in the thalamic and frontal areas.

  20. Gene × Environment interaction and resilience: effects of child maltreatment and serotonin, corticotropin releasing hormone, dopamine, and oxytocin genes.

    PubMed

    Cicchetti, Dante; Rogosch, Fred A

    2012-05-01

    In this investigation, gene-environment interaction effects in predicting resilience in adaptive functioning among maltreated and nonmaltreated low-income children (N = 595) were examined. A multicomponent index of resilient functioning was derived and levels of resilient functioning were identified. Variants in four genes (serotonin transporter linked polymorphic region, corticotropin releasing hormone receptor 1, dopamine receptor D4-521C/T, and oxytocin receptor) were investigated. In a series of analyses of covariance, child maltreatment demonstrated a strong negative main effect on children's resilient functioning, whereas no main effects for any of the genotypes of the respective genes were found. However, gene-environment interactions involving genotypes of each of the respective genes and maltreatment status were obtained. For each respective gene, among children with a specific genotype, the relative advantage in resilient functioning of nonmaltreated compared to maltreated children was stronger than was the case for nonmaltreated and maltreated children with other genotypes of the respective gene. Across the four genes, a composite of the genotypes that more strongly differentiated resilient functioning between nonmaltreated and maltreated children provided further evidence of genetic variations influencing resilient functioning in nonmaltreated children, whereas genetic variation had a negligible effect on promoting resilience among maltreated children. Additional effects were observed for children based on the number of subtypes of maltreatment children experienced, as well as for abuse and neglect subgroups. Finally, maltreated and nonmaltreated children with high levels of resilience differed in their average number of differentiating genotypes. These results suggest that differential resilient outcomes are based on the interaction between genes and developmental experiences.

  1. Ethanol and acetaldehyde differentially alter extracellular dopamine and serotonin in Aldh2-knockout mouse dorsal striatum: A reverse microdialysis study.

    PubMed

    Jamal, Mostofa; Ameno, Kiyoshi; Miki, Takanori; Tanaka, Naoko; Ito, Asuka; Ono, Junichiro; Takakura, Ayaka; Kumihashi, Mitsuru; Kinoshita, Hiroshi

    2016-01-01

    Dopamine (DA) and serotonin (5-HT) seem to be involved in several of the effects of ethanol (EtOH). Acetaldehyde (AcH), especially in the brain, induces effects that mimic those of EtOH. The purpose of this study was to investigate the effects of local perfusion of EtOH and AcH on extracellular DA and 5-HT in the dorsal striatum of Aldh2-knockout (Aldh2-KO) and wild-type (WT) mice. Aldh2-KO mice were used as a model of aldehyde dehydrogenase 2 deficiency in humans to examine the effects of AcH. Mice were perfused with Ringer's solution (control), EtOH (100, 200, or 500mM) and AcH (100, 200, or 500μM) into the dorsal striatum. Dialysate samples were collected every 5min, and then analyzed with HPLC coupled to an ECD. We found that local perfusion with 500mM EtOH increased extracellular levels of DA (p<0.05) in both Aldh2-KO and WT mice, while 5-HT levels remain unchanged. EtOH at a dose of 200mM also increased DA in WT mice, but this was limited to a 30-40-min time-point. In contrast, perfusion with 200 and 500μM AcH decreased both DA and 5-HT (p<0.05) in Aldh2-KO mice, but this decrease was not found in WT mice at any AcH dose, indicating an effect of AcH on DA and 5-HT levels. There were no genotype effects on the basal levels of DA and 5-HT. These results indicate that high EtOH can stimulate DA, whereas high AcH can depress both DA and 5-HT in the dorsal striatum of mice.

  2. Effects of exposure to pyrethroid cyfluthrin on serotonin and dopamine levels in brain regions of male rats.

    PubMed

    Rodríguez, J L; Ares, I; Castellano, V; Martínez, M; Martínez-Larrañaga, M R; Anadón, A; Martínez, M A

    2016-04-01

    The effects of cyfluthrin oral exposure (1, 5, 10 and 20mg/kg bw, 6 days) on brain region monoamine levels of male rats were examined. Cyfluthrin-treated rats (1, 5 and 10mg/kg bw, orally 6 days), had no visible injury, i.e., no clinical signs of dysfunction were observed. However, rats treated with cyfluthrin at the highest dose (20mg/kg bw, orally 6 days) showed skeletal muscle contraction in the hind limbs, slight movement incoordination without any signs of dyskinesia and tremor after 1-2h of treatment. These signs were reversible at 6h after dose. After last dose of cyfluthrin, dopamine (DA) and serotonin (5-HT) and its metabolites levels were determined in brain regions hypothalamus, midbrain, hippocampus, striatum and prefrontal cortex by HPLC. Cyfluthrin (1mg/kg bw, orally 6 days) did not affect the DA, 5-HT and metabolites levels in the brain regions studied. Cyfluthrin (5, 10 and 20mg/kg bw, orally 6 days) caused a statistically significant decrease in DA and its metabolites DOPAC and HVA levels and in 5-HT and its metabolite 5-HIAA levels in a brain region- and dose-related manner. Moreover, cyfluthrin (20mg/kg bw, orally 6 days) evoked a statistically significant increase in 5-HT turnover in striatum and midbrain, and in DA turnover in striatum and prefrontal cortex. These findings indicate that serotoninergic and dopaminergic neurotransmission is affected by exposure to cyfluthrin and may contribute to the overall spectrum of neurotoxicity caused by this pyrethroid.

  3. Serotonin, but not dopamine, controls the stress response and anxiety-like behavior in the crayfish Procambarus clarkii.

    PubMed

    Fossat, Pascal; Bacqué-Cazenave, Julien; De Deurwaerdère, Philippe; Cattaert, Daniel; Delbecque, Jean-Paul

    2015-09-01

    In the animal kingdom, biogenic amines are widespread modulators of the nervous system that frequently interact to control mood. Our previous investigations in crayfish (Procambarus clarkii) have established that stress induces changes in brain serotonin (5-HT) concentrations that are responsible for the appearance of anxiety-like behavior (ALB). Here, we further analyze the roles of 5-HT and another biogenic amine, dopamine (DA), on the crayfish response to stress. We show that the intensity of crayfish ALB depends on the intensity of stressful stimulation and is associated with increased concentrations of 5-HT in the brain. These 5-HT levels were significantly correlated, before, as well as after stress, with those of DA, which were approximately 3- to 5-times less abundant. However, whereas the degree of ALB was clearly correlated with brain 5-HT concentrations, it was not significantly correlated with DA. Moreover, in contrast to injections of 5-HT, DA injections were not able to elicit a stress response or ALB. In addition, 5-HT and DA levels were not modified by treatment with the anxiolytic chlordiazepoxide, confirming that suppression of ALB by this GABA-A receptor ligand acts downstream and is independent of changes in crayfish bioamine levels. Our study also provides evidence that the anxiogenic effect of 5-HT injections can be prevented by a preliminary injection of 5-HT antagonists. Altogether, our results emphasize that the rises in brain concentrations of 5-HT, but not DA, play a role in controlling the induction and the intensity of crayfish ALB.

  4. Quantitative mapping shows that serotonin rather than dopamine receptor mRNA expressions are affected after repeated intermittent administration of MDMA in rat brain.

    PubMed

    Kindlundh-Högberg, Anna M S; Svenningsson, Per; Schiöth, Helgi B

    2006-09-01

    Ecstasy, (+/-)-3,4-methylenedioxy-metamphetamine (MDMA), is a popular recreational drug among young people. The present study aims to mimic MDMA intake among adolescents at dance clubs, taking repeated doses in the same evening on an intermittent basis. Male Sprague-Dawley rats received either 3x1 or 3x5 mg/kg/day (3 h apart) every seventh day during 4 weeks. We used real-time RT-PCR to determine the gene expression of serotonin 5HT1A, 5HT1B, 5HT2A, 5HT2C, 5HT3, 5HT6 receptors and dopamine D1, D2, D3 receptors in seven brain nuclei. The highest dose of MDMA extensively increased the 5HT1B-receptor mRNA in the cortex, caudate putamen, nucleus accumbens, and hypothalamus. The 5HT2A-receptor mRNA was reduced at the highest MDMA dose in the cortex. The 5HT2C mRNA was significantly increased in a dose-dependent manner in the cortex and the hypothalamus, as well as the 5HT3-receptor mRNA was in the hypothalamus. The 5HT6 mRNA level was increased in the forebrain cortex and the amygdala. Dopamine receptor mRNAs were only affected in the hypothalamus. In conclusion, this study provides evidence for a unique implication of serotonin rather than dopamine receptor mRNA levels, in response to repeated intermittent MDMA administration. We therefore suggest that serotonin regulated functions also primarily underlie repeated MDMA intake at rave parties.

  5. [Neurotransmitters, calcium signalling and neuronal communication].

    PubMed

    Eguiagaray, J G; Egea, J; Bravo-Cordero, J J; García, A G

    2004-04-01

    In this article we show some recent findings that constitute a great progress in the molecular knowledge of synaptic dynamics. To communicate, neurons use a code that includes electrical (action potentials) and chemical signals (neurotransmitters, neuromodulators). At the moment a great variety of molecules are known, whose neurotransmitter function in brain and the peripheral nervous system are out of question. Monoamines like acetylcholine, dopamine, noradrenaline, adrenaline, histamine, serotonin, glutamate, aspartate, glycine, ATP and GABA are good examples. Opioid neuropeptides, vasoactive intestinal peptide (VIP), neurokinines (substance P), somatostatin, neurotensin, neuropeptide Y, cholecystokinine, vasopressin or oxitocin have been related to the control of the stress response, sexual behaviour, food intake, pain, learning and memory, qualities that are also related to nitric oxide (NO). A great part of the molecular structure of the secretory machinery is known to be responsible for fast neurotransmitter release at the synapse, in response to action potentials. Proteins like sinaptobrevin (located in the membrane of the synaptic vesicle), sintaxin and SNAP-25 (both located at the presynaptic plasma membrane) constitute a trimeric complex which is responsible of the vesicular docking at the active sites for exocytosis. From this strategic location, vesicles release their neurotransmitter within few milliseconds, when the action potential invades the nerve terminal and activates the opening of the different subtypes of voltage-dependent Ca2+ channels. The asymmetric geographical distribution of each type of channel, in different neurons, rose the hypothesis that Ca2+ that enters through each subtype of channel is compartmentalised, thus favouring the generation of Ca2+ microdomains, in the cytosol and the nucleus, involved in different cellular functions. This great biochemical synaptic heterogeneity is facilitating the selection of many biological targets

  6. Targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors for developing effective antipsychotics: synthesis, biological characterization, and behavioral studies.

    PubMed

    Brindisi, Margherita; Butini, Stefania; Franceschini, Silvia; Brogi, Simone; Trotta, Francesco; Ros, Sindu; Cagnotto, Alfredo; Salmona, Mario; Casagni, Alice; Andreassi, Marco; Saponara, Simona; Gorelli, Beatrice; Weikop, Pia; Mikkelsen, Jens D; Scheel-Kruger, Jorgen; Sandager-Nielsen, Karin; Novellino, Ettore; Campiani, Giuseppe; Gemma, Sandra

    2014-11-26

    Combination of dopamine D3 antagonism, serotonin 5-HT1A partial agonism, and antagonism at 5-HT2A leads to a novel approach to potent atypical antipsychotics. Exploitation of the original structure-activity relationships resulted in the identification of safe and effective antipsychotics devoid of extrapyramidal symptoms liability, sedation, and catalepsy. The potential atypical antipsychotic 5bb was selected for further pharmacological investigation. The distribution of c-fos positive cells in the ventral striatum confirmed the atypical antipsychotic profile of 5bb in agreement with behavioral rodent studies. 5bb administered orally demonstrated a biphasic effect on the MK801-induced hyperactivity at dose levels not able to induce sedation, catalepsy, or learning impairment in passive avoidance. In microdialysis studies, 5bb increased the dopamine efflux in the medial prefrontal cortex. Thus, 5bb represents a valuable lead for the development of atypical antipsychotics endowed with a unique pharmacological profile for addressing negative symptoms and cognitive deficits in schizophrenia.

  7. Modulation of monoamine neurotransmitters in fighting fish Betta splendens exposed to waterborne phytoestrogens.

    PubMed

    Clotfelter, Ethan D; McNitt, Meredith M; Carpenter, Russ E; Summers, Cliff H

    2010-12-01

    Endogenous estrogens are known to affect the activity of monoamine neurotransmitters in vertebrate animals, but the effects of exogenous estrogens on neurotransmitters are relatively poorly understood. We exposed sexually mature male fighting fish Betta splendens to environmentally relevant and pharmacological doses of three phytoestrogens that are potential endocrine disruptors in wild fish populations: genistein, equol, and β-sitosterol. We also exposed fish to two doses of the endogenous estrogen 17β-estradiol, which we selected as a positive control because phytoestrogens are putative estrogen mimics. Our results were variable, but the effects were generally modest. Genistein increased dopamine levels in the forebrains of B. splendens at both environmentally relevant and pharmacological doses. The environmentally relevant dose of equol increased dopamine levels in B. splendens forebrains, and the pharmacological dose decreased norepinephrine (forebrain), dopamine (hindbrain), and serotonin (forebrain) levels. The environmentally relevant dose of β-sitosterol decreased norepinephrine and dopamine in the forebrain and hindbrain, respectively. Our results suggest that sources of environmental phytoestrogens, such as runoff or effluent from agricultural fields, wood pulp mills, and sewage treatment plants, have the potential to modulate neurotransmitter activity in free-living fishes in a way that could interfere with normal behavioral processes.

  8. Evidence for genetic influences on neurotransmitter content of identified neurones of Lymnaea stagnalis.

    PubMed

    Audesirk, G; Audesirk, T; McCaman, R E; Ono, J K

    1985-01-01

    Neurotransmitter content was measured in two identified giant neurones in isogenic and wild-type populations of the freshwater pond snail Lymnaea stagnalis. The paired serotonergic cerebral giant neurones (LC1 and RC1) have higher transmitter levels and less variability in inbred animals than in wild-type animals. The transmitter content of the unpaired dopaminergic right pedal giant neurone (RPeD1) does not differ between inbred and wild-type animals in either level or variability. It is proposed that serotonin content of the cerebral giant neurones is under partial genetic control, and that animals of the wild-type population may possess a number of different alleles for the genes influencing serotonin levels. Inbreeding resulted in fixation of an allele promoting high serotonin levels. This particular wild-type population is probably already isogenic for genes influencing dopamine content in the right pedal giant neurone.

  9. Bound to be different: neurotransmitter transporters meet their bacterial cousins.

    PubMed

    Henry, L Keith; Meiler, Jens; Blakely, Randy D

    2007-12-01

    The neurotransmitter transporters belonging to the solute carrier 6 (SLC6) family, including the gamma-aminobutyric acid (GAT), norepinephrine (NET), serotonin (SERT) and dopamine (DAT) transporters are extremely important drug targets of great clinical relevance. These Na+, Cl(-)-dependent transporters primarily function following neurotransmission to reset neuronal signaling by transporting neurotransmitter out of the synapse and back into the pre-synaptic neuron. Recent studies have tracked down an elusive binding site for Cl(-) that facilitates neurotransmitter transport using structural differences evident with bacterial family members (e.g., the Aquifex aeolicus leucine transporter LeuT Aa) that lack Cl(-) dependence. Additionally, the crystal structures of antidepressant-bound LeuT Aa reveals a surprising mode of drug interaction that may have relevance for medication development. The study of sequence and structural divergence between LeuT Aa and human SLC6 family transporters can thus inform us as to how and why neurotransmitter transporters evolved a reliance on extracellular Cl(-) to propel the transport cycle; what residue changes and helical rearrangements give rise to recognition of different substrates; and how drugs such as antidepressants, cocaine, and amphetamines halt (or reverse) the transport process.

  10. The Role of Serotonin (5-HT) in Behavioral Control: Findings from Animal Research and Clinical Implications.

    PubMed

    Sanchez, C L; Biskup, C S; Herpertz, S; Gaber, T J; Kuhn, C M; Hood, S H; Zepf, F D

    2015-05-19

    The neurotransmitters serotonin and dopamine both have a critical role in the underlying neurobiology of different behaviors. With focus on the interplay between dopamine and serotonin, it has been proposed that dopamine biases behavior towards habitual responding, and with serotonin offsetting this phenomenon and directing the balance toward more flexible, goal-directed responding. The present focus paper stands in close relationship to the publication by Worbe et al. (2015), which deals with the effects of acute tryptophan depletion, a neurodietary physiological method to decrease central nervous serotonin synthesis in humans for a short period of time, on the balance between hypothetical goal-directed and habitual systems. In that research, acute tryptophan depletion challenge administration and a following short-term reduction in central nervous serotonin synthesis were associated with a shift of behavioral performance towards habitual responding, providing further evidence that central nervous serotonin function modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. In the present focus paper, we discuss the findings by Worbe and colleagues in light of animal experiments as well as clinical implications and discuss potential future avenues for related research.

  11. The Role of Serotonin (5-HT) in Behavioral Control: Findings from Animal Research and Clinical Implications

    PubMed Central

    Sanchez, CL; Biskup, CS; Herpertz, S; Gaber, TJ; Kuhn, CM; Hood, SH

    2015-01-01

    The neurotransmitters serotonin and dopamine both have a critical role in the underlying neurobiology of different behaviors. With focus on the interplay between dopamine and serotonin, it has been proposed that dopamine biases behavior towards habitual responding, and with serotonin offsetting this phenomenon and directing the balance toward more flexible, goal-directed responding. The present focus paper stands in close relationship to the publication by Worbe et al. (2015), which deals with the effects of acute tryptophan depletion, a neurodietary physiological method to decrease central nervous serotonin synthesis in humans for a short period of time, on the balance between hypothetical goal-directed and habitual systems. In that research, acute tryptophan depletion challenge administration and a following short-term reduction in central nervous serotonin synthesis were associated with a shift of behavioral performance towards habitual responding, providing further evidence that central nervous serotonin function modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. In the present focus paper, we discuss the findings by Worbe and colleagues in light of animal experiments as well as clinical implications and discuss potential future avenues for related research. PMID:25991656

  12. An interaction between the serotonin transporter promoter region and dopamine transporter polymorphisms contributes to harm avoidance and reward dependence traits in normal healthy subjects.

    PubMed

    Kim, S J; Kim, Y S; Lee, H S; Kim, S Y; Kim, C-H

    2006-07-01

    There is evidence for an association between polymorphisms of serotonin- and dopamine-related genes and temperamental personality traits. Recent findings have shown that interactions between allelic variants of the different genes may contribute to personality traits. We examined the effects of serotonin transporter-linked promoter region (5-HTTLPR) and dopamine transporter (DAT1) gene polymorphisms for associations with the Temperament and Character Inventory (TCI) temperament subscales in 209 Koreans. We found that the variants of 5-HTTLPR interacted with the DAT1 gene polymorphism to influence the HA and RD temperament subscales of TCI. Neither of these two genes affected any subscales of TCI alone.Controlling for the effects of gender and age, we found significant interactions between 5-HTTLPR and DAT1 genes on Harm Avoidance (HA) and Reward Dependence (RD) as measured by the TCI (Hotelling's Trace = 3.0, P = 0.02). In the presence of the DAT1 10/10 genotype, subjects of group L of 5-HTTLPR had a significantly higher HA score and significantly lower RD score than those of group S (F = 5.04, df = 1, p = 0.03 and F = 8.35, df = 1, p = 0.004, respectively). These findings suggest that the variants of 5-HTTLPR interacted with the DAT1 gene polymorphism to influence the HA and RD temperament subscales of TCI.

  13. The roles of the orbitofrontal cortex via the habenula in non-reward and depression, and in the responses of serotonin and dopamine neurons.

    PubMed

    Rolls, Edmund T

    2017-02-14

    Cortical regions such as the orbitofrontal cortex involved in reward and in non-reward and which are implicated in depression, and the amygdala, are connected to the habenula via the striatum and pallidum, and via subcortical limbic structures. The habenula in turn projects to the raphe nuclei, the source of the serotonin-containing neurons that project to the forebrain. It is proposed that this provides a route for cortical signals related to reward, and to not obtaining expected rewards, to influence the serotonin-containing neuronal system that is influenced by many antidepressant treatments. This helps to provide a more circuit-based understanding of the brain mechanisms related to depression, and how some treatments influence this system. The habenula also projects via the rostromedial tegmental nucleus to the dopamine-containing neurons, and this, it is proposed, provides a route for reward prediction error signals and other reward- and punishment-related signals of cortical and striatal origin to influence the dopamine system.

  14. Seasonal changes in circadian peripheral plasma concentrations of melatonin, serotonin, dopamine and cortisol in aged horses with Cushing's disease under natural photoperiod.

    PubMed

    Haritou, S J A; Zylstra, R; Ralli, C; Turner, S; Tortonese, D J

    2008-08-01

    Equine pituitary pars intermedia dysfunction (PPID) is a common and serious condition that gives rise to Cushing's disease. In the older horse, it results in hyperadrenocorticism and disrupted energy metabolism, the severity of which varies with the time of year. To gain insight into the mechanism of its pathogenesis, 24-h profiles for peripheral plasma melatonin, serotonin, dopamine and cortisol concentrations were determined at the winter and summer solstices, and the autumn and spring equinoxes in six horses diagnosed with Cushing's disease and six matched controls. The nocturnal rises in plasma melatonin concentrations, although different across seasons, were broadly of the same duration and similar amplitude in both groups of animals (P > 0.05). The plasma concentrations of cortisol did not show seasonal variation and were different in diseased horses only in the summer when they were higher across the entire 24-h period (P < 0.05). Serotonin concentrations were not significantly affected by time of year but tended to be lower in Cushingoid horses (P = 0.07). By contrast, dopamine output showed seasonal variation and was significantly lower in the Cushing's group in the summer and autumn (P < 0.05). The finding that the profiles of circulating melatonin are similar in Cushingoid and control horses reveals that the inability to read time of year by animals suffering from Cushing's syndrome is an unlikely reason for the disease. In addition, the results provide evidence that alterations in the dopaminergic and serotoninergic systems may participate in the pathogenesis of PPID.

  15. Treatment of Congenital Neurotransmitter Deficiencies by Intracerebral Ventricular Injection of an Adeno-Associated Virus Serotype 9 Vector

    PubMed Central

    Lee, Ni-Chung; Chien, Yin-Hsiu; Hu, Min-Hsiu; Liu, Wen-Shin; Chen, Pin-Wen; Wang, Wei-Hua; Tzen, Kai-Yuan; Byrne, Barry J.

    2014-01-01

    Abstract Dopamine and serotonin are produced by distinct groups of neurons in the brain, and gene therapies other than direct injection have not been attempted to correct congenital deficiencies in such neurotransmitters. In this study, we performed gene therapy to treat knock-in mice with dopamine and serotonin deficiencies caused by a mutation in the aromatic l-amino acid decarboxylase (AADC) gene (DdcKI mice). Intracerebral ventricular injection of neonatal mice with an adeno-associated virus (AAV) serotype 9 (AAV9) vector expressing the human AADC gene (AAV9-hAADC) resulted in widespread AADC expression in the brain. Without treatment, 4-week-old DdcKI mice exhibited whole-brain homogenate dopamine and serotonin levels of 25% and 15% of normal, respectively. After gene therapy, the levels rose to 100% and 40% of normal, respectively. The gene therapy improved the growth rate and survival of DdcKI mice and normalized their hindlimb clasping and cardiovascular dysfunctions. The behavioral abnormalities of the DdcKI mice were partially corrected, and the treated DdcKI mice were slightly more active than normal mice. No immune reactions resulted from the treatment. Therefore, a congenital neurotransmitter deficiency can be treated safely through inducing widespread expression of the deficient gene in neonatal mice. PMID:24251946

  16. Effects of monoamine releasers with varying selectivity for releasing dopamine/norepinephrine versus serotonin on choice between cocaine and food in rhesus monkeys.

    PubMed

    Banks, Matthew L; Blough, Bruce E; Negus, S Stevens

    2011-12-01

    Monoamine releasers constitute one class of candidate medications for the treatment of cocaine abuse, and concurrent cocaine-versus-food choice procedures are potentially valuable as experimental tools to evaluate the efficacy and safety of candidate medications. This study assessed the choice between cocaine and food by rhesus monkeys during treatment with five monoamine releasers that varied in selectivity to promote the release of dopamine and norepinephrine versus serotonin (5HT) [m-fluoroamphetamine, (+)-phenmetrazine, (+)-methamphetamine, napthylisopropylamine and (±)-fenfluramine]. Rhesus monkeys (n=8) responded under a concurrent-choice schedule of food delivery (1-g pellets, fixed ratio 100 schedule) and cocaine injections (0-0.1 mg/kg/injection, fixed ratio 10 schedule). Cocaine choice dose-effect curves were determined daily during continuous 7-day treatment with saline or with each test compound dose. During saline treatment, cocaine maintained a dose-dependent increase in cocaine choice, and the highest cocaine doses (0.032-0.1 mg/kg/injection) maintained almost exclusive cocaine choice. Efficacy of monoamine releasers to decrease cocaine choice corresponded to their pharmacological selectivity to release dopamine and norepinephrine versus 5HT. None of the releasers reduced cocaine choice or promoted reallocation of responding to food choice to the same extent as when saline was substituted for cocaine. These results extend the range of conditions across which dopamine and norepinephrine-selective releasers have been shown to reduce cocaine self-administration.

  17. Determination of Serotonin and Dopamine Metabolites in Human Brain Microdialysis and Cerebrospinal Fluid Samples by UPLC-MS/MS: Discovery of Intact Glucuronide and Sulfate Conjugates

    PubMed Central

    Suominen, Tina; Uutela, Päivi; Ketola, Raimo A.; Bergquist, Jonas; Hillered, Lars; Finel, Moshe; Zhang, Hongbo; Laakso, Aki; Kostiainen, Risto

    2013-01-01

    An UPLC-MS/MS method was developed for the determination of serotonin (5-HT), dopamine (DA), their phase I metabolites 5-HIAA, DOPAC and HVA, and their sulfate and glucuronide conjugates in human brain microdialysis samples obtained from two patients with acute brain injuries, ventricular cerebrospinal fluid (CSF) samples obtained from four patients with obstructive hydrocephalus, and a lumbar CSF sample pooled mainly from patients undergoing spinal anesthesia in preparation for orthopedic surgery. The method was validated by determining the limits of detection and quantification, linearity, repeatability and specificity. The direct method enabled the analysis of the intact phase II metabolites of 5-HT and DA, without hydrolysis of the conjugates. The method also enabled the analysis of the regioisomers of the conjugates, and several intact glucuronide and sulfate conjugates were identified and quantified for the first time in the human brain microdialysis and CSF samples. We were able to show the presence of 5-HIAA sulfate, and that dopamine-3-O-sulfate predominates over dopamine-4-O-sulfate in the human brain. The quantitative results suggest that sulfonation is a more important phase II metabolism pathway than glucuronidation in the human brain. PMID:23826355

  18. Noncovalent Complexation of Monoamine Neurotransmitters and Related Ammonium Ions by Tetramethoxy Tetraglucosylcalix[4]arene

    NASA Astrophysics Data System (ADS)

    Torvinen, Mika; Kalenius, Elina; Sansone, Francesco; Casnati, Alessandro; Jänis, Janne

    2012-02-01

    The noncovalent complexation of monoamine neurotransmitters and related ammonium and quaternary ammonium ions by a conformationally flexible tetramethoxy glucosylcalix[4]arene was studied by electrospray ionization Fourier transform ion cyclotron resonance (ESI-FTICR) mass spectrometry. The glucosylcalixarene exhibited highest binding affinity towards serotonin, norepinephrine, epinephrine, and dopamine. Structural properties of the guests, such as the number, location, and type of hydrogen bonding groups, length of the alkyl spacer between the ammonium head-group and the aromatic ring structure, and the degree of nitrogen substitution affected the complexation. Competition experiments and guest-exchange reactions indicated that the hydroxyl groups of guests participate in intermolecular hydrogen bonding with the glucocalixarene.

  19. Coexistence of Several Putative Neurotransmitters in Single Identified Neurosn of Aplysia

    PubMed Central

    Brownstein, Michael J.; Saavedra, Juan M.; Axelrod, Julius; Zeman, Gary H.; Carpenter, David O.

    1974-01-01

    By sensitive enzymatic micromethods several putative neurotransmitters were measured in four identifiable neurons of Aplysia californica (R-2, R-14, L-11, and C-1). Serotonin was found in all of these neurons, and octopamine in all but C-1. Acetylcholine has been previously reported to be present in R-2 and L-11. The catecholamines, norepinephrine and dopamine, were not detected in the four cells examined. The possible biological consequence of the presence of several putative transmitters in single identifiable neurons is discussed. PMID:4373726

  20. Glucocorticoid Receptors, Brain-Derived Neurotrophic Factor, Serotonin and Dopamine Neurotransmission are Associated with Interferon-Induced Depression

    PubMed Central

    Udina, M; Navinés, R; Egmond, E; Oriolo, G; Langohr, K; Gimenez, D; Valdés, M; Gómez-Gil, E; Grande, I; Gratacós, M; Kapczinski, F; Artigas, F; Vieta, E; Solà, R

    2016-01-01

    Background: The role of inflammation in mood disorders has received increased attention. There is substantial evidence that cytokine therapies, such as interferon alpha (IFN-alpha), can induce depressive symptoms. Indeed, proinflammatory cytokines change brain function in several ways, such as altering neurotransmitters, the glucocorticoid axis, and apoptotic mechanisms. This study aimed to evaluate the impact on mood of initiating IFN-alpha and ribavirin treatment in a cohort of patients with chronic hepatitis C. We investigated clinical, personality, and functional genetic variants associated with cytokine-induced depression. Methods: We recruited 344 Caucasian outpatients with chronic hepatitis C, initiating IFN-alpha and ribavirin therapy. All patients were euthymic at baseline according to DSM-IV-R criteria. Patients were assessed at baseline and 4, 12, 24, and 48 weeks after treatment initiation using the Patient Health Questionnaire (PHQ), the Hospital Anxiety and Depression Scale (HADS), and the Temperament and Character Inventory (TCI). We genotyped several functional polymorphisms of interleukin-28 (IL28B), indoleamine 2,3-dioxygenase (IDO-1), serotonin receptor-1A (HTR1A), catechol-O-methyl transferase (COMT), glucocorticoid receptors (GCR1 and GCR2), brain-derived neurotrophic factor (BDNF), and FK506 binding protein 5 (FKBP5) genes. A survival analysis was performed, and the Cox proportional hazards model was used for the multivariate analysis. Results: The cumulative incidence of depression was 0.35 at week 24 and 0.46 at week 48. The genotypic distributions were in Hardy-Weinberg equilibrium. Older age (p = 0.018, hazard ratio [HR] per 5 years = 1.21), presence of depression history (p = 0.0001, HR = 2.38), and subthreshold depressive symptoms at baseline (p = 0.005, HR = 1.13) increased the risk of IFN-induced depression. So too did TCI personality traits, with high scores on fatigability (p = 0.0037, HR = 1.17), impulsiveness (p = 0.0200 HR = 1

  1. STRESS-INDUCED CHANGES IN EXTRACELLULAR DOPAMINE AND SEROTONIN IN THE MEDIAL PREFRONTAL CORTEX AND DORSAL HIPPOCAMPUS OF PRENATALLY MALNOURISHED RATS

    PubMed Central

    Mokler, David J.; Torres, Olga I.; Galler, Janina R.; Morgane, Peter J.

    2009-01-01

    Prenatal protein malnutrition continues to be a significant problem in the world today. Exposure to prenatal protein malnutrition increases the risk of a number of neuropsychiatric disorders in adulthood including depression, schizophrenia and attentional deficit disorder. In the present experiment we have examined the effects of stress on extracellular serotonin (5-HT) and dopamine in the medial prefrontal cortex and dorsal hippocampus of rats exposed in utero to protein malnutrition. The medial prefrontal cortex and dorsal hippocampus were chosen as two limbic forebrain regions involved in learning and memory, attention and the stress response. Extracellular 5-HT and dopamine were determined in the medial prefrontal cortex and dorsal hippocampus of adult male Sprague-Dawley rats using dual probe in vivo microdialysis. Basal extracellular 5-HT did not differ between malnourished and well-nourished controls in either the medial prefrontal cortex or the dorsal hippocampus. Basal extracellular dopamine was significantly decreased in the medial prefrontal cortex of malnourished animals. Restraint stress (20 m) produced a significant rise in extracellular dopamine in the medial prefrontal cortex of well-nourished rats but did not alter release in malnourished rats. In malnourished rats, stress produced an increase in 5-HT in the hippocampus, whereas stress produced a decrease in 5-HT in the hippocampus of well-nourished rats. These data demonstrate that prenatal protein malnutrition alters dopaminergic neurotransmission in the medial prefrontal cortex as well as altering the dopaminergic and serotonergic response to stress. These changes may provide part of the bases for alterations in malnourished animals’ response to stress. PMID:17368432

  2. Could dopamine agonists aid in drug development for anorexia nervosa?

    PubMed

    Frank, Guido K W

    2014-01-01

    Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways.

  3. Ethylenedioxy homologs of N-methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) and its corresponding cathinone analog methylenedioxymethcathinone: Interactions with transporters for serotonin, dopamine, and norepinephrine.

    PubMed

    Del Bello, Fabio; Sakloth, Farhana; Partilla, John S; Baumann, Michael H; Glennon, Richard A

    2015-09-01

    N-Methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA; 'Ecstasy'; 1) and its β-keto analog methylone (MDMC; 2) are popular drugs of abuse. Little is known about their ring-expanded ethylenedioxy homologs. Here, we prepared N-methyl-(3,4-ethylenedioxyphenyl)-2-aminopropane (EDMA; 3), both of its optical isomers, and β-keto EDMA (i.e., EDMC; 4) to examine their effects at transporters for serotonin (SERT), dopamine (DAT), and norepinephrine (NET). In general, ring-expansion of the methylenedioxy group led to a several-fold reduction in potency at all three transporters. With respect to EDMA (3), S(+)3 was 6-fold, 50-fold, and 8-fold more potent than its R(-) enantiomer at SERT, DAT, and NET, respectively. Overall, in the absence of a β-carbonyl group, the ethylenedioxy (i.e., 1,4-dioxane) substituent seems better accommodated at SERT than at DAT and NET.

  4. Seasonal Changes in Circadian Peripheral Plasma Concentrations of Melatonin, Serotonin, Dopamine and Cortisol in Aged Horses with Cushing’s Disease under Natural Photoperiod

    PubMed Central

    Haritou, S J A; Zylstra, R; Ralli, C; Turner, S; Tortonese, D J

    2008-01-01

    Equine pituitary pars intermedia dysfunction (PPID) is a common and serious condition that gives rise to Cushing’s disease. In the older horse, it results in hyperadrenocorticism and disrupted energy metabolism, the severity of which varies with the time of year. To gain insight into the mechanism of its pathogenesis, 24-h profiles for peripheral plasma melatonin, serotonin, dopamine and cortisol concentrations were determined at the winter and summer solstices, and the autumn and spring equinoxes in six horses diagnosed with Cushing’s disease and six matched controls. The nocturnal rises in plasma melatonin concentrations, although different across seasons, were broadly of the same duration and similar amplitude in both groups of animals (P > 0.05). The plasma concentrations of cortisol did not show seasonal variation and were different in diseased horses only in the summer when they were higher across the entire 24-h period (P < 0.05). Serotonin concentrations were not significantly affected by time of year but tended to be lower in Cushingoid horses (P = 0.07). By contrast, dopamine output showed seasonal variation and was significantly lower in the Cushing’s group in the summer and autumn (P < 0.05). The finding that the profiles of circulating melatonin are similar in Cushingoid and control horses reveals that the inability to read time of year by animals suffering from Cushing’s syndrome is an unlikely reason for the disease. In addition, the results provide evidence that alterations in the dopaminergic and serotoninergic systems may participate in the pathogenesis of PPID. PMID:18540997

  5. Effect of aging on 24-hour changes in dopamine and serotonin turnover and amino acid and somatostatin contents of rat corpus striatum.

    PubMed

    Esquifino, Ana I; Cano, Pilar; Chacon, Fernando; Reyes Toso, Carlos F; Cardinali, Daniel P

    2002-01-01

    This study examined the 24-hour changes in a number of transmitters in the corpus striatum of young and middle-aged male Wistar rats. The contents of excitatory amino acids (glutamate, aspartate) and inhibitory amino acids (gamma-aminobutyric acid, GABA; taurine, glycine) and of somatostatin were measured in 2-month- and 18- to 20-month-old rats killed at six different time points along the 24-hour cycle. The striatal serotonin and dopamine turnover was also measured. Both young and middle-aged rats showed significant 24-hour variations in striatal glutamate and aspartate contents; only in young rats these variations fitted a cosine function, with acrophase during the first part of rest span. Mesor values of striatal excitatory amino acid contents were lowest in middle-aged rats. Significant 24-hour variations in striatal contents of GABA, taurine, and glycine occurred in young rats, while only striatal GABA exhibited 24-hour changes in middle- aged rats (acrophases during the first part of rest span). For every inhibitory transmitter, the mesor values in middle-aged rats were significantly lower than in young rats. The 24-hour variation of the striatal somatostatin content showed acrophase during the first part of rest span, mesor values and amplitude being lowest in middle-aged rats. Aging rats exhibited significantly higher mesor values of striatal serotonin turnover (34% increase) and lower mesor values of dopamine turnover (69% decrease) than their younger counterparts. Some of the circadian modifications of motor function seen in aging rats could be related to the striatal transmitter changes reported herein.

  6. Pharmacologic inhibition of L-tyrosine degradation ameliorates cerebral dopamine deficiency in murine phenylketonuria (PKU).

    PubMed

    Harding, Cary O; Winn, Shelley R; Gibson, K Michael; Arning, Erland; Bottiglieri, Teodoro; Grompe, Markus

    2014-09-01

    Monoamine neurotransmitter deficiency has been implicated in the etiology of neuropsychiatric symptoms associated with chronic hyperphenylalaninemia in phenylketonuria (PKU). Two proposed explanations for neurotransmitter deficiency in PKU include first, that chronically elevated blood L-phenylalanine (Phe) inhibits the transport of L-tyrosine (Tyr) and L-tryptophan (Trp), the substrates for dopamine and serotonin synthesis respectively, into brain. In the second hypothesis, elevated Phe competitively inhibits brain tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities, the rate limiting steps in dopamine and serotonin synthesis. Dietary supplementation with large neutral amino acids (LNAA) including Tyr and Trp has been recommended for individuals with chronically elevated blood Phe in an attempt to restore amino acid and monoamine homeostasis in brain. As a potential alternative treatment approach, we demonstrate that pharmacologic inhibition of Tyr degradation through oral administration of nitisinone (NTBC) yielded sustained increases in blood and brain Tyr, decreased blood and brain Phe, and consequently increased dopamine synthesis in a murine model of PKU. Our results suggest that Phe-mediated inhibition of TH activity is the likely mechanism of impaired dopamine synthesis in PKU. Pharmacologic inhibition of Tyr degradation may be a promising adjunct therapy for CNS monoamine neurotransmitter deficiency in hyperphenylalaninemic individuals with PKU.

  7. Determination of neurotransmitter levels in models of Parkinson's disease by HPLC-ECD.

    PubMed

    Yang, Lichuan; Beal, M Flint

    2011-01-01

    Parkinson's disease (PD) is a neurological disorder caused by progressive degeneration of dopaminergic neurons in the nigrostriatal area of the brain. The decrease in dopamine (DA) neurotransmitter levels in the striatum and substantia nigra pars compacta is a neurochemistry hallmark of PD. Therefore, determination of dopamine and its metabolites levels in biological samples provides an important key to understanding the neurochemistry profile of PD. This chapter describes the use of reversed-phase HPLC with electrochemical detection (ECD) for simultaneously measuring monoamine neurotransmitters, including dopamine and its metabolites, norepinephrine as well as serotonin and its metabolite. ECD provides an ultrasensitive measurement, which detects at the picogram level. One run for each sample finishes within 18 min, shows clear chromatographic peaks and a complete separation, and produces excellent precision and reproducibility. Once set up, HPLC-ECD is economic and efficient for analyzing a large number of samples. This method has been broadly used for analyzing a variety of biological samples, such as cerebrospinal fluids, plasma, microdialysis elutes, tissues, and cultured cells. In recent days, it has been reported to be able to detect the dopamine level in a single drosophila head.

  8. An extended reinforcement learning model of basal ganglia to understand the contributions of serotonin and dopamine in risk-based decision making, reward prediction, and punishment learning.

    PubMed

    Balasubramani, Pragathi P; Chakravarthy, V Srinivasa; Ravindran, Balaraman; Moustafa, Ahmed A

    2014-01-01

    Although empirical and neural studies show that serotonin (5HT) plays many functional roles in the brain, prior computational models mostly focus on its role in behavioral inhibition. In this study, we present a model of risk based decision making in a modified Reinforcement Learning (RL)-framework. The model depicts the roles of dopamine (DA) and serotonin (5HT) in Basal Ganglia (BG). In this model, the DA signal is represented by the temporal difference error (δ), while the 5HT signal is represented by a parameter (α) that controls risk prediction error. This formulation that accommodates both 5HT and DA reconciles some of the diverse roles of 5HT particularly in connection with the BG system. We apply the model to different experimental paradigms used to study the role of 5HT: (1) Risk-sensitive decision making, where 5HT controls risk assessment, (2) Temporal reward prediction, where 5HT controls time-scale of reward prediction, and (3) Reward/Punishment sensitivity, in which the punishment prediction error depends on 5HT levels. Thus the proposed integrated RL model reconciles several existing theories of 5HT and DA in the BG.

  9. An extended reinforcement learning model of basal ganglia to understand the contributions of serotonin and dopamine in risk-based decision making, reward prediction, and punishment learning

    PubMed Central

    Balasubramani, Pragathi P.; Chakravarthy, V. Srinivasa; Ravindran, Balaraman; Moustafa, Ahmed A.

    2014-01-01

    Although empirical and neural studies show that serotonin (5HT) plays many functional roles in the brain, prior computational models mostly focus on its role in behavioral inhibition. In this study, we present a model of risk based decision making in a modified Reinforcement Learning (RL)-framework. The model depicts the roles of dopamine (DA) and serotonin (5HT) in Basal Ganglia (BG). In this model, the DA signal is represented by the temporal difference error (δ), while the 5HT signal is represented by a parameter (α) that controls risk prediction error. This formulation that accommodates both 5HT and DA reconciles some of the diverse roles of 5HT particularly in connection with the BG system. We apply the model to different experimental paradigms used to study the role of 5HT: (1) Risk-sensitive decision making, where 5HT controls risk assessment, (2) Temporal reward prediction, where 5HT controls time-scale of reward prediction, and (3) Reward/Punishment sensitivity, in which the punishment prediction error depends on 5HT levels. Thus the proposed integrated RL model reconciles several existing theories of 5HT and DA in the BG. PMID:24795614

  10. Interaction between serotonin 5-HT2A receptor gene and dopamine transporter (DAT1) gene polymorphisms influences personality trait of persistence in Austrian Caucasians.

    PubMed

    Schosser, Alexandra; Fuchs, Karoline; Scharl, Theresa; Schloegelhofer, Monika; Kindler, Jochen; Mossaheb, Nilufar; Kaufmann, Rainer M; Leisch, Friedrich; Kasper, Siegfried; Sieghart, Werner; Aschauer, Harald N

    2010-03-01

    We examined 89 normal volunteers using Cloninger's Temperament and Character Inventory (TCI). Genotyping the 102T/C polymorphism of the serotonin 5HT2A receptor gene and the ser9gly polymorphism in exon 1 of the dopamine D3 receptor (DRD3) gene was performed using PCR-RFLP, whereas the dopamine transporter (DAT1) gene variable number of tandem repeats (VNTR) polymorphism was investigated using PCR amplification followed by electrophoresis in an 8% acrylamide gel with a set of size markers. We found a nominally significant association between gender and harm avoidance (P=0.017; women showing higher scores). There was no association of either DAT1, DRD3 or 5HT2A alleles or genotypes with any dimension of the TCI applying Kruskal-Wallis rank-sum tests. Comparing homozygote and heterozygote DAT1 genotypes, we found higher novelty seeking scores in homozygotes (P=0.054). We further found a nominally significant interaction between DAT1 and 5HT2A homo-/heterozygous gene variants (P=0.0071; DAT1 and 5HT2A genotypes P value of 0.05), performing multivariate analysis of variance (MANOVA). Examining the temperamental TCI subscales, this interaction was associated with persistence (genotypes: P=0.004; homo-/heterozygous gene variants: P=0.0004). We conclude that an interaction between DAT1 and 5HT2A genes might influence the temperamental personality trait persistence.

  11. Dendritic Release of Neurotransmitters.

    PubMed

    Ludwig, Mike; Apps, David; Menzies, John; Patel, Jyoti C; Rice, Margaret E

    2016-12-06

    Release of neuroactive substances by exocytosis from dendrites is surprisingly widespread and is not confined to a particular class of transmitters: it occurs in multiple brain regions, and includes a range of neuropeptides, classical neurotransmitters, and signaling molecules, such as nitric oxide, carbon monoxide, ATP, and arachidonic acid. This review is focused on hypothalamic neuroendocrine cells that release vasopressin and oxytocin and midbrain neurons that release dopamine. For these two model systems, the stimuli, mechanisms, and physiological functions of dendritic release have been explored in greater detail than is yet available for other neurons and neuroactive substances. © 2017 American Physiological Society. Compr Physiol 7:235-252, 2017.

  12. Amyloid Precursor Protein 96–110 and β-Amyloid 1–42 Elicit Developmental Anomalies in Sea Urchin Embryos and Larvae that are Alleviated by Neurotransmitter Analogs for Acetylcholine, Serotonin and Cannabinoids

    PubMed Central

    Buznikov, Gennady A.; Nikitina, Lyudmila A.; Seidler, Frederic J.; Slotkin, Theodore A.; Bezuglov, Vladimir V.; Milošević, Ivan; Lazarević, Lidija; Rogač, Ljubica; Ruzdijić, Sabera; Rakić, Ljubiša M.

    2008-01-01

    Amyloid precursor protein (APP) is overexpressed in the developing brain and portions of its extracellular domain, especially amino acid residues 96–110, play an important role in neurite outgrowth and neural cell differentiation. In the current study, we evaluated the developmental abnormalities caused by administration of exogenous APP96–110 in sea urchin embryos and larvae, which, like the developing mammalian brain, utilize acetylcholine and other neurotransmitters as morphogens; effects were compared to those of β-amyloid 1–42 (Aβ42), the neurotoxic APP fragment contained within neurodegenerative plaques in Alzheimer’s Disease. Although both peptides elicited dysmorphogenesis, Aβ42 was far more potent; in addition, whereas Aβ42 produced abnormalities at developmental stages ranging from early cleavage divisions to the late pluteus, APP96–110 effects were restricted to the intermediate, mid-blastula stage. For both agents, anomalies were prevented or reduced by addition of lipid-permeable analogs of acetylcholine, serotonin or cannabinoids; physostigmine, a carbamate-derived cholinesterase inhibitor, was also effective. In contrast, agents that act on NMDA receptors (memantine) or α-adrenergic receptors (nicergoline), and that are therapeutic in Alzheimer’s Disease, were themselves embryotoxic, as was tacrine, a cholinesterase inhibitor from a different chemical class than physostigmine. Protection was also provided by agents acting downstream from receptor-mediated events: increasing cyclic AMP with caffeine or isobutylmethylxanthine, or administering the antioxidant, α-tocopherol, were all partially effective. Our findings reinforce a role for APP in development and point to specific interactions with neurotransmitter systems that act as morphogens in developing sea urchins as well as in the mammalian brain. PMID:18565728

  13. Classical neurotransmitters and neuropeptides involved in major depression in a multi-neurotransmitter system: a focus on antidepressant drugs.

    PubMed

    Werner, Felix-Martin; Coveñas, R

    2013-01-01

    We summarize the alterations of classical neurotransmitters and neuropeptides and the corresponding subreceptors involved in major depression. Neuronal circuits in the brainstem, hippocampus and hypothalamus are developed, since they can be used to derive a multimodal pharmacotherapy. In this sense, serotonin hypoactivity could occur through a strong presynaptic inhibition of glutaminergic neurons via the subtype 5 of metabotropic glutaminergic receptors, and noradrenaline hypoactivity could be due to an enhanced presynaptic inhibition of GABAergic neurons via GABAB receptors. In the hippocampus, dopamine hypoactivity leads to a decreased positive effect. In clinical trials, the antidepressant effect of drugs interfering with the mentioned subreceptors, for example the triple reuptake inhibitor amitifadine, is being investigated. Moreover, the alterations of neuropeptides, such as corticotropin-releasing hormone, neuropeptide Y and galanin are pointed out. The additional antidepressant effect of analogs, agonists and antagonists of the mentioned neuropeptides should be examined.

  14. Microfluidic in-channel multi-electrode platform for neurotransmitter sensing

    NASA Astrophysics Data System (ADS)

    Kara, A.; Mathault, J.; Reitz, A.; Boisvert, M.; Tessier, F.; Greener, J.; Miled, A.

    2016-03-01

    In this project we present a microfluidic platform with in-channel micro-electrodes for in situ screening of bio/chemical samples through a lab-on-chip system. We used a novel method to incorporate electrochemical sensors array (16x20) connected to a PCB, which opens the way for imaging applications. A 200 μm height microfluidic channel was bonded to electrochemical sensors. The micro-channel contains 3 inlets used to introduce phosphate buffer saline (PBS), ferrocynide and neurotransmitters. The flow rate was controlled through automated micro-pumps. A multiplexer was used to scan electrodes and perform individual cyclic voltammograms by a custom potentiostat. The behavior of the system was linear in terms of variation of current versus concentration. It was used to detect the neurotransmitters serotonin, dopamine and glutamate.

  15. LeuT-Desipramine Structure Reveals How Antidepressants Block Neurotransmitter Reuptake

    SciTech Connect

    Zhou,Z.; Zhen, J.; Karpowich, N.; Goetz, R.; Law, C.; Reith, M.; Wang, D.

    2007-01-01

    Tricyclic antidepressants exert their pharmacological effect -- inhibiting the reuptake of serotonin, norepinephrine, and dopamine -- by directly blocking neurotransmitter transporters (SERT, NET, and DAT, respectively) in the presynaptic membrane. The drug-binding site and the mechanism of this inhibition are poorly understood. We determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT, NET, and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This binding site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters.

  16. LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake.

    PubMed

    Zhou, Zheng; Zhen, Juan; Karpowich, Nathan K; Goetz, Regina M; Law, Christopher J; Reith, Maarten E A; Wang, Da-Neng

    2007-09-07

    Tricyclic antidepressants exert their pharmacological effect-inhibiting the reuptake of serotonin, norepinephrine, and dopamine-by directly blocking neurotransmitter transporters (SERT, NET, and DAT, respectively) in the presynaptic membrane. The drug-binding site and the mechanism of this inhibition are poorly understood. We determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT, NET, and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This binding site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters.

  17. Two-step production of monoamines in monoenzymatic cells in the spinal cord: a different control strategy of neurotransmitter supply?

    PubMed Central

    Zhang, Mengliang

    2016-01-01

    Monoamine neurotransmitters play an important role in the modulation of sensory, motor and autonomic functions in the spinal cord. Although traditionally it is believed that in mammalian spinal cord, monoamine neurotransmitters mainly originate from the brain, accumulating evidence indicates that especially when the spinal cord is injured, they can also be produced in the spinal cord. In this review, I will present evidence for a possible pathway for two-step synthesis of dopamine and serotonin in the spinal cord. Published data from different sources and unpublished data from my own ongoing projects indicate that monoenzymatic cells expressing aromatic L-amino acid decarboxylase (AADC), tyrosine hydroxylase (TH) or tryptophan hydroxylase (TPH) are present in the spinal cord and that these TH and THP cells often lie in close proximity to AADC cells. Prompted by the above evidence, I hypothesize that dopamine and serotonin could be synthesized sequentially in two monoenzymatic cells in the spinal cord via a TH-AADC and a TPH-AADC cascade respectively. The monoamines synthesized through this pathway may compensate for lost neurotransmitters following spinal cord injury and also may play specific roles in the recovery of sensory, motor and autonomic functions. PMID:28197177

  18. Two-step production of monoamines in monoenzymatic cells in the spinal cord: a different control strategy of neurotransmitter supply?

    PubMed

    Zhang, Mengliang

    2016-12-01

    Monoamine neurotransmitters play an important role in the modulation of sensory, motor and autonomic functions in the spinal cord. Although traditionally it is believed that in mammalian spinal cord, monoamine neurotransmitters mainly originate from the brain, accumulating evidence indicates that especially when the spinal cord is injured, they can also be produced in the spinal cord. In this review, I will present evidence for a possible pathway for two-step synthesis of dopamine and serotonin in the spinal cord. Published data from different sources and unpublished data from my own ongoing projects indicate that monoenzymatic cells expressing aromatic L-amino acid decarboxylase (AADC), tyrosine hydroxylase (TH) or tryptophan hydroxylase (TPH) are present in the spinal cord and that these TH and THP cells often lie in close proximity to AADC cells. Prompted by the above evidence, I hypothesize that dopamine and serotonin could be synthesized sequentially in two monoenzymatic cells in the spinal cord via a TH-AADC and a TPH-AADC cascade respectively. The monoamines synthesized through this pathway may compensate for lost neurotransmitters following spinal cord injury and also may play specific roles in the recovery of sensory, motor and autonomic functions.

  19. Serum serotonin as unexpected potential marker for staging of experimental hepatocellular carcinoma.

    PubMed

    Abdel-Hamid, N M; Shehata, Dalia E; Abdel-Ghany, Ahmed A; Ragaa, Ahmed; Wahid, Ahmed

    2016-10-01

    Hepatocellular carcinoma (HCC) is the primary cancer of the liver. The present study aimed to assess the potential role of the endogenous regulators of angiogenesis like neurotransmitters, as possible HCC biomarkers. Five groups of rats were used in this study (8 rats per each): control healthy group (I), four intoxicated groups (II, III, IV, and V) used for induction of HCC with a single IP dose of diethylnitrosamine (DENA), 200mg/kg. Groups II, III, IV, and V were sacrificed after 8, 16, 24, and 32 weeks of DENA injection respectively. Serum levels of epinephrine, nor-epinephrine, serotonin, and dopamine of all animals were estimated using high performance liquid chromatography technique coupled with fluorescence detector (HPLC-FLD). Development of HCC was confirmed histopathologically. Our results showed a significant increase in 3 neurotransmitters (epinephrine, nor-epinephrine, and serotonin) in DENA intoxicated HCC rat model. Only serotonin exhibited a significant increase in early histological stage HCC development (16 weeks post DENA injection) in comparison to alpha-fetoprotein (AFP), (24 weeks post DENA injection). These results suggest that neurotransmitters (Epinephrine and Norepinephrine) may have a role as a biomarker for late histological stage HCC. Like AFP, while serotonin may be used for early stage HCC.

  20. Neurotransmitter properties of the newborn human retina

    SciTech Connect

    Hollyfield, J.G.; Frederick, J.M.; Rayborn, M.E.

    1983-07-01

    Human retinal tissue from a newborn was examined autoradiographically for the presence of high-affinity uptake and localization of the following putative neurotransmitters: dopamine, glycine, GABA, aspartate, and glutamate. In addition, the dopamine content of this newborn retina was measured by high pressure liquid chromatography. Our study reveals that specific uptake mechanisms for /sup 3/H-glycine, /sup 3/H-dopamine, and /sup 3/H-GABA are present at birth. However, the number and distribution of cells labeled with each of these /sup 3/H-transmitters are not identical to those observed in adult human retinas. Furthermore, the amount of endogenous dopamine in the newborn retina is approximately 1/20 the adult level. Photoreceptor-specific uptake of /sup 3/H-glutamate and /sup 3/H-aspartate are not observed. These findings indicate that, while some neurotransmitter-specific properties are present at birth, significant maturation of neurotransmitter systems occurs postnatally.

  1. Anxiety and affective disorder comorbidity related to serotonin and other neurotransmitter systems: obsessive-compulsive disorder as an example of overlapping clinical and genetic heterogeneity.

    PubMed

    Murphy, Dennis L; Moya, Pablo R; Fox, Meredith A; Rubenstein, Liza M; Wendland, Jens R; Timpano, Kiara R

    2013-01-01

    Individuals with obsessive-compulsive disorder (OCD) have also been shown to have comorbid lifetime diagnoses of major depressive disorder (MDD; rates greater than 70%), bipolar disorder (rates greater than 10%) and other anxiety disorders (e.g. panic disorder, post-traumatic stress disorder (PTSD)). In addition, overlap exists in some common genetic variants (e.g. the serotonin transporter gene (SLC6A4), the brain-derived neurotrophic factor (BDNF) gene), and rare variants in genes/chromosomal abnormalities (e.g. the 22q11 microdeletion syndrome) found across the affective/anxiety disorder spectrums. OCD has been proposed as a possible independent entity for DSM-5, but by others thought best retained as an anxiety disorder subtype (its current designation in DSM-IV), and yet by others considered best in the affective disorder spectrum. This review focuses on OCD, a well-studied but still puzzling heterogeneous disorder, regarding alterations in serotonergic, dopaminergic and glutamatergic neurotransmission in addition to other systems involved, and how related genes may be involved in the comorbidity of anxiety and affective disorders. OCD resembles disorders such as depression, in which gene × gene interactions, gene × environment interactions and stress elements coalesce to yield OC symptoms and, in some individuals, full-blown OCD with multiple comorbid disorders.

  2. Anxiety and affective disorder comorbidity related to serotonin and other neurotransmitter systems: obsessive–compulsive disorder as an example of overlapping clinical and genetic heterogeneity

    PubMed Central

    Murphy, Dennis L.; Moya, Pablo R.; Fox, Meredith A.; Rubenstein, Liza M.; Wendland, Jens R.; Timpano, Kiara R.

    2013-01-01

    Individuals with obsessive–compulsive disorder (OCD) have also been shown to have comorbid lifetime diagnoses of major depressive disorder (MDD; rates greater than 70%), bipolar disorder (rates greater than 10%) and other anxiety disorders (e.g. panic disorder, post-traumatic stress disorder (PTSD)). In addition, overlap exists in some common genetic variants (e.g. the serotonin transporter gene (SLC6A4), the brain-derived neurotrophic factor (BDNF) gene), and rare variants in genes/chromosomal abnormalities (e.g. the 22q11 microdeletion syndrome) found across the affective/anxiety disorder spectrums. OCD has been proposed as a possible independent entity for DSM-5, but by others thought best retained as an anxiety disorder subtype (its current designation in DSM-IV), and yet by others considered best in the affective disorder spectrum. This review focuses on OCD, a well-studied but still puzzling heterogeneous disorder, regarding alterations in serotonergic, dopaminergic and glutamatergic neurotransmission in addition to other systems involved, and how related genes may be involved in the comorbidity of anxiety and affective disorders. OCD resembles disorders such as depression, in which gene × gene interactions, gene × environment interactions and stress elements coalesce to yield OC symptoms and, in some individuals, full-blown OCD with multiple comorbid disorders. PMID:23440468

  3. The presence of both serotonin 1A receptor (HTR1A) and dopamine transporter (DAT1) gene variants increase the risk of borderline personality disorder

    PubMed Central

    Joyce, Peter R.; Stephenson, John; Kennedy, Martin; Mulder, Roger T.; McHugh, Patrick C.

    2014-01-01

    Dysfunction in the dopaminergic and serotonergic neurotransmitter systems has been demonstrated to be important in the etiology of borderline personality disorder (BPD). We investigated the relationship of two BPD risk factors, the HTR1A promoter polymorphism -1019C > G (rs6295) and the dopamine transporter (DAT1) repeat allele, with BPD in a major depressive disorder cohort of 367 patients. Out-patients with major depressive disorder were recruited for two treatment trials and assessed for personality disorders, including BPD. DNA samples were collected and the rs6295 polymorphism was detected with a TaqMan® assay. The DAT1 repeat allele was genotyped using a modified PCR method. The impact of polymorphisms on BPD was statistically analyzed using uncontrolled logistic and multiple logistic regression models. BPD patients had higher frequencies of the DAT1 9,9 (OR = 2.67) and 9,10 (OR = 3.67) genotypes and also those homozygous HTR1A G allele (OR = 2.03). No significant interactions between HTR1A and DAT1 genotypes, were observed; however, an increased risk of BPD was observed for those patients who were either 9,10; G,G (OR = 6.64) and 9,9; C,G (OR = 5.42). Furthermore, the odds of BPD in patients exhibiting high-risk variants of these two genes differed from those of patients in low-risk groups by up to a factor of 9. Our study provides evidence implicating the importance of the serotonergic and dopaminergic systems in BPD and that the interaction between genes from different neurotransmitters may play a role in the susceptibility to BPD. PMID:24432029

  4. Altered levels of brain neurotransmitter from new born rabbits with intrauterine restriction.

    PubMed

    Hernández-Andrade, E; Cortés-Camberos, A J; Díaz, N F; Flores-Herrera, H; García-López, G; González-Jiménez, M; Santamaría, A; Molina-Hernández, A

    2015-01-01

    Fetal intrauterine growth restriction generates chronic hypoxia due to placental insufficiency. Despite the hemodynamic process of blood flow, redistributions are taking place in key organs such as the fetal brain during intrauterine growth restriction, in order to maintain oxygen and nutrients supply. The risk of short- and long-term neurological effects are still present in hypoxic offspring. Most studies previously reported the effect of hypoxia on the levels of a single neurotransmitter, making it difficult to have a better understanding of the relationship among neurotransmitter levels and the defects reported in products that suffer intrauterine growth restriction, such as motor development, coordination and execution of movement, and the learning-memory process. The aim of this study was to evaluate the levels of gamma-aminobutyric acid, glutamate, dopamine and serotonin in three structures of the brain related to the above-mentioned function such as the cerebral cortex, the striatum, and the hippocampus in the chronic hypoxic newborn rabbit model. Our results showed a significant increase in glutamate and dopamine levels in all studied brain structures and a significant decrease in gamma-aminobutyric acid levels but only in the striatum, suggesting that the imbalance on the levels of several neurotransmitters could be involved in new born brain damage due to perinatal hypoxia.

  5. Carbon Nanotube-based microelectrodes for enhanced detection of neurotransmitters

    NASA Astrophysics Data System (ADS)

    Jacobs, Christopher B.

    Fast-scan cyclic voltammetry (FSCV) is one of the common techniques used for rapid measurement of neurotransmitters in vivo. Carbon-fiber microelectrodes (CFMEs) are typically used for neurotransmitter detection because of sub-second measurement capabilities, ability to measure changes in neurotransmitter concentration during neurotransmission, and the small size electrode diameter, which limits the amount of damage caused to tissue. Cylinder CFMEs, typically 50 -- 100 microm long, are commonly used for in vivo experiments because the electrode sensitivity is directly related to the electrode surface area. However the length of the electrode can limit the spatial resolution of neurotransmitter detection, which can restrict experiments in Drosophila and other small model systems. In addition, the electrode sensitivity toward dopamine and serotonin detection drops significantly for measurements at rates faster than 10 Hz, limiting the temporal resolution of CFMEs. While the use of FSCV at carbon-fiber microelectrodes has led to substantial strides in our understanding of neurotransmission, techniques that expand the capabilities of CFMEs are crucial to fully maximize the potential uses of FSCV. This dissertation introduces new methods to integrate carbon nanotubes (CNT) into microelectrodes and discusses the electrochemical enhancements of these CNT-microelectrodes. The electrodes are specifically designed with simple fabrication procedures so that highly specialized equipment is not necessary, and they utilize commercially available materials so that the electrodes could be easily integrated into existing systems. The electrochemical properties of CNT modified CFMEs are characterized using FSCV and the effect of CNT functionalization on these properties is explored in Chapter 2. For example, CFME modification using carboxylic acid functionalized CNTs yield about a 6-fold increase in dopamine oxidation current, but modification with octadecylamine CNTs results in a

  6. Inhibition of K+-stimulated [3H]dopamine and [14C]acetylcholine release by the putative dopamine autoreceptor agonist, B-HT 920.

    PubMed

    Schmidt, C J; Lobur, A; Lovenberg, W

    1986-12-01

    The inhibition of K+-stimulated [3H]dopamine and [14C]acetylcholine release from preloaded rat striatal slices was used to examine the presynaptic selectivity of the putative dopamine autoreceptor agonist, B-HT 920. In the micromolar range, B-HT 920 caused a concentration-dependent inhibition of the release of both labeled neurotransmitters as evoked by 20 mM K+. The effect of B-HT 920 on both [3H]dopamine and [14C]acetylcholine release was completely blocked by (+) butaclamol but not by (-) butaclamol. Sulpiride, a selective D2 antagonist, similarly blocked the inhibitory effect of B-HT 920 on the release of both labeled neurotransmitters indicating both responses were mediated by D2 receptors. (+) Butaclamol alone elevated stimulated [3H]dopamine release suggesting a significant amount of autoreceptor occupancy by endogenously released dopamine. Experiments with tolazoline and the alpha 2 agonist, B-HT 933, did not suggest any involvement of alpha-adrenoceptor activity in the inhibitory effects of B-HT 920 on the release of either transmitter. Inhibition of release was a selective effect of B-HT 920 as the drug was without effect on the K+-stimulated release of [3H]serotonin. The results indicate that in vitro B-HT 920 is active of both pre- and postsynaptic dopamine receptors in contrast to the pattern of effects observed after its in vivo administration.

  7. Serotonin Receptors in Hippocampus

    PubMed Central

    Berumen, Laura Cristina; Rodríguez, Angelina; Miledi, Ricardo; García-Alcocer, Guadalupe

    2012-01-01

    Serotonin is an ancient molecular signal and a recognized neurotransmitter brainwide distributed with particular presence in hippocampus. Almost all serotonin receptor subtypes are expressed in hippocampus, which implicates an intricate modulating system, considering that they can be localized as autosynaptic, presynaptic, and postsynaptic receptors, even colocalized within the same cell and being target of homo- and heterodimerization. Neurons and glia, including immune cells, integrate a functional network that uses several serotonin receptors to regulate their roles in this particular part of the limbic system. PMID:22629209

  8. Serotonergic properties of cocaine: effects on a 5-HT2 receptor-mediated behavior and on extracellular concentrations of serotonin and dopamine.

    PubMed

    Essman, W D; Singh, A; Lucki, I

    1994-09-01

    The present study examined the ability of cocaine to produce behavioral and neuropharmacological effects through serotonin (5-HT) systems. Pretreatment with fluoxetine or cocaine potentiated the head-shake response to the 5-HT precursor, 5-hydroxytryptophan (5-HTP; 75 mg/kg), a behavior mediated by the activation of 5-HT2 receptors. This effect was antagonized by the selective 5-HT2 receptor antagonist ketanserin (1 mg/kg). In contrast, pretreatment with the selective norepinephrine uptake inhibitor desipramine (10 mg/kg) or the selective dopamine (DA) uptake inhibitor GBR 12909 (32 mg/kg) failed to potentiate the head-shake response. The effects of cocaine on extracellular concentrations of DA and 5-HT in the nucleus accumbens were examined using in vivo microdialysis in a separate group of anesthetized rats. Cocaine (10 mg/kg) increased the extracellular concentrations of DA and 5-HT by 300-350% over baseline levels. Cocaine's ability to increase the head-shake response and to increase extracellular concentrations of 5-HT may be due to its ability to block 5-HT uptake.

  9. Stimulation of glutamate receptors in the ventral tegmental area is necessary for serotonin-2 receptor-induced increases in mesocortical dopamine release

    PubMed Central

    Pehek, E.A.; Hernan, A.E.

    2017-01-01

    Modulation of dopamine (DA) released by serotonin-2 (5-HT2) receptors has been implicated in the mechanism of action of antipsychotic drugs. The mesocortical DA system has been implicated particularly in the cognitive deficits observed in schizophrenia. Agonism at 5-HT2A receptors in the prefrontal cortex is associated with increases in cortical DA release. Evidence indicates that 5-HT2A receptors in the cortex regulate mesocortical DA release through stimulation of a “long-loop” feedback system from the PFC to the VTA and back. However, a causal role for VTA glutamate in the 5-HT2-induced increases in PFC DA has not been established. The present study does so by measuring 5-HT2 agonist-induced DA release in the cortex after infusions of glutamate antagonists into the VTA. Infusions of a combination of a NMDA (AP-5: 2-amino-5-phosphopentanoic acid) and an AMPA/kainate (CNQX: 6-cyano-7-nitroquinoxaline-2,3-dione) receptor antagonist into the VTA blocked the increases in cortical DA produced by administration of the 5-HT2 agonist DOI [(±)-2,5-Dimethoxy-4-iodoamphetamine] (2.5 mg/kg s.c.). These results demonstrate that stimulation of glutamate receptors in the VTA is necessary for 5-HT2 agonist-induced increases in cortical DA. PMID:25637799

  10. Candidate-gene approach in posttraumatic stress disorder after urban violence: association analysis of the genes encoding serotonin transporter, dopamine transporter, and BDNF.

    PubMed

    Valente, Nina Leão Marques; Vallada, Homero; Cordeiro, Quirino; Miguita, Karen; Bressan, Rodrigo Affonseca; Andreoli, Sergio Baxter; Mari, Jair Jesus; Mello, Marcelo Feijó

    2011-05-01

    Posttraumatic stress disorder (PTSD) is a prevalent, disabling anxiety disorder marked by behavioral and physiologic alterations which commonly follows a chronic course. Exposure to a traumatic event constitutes a necessary, but not sufficient, factor. There is evidence from twin studies supporting a significant genetic predisposition to PTSD. However, the precise genetic loci still remain unclear. The objective of the present study was to identify, in a case-control study, whether the brain-derived neurotrophic factor (BDNF) val66met polymorphism (rs6265), the dopamine transporter (DAT1) three prime untranslated region (3'UTR) variable number of tandem repeats (VNTR), and the serotonin transporter (5-HTTPRL) short/long variants are associated with the development of PTSD in a group of victims of urban violence. All polymorphisms were genotyped in 65 PTSD patients as well as in 34 victims of violence without PTSD and in a community control group (n = 335). We did not find a statistical significant difference between the BDNF val66met and 5-HTTPRL polymorphism and the traumatic phenotype. However, a statistical association was found between DAT1 3'UTR VNTR nine repeats and PTSD (OR = 1.82; 95% CI, 1.20-2.76). This preliminary result confirms previous reports supporting a susceptibility role for allele 9 and PTSD.

  11. Coordinated Recruitment of Cortical-Subcortical Circuits and Ascending Dopamine and Serotonin Neurons During Inhibitory Control of Cocaine Seeking in Rats.

    PubMed

    Navailles, Sylvia; Guillem, Karine; Vouillac-Mendoza, Caroline; Ahmed, Serge H

    2015-09-01

    People with cocaine addiction retain some degree of prefrontal cortex (PFC) inhibitory control of cocaine craving, a brain capacity that may underlie the efficacy of cognitive behavioral therapy for addiction. Similar findings were recently found in rats after extended access to and escalation of cocaine self-administration. Rats' inhibitory control of cocaine seeking was flexible, sufficiently strong to suppress cocaine-primed reinstatement and depended, at least in part, on neuronal activity within the prelimbic (PL) PFC. Here, we used a large-scale and high-resolution Fos mapping approach to identify, beyond the PL PFC, how top-down and/or bottom-up PFC-subcortical circuits are recruited during inhibition of cocaine seeking. Overall, we found that effective inhibitory control of cocaine seeking is associated with the coordinated recruitment of different top-down cortical-striatal circuits originating from different PFC territories, and of different bottom-up dopamine (DA) and serotonin (5-HT) midbrain subsystems that normally modulate activity in these circuits. This integrated brain response suggests that rats concomitantly engage and experience intricate cognitive and affective processes when they have to inhibit intense cocaine seeking. Thus, even after extended drug use, rats can be successfully trained to engage whole-brain inhibitory control mechanisms to suppress cocaine seeking.

  12. Simultaneous quantification of neuroactive dopamine serotonin and kynurenine pathway metabolites in gender-specific youth urine by ultra performance liquid chromatography tandem high resolution mass spectrometry.

    PubMed

    Lu, Haihua; Yu, Jing; Wang, Jun; Wu, Linlin; Xiao, Hang; Gao, Rong

    2016-04-15

    Neuroactive metabolites in dopamine, serotonin and kynurenine metabolic pathways play key roles in several physiological processes and their imbalances have been implicated in the pathophysiology of a wide range of disorders. The association of these metabolites' alterations with various pathologies has raised interest in analytical methods for accurate quantification in biological fluids. However, simultaneous measurement of various neuroactive metabolites represents great challenges due to their trace level, high polarity and instability. In this study, an analytical method was developed and validated for accurately quantifying 12 neuroactive metabolites covering three metabolic pathways in youth urine by ultra performance liquid chromatography coupled to electrospray tandem high resolution mass spectrometry (UPLC-ESI-HRMS/MS). The strategy of dansyl chloride derivatization followed by solid phase extraction on C18 cartridges were employed to reduce matrix interference and improve the extraction efficiency. The reverse phase chromatographic separation was achieved with a gradient elution program in 20 min. The high resolution mass spectrometer (Q Exactive) was employed, with confirmation and quantification by Target-MS/MS scan mode. Youth urine samples collected from 100 healthy volunteers (Female:Male=1:1) were analyzed to explore the differences in metabolite profile and their turnover between genders. The results demonstrated that the UPLC-ESI-HRMS/MS method is sensitive and robust, suitable for monitoring a large panel of metabolites and for discovering new biomarkers in the medical fields.

  13. Developmental Exposure to Fluoxetine Modulates the Serotonin System in Hypothalamus

    PubMed Central

    Berg, Cecilia; Backström, Tobias; Winberg, Svante; Lindberg, Richard; Brandt, Ingvar

    2013-01-01

    The selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLU, Prozac®) is commonly prescribed for depression in pregnant women. This results in SSRI exposure of the developing fetus. However, there are knowledge gaps regarding the impact of SSRI exposure during development. Given the role of serotonin in brain development and its cross-talk with sex hormone function, we investigated effects of developmental exposure to pharmacologically relevant concentrations of FLU (3 and 30 nM (measured)) on brain neurotransmitter levels, gonadal differentiation, aromatase activity in brain and gonads, and the thyroid system, using the Xenopus tropicalis model. Tadpoles were chronically exposed (8 weeks) until metamorphosis. At metamorphosis brains were cryosectioned and levels of serotonin, dopamine, norepinephrine, and their metabolites 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, and homovanillic acid were measured in discrete regions (telencephalon, hypothalamus and the reticular formation) of the cryosections using high-performance liquid chromatography. Exposure to 30 nM FLU increased the concentration of 5-hydroxyindoleacetic acid in hypothalamus compared with controls. FLU exposure did not affect survival, time to metamorphosis, thyroid histology, gonadal sex differentiation, or aromatase activity implying that the effect on the serotonergic neurotransmitter system in the hypothalamus region was specific. The FLU concentration that impacted the serotonin system is lower than the concentration measured in umbilical cord serum, suggesting that the serotonin system of the developing brain is highly sensitive to in utero exposure to FLU. To our knowledge this is the first study showing effects of developmental FLU exposure on brain neurochemistry. Given that SSRIs are present in the aquatic environment the current results warrant further investigation into the neurobehavioral effects of SSRIs in aquatic wildlife. PMID:23383055

  14. Does chronic nicotine alter neurotransmitter receptors involved in Parkinson's disease

    SciTech Connect

    Reilly, M.A.; Lapin, E.P.; Lajtha, A.; Maker, H.S.

    1986-03-05

    Cigarette smokers are fewer in number among Parkinson's Disease (PD) patients than among groups of persons who do not have PD. Several hypotheses have been proposed to explain this observation. One which must be tested is the possibility that some pharmacologic agent present in cigarette smoke may interact with some central nervous system component involved in PD. To this end, they have investigated the effect of chronic nicotine administration on receptors for some of the neurotransmitters that are affected in PD. Rats were injected for six weeks with saline or nicotine 0.8 mg/kg S.C., then killed and brains removed and dissected. The binding of (/sup 3/H)-ketanserin to serotonin receptors in frontal cortex and of (/sup 3/H)-domperidone to dopamine receptors in caudate was not affected. However, the binding of (/sup 3/H)-domperidone in nucleus accumbens was altered: the K/sub d/ increased from 0.16 +/- 0.02 nM to 0.61 +/- 0.07 nM, and the B/sub max/ increased from 507 +/- 47 fmol/mg protein to 910 +/- 43 fmol/mg (p < 0.001 for both comparisons). These values are based on three ligand concentrations. Additional studies are in progress to substantiate the data. It is concluded that chronic nicotine administration may alter dopamine receptors in nucleus accumbens.

  15. Unraveling the modulatory actions of serotonin on male rat sexual responses.

    PubMed

    Rubio-Casillas, A; Rodríguez-Quintero, C M; Rodríguez-Manzo, G; Fernández-Guasti, A

    2015-08-01

    Animal studies and clinical investigations reveal that serotonin plays a central role in the control of the ejaculatory threshold. The chronic use of selective serotonin reuptake inhibitors (SSRIs) frequently results in sexual dysfunction, inviting to analyze the modulatory actions of serotonin on male sexual function in depth. Even though the main effect of serotonin on male sexual responses is inhibitory, this neuromodulator also mediates brief important stimulatory actions. Serotonin (5-HT) can activate two intracellular signaling pathways: a lower-threshold facilitatory pathway, and a higher-threshold inhibitory pathway, leading to biphasic effects. We propose that these divergent actions are related to the stimulation or inhibition of glutamatergic and GABAergic interneurons. Experimental evidence suggests that low 5-HT concentrations produce stimulatory actions on male ejaculatory aspects that might be mediated by the blockade of the GABAergic neurotransmission in the MPOA and spinal cord, which in turn releases a tonic inhibition that allows other neurotransmitters such as glutamate, noradrenaline, oxytocin and dopamine to initiate a sequence of molecular events resulting in the expression of ejaculation. Similar serotonin actions, mediated via interneurons, have been proposed for the regulation of other processes and occur in many central nervous system areas, indicating that it is not an isolated phenomenon.

  16. Effects of intracerebroventricular administration of 5-(glutathion-S-yl)-alpha-methyldopamine on brain dopamine, serotonin, and norepinephrine concentrations in male Sprague-Dawley rats.

    PubMed

    Miller, R T; Lau, S S; Monks, T J

    1996-03-01

    alpha-Methyldopamine (alpha-MeDA) is a metabolite of the serotonergic neurotoxicants 3,4-(+/-)-(methylenedioxy)amphetamine (MDA) and 3,4-(+/-)-(methylenedioxy)methamphetamine (MDMA). alpha-MeDA readily oxidizes, and in the presence of glutathione (GSH) it forms 5-(glutathion-S-yl)-alpha-methyldopamine [5-(glutathion-S-yl)-alpha-MeDA]. Since GSH conjugates of many polyphenols are biologically (re)active, we investigated the role of 5-(glutathion-S-yl)-alpha-MeDA in the acute and long-term neurochemical changes observed after administration of MDA. Intracerebroventricular (icv) administration of 5-(glutathion-S-yl)-alpha-MeDA (720 nmol) to male Sprague-Dawley rats produced behavioral changes similar to those reported after subcutaneous administration of MDA. Thus, animals became hyperactive and aggressive and displayed forepaw treading and Straub tails, behaviors usually seen after administration of serotonin (5-HT) releasers, and consistent with a role for 5-(glutathion-S-yl)-alpha-MeDA in some of the behavioral alterations seen after administration of MDA and MDMA. In addition to the behavioral changes, 5-(glutathion-S-yl)-alpha-MeDA also caused short-term alterations in the dopaminergic, serotonergic, and noradrenergic systems. An increase in dopamine synthesis appears to be a prerequisite for the long-term depletion of brain 5-HT following MDMA administration. However, although 5-(glutathion-S-yl)-alpha-MeDA reproduced some of the effects of MDA on the dopaminergic system and was capable of causing acute increases in 5-HT turnover, a single icv injection of 5-(glutathion-S-yl)-alpha-MeDA did not result in long-term serotonergic toxicity. Thus, although acute stimulation of dopamine turnover may be necessary for long-term serotonergic toxicity, such changes are not sufficient to produce these effects. The effects of a multiple dosing schedule of 5-(glutathion-S-yl)-alpha-MeDA will therefore require investigation before we can define a role for this metabolite in

  17. [Effect of phenibut on the content of monoamines, their metabolites, and neurotransmitter amino acids in rat brain structures].

    PubMed

    Borodkina, L E; Kudrin, V S; Klodt, P M; Narkevich, V B; Tiurenkov, I N

    2009-01-01

    Effects of the nootropic drug phenibut, which is a structural analog of gamma-aminobutyric acid (GABA), on the content of monoamines, their metabolites, and neurotransmitter amino acids in brain structures have been studied on Wistar rats. It is established that a single administration of phenibut in a dose of 25 mg/kg (i.p.) produces a statistically significant increase in the content of dopamine metabolite (3,4-dioxyphenylacetic acid) and the retarding amino acid taurine in striatum. At the same time, phenibut did not significantly influence the levels of GABA, serotonin, and dopamine in various brain structures and produce a moderate decrease in the level of norepinephrine in the hippocampus.

  18. Striatal Serotonin 2C receptors decrease nigrostriatal dopamine release by increasing GABA-A receptor tone in the substantia nigra

    PubMed Central

    Burke, M.V.; Nocjar, C.; Sonneborn, A.J.; McCreary, A.C.

    2017-01-01

    Drugs acting at the serotonin-2C (5-HT2C) receptor subtype have shown promise as therapeutics in multiple syndromes including obesity, depression, and Parkinson’s disease. While it is established that 5-HT2C receptor stimulation inhibits DA release, the neural circuits and the localization of the relevant 5-HT2C receptors remain unknown. The present study used dual-probe in vivo microdialysis to investigate the relative contributions of 5-HT2C receptors localized in the rat substantia nigra (SN) and caudate-putamen (CP) in the control of nigrostriatal DA release. Systemic administration (3.0 mg/kg) of the 5-HT2C receptor selective agonist Ro 60-0175 [(α S )-6-Chloro-5-fluoro-α-methyl-1 H-indole-1-ethanamine fumarate] decreased, whereas intrastriatal infusions of the selective 5-HT2C antagonist SB 242084 [6-Chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1 H-indole-1-carboxyamide; 1.0 µM] increased, basal DA in the CP. Depending on the site within the SN pars reticulata (SNpr), infusions of SB 242084 had more modest but significant effects. Moreover, infusions of the GABA-A receptor agonist muscimol (10 µM) into the SNpr completely reversed the increases in striatal DA release produced by intrastriatal infusions of SB 242084. These findings suggest a role for 5-HT2C receptors regulating striatal DA release that is highly localized. 5-HT2C receptors localized in the striatum may represent a primary site of action that is mediated by actions on GABAergic activity in the SN. PMID:25073477

  19. Effect of long-term actual spaceflight on the expression of key genes encoding serotonin and dopamine system

    NASA Astrophysics Data System (ADS)

    Popova, Nina; Shenkman, Boris; Naumenko, Vladimir; Kulikov, Alexander; Kondaurova, Elena; Tsybko, Anton; Kulikova, Elisabeth; Krasnov, I. B.; Bazhenova, Ekaterina; Sinyakova, Nadezhda

    The effect of long-term spaceflight on the central nervous system represents important but yet undeveloped problem. The aim of our work was to study the effect of 30-days spaceflight of mice on Russian biosatellite BION-M1 on the expression in the brain regions of key genes of a) serotonin (5-HT) system (main enzymes in 5-HT metabolism - tryptophan hydroxylase-2 (TPH-2), monoamine oxydase A (MAO A), 5-HT1A, 5-HT2A and 5-HT3 receptors); b) pivotal enzymes in DA metabolism (tyrosine hydroxylase, COMT, MAO A, MAO B) and D1, D2 receptors. Decreased expression of genes encoding the 5-HT catabolism (MAO A) and 5-HT2A receptor in some brain regions was shown. There were no differences between “spaceflight” and control mice in the expression of TPH-2 and 5-HT1A, 5-HT3 receptor genes. Significant changes were found in genetic control of DA system. Long-term spaceflight decreased the expression of genes encoding the enzyme in DA synthesis (tyrosine hydroxylase in s.nigra), DA metabolism (MAO B in the midbrain and COMT in the striatum), and D1 receptor in hypothalamus. These data suggested that 1) microgravity affected genetic control of 5-HT and especially the nigrostriatal DA system implicated in the central regulation of muscular tonus and movement, 2) the decrease in the expression of genes encoding key enzyme in DA synthesis, DA degradation and D1 receptor contributes to the movement impairment and dyskinesia produced by the spaceflight. The study was supported by Russian Foundation for Basic Research grant № 14-04-00173.

  20. Twenty-four hour rhythm of plasma prolactin in female rabbit pups. Correlation with hypothalamic and adenohypophysial dopamine, serotonin, gamma-aminobutyric acid and taurine content.

    PubMed

    Alvarez, M P; Cardinali, D P; Jiménez, V; Alvariño, M; Esquifino, A I

    2006-01-01

    Lactation in the rabbit is a nocturnal activity, extremely short and regular, that can be a strong synchronizer for the development of circadian rhythmicity in the pups. In the present study, 24-h rhythmicity of plasma prolactin and median eminence and anterior pituitary content of dopamine (DA), serotonin (5HT), gamma-aminobutyric acid (GABA) and taurine were examined in 11 days old female pups kept under 16 h light:8 h dark photoperiods (lights on at 08:00 h). Groups of six to seven female rabbit pups were killed by decapitation at six different time points throughout a 24-h cycle, starting at 09:00 h. Plasma prolactin levels changed significantly throughout the day, showing two peaks, one at first half of rest span (at 13:00 h) and another one at the beginning of the scotophase (at 01:00 h), just preceding doe visit. Median eminence DA content changed in a bimodal way as a function of time of day, displaying two maxima, at the beginning of the rest span and of the activity phase. Median eminence DA and plasma prolactin correlated significantly in an inverse way. Two maxima in median eminence 5HT levels were found, about 4 h in advance to the prolactin peaks. Circulating prolactin correlated inversely with median eminence 5HT content and directly with adenohypophysial 5HT content. Median eminence GABA content reached its maximum at the beginning of the scotophase and correlated significantly with plasma prolactin concentration. A positive correlation between plasma prolactin and adenohypophysial taurine content was observed. These results show that the circadian rhythmicity in prolactin secretory mechanisms in female rabbit pups develops during the early neonatal life.

  1. Interaction between serotonin transporter and dopamine D2/D3 receptor radioligand measures is associated with harm avoidant symptoms in anorexia and bulimia nervosa

    PubMed Central

    Bailer, Ursula F.; Frank, Guido K.; Price, Julie C.; Meltzer, Carolyn C.; Becker, Carl; Mathis, Chester A.; Wagner, Angela; Barbarich-Marsteller, Nicole C.; Bloss, Cinnamon S.; Putnam, Karen; Schork, Nicholas J.; Gamst, Anthony; Kaye, Walter H.

    2013-01-01

    Rationale Individuals with anorexia nervosa (AN) and bulimia nervosa (BN) have alterations of measures of serotonin (5-HT) and dopamine (DA) function, which persist after long-term recovery and are associated with elevated harm avoidance (HA), a measure of anxiety and behavioral inhibition. Objective Based on theories that 5-HT is an aversive motivational system that may oppose a DA-related appetitive system, we explored interactions of positron emission tomography (PET) radioligand measures that reflect portions of these systems. Methods Twenty-seven individuals recovered (REC) from eating disorders (EDs) (7 AN-BN, 11 AN, 9 BN) and 9 control women (CW) were analyzed for correlations between [11C]McN5652 and [11C]raclopride binding. Results There was a positive correlation between [11C]McN5652 binding potential BPnon displaceable(ND)) and [11C]raclopride BPND for the dorsal caudate (r(27) = .62; p < .001), antero-ventral striatum (r(27) = .55, p = .003), middle caudate (r(27) = .68; p < .001), ventral (r(27) = .64; p < .001) and dorsal putamen (r(27) = .42; p = .03). No significant correlations were found in CW. [11C]raclopride BPND, but not [11C]McN5652 BPND, was significantly related to HA in REC EDs. A linear regression analysis showed that the interaction between [11C]McN5652 BPND and [11C]raclopride BPND in the dorsal putamen significantly (b = 140.04; t (22) = 2.21; p = .04) predicted HA. Conclusions This is the first study using PET and the radioligands [11C]McN5652 and [11C]raclopride to show a direct relationship between 5-HT transporter and striatal DA D2/D3 receptor binding in humans, supporting the possibility that 5-HT and DA interactions contribute to HA behaviors in EDs. PMID:23154100

  2. Serotonin2C receptor stimulation inhibits cocaine-induced Fos expression and DARPP-32 phosphorylation in the rat striatum independently of dopamine outflow.

    PubMed

    Devroye, Céline; Cathala, Adeline; Maitre, Marlène; Piazza, Pier Vincenzo; Abrous, Djoher Nora; Revest, Jean-Michel; Spampinato, Umberto

    2015-02-01

    The serotonin(2C) receptor (5-HT(2C)R) is known to control dopamine (DA) neuron function by modulating DA neuronal firing and DA exocytosis at terminals. Recent studies assessing the influence of 5-HT(2C)Rs on cocaine-induced neurochemical and behavioral responses have shown that 5-HT2CRs can also modulate mesoaccumbens DA pathway activity at post-synaptic level, by controlling DA transmission in the nucleus accumbens (NAc), independently of DA release itself. A similar mechanism has been proposed to occur at the level of the nigrostriatal DA system. Here, using in vivo microdialysis in freely moving rats and molecular approaches, we assessed this hypothesis by studying the influence of the 5-HT(2C)R agonist Ro 60-0175 on cocaine-induced responses in the striatum. The intraperitoneal (i.p.) administration of 1 mg/kg Ro 60-0175 had no effect on the increase in striatal DA outflow induced by cocaine (15 mg/kg, i.p.). Conversely, Ro 60-0175 inhibited cocaine-induced Fos immunoreactivity and phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine 75 residue in the striatum. Finally, the suppressant effect of Ro 60-0175 on cocaine-induced DARPP-32 phosphorylation was reversed by the selective 5-HT(2C)R antagonist SB 242084 (0.5 mg/kg, i.p.). In keeping with the key role of DARPP-32 in DA neurotransmission, our results demonstrate that 5-HT(2C)Rs are capable of modulating nigrostriatal DA pathway activity at post-synaptic level, by specifically controlling DA signaling in the striatum.

  3. Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin

    PubMed Central

    Suyama, Julie A.; Sakloth, Farhana; Kolanos, Renata; Glennon, Richard A.; Lazenka, Matthew F.; Negus, S. Stevens

    2016-01-01

    Methcathinone (MCAT) is a monoamine releaser and parent compound to a new class of designer drugs that includes the synthetic cathinones mephedrone and flephedrone. Using MCAT and a series of para-substituted (or 4-substituted) MCAT analogs, it has been previously shown that expression of abuse-related behavioral effects in rats correlates both with the volume of the para substituent and in vitro neurochemical selectivity to promote monoamine release via the dopamine (DA) versus serotonin (5-HT) transporters in rat brain synaptosomes. The present study used in vivo microdialysis to determine the relationship between these previous measures and the in vivo neurochemical selectivity of these compounds to alter nucleus accumbens (NAc) DA and 5-HT levels. Male Sprague-Dawley rats were implanted with bilateral guide cannulae targeting the NAc. MCAT and five para-substituted analogs (4-F, 4-Cl, 4-Br, 4-CH3, and 4-OCH3) produced dose- and time-dependent increases in NAc DA and/or 5-HT levels. Selectivity was determined as the dose required to increase peak 5-HT levels by 250% divided by the dose required to increase peak DA levels by 250%. This measure of in vivo neurochemical selectivity varied across compounds and correlated with 1) in vivo expression of abuse-related behavioral effects (r = 0.89, P = 0.02); 2) in vitro selectivity to promote monoamine release via DA and 5-HT transporters (r = 0.95, P < 0.01); and 3) molecular volume of the para substituent (r = −0.85, P = 0.03). These results support a relationship between these molecular, neurochemical, and behavioral measures and support a role for molecular structure as a determinant of abuse-related neurochemical and behavioral effects of MCAT analogs. PMID:26645638

  4. Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

    PubMed Central

    Blasi, Giuseppe; Selvaggi, Pierluigi; Fazio, Leonardo; Antonucci, Linda Antonella; Taurisano, Paolo; Masellis, Rita; Romano, Raffaella; Mancini, Marina; Zhang, Fengyu; Caforio, Grazia; Popolizio, Teresa; Apud, Jose; Weinberger, Daniel R; Bertolino, Alessandro

    2015-01-01

    Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with second-generation antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment in two independent samples of patients with schizophrenia (n=63 and n=54, respectively), consistent with the previously reported separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that further exploration is needed to better understand the clinical consequences of these genotype–phenotype relationships. PMID:25563748

  5. L-DOPA-induced dyregulation of extrastriatal dopamine and serotonin and affective symptoms in a bilateral rat model of Parkinson’s disease

    PubMed Central

    Jaunarajs, Karen L. Eskow; George, Jessica A.; Bishop, Christopher

    2012-01-01

    Convergent evidence indicates that raphestriatal serotonin (5-HT) neurons can convert and release dopamine (DA) derived from exogenous administration of the pharmacotherapeutic L-3,4-dihydroxyphenyl-L-alanine(L-DOPA) as a treatment for Parkinson’s disease (PD). While aspects of such neuroplasticity may be beneficial, chronic L-DOPA may also modify native 5-HT function, precipitating the appearance prevalent non-motor PD symptoms such as anxiety and depression. To examine this, male Sprague-Dawley rats were rendered parkinsonian with bilateral medial forebrain bundle 6-OHDA infusions and treated for at least 28 days with vehicle or L-DOPA. In the first experiment, striatal, hippocampal, amygdalar, and prefrontal cortex DA and 5-HT levels were examined at various post-treatment time-points. In experiment 2, L-DOPA’s effects on DA and 5-HT cell bodies in the substantia nigra pars compacta and dorsal raphe, respectively, were examined. Finally, the effects of L-DOPA on affective behaviors were assessed in locomotor chambers, social interaction, forced swim, and elevated plus maze behavioral tests. Bilateral 6-OHDA lesion induced approximately 80% DA and 30% 5-HT depletion in the striatum compared to sham-lesioned controls, while monoamine levels remained largely unchanged in extrastriatal regions. Tissue levels of DA were increased at the expense of 5-HT levels in parkinsonian rats subjected to chronic L-DOPA injections in all regions sampled, though DA or 5-HT cell bodies were unaffected. Behaviorally, rats could only be tested 24 hours after their last L-DOPA injection due to severe dyskinesia. Despite this, prior exposure to chronic L-DOPA treatment exerted a pronounced anxiogenic phenotype. Collectively, these results suggest that chronic L-DOPA treatment may interfere with the balance of DA and 5-HT function in affect-related brain regions and could induce and/or exacerbate non-motor symptoms in PD. PMID:22659568

  6. Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys.

    PubMed

    Banks, Matthew L; Bauer, Clayton T; Blough, Bruce E; Rothman, Richard B; Partilla, John S; Baumann, Michael H; Negus, S Stevens

    2014-06-01

    d-Amphetamine selectively promotes release of both dopamine (DA) and norepinephrine (NE) versus serotonin (5HT), and chronic d-amphetamine treatment decreases cocaine-taking behavior in rats, nonhuman primates, and humans. However, abuse liability limits the clinical utility of amphetamine maintenance for treating cocaine abuse. One strategy to improve safety and efficacy of monoamine releasers as candidate anticocaine medications has been to develop dual DA/5HT releasers like 1-napthyl-2-aminopropane (PAL-287), but the pharmacology of this class of compounds has not been extensively examined. In particular, PAL-287 has similar potencies to release DA, 5HT, and NE, and the role of manipulating NE release potency on abuse-related or anticocaine effects of dual DA/5HT releasers is not known. To address this issue, the present study compared effects of four novel DA/5HT releasers that varied >800-fold in their selectivities to release DA/5HT versus NE: [1-(5-chloro-1H-indol-3-yl)propan-2-amine (PAL-542), 1-(5-fluoro-1H-indol-3-yl)propan-2-amine (PAL-544), 1-(1H-indol-5-yl)propan-2-amine (PAL-571), and (R)-1-(1H-indol-1-yl)propain-2-amine (PAL-569). Abuse-related effects of all four compounds were evaluated in assays of intracranial self-stimulation (ICSS) in rats and cocaine discrimination in rats and monkeys, and none of the compounds reliably facilitated ICSS or substituted for cocaine. Anticocaine effects of the compound with highest selectivity to release DA/5HT versus NE (PAL-542) were tested in an assay of cocaine versus food choice in rhesus monkeys, and PAL-542 failed to reduce cocaine choice. These results suggests that potency to release NE has minimal influence on abuse liability of dual DA/5HT releasers, and reducing relative potency to release NE versus DA/5HT does not improve anticocaine efficacy.

  7. Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin.

    PubMed

    Suyama, Julie A; Sakloth, Farhana; Kolanos, Renata; Glennon, Richard A; Lazenka, Matthew F; Negus, S Stevens; Banks, Matthew L

    2016-01-01

    Methcathinone (MCAT) is a monoamine releaser and parent compound to a new class of designer drugs that includes the synthetic cathinones mephedrone and flephedrone. Using MCAT and a series of para-substituted (or 4-substituted) MCAT analogs, it has been previously shown that expression of abuse-related behavioral effects in rats correlates both with the volume of the para substituent and in vitro neurochemical selectivity to promote monoamine release via the dopamine (DA) versus serotonin (5-HT) transporters in rat brain synaptosomes. The present study used in vivo microdialysis to determine the relationship between these previous measures and the in vivo neurochemical selectivity of these compounds to alter nucleus accumbens (NAc) DA and 5-HT levels. Male Sprague-Dawley rats were implanted with bilateral guide cannulae targeting the NAc. MCAT and five para-substituted analogs (4-F, 4-Cl, 4-Br, 4-CH3, and 4-OCH3) produced dose- and time-dependent increases in NAc DA and/or 5-HT levels. Selectivity was determined as the dose required to increase peak 5-HT levels by 250% divided by the dose required to increase peak DA levels by 250%. This measure of in vivo neurochemical selectivity varied across compounds and correlated with 1) in vivo expression of abuse-related behavioral effects (r = 0.89, P = 0.02); 2) in vitro selectivity to promote monoamine release via DA and 5-HT transporters (r = 0.95, P < 0.01); and 3) molecular volume of the para substituent (r = -0.85, P = 0.03). These results support a relationship between these molecular, neurochemical, and behavioral measures and support a role for molecular structure as a determinant of abuse-related neurochemical and behavioral effects of MCAT analogs.

  8. Bifeprunox: a partial agonist at dopamine D2 and serotonin 1A receptors, influences nicotine-seeking behaviour in response to drug-associated stimuli in rats.

    PubMed

    Di Clemente, Angelo; Franchi, Carlotta; Orrù, Alessandro; Arnt, Jorn; Cervo, Luigi

    2012-03-01

    Environmental stimuli repeatedly associated with the self-administered drugs may acquire motivational importance. Because dopamine (DA) D(2) /D(3) partial agonists and D(3) antagonists interfere with the ability of drug-associated cues to induce drug-seeking behaviour, the present study investigated whether bifeprunox, 7-[4-([1,1'biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone mesylate), a high-affinity partial agonist of the D(2) subfamily of DA receptors and of serotonin(1A) receptors, influences reinstatement of drug-associated cue-induced nicotine-seeking behaviour. The study also explored whether bifeprunox reduced motivated behaviour by evaluating its effects on reinstatement induced by stimuli conditioned to sucrose. To verify whether bifeprunox interferes with the primary reinforcing properties of either drug or sucrose, we compared its effects on nicotine self-administration and on sucrose-reinforced behaviour. Different groups of experimentally naïve, food-restricted Wistar rats were trained to associate a discriminative stimulus with response-contingent availability of nicotine or sucrose and tested for reinstatement after extinction of nicotine or sucrose-reinforced behaviour. Bifeprunox (4-16 µg/kg, s.c.) dose-dependently attenuated the response-reinstating effects of nicotine-associated cues. Higher doses (64-250 µg/kg, s.c.) reduced spontaneous locomotor activity and suppressed operant responding induced by sucrose-associated cues and by the primary reinforcing properties of nicotine or sucrose. Provided they can be extrapolated to abstinent human addicts, these results suggest the potential therapeutic use of partial DA D(2) receptor agonist to prevent cue-controlled nicotine-seeking and relapse. The profile of action of high doses of bifeprunox remains to be examined for potential sedation or anhedonia effects.

  9. Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine.

    PubMed

    Busch, A E; Karbach, U; Miska, D; Gorboulev, V; Akhoundova, A; Volk, C; Arndt, P; Ulzheimer, J C; Sonders, M S; Baumann, C; Waldegger, S; Lang, F; Koepsell, H

    1998-08-01

    Recently, we cloned the human cation transporter hOCT2, a member of a new family of polyspecific transporters from kidney, and demonstrated electrogenic uptake of tetraethylammonium, choline, N1-methylnicotinamide, and 1-methyl-4-phenylpyridinium. Using polymerase chain reaction amplification, cDNA sequencing, in situ hybridization, and immunohistochemistry, we now show that hOCT2 message and protein are expressed in neurons of the cerebral cortex and in various subcortical nuclei. In Xenopus laevis oocytes expressing hOCT2, electrogenic transport of norepinephrine, histamine, dopamine, serotonin, and the antiparkinsonian drugs memantine and amantadine was demonstrated by tracer influx, tracer efflux, electrical measurements, or a combination. Apparent Km values of 1.9 +/- 0.6 mM (norepinephrine), 1.3 +/- 0.3 mM (histamine), 0.39 +/- 0.16 mM (dopamine), 80 +/- 20 microM (serotonin), 34 +/- 5 microM (memantine), and 27 +/- 3 microM (amantadine) were estimated. Measurement of trans-effects in depolarized oocytes and human embryonic kidney cells expressing hOCT2 suggests that there were different rates and specificities for cation influx and efflux. The hypothesis is raised that hOCT2 plays a physiological role in the central nervous system by regulating interstitial concentrations of monoamine neurotransmitters that have evaded high affinity uptake mechanisms. We show that amantadine does not interact with the expressed human Na+/Cl- dopamine cotransporter. However, concentrations of amantadine that are effective for the treatment of Parkinson's disease may increase the interstitial concentrations of dopamine and other aminergic neurotransmitters by competitive inhibition of hOCT2.

  10. Sonochemical synthesis of Ag nanoclusters: electrogenerated chemiluminescence determination of dopamine.

    PubMed

    Liu, Tao; Zhang, Lichun; Song, Hongjie; Wang, Zhonghui; Lv, Yi

    2013-01-01

    We report a facile one-pot sonochemical approach to preparing highly water-soluble Ag nanoclusters (NCs) using bovine serum albumin as a stabilizing agent and reducing agent in aqueous solution. Intensive electrogenerated chemiluminescence (ECL) was observed from the as-prepared Ag (NCs) and successfully applied for the ECL detection of dopamine with high sensitivity and a wide detection range. A possible ECL mechanism is proposed for the preparation of Ag NCs. With this method, the dopamine concentration was determined in the range of 8.3 × 10(-9) to 8.3 × 10(-7) mol/L without the obvious interference of uric acid, ascorbic acid and some other neurotransmitters, such as serotonin, epinephrine and norepinephrine, and the detection limit was 9.2 × 10(-10) mol/L at a signal/noise ratio of 3.

  11. Effect of handling on neurotransmitter profile in pig brain according to fear related behaviour.

    PubMed

    Arroyo, Laura; Carreras, Ricard; Valent, Daniel; Peña, Raquel; Mainau, Eva; Velarde, Antonio; Sabrià, Josefa; Bassols, Anna

    2016-12-01

    Chemical neurotransmitters (NT) are principal actors in all neuronal networks of animals. The central nervous system plays an important role in stress susceptibility and organizes the response to a stressful situation through the interaction of the dopaminergic and the serotonergic pathways, leading to the activation of the hypothalamus-pituitary-adrenal axis (HPA). This study was designed to investigate: a) the effects of stressful handling of pigs at the slaughterhouse on the neurotransmitter profile in four brain areas: amygdala, prefrontal cortex (PFC), hippocampus and hypothalamus, and b) whether the alterations in the brain NT profile after stressful handling were associated with fear, determined by the tonic immobility (TI) test. In the first place, the characterization of the NT profile allowed to distinguish the four brain areas in a principal component analysis. The most crucial pathway involved in the reaction of pigs to a stressful handling was the serotonergic system, and changes were observed in the amygdala with a decrease in serotonin (5-HT) and total indoleamines, and in the hippocampus, where this pathway was activated. Fearful and non-fearful pigs did not show significant differences in their NT profile in control conditions, but when subjected to a stressful handling in the slaughterhouse, fearful animals showed a significant variation in the serotonin pathway and, in a lesser extent, the dopamine (DA) pathway. In conclusion, the existence of an underlying biological trait - possibly fearfulness - may be involved in the pig's response toward stressful challenges, and the serotonergic system seems to play a central role in this response.

  12. Changes in cerebral neurotransmitters and metabolites induced by acute donepezil and memantine administrations: a microdialysis study.

    PubMed

    Shearman, E; Rossi, S; Szasz, B; Juranyi, Z; Fallon, S; Pomara, N; Sershen, H; Lajtha, A

    2006-03-31

    Cholinesterase inhibitors including donepezil, rivastigmine, and galantamine and the N-methyl-D-aspartate (NMDA) antagonist, memantine are the medications currently approved for the treatment of Alzheimer's disease (AD). In addition to their beneficial effects on cognitive and functional domains typically disrupted in AD, these agents have also been shown to slow down the emergence of behavioral and psychotic symptoms associated with this disease. However, the underlying mechanisms for these therapeutic effects remain poorly understood and could involve effects of these medications on non-cholinergic or non-glutamatergic neurotransmitter systems respectively. These considerations prompted us to initiate a series of investigations to examine the acute and chronic effects of donepezil (Aricept (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-1 hydrochloride and memantine (1-amino-3,5-dimethyladamantane hydrochloride C12H21N.HCl)). The present study focuses on the acute effects of donepezil and memantine on brain extracellular levels of acetylcholine, dopamine, serotonin, norepinephrine and their metabolites. We assayed changes in the ventral and dorsal hippocampus and the prefrontal and medial temporal cortex by microdialysis. Memantine resulted in significant increases in extracellular dopamine (DA), norepinephrine (NE), and their metabolites, in the cortical regions, and in a reduction of DA in the hippocampus. Donepezil produced an increase in extracellular DA in the cortex and in the dorsal hippocampus. Norepinephrine increased in the cortex; with donepezil it increased in the dorsal hippocampus and the medial temporal cortex, and decreased in the ventral hippocampus. Interestingly both compounds decreased extracellular serotonin (5HT) levels. The metabolites of the neurotransmitters were increased in most areas. We also found an increase in extracellular acetylcholine (ACh) by memantine in the nucleus accumbens and the

  13. Classical Neurotransmitters and their Significance within the Nervous System.

    ERIC Educational Resources Information Center

    Veca, A.; Dreisbach, J. H.

    1988-01-01

    Describes some of the chemical compounds involved in the nervous system and their roles in transmitting nerve signals. Discusses acetylcholine, dopamine, norepinephrine, serotonin, histamine, glycine, glutemate, and gamma-aminobutyric acid and their effects within the nervous system. (CW)

  14. Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3.

    PubMed

    Duan, Haichuan; Wang, Joanne

    2010-12-01

    The plasma membrane monoamine transporter (PMAT) and organic cation transporter 3 (OCT3) are the two most prominent low-affinity, high-capacity (i.e., uptake(2)) transporters for endogenous biogenic amines. Using the Flp-in system, we expressed human PMAT (hPMAT) and human OCT3 (hOCT3) at similar levels in human embryonic kidney 293 cells. Parallel and detailed kinetics analysis revealed distinct and seemingly complementary patterns for the two transporters in transporting monoamine neurotransmitters. hPMAT is highly selective toward serotonin (5-HT) and dopamine, with the rank order of transport efficiency (V(max)/K(m)) being: dopamine, 5-HT ≫ histamine, norepinephrine, epinephrine. The substrate preference of hPMAT toward these amines is substantially driven by large (up to 15-fold) distinctions in its apparent binding affinities (K(m)). In contrast, hOCT3 is less selective than hPMAT toward the monoamines, and the V(max)/K(m) rank order for hOCT3 is: histamine > norepinephrine, epinephrine > dopamine >5-HT. It is noteworthy that hOCT3 demonstrated comparable (≤2-fold difference) K(m) toward all amines, and distinctions in V(max) played an important role in determining its differential transport efficiency toward the monoamines. Real-time reverse transcription-polymerase chain reaction revealed that hPMAT is expressed at much higher levels than hOCT3 in most human brain areas, whereas hOCT3 is selectively and highly expressed in adrenal gland and skeletal muscle. Our results suggest that hOCT3 represents a major uptake(2) transporter for histamine, epinephrine, and norepinephrine. hPMAT, on the other hand, is a major uptake(2) transporter for 5-HT and dopamine and may play a more important role in transporting these two neurotransmitters in the central nervous system.

  15. Sex and intrauterine growth restriction modify brain neurotransmitters profile of newborn piglets.

    PubMed

    Vázquez-Gómez, M; Valent, D; García-Contreras, C; Arroyo, L; Óvilo, C; Isabel, B; Bassols, A; González-Bulnes, A

    2016-12-01

    The current study aimed to determine, using a swine model of intrauterine growth restriction (IUGR), whether short- and long-term neurological deficiencies and interactive dysfunctions of Low Birth-Weight (LBW) offspring might be related to altered pattern of neurotransmitters. Hence, we compared the quantities of different neurotransmitters (catecholamines and indoleamines), which were determined by HPLC, at brain structures related to the limbic system (hippocampus and amygdala) in 14 LBW and 10 Normal Body-Weight (NBW) newborn piglets. The results showed, firstly, significant effects of sex on the NBW newborns, with females having higher dopamine (DA) concentrations than males. The IUGR processes affected DA metabolism, with LBW piglets having lower concentrations of noradrenaline at the hippocampus and higher concentrations of the DA metabolites, homovanillic acid (HVA), at both the hippocampus and the amygdala than NBW neonates. The effects of IUGR were modulated by sex; there were no significant differences between LBW and NBW females, but LBW males had higher HVA concentration at the amygdala and higher concentration of 5-hydroxyindoleacetic acid, the serotonin metabolite, at the hippocampus than NBW males. In conclusion, the present study shows that IUGR is mainly related to changes, modulated by sex, in the concentrations of catecholamine neurotransmitters, which are related to adaptation to physical activity and to essential cognitive functions such as learning, memory, reward-motivated behavior and stress.

  16. Simultaneous analysis of multiple neurotransmitters by hydrophilic interaction liquid chromatography coupled to tandem mass spectrometry.

    PubMed

    Tufi, Sara; Lamoree, Marja; de Boer, Jacob; Leonards, Pim

    2015-05-22

    Neurotransmitters are endogenous metabolites that allow the signal transmission across neuronal synapses. Their biological role is crucial for many physiological functions and their levels can be changed by several diseases. Because of their high polarity, hydrophilic interaction liquid chromatography (HILIC) is a promising tool for neurotransmitter analysis. Due to the large number of HILIC stationary phases available, an evaluation of the column performances and retention behaviors has been performed on five different commercial HILIC packing materials (silica, amino, amide and two zwitterionic stationary phases). Several parameters like the linear correlation between retention and the distribution coefficient (logD), the separation factor k and the column resolution Rs have been investigated and the column performances have been visualized with a heat map and hierarchical clustering analysis. An optimized and validated HILIC-MS/MS method based on the ZIC-cHILIC column is proposed for the simultaneous detection and quantification of twenty compounds consisting of neurotransmitters, precursors and metabolites: 3-methoxytyramine (3-MT), 5-hydroxyindoleacetic acid (5-HIAA), 5-hydroxy-L-tripthophan, acetylcholine, choline, L-3,4-dihydroxyphenylalanine (L-DOPA), dopamine, epinephrine, γ-aminobutyric acid (GABA), glutamate, glutamine, histamine, histidine, L-tryptophan, L-tyrosine, norepinephrine, normetanephrine, phenylalanine, serotonin and tyramine. The method was applied to neuronal metabolite profiling of the central nervous system of the freshwater snail Lymnaea stagnalis. This method is suitable to explore neuronal metabolism and its alteration in different biological matrices.

  17. Biochemical and Neurotransmitters Changes Associated with Tramadol in Streptozotocin-Induced Diabetes in Rats

    PubMed Central

    Ezzeldin, Essam; Souror, Wafaa A. H.; El-Nahhas, Toqa; Soudi, Abdel Nasser M. M.; Shahat, Abdelaaty A.

    2014-01-01

    The incidence of diabetes is increasing worldwide. Chronic neuropathic pain occurs in approximately 25% of diabetic patients. Tramadol, an atypical analgesic with a unique dual mechanism of action, is used in the management of painful diabetic neuropathy. It acts on monoamine transporters to inhibit the reuptake of norepinephrine (NE), serotonin (5-HT), and dopamine (DA). The purpose of this study was to evaluate the effects of diabetes on the brain neurotransmitter alterations induced by tramadol in rats, and to study the hepatic and renal toxicities of the drug. Eighty Sprague-Dawley rats were divided randomly into two sets: the normal set and the diabetic set. Diabetes was induced in rats. Tramadol was administered orally once daily for 28 days. The levels of DA, NE, and 5-HT in cerebral cortex, thalamus/hypothalamus, midbrain, and brainstem were evaluated in rats. In addition, the renal toxicity and histopathological effects of the drug were assessed. The induction of diabetes altered neurotransmitter levels. Oral administration of tramadol significantly decreased the neurotransmitter levels. Diabetes significantly altered the effects of tramadol in all brain regions. Tramadol affected function and histology of the liver and kidney. The clinical effects of tramadol in diabetic patients should be stressed. PMID:24971322

  18. Imaging neurotransmitter release kinetics in living cells

    SciTech Connect

    Tan, Weihong; Yeung, E.S.; Haydon, P.G.

    1996-12-31

    A new UV-laser based optical microscope and CCD detection system has been developed to image neurotransmitter in living biological cells. We demonstrate the detection of serotonin that has been taken up into and released from individual living glial cells (astrocytes) based on its native fluorescence. The detection methodology has high sensitivity, low limit of detection and does not require coupling to fluorescence dyes. We have studied serotonin uptake kinetics and its release dynamics in single glial cells. Different regions of a glial cell have taken up different amounts of serotonin with a variety of kinetics. Similarly, different serotonin release mechanisms have been observed in different astrocyte cell regions. The temporal resolution of this detection system is as fast as 50 ms, and the spatial resolution is diffraction limited. We will also report on single enzyme molecule reaction studies and single metal ion detection based on CCD imaging of pL reaction vials formed by micromachining on fused silica.

  19. A network model of basal ganglia for understanding the roles of dopamine and serotonin in reward-punishment-risk based decision making.

    PubMed

    Balasubramani, Pragathi P; Chakravarthy, V Srinivasa; Ravindran, Balaraman; Moustafa, Ahmed A

    2015-01-01

    There is significant evidence that in addition to reward-punishment based decision making, the Basal Ganglia (BG) contributes to risk-based decision making (Balasubramani et al., 2014). Despite this evidence, little is known about the computational principles and neural correlates of risk computation in this subcortical system. We have previously proposed a reinforcement learning (RL)-based model of the BG that simulates the interactions between dopamine (DA) and serotonin (5HT) in a diverse set of experimental studies including reward, punishment and risk based decision making (Balasubramani et al., 2014). Starting with the classical idea that the activity of mesencephalic DA represents reward prediction error, the model posits that serotoninergic activity in the striatum controls risk-prediction error. Our prior model of the BG was an abstract model that did not incorporate anatomical and cellular-level data. In this work, we expand the earlier model into a detailed network model of the BG and demonstrate the joint contributions of DA-5HT in risk and reward-punishment sensitivity. At the core of the proposed network model is the following insight regarding cellular correlates of value and risk computation. Just as DA D1 receptor (D1R) expressing medium spiny neurons (MSNs) of the striatum were thought to be the neural substrates for value computation, we propose that DA D1R and D2R co-expressing MSNs are capable of computing risk. Though the existence of MSNs that co-express D1R and D2R are reported by various experimental studies, prior existing computational models did not include them. Ours is the first model that accounts for the computational possibilities of these co-expressing D1R-D2R MSNs, and describes how DA and 5HT mediate activity in these classes of neurons (D1R-, D2R-, D1R-D2R- MSNs). Starting from the assumption that 5HT modulates all MSNs, our study predicts significant modulatory effects of 5HT on D2R and co-expressing D1R-D2R MSNs which in turn

  20. [C-11]{beta}CNT: A new monoamine uptake ligand for studying serotonin and dopamine transporter sites in the living brain with PET

    SciTech Connect

    Mulholland, G.K.; Zheng, Q.H.; Zhou, F.C.

    1996-05-01

    There is considerable interest in measuring serotonin (5HT) and dopamine (DA) function in the human brain. Altered levels of 5HT and DA are recognized in drug abuse, neurotoxicities, psychiatric disorders, and neurodegenerative conditions including Alzheimer`s and Parkinson`s disease. Several phenyltropane analogs of cocaine bind tightly to both DA and 5HT uptake proteins. We have made a new agent from this class called {beta}CNT, 2{beta}-carboxymethyl-3{beta}-(2-naphthyl)-tropane, the isosteric O-for-CH{sub 2} analog of a compound reported to have among the highest measured affinities for DA and 5HT transporters and studied its in vivo brain distributions in animals for the first time. Optically pure {beta}CNT was made from cocaine, and labeled at the O-methyl position by esterification of {beta}CNT-acid with [C-11]CH{sub 3}OTfl under conditions similar to Wilson`s. HPLC-purified (99+%) final products (15-50% eob yield from CO{sub 2}, 40 min synth) had specific activities 0.1-1.2 Ci/{mu}mol at the time of injection. Preliminary [C-11]{beta}{beta}CNT rodent distribution showed very high brain uptake (3% ID at 60 min) and localization (striat: fr cort: hypo: cer: blood, 11: 5: 4: 1: 06). {beta}CNT-PET studies in juvenile pigs (5-20 mCi, 20-35 kg) found rapid brain uptake, and prominent retention (85 min) in midbrain, anterior brainstem and striatum, followed by cortex and olfactory bulb. Paroxetine pretreatment (5HT uptake blocker, 2mg/kg), diminished retention in most brain areas; nomifensine (DA/NE uptake blocker, 6 mg/kg) reduced striatum selectively. Direct comparisons of [C-11]{beta}CNT with other PET transporter radioligands {beta}CFT, {beta}CIT, and {beta}CTT (RTI-32) in the same pig found {beta}CNT had highest overall brain uptake among the agents. These initial results suggest {beta}CNT has favorable properties for imaging both 5HT and DA transporters in vivo, and further evaluation of its potential as a human PET agent is warranted.

  1. Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter.

    PubMed

    Giros, B; el Mestikawy, S; Godinot, N; Zheng, K; Han, H; Yang-Feng, T; Caron, M G

    1992-09-01

    We have screened a human substantia nigra cDNA library with probes derived from the rat dopamine transporter. A 3.5-kilobase cDNA clone was isolated and its corresponding gene was located on the distal end of chromosome 5 (5p15.3). This human clone codes for a 620-amino acid protein with a calculated molecular weight of 68,517. Hydropathicity analysis suggests the presence of 12 putative transmembrane domains, a characteristic feature of sodium-dependent neurotransmitter carriers. The rat and the human dopamine transporters are 92% homologous. When permanently expressed in mouse fibroblast Ltk- cells, the human clone is able to induce a saturable, time- and sodium-dependent, dopamine uptake. This transport is blocked by psychostimulant drugs (cocaine, l- and d-amphetamine, and phenyclidine), neurotoxins (6-hydroxydopamine and N-methyl-4-phenylpyridine (MPP))+), neurotransmitters (epinephrine, norepinephrine, gamma-aminobutyric acid, and serotonin), antidepressants (amitriptyline, bupropion, desipramine, mazindol, nomifensine, and nortriptyline), and various uptake inhibitors (mazindol, GBR 12783, GBR 12909, and amfonelic acid). The rank orders of the Ki values of these substances at the human and the rat dopamine transporters are highly correlated (r = 0.998). The cloning of DNA human dopamine transporter gene has allowed establishment of a cell line stably expressing the human dopamine transporter and, for the first time, an extensive characterization of its pharmacology. Furthermore, these newly developed tools will help in the study of the regulation of dopamine transport in humans and in the clarification of the potential role of the dopamine transporter in a variety of disease states.

  2. 2,5-Disubstituted tetrahydrofurans as selective serotonin re-uptake inhibitors.

    PubMed

    Voelker, Troy; Xia, Haiji; Fandrick, Keith; Johnson, Robert; Janowsky, Aaron; Cashman, John R

    2009-03-01

    Enhancement of 5-hydroxytryptamine (5-HT, serotonin) neurotransmission is a viable means of treating depression. On the basis of this observation, agents that inhibit re-uptake of 5-HT were prepared based on (-)-cocaine and aryltropanes as lead compounds because they are reasonably potent 5-HT re-uptake inhibitors. Molecular dissection of an aryltropane provided a series of 5- and 6-membered ring compounds. From among this library of compounds a series of disubstituted tetrahydrofurans bearing 2-alkyl aryl and 5-alkyl amino groups were identified as having highly potent and selective 5-HT re-uptake inhibition. The compounds were evaluated for their ability to compete with radiolabeled RTI-55 binding and to inhibit re-uptake of neurotransmitters at the human dopamine, serotonin and norepinephrine transporters. Based on potency (e.g., K(i)=800 pM) and significant functional selectivity (e.g., IC(50) ratios for human dopamine:serotonin or norepinephrine:serotonin, >or=1397) highly potent and selective serotonin re-uptake inhibitors were identified. Optimal features playing a dominant role in binding affinity and re-uptake inhibition included lipophilic substitution on the aromatic moiety, trans relative stereochemistry of the 2,5-disubstituted tetrahydrofuran ring, and a total of four or five methylene groups between the alkyl amine and the alkyl aryl moiety and the tetrahydrofuran group. A number of the most potent serotonin re-uptake inhibitors were tested in Balb/c mice in the forced-swim test (FST), a behavioral test used to measure the effects of antidepressant agents. Acute administration of 32c (10mg/kg), or 32d (10mg/kg) ip tended to decrease the duration of mouse immobility in the FST although the effect was not statistically significant.

  3. [Increased spontaneous uterine motility with serotonin].

    PubMed

    Lechner, W; Sölder, E; Sölder, B; Kölle, D; Huter, O

    1992-01-01

    The influence of serotonine, a vasoactive neurotransmitter, on the spontaneous motility of uterine strips was investigated. A highly significant (p less than 0.001) increase of uterine activity was observed when serotonine 10(-6) M was added to the perfusing medium.

  4. Serotonin is necessary for place memory in Drosophila

    PubMed Central

    Sitaraman, Divya; Zars, Melissa; LaFerriere, Holly; Chen, Yin-Chieh; Sable-Smith, Alex; Kitamoto, Toshihiro; Rottinghaus, George E.; Zars, Troy

    2008-01-01

    Biogenic amines, such as serotonin and dopamine, can be important in reinforcing associative learning. This function is evident as changes in memory performance with manipulation of either of these signals. In the insects, evidence begins to argue for a common role of dopamine in negatively reinforced memory. In contrast, the role of the serotonergic system in reinforcing insect associative learning is either unclear or controversial. We investigated the role of both of these signals in operant place learning in Drosophila. By genetically altering serotonin and dopamine levels, manipulating the neurons that make serotonin and dopamine, and pharmacological treatments we provide clear evidence that serotonin, but not dopamine, is necessary for place memory. Thus, serotonin can be critical for memory formation in an insect, and dopamine is not a universal negatively reinforcing signal. PMID:18385379

  5. Neonatal +-methamphetamine exposure in rats alters adult locomotor responses to dopamine D1 and D2 agonists and to a glutamate NMDA receptor antagonist, but not to serotonin agonists.

    PubMed

    Graham, Devon L; Amos-Kroohs, Robyn M; Braun, Amanda A; Grace, Curtis E; Schaefer, Tori L; Skelton, Matthew R; Williams, Michael T; Vorhees, Charles V

    2013-03-01

    Neonatal exposure to (+)-methamphetamine (Meth) results in long-term behavioural abnormalities but its developmental mechanisms are unknown. In a series of experiments, rats were treated from post-natal days (PD) 11-20 (stage that approximates human development from the second to third trimester) with Meth or saline and assessed using locomotor activity as the readout following pharmacological challenge doses with dopamine, serotonin and glutamate agonists or antagonists during adulthood. Exposure to Meth early in life resulted in an exaggerated adult locomotor hyperactivity response to the dopamine D1 agonist SKF-82958 at multiple doses, a high dose only under-response activating effect of the D2 agonist quinpirole, and an exaggerated under-response to the activating effect of the N-methyl-d-aspartic acid (NMDA) receptor antagonist, MK-801. No change in locomotor response was seen following challenge with the 5-HT releaser p-chloroamphetamine or the 5-HT2/3 receptor agonist, quipazine. These are the first data to show that PD 11-20 Meth exposure induces long-lasting alterations to dopamine D1, D2 and glutamate NMDA receptor function and may suggest how developmental Meth exposure leads to many of its long-term adverse effects.

  6. Beneficial Effects of a Protein Rich Diet on Coping Neurotrans-mitter Levels During Ampicillin-Induced Neurotoxicity Compared to Propionic-Acid Induced Autistic Biochemical Features

    PubMed Central

    Bhat, Ramesa Shafi; Chandrul, Kaushal Kishore; El-Ansary, Afaf

    2016-01-01

    This study examined the effects of a protein rich diet on coping neurotransmitter levels in orally administered ampicillin–induced neurotoxic rats compared with propionic acid (PA) models of autism. 40 young male western albino rats were divided into four groups. The first group served as control and received phosphate buffered saline orally; the second group serving as autistic model was treated with oral dose of PA (250 mg/kg body weight/day for 3 days); the third group was treated with the neurotoxic dose of ampicillin (50 mg/kg for three weeks); the fourth group received the same dose of ampicillin and was fed with special protein rich diets. Noradrenaline, dopamine, serotonin glutamate, glutamine and interleukin 6 (IL-6) were measured in the brain homogenate of all tested groups. Specified doses of PA and ampicillin significantly (P<0.001) decreased noradrenaline, dopamine, and serotonin levels when compared to control. Also glutamate, IL-6 levels were significantly (P<0.001) increased in PA treated group while non-significant increase was found in ampicillin treated group. Non-significant increase of glutamine was found in PA treated group with a significant increase in ampicillin treated group. The effects of ampicillin on these parameters were found to be potentiated when the rats were fed on a protein rich diet. Our results end with the conclusion that dietary protein level may be a useful tool to find out a path to restrict neurotransmitter alterations in neurodevelopmental disorders like autism. PMID:27942501

  7. Amino Acid Neurotransmitters; Mechanisms of Their Uptake into Synaptic Vesicles

    DTIC Science & Technology

    1991-08-01

    same neuron, at least from the cerebellar Golgi cell terminals. It should be kept in mind that the uptake of noradrenaline and dopamine in synaptic...vesicles prepared from rat brain is relatively non-specific. Noradrenaline containing vesicles can take up noradrenaline, dopamine and serotonin. In...also shown that the vesicles isolated from corpus striatum exhibited the same ratio of uptake of dopamine /noradrenaline as did vesicles from cerebral

  8. Effect of Low-Intensity Microwave Radiation on Monoamine Neurotransmitters and Their Key Regulating Enzymes in Rat Brain.

    PubMed

    Megha, Kanu; Deshmukh, Pravin S; Ravi, Alok K; Tripathi, Ashok K; Abegaonkar, Mahesh P; Banerjee, Basu D

    2015-09-01

    The increasing use of wireless communication devices has raised major concerns towards deleterious effects of microwave radiation on human health. The aim of the study was to demonstrate the effect of low-intensity microwave radiation on levels of monoamine neurotransmitters and gene expression of their key regulating enzymes in brain of Fischer rats. Animals were exposed to 900 MHz and 1800 MHz microwave radiation for 30 days (2 h/day, 5 days/week) with respective specific absorption rates as 5.953 × 10(-4) and 5.835 × 10(-4) W/kg. The levels of monoamine neurotransmitters viz. dopamine (DA), norepinephrine (NE), epinephrine (E) and serotonin (5-HT) were detected using LC-MS/MS in hippocampus of all experimental animals. In addition, mRNA expression of key regulating enzymes for these neurotransmitters viz. tyrosine hydroxylase (TH) (for DA, NE and E) and tryptophan hydroxylase (TPH1 and TPH2) (for serotonin) was also estimated. Results showed significant reduction in levels of DA, NE, E and 5-HT in hippocampus of microwave-exposed animals in comparison with sham-exposed (control) animals. In addition, significant downregulation in mRNA expression of TH, TPH1 and TPH2 was also observed in microwave-exposed animals (p < 0.05). In conclusion, the results indicate that low-intensity microwave radiation may cause learning and memory disturbances by altering levels of brain monoamine neurotransmitters at mRNA and protein levels.

  9. Treatment with the MAO-A inhibitor clorgyline elevates monoamine neurotransmitter levels and improves affective phenotypes in a mouse model of Huntington disease.

    PubMed

    Garcia-Miralles, Marta; Ooi, Jolene; Ferrari Bardile, Costanza; Tan, Liang Juin; George, Maya; Drum, Chester L; Lin, Rachel Yanping; Hayden, Michael R; Pouladi, Mahmoud A

    2016-04-01

    Abnormal monoamine oxidase A and B (MAO-A/B) activity and an imbalance in monoamine neurotransmitters have been suggested to underlie the pathobiology of depression, a major psychiatric symptom observed in patients with neurodegenerative diseases, such as Huntington disease (HD). Increased MAO-A/B activity has been observed in brain tissue from patients with HD and in human and rodent HD neural cells. Using the YAC128 mouse model of HD, we studied the effect of an irreversible MAO-A inhibitor, clorgyline, on the levels of select monoamine neurotransmitters associated with affective function. We observed a decrease in striatal levels of the MAO-A/B substrates, dopamine and norepinephrine, in YAC128 HD mice compared with wild-type mice, which was accompanied by increased anxiety- and depressive-like behaviour at five months of age. Treatment for 26 days with clorgyline restored dopamine, serotonin, and norepinephrine neurotransmitter levels in the striatum and reduced anxiety- and depressive-like behaviour in YAC128 HD mice. This study supports a potential therapeutic use for MAO-A inhibitors in the treatment of depression and anxiety in patients with HD.

  10. Role of serotonin in fish reproduction

    PubMed Central

    Prasad, Parvathy; Ogawa, Satoshi; Parhar, Ishwar S.

    2015-01-01

    The neuroendocrine mechanism regulates reproduction through the hypothalamo-pituitary-gonadal (HPG) axis which is evolutionarily conserved in vertebrates. The HPG axis is regulated by a variety of internal as well as external factors. Serotonin, a monoamine neurotransmitter, is involved in a wide range of reproductive functions. In mammals, serotonin regulates sexual behaviors, gonadotropin release and gonadotropin-release hormone (GnRH) secretion. However, the serotonin system in teleost may also play unique role in the control of reproduction as the mechanism of reproductive control in teleosts is not always the same as in the mammalian models. In fish, the serotonin system is also regulated by natural environmental factors as well as chemical substances. In particular, selective serotonin reuptake inhibitors (SSRIs) are commonly detected as pharmaceutical contaminants in the natural environment. Those factors may influence fish reproductive functions via the serotonin system. This review summarizes the functional significance of serotonin in the teleosts reproduction. PMID:26097446

  11. Role of serotonin in fish reproduction.

    PubMed

    Prasad, Parvathy; Ogawa, Satoshi; Parhar, Ishwar S

    2015-01-01

    The neuroendocrine mechanism regulates reproduction through the hypothalamo-pituitary-gonadal (HPG) axis which is evolutionarily conserved in vertebrates. The HPG axis is regulated by a variety of internal as well as external factors. Serotonin, a monoamine neurotransmitter, is involved in a wide range of reproductive functions. In mammals, serotonin regulates sexual behaviors, gonadotropin release and gonadotropin-release hormone (GnRH) secretion. However, the serotonin system in teleost may also play unique role in the control of reproduction as the mechanism of reproductive control in teleosts is not always the same as in the mammalian models. In fish, the serotonin system is also regulated by natural environmental factors as well as chemical substances. In particular, selective serotonin reuptake inhibitors (SSRIs) are commonly detected as pharmaceutical contaminants in the natural environment. Those factors may influence fish reproductive functions via the serotonin system. This review summarizes the functional significance of serotonin in the teleosts reproduction.

  12. The conditioning of intervention effects on early adolescent alcohol use by maternal involvement and dopamine receptor D4 (DRD4) and serotonin transporter linked polymorphic region (5-HTTLPR) genetic variants.

    PubMed

    Cleveland, H Harrington; Schlomer, Gabriel L; Vandenbergh, David J; Feinberg, Mark; Greenberg, Mark; Spoth, Richard; Redmond, Cleve; Shriver, Mark D; Zaidi, Arslan A; Hair, Kerry L

    2015-02-01

    Data drawn from the in-home subsample of the PROSPER intervention dissemination trial were used to investigate the moderation of intervention effects on underage alcohol use by maternal involvement and candidate genes. The primary gene examined was dopamine receptor D4 (DRD4). Variation in this gene and maternal involvement were hypothesized to moderate the influence of intervention status on alcohol use. The PROSPER data used were drawn from 28 communities randomly assigned to intervention or comparison conditions. Participating youth were assessed in five in-home interviews from sixth to ninth grades. A main effect of sixth-grade pretest maternal involvement on ninth-grade alcohol use was found. Neither intervention status nor DRD4 variation was unconditionally linked to ninth-grade drinking. However, moderation analyses revealed a significant three-way interaction among DRD4 status, maternal involvement, and intervention condition. Follow-up analyses revealed that prevention reduced drinking risk, but only for youth with at least one DRD4 seven-repeat allele who reported average or greater pretest levels of maternal involvement. To determine if this conditional pattern was limited to the DRD4 gene, we repeated analyses using the serotonin transporter linked polymorphic region site near the serotonin transporter gene. The results for this supplemental analysis revealed a significant three-way interaction similar but not identical to that found for DRD4.

  13. Simultaneous imaging of multiple neurotransmitters and neuroactive substances in the brain by desorption electrospray ionization mass spectrometry.

    PubMed

    Shariatgorji, Mohammadreza; Strittmatter, Nicole; Nilsson, Anna; Källback, Patrik; Alvarsson, Alexandra; Zhang, Xiaoqun; Vallianatou, Theodosia; Svenningsson, Per; Goodwin, Richard J A; Andren, Per E

    2016-08-01

    With neurological processes involving multiple neurotransmitters and neuromodulators, it is important to have the ability to directly map and quantify multiple signaling molecules simultaneously in a single analysis. By utilizing a molecular-specific approach, namely desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we demonstrated that the technique can be used to image multiple neurotransmitters and their metabolites (dopamine, dihydroxyphenylacetic acid, 3-methoxytyramine, serotonin, glutamate, glutamine, aspartate, γ-aminobutyric acid, adenosine) as well as neuroactive drugs (amphetamine, sibutramine, fluvoxamine) and drug metabolites in situ directly in brain tissue sections. The use of both positive and negative ionization modes increased the number of identified molecular targets. Chemical derivatization by charge-tagging the primary amines of molecules significantly increased the sensitivity, enabling the detection of low abundant neurotransmitters and other neuroactive substances previously undetectable by MSI. The sensitivity of the imaging approach of neurochemicals has a great potential in many diverse applications in fields such as neuroscience, pharmacology, drug discovery, neurochemistry, and medicine.

  14. Vanillin-induced amelioration of depression-like behaviors in rats by modulating monoamine neurotransmitters in the brain.

    PubMed

    Xu, Jinyong; Xu, Hui; Liu, Yang; He, Haihui; Li, Guangwu

    2015-02-28

    Olfaction plays an important role in emotions in our daily life. Pleasant odors are known to evoke positive emotions, inducing relaxation and calmness. The beneficial effects of vanillin on depressive model rats were investigated using a combination of behavioral assessments and neurotransmitter measurements. Before and after chronic stress condition (or olfactory bulbectomy), and at the end of vanillin or fluoxetine treatment, body weight, immobility time on the forced swimming test and sucrose consumption in the sucrose consumption test were measured. Changes in these assessments revealed the characteristic phenotypes of depression in rats. Neurotransmitters were measured using ultrahigh-performance liquid chromatography. Our results indicated that vanillin could alleviate depressive symptoms in the rat model of chronic depression via the olfactory pathway. Preliminary analysis of the monoamine neurotransmitters revealed that vanillin elevated both serotonin and dopamine levels in brain tissue. These results provide important mechanistic insights into the protective effect of vanillin against chronic depressive disorder via olfactory pathway. This suggests that vanillin may be a potential pharmacological agent for the treatment of major depressive disorder.

  15. Use of LC/MS to assess brain tracer distribution in preclinical, in vivo receptor occupancy studies: dopamine D2, serotonin 2A and NK-1 receptors as examples.

    PubMed

    Chernet, Eyassu; Martin, Laura J; Li, Dominic; Need, Anne B; Barth, Vanessa N; Rash, Karen S; Phebus, Lee A

    2005-12-12

    High performance liquid chromatography combined with either single quad or triple quad mass spectral detectors (LC/MS) was used to measure the brain distribution of receptor occupancy tracers targeting dopamine D2, serotonin 5-HT2A and neurokinin NK-1 receptors using the ligands raclopride, MDL-100907 and GR205171, respectively. All three non-radiolabeled tracer molecules were easily detectable in discrete rat brain areas after intravenous doses of 3, 3 and 30 microg/kg, respectively. These levels showed a differential brain distribution caused by differences in receptor density, as demonstrated by the observation that pretreatment with compounds that occupy these receptors reduced this differential distribution in a dose-dependent manner. Intravenous, subcutaneous and oral dose-occupancy curves were generated for haloperidol at the dopamine D2 receptor as were oral curves for the antipsychotic drugs olanzapine and clozapine. In vivo dose-occupancy curves were also generated for orally administered clozapine, olanzapine and haloperidol at the cortical 5-HT2A binding site. In vivo occupancy at the striatal neurokinin NK-1 binding site by various doses of orally administered MK-869 was also measured. Our results demonstrate the utility of LC/MS to quantify tracer distribution in preclinical brain receptor occupancy studies.

  16. Biophysical Approaches to the Study of LeuT, a Prokaryotic Homolog of Neurotransmitter Sodium Symporters.

    PubMed

    Singh, Satinder K; Pal, Aritra

    2015-01-01

    Ion-coupled secondary transport is utilized by multiple integral membrane proteins as a means of achieving the thermodynamically unfavorable translocation of solute molecules across the lipid bilayer. The chemical nature of these molecules is diverse and includes sugars, amino acids, neurotransmitters, and other ions. LeuT is a sodium-coupled, nonpolar amino acid symporter and eubacterial member of the solute carrier 6 (SLC6) family of Na(+)/Cl(-)-dependent neurotransmitter transporters. Eukaryotic counterparts encompass the clinically and pharmacologically significant transporters for γ-aminobutyric acid (GABA), glycine, serotonin (5-hydroxytryptamine, 5-HT), dopamine (DA), and norepinephrine (NE). Since the crystal structure of LeuT was first solved in 2005, subsequent crystallographic, binding, flux, and spectroscopic studies, complemented with homology modeling and molecular dynamic simulations, have allowed this protein to emerge as a remarkable mechanistic paradigm for both the SLC6 class as well as several other sequence-unrelated SLCs whose members possess astonishingly similar architectures. Despite yielding groundbreaking conceptual advances, this vast treasure trove of data has also been the source of contentious hypotheses. This chapter will present a historical scientific overview of SLC6s; recount how the initial and subsequent LeuT structures were solved, describing the insights they each provided; detail the accompanying functional techniques, emphasizing how they either supported or refuted the static crystallographic data; and assemble these individual findings into a mechanism of transport and inhibition.

  17. Biophysical Approaches to the Study of LeuT, a Prokaryotic Homolog of Neurotransmitter Sodium Symporters

    PubMed Central

    Singh, Satinder K.; Pal, Aritra

    2016-01-01

    Ion-coupled secondary transport is utilized by multiple integral membrane proteins as a means of achieving the thermodynamically unfavorable translocation of solute molecules across the lipid bilayer. The chemical nature of these molecules is diverse and includes sugars, amino acids, neurotransmitters, and other ions. LeuT is a sodium-coupled, nonpolar amino acid symporter and eubacterial member of the solute carrier 6 (SLC6) family of Na+/Cl−-dependent neurotransmitter transporters. Eukaryotic counterparts encompass the clinically and pharmacologically significant transporters for γ-aminobutyric acid (GABA), glycine, serotonin (5-hydroxytryptamine, 5-HT), dopamine (DA), and norepinephrine (NE). Since the crystal structure of LeuT was first solved in 2005, subsequent crystallographic, binding, flux, and spectroscopic studies, complemented with homology modeling and molecular dynamic simulations, have allowed this protein to emerge as a remarkable mechanistic paradigm for both the SLC6 class as well as several other sequence-unrelated SLCs whose members possess astonishingly similar architectures. Despite yielding groundbreaking conceptual advances, this vast treasure trove of data has also been the source of contentious hypotheses. This chapter will present a historical scientific overview of SLC6s; recount how the initial and subsequent LeuT structures were solved, describing the insights they each provided; detail the accompanying functional techniques, emphasizing how they either supported or refuted the static crystallographic data; and assemble these individual findings into a mechanism of transport and inhibition. PMID:25950965

  18. Effects of amantadine on circulating neurotransmitters in healthy subjects.

    PubMed

    Lechin, Fuad; van der Dijs, Bertha; Pardey-Maldonado, Betty; Rivera, Jairo E; Baez, Scarlet; Lechin, Marcel E

    2010-03-01

    Considering that glutamatergic axons innervate the C1(Ad) medullary nuclei, which are responsible for the excitation of the peripheral adrenal glands, we decided to investigate catecholamines (noradrenaline, adrenaline and dopamine) plus indolamines (plasma serotonin and platelet serotonin) at the blood level, before and after a small oral dose of amantadine, a selective NMDA antagonist. We found that the drug provoked a selective enhancement of noradrenaline plus a minimization of adrenaline, dopamine, plasma serotonin and platelet serotonin circulating levels. Significant enhancement of diastolic blood pressure plus reduction of systolic blood pressure and heart rate paralleled the circulating parameter changes. The above findings allow us to postulate that the drug was able to enhance the peripheral neural sympathetic activity. Minimization of both adrenal sympathetic and parasympathetic activities was also registered after the amantadine challenge. The above findings supported the postulation that this drug should be a powerful therapeutic tool for treating diseases affected by adrenal sympathetic hyperactivity.

  19. Nicotine-induced monoamine neurotransmitter changes in the brain of young rats.

    PubMed

    Shearman, E; Fallon, S; Sershen, H; Lajtha, A

    2008-08-15

    A number of studies in various species including man indicated a greater risk of drug preference and addictive behavior in young as compared to adults. Such age dependent preference was also found with nicotine. To examine possible mechanisms for this difference in our continuing study of reward mechanisms, we compared nicotine-induced neurotransmitter changes in the brain regions of adult and young Sprague-Dawley rats, assaying the transmitters via microdialysis in conscious freely moving animals. In general, nicotine-induced changes were significantly less in the regions measured in the young. Nicotine-induced effects on dopamine in the dorsal and ventral hippocampus (VH), prefrontal and medial temporal cortex, and superior cerebral peduncle were lower in the young than in adult, the same in the ventral tegmental area (VTA) and lateral septal nucleus (LS), and somewhat higher in the nucleus accumbens shell (NAccS). Norepinephrine levels in the young were lower in all areas except in the VH where they were the same, and serotonin levels were lower except in the VTA and LS where they remained the same, and higher in the NAccS. Age-dependent differences in the metabolites measured were more mixed. We conclude that the greater nicotine preference in young is not paralleled by a greater effect of nicotine on the release of monoamines at least in most of the brain areas assayed. Thus, increases of nicotine reward are not likely due to increases of monoamines in reward and cognitive areas. The small increase of dopamine (DA) and more significant increase of serotonin (5-HT) only in the NAccS are of significance, and would indicate a more significant role of 5-HT than of DA at least in the age difference in nicotine preference. Developmental changes in receptor composition and distribution involving several transmitter systems and other components such as neuropeptides are also likely to play a role.

  20. Two functional serotonin polymorphisms moderate the effect of food reinforcement on BMI.

    PubMed

    Carr, Katelyn A; Lin, Henry; Fletcher, Kelly D; Sucheston, Lara; Singh, Prashant K; Salis, Robbert J; Erbe, Richard W; Faith, Myles S; Allison, David B; Stice, Eric; Epstein, Leonard H

    2013-06-01

    Food reinforcement, or the motivation to eat, has been associated with increased energy intake, greater body weight, and prospective weight gain. Much of the previous research on the reinforcing value of food has focused on the role of dopamine, but it may be worthwhile to examine genetic polymorphisms in the serotonin and opioid systems as these neurotransmitters have been shown to be related to reinforcement processes and to influence energy intake. We examined the relationship among 44 candidate genetic polymorphisms in the dopamine, serotonin, and opioid systems, as well as food reinforcement and body mass index (BMI) in a sample of 245 individuals. Polymorphisms in the monoamine oxidase A (MAOA-LPR) and serotonin receptor 2A genes (rs6314) moderated the effect of food reinforcement on BMI, accounting for an additional 5-10% variance and revealed a potential role of the single nucleotide polymorphism, rs6314, in the serotonin 2A receptor as a differential susceptibility factor for obesity. Differential susceptibility describes a factor that can confer either risk or protection depending on a second variable, such that rs6314 is predictive of both high and low BMI based on the level of food reinforcement, while the diathesis stress or dual-gain model only influences one end of the outcome measure. The interaction with MAOA-LPR better fits the diathesis stress model, with the 3.5R/4R allele conferring protection for individuals low in food reinforcement. These results provide new insight into genes theoretically involved in obesity, and support the hypothesis that genetics moderate the association between food reinforcement and BMI.

  1. Secondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: A potential treatment target?

    PubMed

    Horvath, Gabriella A; Demos, Michelle; Shyr, Casper; Matthews, Allison; Zhang, Linhua; Race, Simone; Stockler-Ipsiroglu, Sylvia; Van Allen, Margot I; Mancarci, Ogan; Toker, Lilah; Pavlidis, Paul; Ross, Colin J; Wasserman, Wyeth W; Trump, Natalie; Heales, Simon; Pope, Simon; Cross, J Helen; van Karnebeek, Clara D M

    2016-01-01

    We describe neurotransmitter abnormalities in two patients with drug-resistant epilepsy resulting from deleterious de novo mutations in sodium channel genes. Whole exome sequencing identified a de novo SCN2A splice-site mutation (c.2379+1G>A, p.Glu717Gly.fs*30) resulting in deletion of exon 14, in a 10-year old male with early onset global developmental delay, intermittent ataxia, autism, hypotonia, epileptic encephalopathy and cerebral/cerebellar atrophy. In the cerebrospinal fluid both homovanillic acid and 5-hydroxyindoleacetic acid were significantly decreased; extensive biochemical and genetic investigations ruled out primary neurotransmitter deficiencies and other known inborn errors of metabolism. In an 8-year old female with an early onset intractable epileptic encephalopathy, developmental regression, and progressive cerebellar atrophy, a previously unreported de novo missense mutation was identified in SCN8A (c.5615G>A; p.Arg1872Gln), affecting a highly conserved residue located in the C-terminal of the Nav1.6 protein. Aside from decreased homovanillic acid and 5-hydroxyindoleacetic acid, 5-methyltetrahydrofolate was also found to be low. We hypothesize that these channelopathies cause abnormal synaptic mono-amine metabolite secretion/uptake via impaired vesicular release and imbalance in electrochemical ion gradients, which in turn aggravate the seizures. Treatment with oral 5-hydroxytryptophan, l-Dopa/Carbidopa, and a dopa agonist resulted in mild improvement of seizure control in the male case, most likely via dopamine and serotonin receptor activated signal transduction and modulation of glutamatergic, GABA-ergic and glycinergic neurotransmission. Neurotransmitter analysis in other sodium channelopathy patients will help validate our findings, potentially yielding novel treatment opportunities.

  2. Neurotransmitters and neuronal apoptotic cell death of chronically aluminum intoxicated Nile catfish (Clarias gariepinus) in response to ascorbic acid supplementation.

    PubMed

    Khalil, Samah R; Hussein, Mohamed M A

    2015-12-01

    Few studies have been carried out to assess the neurotoxic effect of aluminum (Al) on the aquatic creatures. This study aims to evaluate the neurotoxic effects of long term Al exposure on the Nile catfish (Clarias gariepinus) and the potential ameliorative influence of ascorbic acid (ASA) over a 180 days exposure period. Forty eight Nile catfish were divided into four groups: control group, placed in clean water, ASA exposed group (5mg/l), AlCl3 received group (28.96 μg/l; 1/20 LC50), and group received AlCl3 concomitantly with ASA. Brain tissue was examined by using flow cytometry to monitor the apoptotic cell population, HPLC analysis for the quantitative estimation of brain monoamine neurotransmitters [serotonin (5-HT), dopamine (DA), norepinephrine (NE)]. The amino acid neurotransmitters [serum taurine, glycine, aspartate and glutamine and brain gamma aminobutyric acid (GABA)] levels were assessed, plus changes in brain tissue structure using light microscopy. The concentration of Al in both brain tissue and serum was determined by using atomic absorption spectrophotometery. The Al content in serum and brain tissue were both elevated and Al exposure induced an increase in the number of apoptotic cells, a marked reduction of the monoamine and amino acids neurotransmitters levels and changes in tissue morphology. ASA supplementation partially abolished the effects of AL on the reduced neurotransmitter, the degree of apoptosis and restored the morphological changes to the brain. Overall, our results indicate that, ASA is a promising neuroprotective agent against for Al-induced neurotoxicity in the Nile catfish.

  3. Disorders of consciousness and pharmaceuticals that act on oxygen based amino acid and monoamine neurotransmitter pathways of the brain.

    PubMed

    Clauss, Ralf

    2014-01-01

    Oxygen based neurotransmitters in the synapses of the brain are proposed to play an important role in the generation of consciousness. They include the amino acids glutamate and GABA which use Krebs cycle precursors for their synthesis, and the monoamines dopamine, noradrenalin, adrenalin and serotonin, which are derived from tyrosine and tryptophan. During ischemia after an acute brain injury, a GABA surge often initiates brain suppression. It has been proposed that with chronic ischemia, a secondary, possibly epigenetic response occurs when neurotransmitters deplete, a glucose and oxygen saving mechanism termed neurodormancy that may invoke alternative long term low energy metabolic pathways in the brain, encountered in Disorders of Consciousness. Some medications can reverse Disorders of Consciousness in some patients. Virtually all of them act on neurotransmitter systems that use oxygen as a building block or as an energy source within the brain. Pharmaceuticals that act in the oxygen based amino acid systems of the brain include the GABAergic medications zolpidem and baclofen, while those that act in the monoamine axes include the dopaminergic medications L Dopa, amantadine, bromocriptine, apomorphine and methylphenidate, and the noradrenergic and serotonergic medications desipramine, amitriptyline, protriptyline and fluoxetine. Another group are the cholinesterase inhibitors, responsible for increasing acetylcholine, which is synthesized from the Krebs cycle initiator, acetyl CoA. It appears that pharmaceuticals that are active in the oxygen based neurotransmitter pathways of the brain are successful to arouse to consciousness patients that suffer from its disorders. Research needs to be supported as foundation to understand the biochemical mechanisms that are involved in consciousness disorders and to explore further the pharmacological treatment possibilities for these devastating neurological conditions.

  4. Changes of prolactin regulatory mechanisms in aging: 24-h rhythms of serum prolactin and median eminence and adenohypophysial concentration of dopamine, serotonin, (gamma-aminobutyric acid, taurine and somatostatin in young and aged rats.

    PubMed

    Esquifino, A I; Cano, P; Jimenez, V; Reyes Toso, C F; Cardinali, D P

    2004-01-01

    Twenty-four hour rhythmicity of serum prolactin and median eminence and anterior pituitary content of dopamine (DA), serotonin (5HT), gamma-aminobutyric acid (GABA), taurine and somatostatin were examined in 2 months-old and 18-20 months-old Wistar male rats. The concentration of prolactin was higher in aged rats, with peaks in both groups of rats at the early phase of the activity span. Median eminence DA content of young rats attained its maximum at the middle of rest span and decreased as prolactin levels augmented while the lowest values of adenohypophysial DA were observed at the time of prolactin peak. DA rhythmicity disappeared in aged rats. GABA content of median eminence and adenohypophysis was lower in aged rats, with maximal values of median eminence GABA at light-dark transition in young rats and at the second half of activity span in aged rats. Serum prolactin correlated positively with median eminence GABA in young rats and negatively with pituitary GABA in young and aged rats. Median eminence somatostatin peaked at the beginning of the activity phase (young rats) or at the end of the rest phase (aged rats). Prolactin levels and somatostatin content correlated significantly in young rats only. Median eminence and pituitary 5HT and taurine content did not change with age. The results indicate disruption of prolactin regulatory mechanisms with aging in rats.

  5. Non-serotonin anti-depressant actions: direct ion channel modulation by SSRIs and the concept of single agent poly-pharmacy.

    PubMed

    Bianchi, Matt T

    2008-01-01

    Medical therapies targeting infections and neoplasms often involve a multi-pronged strategy sometimes called "rational poly-pharmacy", while other disorders such as Parkinson's disease emphasize targeting a single neurotransmitter system (dopamine). Although the clinical literature favors a "serotonin hypothesis" for depression, a growing basic science literature suggests that selective serotonin reuptake inhibitors (SSRIs) directly modulate neurotransmitter- and voltage-gated neuronal ion channels. In addition, biosynthesis of neurosteroids (themselves promiscuous ion channel modulators), is activated by SSRIs. These non-canonical effects are entirely independent of serotonin signaling, and they occur in the range of SSRI concentrations reported in the brains of treated patients (1-10 microM). The protean impact of these diverse channel targets on neuronal excitability raises interesting and potentially testable hypotheses about depression pathophysiology and treatment. Specifically, emerging network theories are embracing the non-linearity and complexity of brain circuitry and its oscillatory behavior, with clinical correlations in psychiatry and neurology. Is it possible that certain brain dysfunction (such as depression) may be more amenable to a poly-pharmacy approach? The promiscuity of SSRIs suggests that such poly-pharmacy can emerge from a single agent.

  6. Predator Exposure/Psychosocial Stress Animal Model of Post-Traumatic Stress Disorder Modulates Neurotransmitters in the Rat Hippocampus and Prefrontal Cortex

    PubMed Central

    Wilson, C. Brad; Ebenezer, Philip J.; McLaughlin, Leslie D.; Francis, Joseph

    2014-01-01

    Post-Traumatic Stress Disorder (PTSD) can develop in response to a traumatic event involving a threat to life. To date, no diagnostic biomarkers have been identified for PTSD. Recent research points toward physiological abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis, sympathoadrenal medullary and immune system that may be implicated in the disorder. The modulation of neurotransmitters is another possible mechanism, but their role in the progression of PTSD is poorly understood. Low serotonin (5-HT) may be a factor, but it may not be the only neurotransmitter affected as modulation affects levels of other neurotransmitters. In this study, we hypothesized the predator exposure/psychosocial stress rodent model of PTSD may alter levels of 5-HT and other neurotransmitters in the rat hippocampus and prefrontal cortex (PFC). Male Sprague-Dawley rats were used in this experiment. We induced PTSD via a predator exposure/psychosocial stress model, whereby rats were placed in a cage with a cat for 1 hour on days 1 and 11 of the 31-day experiment. Rats also received psychosocial stress via daily cage cohort changes. On day 32, the rats were sacrificed and the brains dissected to remove the hippocampus and PFC. Norepinephrine (NE), 5-Hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), dopamine (DA), and 3,4-Dihydroxyphenylacetic acid (DOPAC), and 5-HT levels in the hippocampus and PFC were measured with high-performance liquid chromatography (HPLC). In the hippocampus, 5-HT and HVA were lower, while NE and DOPAC were higher, in the PTSD group vs. controls. In the PFC, only 5-HT was lower, while NE, DA, and DOPAC were higher, in the PTSD group vs. controls. The rate limiting enzymes tyrosine hydroxylase and tryptophan hydroxylase were also examined and confirmed our findings. These results demonstrate that the predator exposure/psychosocial stress model of PTSD produces neurotransmitter changes similar to those seen in human patients and may cause a

  7. Serotonin and brain development.

    PubMed

    Sodhi, Monsheel S K; Sanders-Bush, Elaine

    2004-01-01

    The role of the serotonergic system in the neuroplastic events that create, repair, and degenerate the brain has been explored. Synaptic plasticity occurs throughout life and is critical during brain development. Evidence from biochemical, pharmacological, and clinical studies demonstrates the huge importance of an intact serotonergic system for normal central nervous system (CNS)function. Serotonin acts as a growth factor during embryogenesis, and serotonin receptor activity forms a crucial part of the cascade of events leading to changes in brain structure. The serotonergic system interacts with brain-derived neurotrophic factor (BDNF), S100beta, and other chemical messengers, in addition to ts cross talk with the GABAergic, glutamatergic, and dopaminergic neurotransmitter systems. Disruption of these processes may contribute to CNS disorders that have been associated with impaired development. Furthermore, many psychiatric drugs alter serotonergic activity and have been shown to create changes in brain structure with long-term treatment. However, the mechanisms for their therapeutic efficacy are still unclear. Treatments for psychiatric illness are usually chronic and alleviate psychiatric symptoms, rather than cure these diseases. Therefore, greater exploration of the serotonin system during brain development and growth could lead to real progress in the discovery of treatments for mental disorders.

  8. Responses of Neurons of the Canine Area Postrema to Neurotransmitters and Peptides

    DTIC Science & Technology

    1983-10-01

    responsive to serotonin, angiotensin II, dopamine or osmotic pressure changes. Proc Univ Otago Med Sch 58:71-72 (1980). 8. Bronzino , J., D. Morgagne, and...W. Stein. EEG synchronization following application of serotonin to area postrema. Am J Physiol 2?3:376-383 (1972). 9. Bronzino , J., W. Stein, J

  9. Effect of repeated co-treatment with fluoxetine and amantadine on the behavioral reactivity of the central dopamine and serotonin system in rats.

    PubMed

    Rogóz, Zofia; Skuza, Grazyna

    2009-01-01

    In the present study we found that repeated co-treatment with fluoxetine and amantadine for 14 days (but not for 7 days) enhanced the hyperactivity induced by amphetamine or quinpirole (a dopamine D(2/3) agonist), compared to treatment with either drug alone. Whereas repeated co-treatment with fluoxetine and amantadine for 7 days more potently inhibited the behavioral syndrome evoked by the 5-hydroxytryptamine (5-HT)(1A) receptor agonist (+/-)-8-hydroxy-2(di-n-propylamino)-tetralin hydrobromide (8-OH-DPAT), it did not change the action of the 5-HT(2) receptor agonist (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (/+/-/-DOI). The obtained results support the hypothesis that repeated co-treatment with fluoxetine and amantadine may evoke more effective antidepressant activity than treatment with fluoxetine alone. Moreover, our results suggest that 5-HT(1A) receptors are useful targets for the development of more rapidly acting and more effective medication.

  10. Carbon nanotubes grown on metal microelectrodes for the detection of dopamine

    DOE PAGES

    Yang, Cheng; Jacobs, Christopher B.; Nguyen, Michael; ...

    2015-12-07

    Microelectrodes modified with carbon nanotubes (CNTs) are useful for the detection of neurotransmitters because the CNTs enhance sensitivity and have electrocatalytic effects. CNTs can be grown on carbon fiber microelectrodes (CFMEs) but the intrinsic electrochemical activity of carbon fibers makes evaluating the effect of CNT enhancement difficult. Metal wires are highly conductive and many metals have no intrinsic electrochemical activity for dopamine, so we investigated CNTs grown on metal wires as microelectrodes for neurotransmitter detection. In this work, we successfully grew CNTs on niobium substrates for the first time. Instead of planar metal surfaces, metal wires with a diameter ofmore » only 25 μm were used as CNT substrates; these have potential in tissue applications due to their minimal tissue damage and high spatial resolution. Scanning electron microscopy shows that aligned CNTs are grown on metal wires after chemical vapor deposition. By use of fast-scan cyclic voltammetry, CNT-coated niobium (CNT-Nb) microelectrodes exhibit higher sensitivity and lower ΔEp value compared to CNTs grown on carbon fibers or other metal wires. The limit of detection for dopamine at CNT-Nb microelectrodes is 11 ± 1 nM, which is approximately 2-fold lower than that of bare CFMEs. Adsorption processes were modeled with a Langmuir isotherm, and detection of other neurochemicals was also characterized, including ascorbic acid, 3,4-dihydroxyphenylacetic acid, serotonin, adenosine, and histamine. CNT-Nb microelectrodes were used to monitor stimulated dopamine release in anesthetized rats with high sensitivity. This research demonstrates that CNT-grown metal microelectrodes, especially CNTs grown on Nb microelectrodes, are useful for monitoring neurotransmitters.« less

  11. Carbon nanotubes grown on metal microelectrodes for the detection of dopamine

    SciTech Connect

    Yang, Cheng; Jacobs, Christopher B.; Nguyen, Michael; Ganesana, Mallikarjunarao; Zestos, Alexander; Ivanov, Ilia N.; Puretzky, Alexander A.; Rouleau, Christopher M.; Geohegan, David B.; Venton, B. Jill

    2015-12-07

    Microelectrodes modified with carbon nanotubes (CNTs) are useful for the detection of neurotransmitters because the CNTs enhance sensitivity and have electrocatalytic effects. CNTs can be grown on carbon fiber microelectrodes (CFMEs) but the intrinsic electrochemical activity of carbon fibers makes evaluating the effect of CNT enhancement difficult. Metal wires are highly conductive and many metals have no intrinsic electrochemical activity for dopamine, so we investigated CNTs grown on metal wires as microelectrodes for neurotransmitter detection. In this work, we successfully grew CNTs on niobium substrates for the first time. Instead of planar metal surfaces, metal wires with a diameter of only 25 μm were used as CNT substrates; these have potential in tissue applications due to their minimal tissue damage and high spatial resolution. Scanning electron microscopy shows that aligned CNTs are grown on metal wires after chemical vapor deposition. By use of fast-scan cyclic voltammetry, CNT-coated niobium (CNT-Nb) microelectrodes exhibit higher sensitivity and lower ΔEp value compared to CNTs grown on carbon fibers or other metal wires. The limit of detection for dopamine at CNT-Nb microelectrodes is 11 ± 1 nM, which is approximately 2-fold lower than that of bare CFMEs. Adsorption processes were modeled with a Langmuir isotherm, and detection of other neurochemicals was also characterized, including ascorbic acid, 3,4-dihydroxyphenylacetic acid, serotonin, adenosine, and histamine. CNT-Nb microelectrodes were used to monitor stimulated dopamine release in anesthetized rats with high sensitivity. This research demonstrates that CNT-grown metal microelectrodes, especially CNTs grown on Nb microelectrodes, are useful for monitoring neurotransmitters.

  12. Carbon Nanotubes Grown on Metal Microelectrodes for the Detection of Dopamine.

    PubMed

    Yang, Cheng; Jacobs, Christopher B; Nguyen, Michael D; Ganesana, Mallikarjunarao; Zestos, Alexander G; Ivanov, Ilia N; Puretzky, Alexander A; Rouleau, Christopher M; Geohegan, David B; Venton, B Jill

    2016-01-05

    Microelectrodes modified with carbon nanotubes (CNTs) are useful for the detection of neurotransmitters because the CNTs enhance sensitivity and have electrocatalytic effects. CNTs can be grown on carbon fiber microelectrodes (CFMEs) but the intrinsic electrochemical activity of carbon fibers makes evaluating the effect of CNT enhancement difficult. Metal wires are highly conductive and many metals have no intrinsic electrochemical activity for dopamine, so we investigated CNTs grown on metal wires as microelectrodes for neurotransmitter detection. In this work, we successfully grew CNTs on niobium substrates for the first time. Instead of planar metal surfaces, metal wires with a diameter of only 25 μm were used as CNT substrates; these have potential in tissue applications due to their minimal tissue damage and high spatial resolution. Scanning electron microscopy shows that aligned CNTs are grown on metal wires after chemical vapor deposition. By use of fast-scan cyclic voltammetry, CNT-coated niobium (CNT-Nb) microelectrodes exhibit higher sensitivity and lower ΔEp value compared to CNTs grown on carbon fibers or other metal wires. The limit of detection for dopamine at CNT-Nb microelectrodes is 11 ± 1 nM, which is approximately 2-fold lower than that of bare CFMEs. Adsorption processes were modeled with a Langmuir isotherm, and detection of other neurochemicals was also characterized, including ascorbic acid, 3,4-dihydroxyphenylacetic acid, serotonin, adenosine, and histamine. CNT-Nb microelectrodes were used to monitor stimulated dopamine release in anesthetized rats with high sensitivity. This study demonstrates that CNT-grown metal microelectrodes, especially CNTs grown on Nb microelectrodes, are useful for monitoring neurotransmitters.

  13. Effects of low dose endosulfan exposure on brain neurotransmitter levels in the African clawed frog Xenopus laevis.

    PubMed

    Preud'homme, Valérie; Milla, Sylvain; Gillardin, Virginie; De Pauw, Edwin; Denoël, Mathieu; Kestemont, Patrick

    2015-02-01

    Understanding the impact of pesticides in amphibians is of growing concern to assess the causes of their decline. Among pesticides, endosulfan belongs to one of the potential sources of danger because of its wide use and known effects, particularly neurotoxic, on a variety of organisms. However, the effect of endosulfan was not yet evaluated on amphibians at levels encompassing simultaneously brain neurotransmitters and behavioural endpoints. In this context, tadpoles of the African clawed frog Xenopus laevis were submitted to four treatments during 27 d: one control, one ethanol control, and two low environmental concentrations of endosulfan (0.1 and 1 μg L(-1)). Endosulfan induced a significant increase of brain serotonin level at both concentrations and a significant increase of brain dopamine and GABA levels at the lower exposure but acetylcholinesterase activity was not modified by the treatment. The gene coding for the GABA transporter 1 was up-regulated in endosulfan contaminated tadpoles while the expression of other genes coding for the neurotransmitter receptors or for the enzymes involved in their metabolic pathways was not significantly modified by endosulfan exposure. Endosulfan also affected foraging, and locomotion in links with the results of the physiological assays, but no effects were seen on growth. These results show that low environmental concentrations of endosulfan can induce adverse responses in X. laevis tadpoles. At a broader perspective, this suggests that more research using and linking multiple markers should be used to understand the complex mode of action of pollutants.

  14. Electrical coupling between the human serotonin transporter and voltage-gated Ca(2+) channels.

    PubMed

    Ruchala, Iwona; Cabra, Vanessa; Solis, Ernesto; Glennon, Richard A; De Felice, Louis J; Eltit, Jose M

    2014-07-01

    Monoamine transporters have been implicated in dopamine or serotonin release in response to abused drugs such as methamphetamine or ecstasy (MDMA). In addition, monoamine transporters show substrate-induced inward currents that may modulate excitability and Ca(2+) mobilization, which could also contribute to neurotransmitter release. How monoamine transporters modulate Ca(2+) permeability is currently unknown. We investigate the functional interaction between the human serotonin transporter (hSERT) and voltage-gated Ca(2+) channels (CaV). We introduce an excitable expression system consisting of cultured muscle cells genetically engineered to express hSERT. Both 5HT and S(+)MDMA depolarize these cells and activate the excitation-contraction (EC)-coupling mechanism. However, hSERT substrates fail to activate EC-coupling in CaV1.1-null muscle cells, thus implicating Ca(2+) channels. CaV1.3 and CaV2.2 channels are natively expressed in neurons. When these channels are co-expressed with hSERT in HEK293T cells, only cells expressing the lower-threshold L-type CaV1.3 channel show Ca(2+) transients evoked by 5HT or S(+)MDMA. In addition, the electrical coupling between hSERT and CaV1.3 takes place at physiological 5HT concentrations. The electrical coupling between monoamine neurotransmitter transporters and Ca(2+) channels such as CaV1.3 is a novel mechanism by which endogenous substrates (neurotransmitters) or exogenous substrates (like ecstasy) could modulate Ca(2+)-driven signals in excitable cells.

  15. Measuring the serotonin uptake site using (/sup 3/H)paroxetine--a new serotonin uptake inhibitor

    SciTech Connect

    Gleiter, C.H.; Nutt, D.J.

    1988-01-01

    Serotonin is an important neurotransmitter that may be involved in ethanol preference and dependence. It is possible to label the serotonin uptake site in brain using the tricyclic antidepressant imipramine, but this also binds to other sites. We have used the new high-affinity uptake blocker paroxetine to define binding to this site and report it to have advantages over imipramine as a ligand.

  16. Role of neurotransmitters in palate development and teratologic implications.

    PubMed

    Zimmerman, E F

    1985-01-01

    It is hypothesized that neuropharmacologic agents are more teratogenic to humans. Since many neuropharmacologic agents function through neurotransmitter mechanisms, then neurotransmitters should function to regulate embryonic development. Evidence has been obtained that neurotransmitters do indeed function as biological signals in palate development. It has been shown that palate reorientation is modulated by neurotransmitters with a wide range of diversity, similar to the CNS. Thus serotonin and acetylcholine stimulate and GABA inhibits the reorientation process. Spatial diversity is also observed: serotonin functions at the anterior and acetylcholine at the posterior end, and GABA functions more efficiently at either end in different inbred strains. Many criteria for functioning neurotransmitters have been obtained. Both serotonin and GABA have been measured in the palate and developmental changes observed. Physiologic responses to serotonin have been monitored. Serotonin has been shown to stimulate palate cell motility as well as protein carboxyl methylation and cyclic GMP. The serotonin effects on protein carboxyl methylation and cyclic GMP could function to stimulate palate reorientation by modulating cell contractility and protein secretion. Further support for the hypothesis that neuropharmacologic agents could be teratogenic by perturbation of neurotransmitter mechanisms comes from studying GABA and diazepam. Evidence has been obtained that diazepam induces cleft palate by mimicking GABA in a functional GABAergic system in palate development. A significant finding is that genetic differences in both diazepam teratogenesis and in a GABAergic system have been observed. Comparing the SWV and AJ strains, the SWV mouse showed (1) a greater sensitivity to diazepam-induced cleft palate, (2) a greater sensitivity to GABA and diazepam inhibition of palate reorientation in embryo culture, (3) a greater concentration of palatal GABA and (4) a more efficient GABA

  17. Developmental fluoxetine and prenatal stress effects on serotonin, dopamine, and synaptophysin density in the PFC and hippocampus of offspring at weaning.

    PubMed

    Gemmel, Mary; Rayen, Ine; Lotus, Tiffany; van Donkelaar, Eva; Steinbusch, Harry W; De Lacalle, Sonsoles; Kokras, Nikolaos; Dalla, Christina; Pawluski, Jodi L

    2016-04-01

    Selective serotonin reuptake inhibitor medication exposure during the perinatal period can have a long term impact in adult offspring on neuroplasticity and the serotonergic system, but the impact of these medications during early development is poorly understood. The aim of this study was to determine the effects of developmental exposure to the SSRI, fluoxetine, on the serotonergic system, dopaminergic system, and synaptophysin density in the prefrontal cortex and hippocampus, as well as number of immature neurons in the dentate gyrus, in juvenile rat offspring at weaning. To model aspects of maternal depression, prenatal restraint stress was used. Sprague-Dawley rat offspring were exposed to either prenatal stress and/or fluoxetine. Main findings show that developmental fluoxetine exposure to prenatally stressed offspring decreased 5-HT and 5-HIAA levels and altered the dopaminergic system in the hippocampus. Prenatal stress, regardless of fluoxetine, increased synaptophysin density in the PFC. This work indicates that early exposure to maternal stress and SSRI medication can alter brain monoamine levels and synaptophysin density in offspring at weaning.

  18. Effects of the antidepressant venlafaxine on fish brain serotonin and predation behavior.

    PubMed

    Bisesi, Joseph H; Bridges, William; Klaine, Stephen J

    2014-03-01

    Antidepressants that enter receiving waters through final treated wastewater effluent have exhibited relatively low acute toxicity in traditional fish tests at currently measured concentrations. However, the psychotropic mode of action of these compounds warrants examination of the behavioral effects these chemicals may have on aquatic organisms. Previous research has demonstrated that exposure to the antidepressant fluoxetine causes decreased brain serotonin levels in fish and results in a decreased ability to capture prey. Another antidepressant, venlafaxine, has been found at low μg/L concentrations in final treated wastewater effluent. The objective of this study was to quantify the effects of venlafaxine on fish predation behavior and determine if this effect was correlated with changes in brain neurotransmitter concentrations. The predator prey bioassay used hybrid striped bass (Morone saxatilis x Morone chrysops) as the predator and fathead minnows (Pimephales promelas) as prey. Bass were exposed to venlafaxine (0-500 μg/L) for a period of 6 days and then allowed to recover for 6 days. During both exposure and recovery, bass were fed four minnows every third day. The time to capture the minnows was quantified and compared among treatments to determine if there was an effect on predation behavior. Brain tissue was analyzed for serotonin, norepinephrine, and dopamine, to determine the relationship between exposure concentration, brain monoamine levels, and predation behavior. Results indicated that venlafaxine exposures increased time to capture prey 1 and 2 by day 6 for the 250 and 500 μg/L treatments. Time to capture prey 3 was increased for all venlafaxine treatments by day 6. Venlafaxine caused a statistically significant decrease in brain serotonin concentrations that initially decreased in a dose dependent manner before reaching a steady state by the end of exposures for all treatments. No significant, dose-dependent changes in dopamine or

  19. Dopamine regulates body size in Caenorhabditis elegans.

    PubMed

    Nagashima, Takashi; Oami, Eitaro; Kutsuna, Natsumaro; Ishiura, Shoichi; Suo, Satoshi

    2016-04-01

    The nervous system plays a critical role in the regulation of animal body sizes. In Caenorhabditis elegans, an amine neurotransmitter, dopamine, is required for the tactile perception of food and food-dependent behavioral changes, while its role in development is unknown. In this study, we show that dopamine negatively regulates body size through a D2-like dopamine receptor, DOP-3, in C. elegans. Dopamine alters body size without affecting food intake or developmental rate. We also found that dopamine promotes egg-laying, although the regulation of body size by dopamine was not solely caused by this effect. Furthermore, dopamine negatively regulates body size through the suppression of signaling by octopamine and Gq-coupled octopamine receptors, SER-3 and SER-6. Our results demonstrate that dopamine and octopamine regulate the body size of C. elegans and suggest a potential role for perception in addition to ingestion of food for growth.

  20. Activity patterns of serotonin neurons underlying cognitive flexibility.

    PubMed

    Matias, Sara; Lottem, Eran; Dugué, Guillaume P; Mainen, Zachary F

    2017-03-21

    Serotonin is implicated in mood and affective disorders. However, growing evidence suggests that a core endogenous role is to promote flexible adaptation to changes in the causal structure of the environment, through behavioral inhibition and enhanced plasticity. We used long-term photometric recordings in mice to study a population of dorsal raphe serotonin neurons, whose activity we could link to normal reversal learning using pharmacogenetics. We found that these neurons are activated by both positive and negative prediction errors, and thus report signals similar to those proposed to promote learning in conditions of uncertainty. Furthermore, by comparing the cue responses of serotonin and dopamine neurons, we found differences in learning rates that could explain the importance of serotonin in inhibiting perseverative responding. Our findings show how the activity patterns of serotonin neurons support a role in cognitive flexibility, and suggest a revised model of dopamine-serotonin opponency with potential clinical implications.

  1. Fast and Selective Plasmonic Serotonin Detection with Aptamer-Gold Nanoparticle Conjugates.

    PubMed

    Chávez, Jorge L; Hagen, Joshua A; Kelley-Loughnane, Nancy

    2017-03-25

    Neurotransmitters detection is critical to understanding communication between the brain and peripheral tissue. Serotonin is a key neurotransmitter linked to a number of conditions, but a full understanding of its role in disease is still lacking. The development of fast and selective serotonin detection platforms will provide researchers with tools to monitor serotonin in individuals before and after treatment for the condition of interest. Aptamer-gold nanoparticles conjugates that responded colorimetrically to serotonin with minimal response to its metabolite and other neurotransmitters were designed by simply adsorbing the DNA on the surface of AuNPs. A plasmonic assay for serotonin detection was designed with a response to biologically relevant serotonin levels. Importantly, the assay performance was not compromised when tested in filtered spiked fetal bovine serum as a mimic of biofluids. This work shows that these simple and stable Apt-AuNP conjugates are promising tools to develop fast assays for point-of-care and personalized diagnostics applications.

  2. Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

    PubMed Central

    Zhang, Xiaowei; Bearer, Elaine L.; Boulat, Benoit; Hall, F. Scott; Uhl, George R.; Jacobs, Russell E.

    2010-01-01

    The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn2+ into the prefrontal cortex indicated that DAT KO mice have a truncated Mn2+ distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn2+ transport into more posterior midbrain nuclei and contralateral mesolimbic structures at

  3. Comparison of the anti-dopamine D₂ and anti-serotonin 5-HT(2A) activities of chlorpromazine, bromperidol, haloperidol and second-generation antipsychotics parent compounds and metabolites thereof.

    PubMed

    Suzuki, Hidenobu; Gen, Keishi; Inoue, Yuichi

    2013-04-01

    Second-generation antipsychotics, which have become the standard drug therapies for schizophrenia, are known to have a serotonin 5-HT(2A) receptor blocking effect in addition to a dopamine D₂ receptor blocking effect. However, although chlorpromazine (CPZ) has a 5-HT(2A) receptor blocking effect and has the profile of a second-generation antipsychotic in vitro, it loses this pharmacological profile in vivo. In order to elucidate the differences between the in vivo and in vitro pharmacological characteristics of CPZ, we used a radioreceptor assay to measure the anti-D₂ activity and the anti-5-HT(2A) activity of CPZ and five major metabolites of CPZ, and compared the results to the anti-D₂ activity and anti-5-HT(2A) activity of risperidone, zotepine, perospirone, the major metabolites of each of these drugs, and olanzapine, bromperidol, and haloperidol. The subjects were 182 patients who had received diagnoses of schizophrenia based on the DSM-IV criteria. The results revealed that CPZ exhibited little anti-5-HT(2A) activity, regardless of the anti-D₂ activity level, and that none of the metabolites possessed anti-5-HT(2A) activity. However, both the parent compounds and the metabolites of each of the second-generation antipsychotics possessed both anti-D₂ activity and anti-5-HT(2A) activity. This clarified that, unlike second-generation antipsychotics, the reason CPZ loses its second-generation antipsychotic profiles in vivo is because it does not have any metabolites that possess anti-5-HT(2A) activity.

  4. Metabolomics of Neurotransmitters and Related Metabolites in Post-Mortem Tissue from the Dorsal and Ventral Striatum of Alcoholic Human Brain.

    PubMed

    Kashem, Mohammed Abul; Ahmed, Selina; Sultana, Nilufa; Ahmed, Eakhlas U; Pickford, Russell; Rae, Caroline; Šerý, Omar; McGregor, Iain S; Balcar, Vladimir J

    2016-02-01

    We report on changes in neurotransmitter metabolome and protein expression in the striatum of humans exposed to heavy long-term consumption of alcohol. Extracts from post mortem striatal tissue (dorsal striatum; DS comprising caudate nucleus; CN and putamen; P and ventral striatum; VS constituted by nucleus accumbens; NAc) were analysed by high performance liquid chromatography coupled with tandem mass spectrometry. Proteomics was studied in CN by two-dimensional gel electrophoresis followed by mass-spectrometry. Proteomics identified 25 unique molecules expressed differently by the alcohol-affected tissue. Two were dopamine-related proteins and one a GABA-synthesizing enzyme GAD65. Two proteins that are related to apoptosis and/or neuronal loss (BiD and amyloid-β A4 precursor protein-binding family B member 3) were increased. There were no differences in the levels of dopamine (DA), 3,4-dihydrophenylacetic acid (DOPAC), serotonin (5HT), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (HIAA), histamine, L-glutamate (Glu), γ-aminobutyric acid (GABA), tyrosine (Tyr) and tryptophan (Tryp) between the DS (CN and P) and VS (NAc) in control brains. Choline (Ch) and acetylcholine (Ach) were higher and norepinephrine (NE) lower, in the VS. Alcoholic striata had lower levels of neurotransmitters except for Glu (30 % higher in the alcoholic ventral striatum). Ratios of DOPAC/DA and HIAA/5HT were higher in alcoholic striatum indicating an increase in the DA and 5HT turnover. Glutathione was significantly reduced in all three regions of alcohol-affected striatum. We conclude that neurotransmitter systems in both the DS (CN and P) and the VS (NAc) were significantly influenced by long-term heavy alcohol intake associated with alcoholism.

  5. Protective effect of taurine on the decreased biogenic amine neurotransmitter levels in the brain of mice exposed to arsenic.

    PubMed

    Liu, Xiaohui; Piao, Fengyuan; Li, Yachen

    2013-01-01

    Arsenic (As) exposure has a toxic effect on the central nervous system, especially on learning and memory. Norepinephrine (NE), dopamine (DA), and serotonin (5-HT) play an important role in learning and memory function of the brain. In the present study, the protective effect of taurine on the disturbed biogenic amine neurotransmitter levels in the mouse brain induced by arsenic was examined. Sixty SPF mice were divided into three groups. The As exposure group was administered with 4 ppm As(2)O(3) through drinking water for 60 days. The protective group was treated with both 4 ppm As(2)O(3) and 150 mg/kg taurine. The control group was given drinking water alone. The levels of NE, DA, and 5-HT were determined by HPLC in the cerebrum and cerebellum of mice. Ultrastructure of synapses in brain tissue of mice was observed in these groups by transmission electron microscopy. The mRNA expressions of dopamine beta hydroxylase (DBH), tyrosine hydroxylase (TH), and tryptophan hydroxylase (TPH) as NE, DA, and 5-HT synzymes were also analyzed by real-time RT-PCR. The results showed that the concentrations of NE, DA, and 5-HT; the number of synaptic vesicles; and the expressions of TH, TPH, and DBH genes in the brains of mice exposed to As alone were significantly decreased. However, administration of taurine significantly alleviated the toxic effect on biochemicals detected in the experiment, compared with that in the brain of mice exposed to As alone. These results indicated that taurine was effective in counteracting the decreased biogenic amine neurotransmitter level and the mRNA expressions of their synzymes induced by arsenic.

  6. Serotonin Selective Reuptake Inhibitors (SSRIs) and Female Sexual Dysfunction (FSD): Hypothesis on Its association and options of treatment.

    PubMed

    Rappek, Nurul Azmi Mahamad; Sidi, Hatta; Kumar, Jaya; Kamarazaman, Sazlina; Das, Srijit; Masiran, Ruziana; Baharudin, Najwa; Hatta, Muhammad

    2016-12-27

    Sexual dysfunctions are commonly seen in women on selective serotonin reuptake inhibitors (SSRIs). The complexities of female sexual functioning are reflected through modulation of inter-playing factors like the neuropsychophysiological factors, inter-personal and relationship issue, psychiatric co-morbidities and physical disorder. The incidence of SSRIs-induced FSD is difficult to estimate because of the potentially confounding effects of SSRIs, presence of polypharmacy, marital effect, socio-cultural factors and due to the design and assessment problems in majority of the studies.The exact mechanism of FSD-induced SSRIs is unknown. It has been postulated that although SSRIs may modulate other neurotransmitter sytem such as nitric oxide (NO), noradgenergic and dopamine in inducing FSD. In the present review, we highlight current evidence regarding potential mechanism of SSRIs in causing FSD, which include low sexual desire (low libido), arousal difficulties (lack of lubrication), and anorgasmia. The specific association of FSD to SSRI use, has not been ellucidated. The relationship is dose-dependent, and may vary among the groups with respect to mechanism of serotonin and dopamine reuptake, induction of release of prolactin from the pituitary gland, anticholinergic side-effects, inhibition of NO synthesis and emotional-memory circuit encryption for sexual experiences. Various interventional strategies exist regarding the treatment of SSRI-induced FSD and this includes tolerance, titration dosage, substitution to another antidepressant drug and psychotherapy. There is a need of better understanding of SSRIs-induced FSD for better treatment outcome.

  7. Beneficial effects of lycopene against haloperidol induced orofacial dyskinesia in rats: Possible neurotransmitters and neuroinflammation modulation.

    PubMed

    Datta, Swati; Jamwal, Sumit; Deshmukh, Rahul; Kumar, Puneet

    2016-01-15

    Tardive Dyskinesia is a severe side effect of chronic neuroleptic treatment consisting of abnormal involuntary movements, characterized by orofacial dyskinesia. The study was designed to investigate the protective effect of lycopene against haloperidol induced orofacial dyskinesia possibly by neurochemical and neuroinflammatory modulation in rats. Rats were administered with haloperidol (1mg/kg, i.p for 21 days) to induce orofacial dyskinesia. Lycopene (5 and 10mg/kg, p.o) was given daily 1hour before haloperidol treatment for 21 days. Behavioral observations (vacuous chewing movements, tongue protrusions, facial jerking, rotarod activity, grip strength, narrow beam walking) were assessed on 0th, 7th(,) 14th(,) 21st day after haloperidol treatment. On 22nd day, animals were killed and striatum was excised for estimation of biochemical parameters (malondialdehyde, nitrite and endogenous enzyme (GSH), pro-inflammatory cytokines [Tumor necrosis factor, Interleukin 1β, Interleukin 6] and neurotransmitters level (dopamine, serotonin, nor epinephrine, 5-Hydroxyindole acetic acid (5-HIAA), Homovanillic acid, 3,4- dihydroxyphenylacetic acid. Haloperidol treatment for 21 days impaired muscle co-ordination, motor activity and grip strength with an increased in orofacial dyskinetic movements. Further free radical generation increases MDA and nitrite levels, decreasing GSH levels in striatum. Neuroinflammatory markers were significantly increased with decrease in neurotransmitters levels. Lycopene (5 and 10mg/kg, p.o) treatment along with haloperidol significantly attenuated impairment in behavioral, biochemical, neurochemical and neuroinflammatory markers. Results of the present study attributed the therapeutic potential of lycopene in the treatment (prevented or delayed) of typical antipsychotic induced orofacial dyskinesia.

  8. Conformational dynamics of a neurotransmitter:sodium symporter in a lipid bilayer.

    PubMed

    Adhikary, Suraj; Deredge, Daniel J; Nagarajan, Anu; Forrest, Lucy R; Wintrode, Patrick L; Singh, Satinder K

    2017-03-07

    Neurotransmitter:sodium symporters (NSSs) are integral membrane proteins responsible for the sodium-dependent reuptake of small-molecule neurotransmitters from the synaptic cleft. The symporters for the biogenic amines serotonin (SERT), dopamine (DAT), and norepinephrine (NET) are targets of multiple psychoactive agents, and their dysfunction has been implicated in numerous neuropsychiatric ailments. LeuT, a thermostable eubacterial NSS homolog, has been exploited as a model protein for NSS members to canvass the conformational mechanism of transport with a combination of X-ray crystallography, cysteine accessibility, and solution spectroscopy. Despite yielding remarkable insights, these studies have primarily been conducted with protein in the detergent-solubilized state rather than embedded in a membrane mimic. In addition, solution spectroscopy has required site-specific labeling of nonnative cysteines, a labor-intensive process occasionally resulting in diminished transport and/or binding activity. Here, we overcome these limitations by reconstituting unlabeled LeuT in phospholipid bilayer nanodiscs, subjecting them to hydrogen-deuterium exchange coupled with mass spectrometry (HDX-MS), and facilitating interpretation of the data with molecular dynamics simulations. The data point to changes of accessibility and dynamics of structural elements previously implicated in the transport mechanism, in particular transmembrane helices (TMs) 1a and 7 as well as extracellular loops (ELs) 2 and 4. The results therefore illuminate the value of this strategy for interrogating the conformational mechanism of the more clinically significant mammalian membrane proteins including SERT and DAT, neither of which tolerates complete removal of endogenous cysteines, and whose activity is heavily influenced by neighboring lipids.

  9. Serotonin, neural markers, and memory

    PubMed Central

    Meneses, Alfredo

    2015-01-01

    Diverse neuropsychiatric disorders present dysfunctional memory and no effective treatment exits for them; likely as result of the absence of neural markers associated to memory. Neurotransmitter systems and signaling pathways have been implicated in memory and dysfunctional memory; however, their role is poorly understood. Hence, neural markers and cerebral functions and dysfunctions are revised. To our knowledge no previous systematic works have been published addressing these issues. The interactions among behavioral tasks, control groups and molecular changes and/or pharmacological effects are mentioned. Neurotransmitter receptors and signaling pathways, during normal and abnormally functioning memory with an emphasis on the behavioral aspects of memory are revised. With focus on serotonin, since as it is a well characterized neurotransmitter, with multiple pharmacological tools, and well characterized downstream signaling in mammals' species. 5-HT1A, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 receptors as well as SERT (serotonin transporter) seem to be useful neural markers and/or therapeutic targets. Certainly, if the mentioned evidence is replicated, then the translatability from preclinical and clinical studies to neural changes might be confirmed. Hypothesis and theories might provide appropriate limits and perspectives of evidence. PMID:26257650

  10. Serotonin, neural markers, and memory.

    PubMed

    Meneses, Alfredo

    2015-01-01

    Diverse neuropsychiatric disorders present dysfunctional memory and no effective treatment exits for them; likely as result of the absence of neural markers associated to memory. Neurotransmitter systems and signaling pathways have been implicated in memory and dysfunctional memory; however, their role is poorly understood. Hence, neural markers and cerebral functions and dysfunctions are revised. To our knowledge no previous systematic works have been published addressing these issues. The interactions among behavioral tasks, control groups and molecular changes and/or pharmacological effects are mentioned. Neurotransmitter receptors and signaling pathways, during normal and abnormally functioning memory with an emphasis on the behavioral aspects of memory are revised. With focus on serotonin, since as it is a well characterized neurotransmitter, with multiple pharmacological tools, and well characterized downstream signaling in mammals' species. 5-HT1A, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 receptors as well as SERT (serotonin transporter) seem to be useful neural markers and/or therapeutic targets. Certainly, if the mentioned evidence is replicated, then the translatability from preclinical and clinical studies to neural changes might be confirmed. Hypothesis and theories might provide appropriate limits and perspectives of evidence.

  11. Sex hormones affect neurotransmitters and shape the adult female brain during hormonal transition periods

    PubMed Central

    Barth, Claudia; Villringer, Arno; Sacher, Julia

    2015-01-01

    Sex hormones have been implicated in neurite outgrowth, synaptogenesis, dendritic branching, myelination and other important mechanisms of neural plasticity. Here we review the evidence from animal experiments and human studies reporting interactions between sex hormones and the dominant neurotransmitters, such as serotonin, dopamine, GABA and glutamate. We provide an overview of accumulating data during physiological and pathological conditions and discuss currently conceptualized theories on how sex hormones potentially trigger neuroplasticity changes through these four neurochemical systems. Many brain regions have been demonstrated to express high densities for estrogen- and progesterone receptors, such as the amygdala, the hypothalamus, and the hippocampus. As the hippocampus is of particular relevance in the context of mediating structural plasticity in the adult brain, we put particular emphasis on what evidence could be gathered thus far that links differences in behavior, neurochemical patterns and hippocampal structure to a changing hormonal environment. Finally, we discuss how physiologically occurring hormonal transition periods in humans can be used to model how changes in sex hormones influence functional connectivity, neurotransmission and brain structure in vivo. PMID:25750611

  12. Amnesia produced by altered release of neurotransmitters after intraamygdala injections of a protein synthesis inhibitor

    PubMed Central

    Canal, Clinton E.; Chang, Qing; Gold, Paul E.

    2007-01-01

    Amnesia produced by protein synthesis inhibitors such as anisomycin provides major support for the prevalent view that the formation of long-lasting memories requires de novo protein synthesis. However, inhibition of protein synthesis might disrupt other neural functions to interfere with memory formation. Intraamygdala injections of anisomycin before inhibitory avoidance training impaired memory in rats tested 48 h later. Release of norepinephrine (NE), dopamine (DA), and serotonin, measured at the site of anisomycin infusions, increased quickly by ≈1,000–17,000%, far above the levels seen under normal conditions. NE and DA release later decreased far below baseline for several hours before recovering at 48 h. Intraamygdala injections of a β-adrenergic receptor antagonist or agonist, each timed to blunt effects of increases and decreases in NE release after anisomycin, attenuated anisomycin-induced amnesia. In addition, similar to the effects on memory seen with anisomycin, intraamygdala injections of a high dose of NE before training impaired memory tested at 48 h after training. These findings suggest that altered release of neurotransmitters may mediate amnesia produced by anisomycin and, further, raise important questions about the empirical bases for many molecular theories of memory formation. PMID:17640910

  13. Amnesia produced by altered release of neurotransmitters after intraamygdala injections of a protein synthesis inhibitor.

    PubMed

    Canal, Clinton E; Chang, Qing; Gold, Paul E

    2007-07-24

    Amnesia produced by protein synthesis inhibitors such as anisomycin provides major support for the prevalent view that the formation of long-lasting memories requires de novo protein synthesis. However, inhibition of protein synthesis might disrupt other neural functions to interfere with memory formation. Intraamygdala injections of anisomycin before inhibitory avoidance training impaired memory in rats tested 48 h later. Release of norepinephrine (NE), dopamine (DA), and serotonin, measured at the site of anisomycin infusions, increased quickly by approximately 1,000-17,000%, far above the levels seen under normal conditions. NE and DA release later decreased far below baseline for several hours before recovering at 48 h. Intraamygdala injections of a beta-adrenergic receptor antagonist or agonist, each timed to blunt effects of increases and decreases in NE release after anisomycin, attenuated anisomycin-induced amnesia. In addition, similar to the effects on memory seen with anisomycin, intraamygdala injections of a high dose of NE before training impaired memory tested at 48 h after training. These findings suggest that altered release of neurotransmitters may mediate amnesia produced by anisomycin and, further, raise important questions about the empirical bases for many molecular theories of memory formation.

  14. Expression of Caenorhabditis elegans neurotransmitter receptors and ion channels in Xenopus oocytes

    PubMed Central

    Martínez-Torres, Ataúlfo; Miledi, Ricardo

    2006-01-01

    Injection of Caenorhabditis elegans polyA RNA into Xenopus laevis oocytes led to the expression of neurotransmitter receptors that generated some unique responses, including ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors as well as receptors that coupled to G proteins, such as those to octopamine, norepinephrine, and angiotensin, which activated the oocyte’s own phosphatidylinositol system and calcium-gated chloride channels. The oocytes also expressed chloride-conducting glutamate receptors, muscarinic acetylcholine receptors, and voltage-operated calcium channels. Unexpectedly, serotonin (5-hydroxytryptamine), dopamine, GABA, and kainate did not generate ionic currents, suggesting that the corresponding receptors were not expressed or were not functional in the oocytes. The use of X. laevis oocytes for expressing worm RNA demonstrates that there are many molecular components whose role remains to be clarified in the nematode. Among them are the nature of the endogenous agonists for the octopamine and angiotensin receptors and the subunits that compose the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and the norepinephrine receptors that couple to the phosphoinositide cascade. PMID:16549772

  15. Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6.

    PubMed

    Chen, Nian-Hang; Reith, Maarten E A; Quick, Michael W

    2004-02-01

    The SLC6 family is a diverse set of transporters that mediate solute translocation across cell plasma membranes by coupling solute transport to the cotransport of sodium and chloride down their electrochemical gradients. These transporters probably have 12 transmembrane domains, with cytoplasmic N- and C-terminal tails, and at least some may function as homo-oligomers. Family members include the transporters for the inhibitory neurotransmitters GABA and glycine, the aminergic transmitters norepinephrine, serotonin, and dopamine, the osmolytes betaine and taurine, the amino acid proline, and the metabolic compound creatine. In addition, this family includes a system B(0+) cationic and neutral amino acid transporter, and two transporters for which the solutes are unknown. In general, SLC6 transporters act to regulate the level of extracellular solute concentrations. In the central and the peripheral nervous system, these transporters can regulate signaling among neurons, are the sites of action of various drugs of abuse, and naturally occurring mutations in several of these proteins are associated with a variety of neurological disorders. For example, transgenic animals lacking specific aminergic transporters show profoundly disturbed behavioral phenotypes and probably represent excellent systems for investigating psychiatric disease. SLC6 transporters are also found in many non-neural tissues, including kidney, intestine, and testis, consistent with their diverse physiological roles. Transporters in this family represent attractive therapeutic targets because they are subject to multiple forms of regulation by many different signaling cascades, and because a number of pharmacological agents have been identified that act specifically on these proteins.

  16. Antiferroptotic activity of non-oxidative dopamine.

    PubMed

    Wang, Ding; Peng, Yingpeng; Xie, Yangchun; Zhou, Borong; Sun, Xiaofang; Kang, Rui; Tang, Daolin

    2016-11-25

    Dopamine is a neurotransmitter that has many functions in the nervous and immune systems. Ferroptosis is a non-apoptotic form of regulated cell death that is involved in cancer and neurodegenerative diseases. However, the role of dopamine in ferroptosis remains unidentified. Here, we show that the non-oxidative form of dopamine is a strong inhibitor of ferroptotic cell death. Dopamine dose-dependently blocked ferroptosis in cancer (PANC1 and HEY) and non-cancer (MEF and HEK293) cells following treatment with erastin, a small molecule ferroptosis inducer. Notably, dopamine reduced erastin-induced ferrous iron accumulation, glutathione depletion, and malondialdehyde production. Mechanically, dopamine increased the protein stability of glutathione peroxidase 4, a phospholipid hydroperoxidase that protects cells against membrane lipid peroxidation. Moreover, dopamine suppressed dopamine receptor D4 protein degradation and promoted dopamine receptor D5 gene expression. Thus, our findings uncover a novel function of dopamine in cell death and provide new insight into the regulation of iron metabolism and lipid peroxidation by neurotransmitters.

  17. Serotonin-Labeled CdSe Nanocrystals: Applications for Neuroscience

    NASA Astrophysics Data System (ADS)

    Kippeny, Tadd; Adkins, Erika; Adams, Scott; Thomlinson, Ian; Schroeter, Sally; Defelice, Louis; Blakely, Randy; Rosenthal, Sandra

    2000-03-01

    Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter which has been linked to the regulation of critical behaviors including sleep, appetite, and mood. The serotonin transporter (SERT) is a 12-transmembrane domain protein responsible for clearance of serotonin from extracellular spaces following release. In order to assess the potential for use of ligand-conjugated nanocrystals to target cell surface receptors, ion channels, and transporters we have measured the ability of serotonin-labeled CdSe nanocrystals (SNACs) to block the uptake of tritiated serotonin by the human and Drosophila serotonin transporters (hSERT and dSERT). Estimated Ki values, the SNAC concentration at which half of the serotonin transport activity is blocked, were determined by nonlinear regression to be Ki (hSERT ) = 74uM and Ki (dSERT ) = 29uM. These values and our inability to detect free serotonin indicate that SNACs selectively interact with the serotonin recognition site of the transporter. We have also exposed the SNACs to cells containing ionotropic serotonin receptors and have measured the electrical response of the cell using a two microelectrode voltage clamp. We find that serotonin receptors do respond to the SNACs and we measure currents similar to the free serotonin response. These results indicate that ligand-conjugated nanocrystals can be used to label both receptor and transporter proteins. Initial fluorescence labeling experiments will be discussed.

  18. Development of the Wireless Instantaneous Neurotransmitter Concentration System for intraoperative neurochemical monitoring using fast-scan cyclic voltammetry

    PubMed Central

    Bledsoe, Jonathan M.; Kimble, Christopher J.; Covey, Daniel P.; Blaha, Charles D.; Agnesi, Filippo; Mohseni, Pedram; Whitlock, Sidney; Johnson, David M.; Horne, April; Bennet, Kevin E.; Lee, Kendall H.; Garris, Paul A.

    2009-01-01

    ); 2) Bluetooth transceiver; 3) microprocessor; and 4) direct-current battery. A Windows-XP laptop computer running custom software and equipped with a Universal Serial Bus–connected Bluetooth transceiver served as the base station. Computer software directed wireless data acquisition at 100 kilosamples/second and remote control of FSCV operation and adjustable waveform parameters. The WINCS provided reliable, high-fidelity measurements of dopamine and other neurochemicals such as serotonin, norepinephrine, and ascorbic acid by using FSCV at CFM and by flow injection analysis. In rats, the WINCS detected subsecond striatal dopamine release at the implanted sensor during high-frequency stimulation of ascending dopaminergic fibers. Overall, in vitro and in vivo testing demonstrated comparable signals to a conventional hardwired electrochemical system for FSCV. Importantly, the WINCS reduced susceptibility to electromagnetic noise typically found in an operating room setting. Conclusions Taken together, these results demonstrate that the WINCS is well suited for intraoperative neurochemical monitoring. It is anticipated that neurotransmitter measurements at an implanted chemical sensor will prove useful for advancing functional neurosurgery. PMID:19425890

  19. Serotonin hypothesis of autism: implications for selective serotonin reuptake inhibitor use during pregnancy.

    PubMed

    Harrington, Rebecca A; Lee, Li-Ching; Crum, Rosa M; Zimmerman, Andrew W; Hertz-Picciotto, Irva

    2013-06-01

    Serotonin, a neurotransmitter found throughout the brain and body, has long been of interest in autism. Repeated findings of elevated platelet serotonin levels in approximately one third of children with autism has led some to believe that dysfunctional serotonin signaling may be a causal mechanism for the disorder. Because serotonin is critical to fetal brain development, concerns have arisen regarding prenatal exposure to substances that manipulate serotonin levels, such as selective serotonin reuptake inhibitors (SSRIs). This review examines evidence regarding the serotonin system and autism spectrum disorders (ASD), as well as what the literature has reported thus far on developmental effects of prenatal exposure to SSRIs. Possible mechanisms by which SSRIs could affect the fetus during pregnancy and clinical implications are also discussed. Though the majority of studies conducted in infants and children suggest prenatal exposure to SSRIs does not affect neurodevelopment, interpretation must be tempered given small sample sizes. The only published study that focused on prenatal SSRI exposure and ASD found an increased risk with exposure to SSRIs, especially during the first trimester. Obstacles that will be faced in future research are isolating medication effects from maternal depression and, given the infrequent occurrence of exposure and outcome, obtaining an adequate sample size. Whether serotonin is an etiologic factor in ASD, and what it points to as a marker for subgrouping, remains unclear. Understanding how the development of ASD might be affected by prenatal factors that influence serotonin levels, such as SSRIs, could identify modifiable targets for prevention.

  20. The levels of monoamine neurotransmitters and measures of mental and emotional health in HCV patients treated with ledipasvir (LDV) and sofosbuvir (SOF) with or without ribavirin (RBV)

    PubMed Central

    Golabi, Pegah; Elsheikh, Elzafir; Karrar, Azza; Estep, James M.; Younossi, Issah; Stepanova, Maria; Gerber, Lynn; Younossi, Zobair M.

    2016-01-01

    Abstract Mental and emotional health (MEH) impairment is commonly encountered in hepatitis C patients. Although the exact mechanism remains unknown, alterations in neurotransmitter and cytokine levels maybe associated with hepatitis C virus (HCV)-related MEH issues. The aim of the study was to assess association of serum biomarkers with self-reports of MEH in HCV patients before treatment and after achieving sustained virologic response (SVR). The HCV genotype-1-infected patients who achieved SVR at 12 weeks after treatment with ledipasvir (LDV)/sofosbuvir (SOF) ± ribavirin (RBV) were selected. Frozen serum samples from baseline, end of treatment (EOT), and posttreatment week 4 (PTW4) were used to assay 16 cytokines and monoamine neurotransmitters. Validated self-reports were used to assess MEH. Hundred patients were evaluated. Mean age was 53 years (57% male, 86% white). Compared with baseline, emotional well-being and emotional health significantly increased by EOT, and role emotional, emotional well-being, and emotional health significantly increased at PTW4 in the RBV-containing arm (P < 0.05). In patients taking LDV/SOF + RBV, serotonin levels were significantly decreased at PTW4 compared with baseline (P = 0.046). Compared with baseline, there were significant decreases in interleukin (IL)-10 levels at EOT and PTW4 in both treatment groups. The changes in IL-8 also differed significantly between LDV/SOF + RBV and LDV/SOF groups (P < 0.05). Changes in dopamine and tryptophan levels at EOT correlated with increasing emotional health scores, whereas changes in monocyte chemoattractant protein-1 at EOT and IL-8 at PTW4 correlated with increasing mental health scores. The neurotransmitters and cytokines were found to be independent predictors of MEH scores in multiple regression analysis. Cytokine and neurotransmitter changes are associated with mental and emotional health. Patient-reported outcome scores change during and after treatment

  1. Mefloquine and Psychotomimetics Share Neurotransmitter Receptor and Transporter Interactions In Vitro

    PubMed Central

    Janowsky, Aaron; Eshleman, Amy J.; Johnson, Robert A.; Wolfrum, Katherine M.; Hinrichs, David J.; Yang, Jongtae; Zabriskie, T. Mark; Smilkstein, Martin J.; Riscoe, Michael K.

    2014-01-01

    Rationale Mefloquine is used for the prevention and treatment of chloroquine-resistant malaria, but its use is associated with nightmares, hallucinations, and exacerbation of symptoms of post-traumatic stress disorder. We hypothesized that potential mechanisms of action for the adverse psychotropic effects of mefloquine resemble those of other known psychotomimetics. Objectives Using in vitro radioligand binding and functional assays, we examined the interaction of (+)- and (−)-mefloquine enantiomers, the non-psychotomimetic anti-malarial agent, chloroquine, and several hallucinogens and psychostimulants with recombinant human neurotransmitter receptors and transporters. Results Hallucinogens and mefloquine bound stereoselectively and with relatively high affinity (Ki = 0.71–341 nM) to serotonin (5-HT) 2A but not 5-HT1A or 5-HT2C receptors. Mefloquine but not chloroquine was a partial 5-HT2A agonist and a full 5-HT2C agonist, stimulating inositol phosphate accumulation, with similar potency and efficacy as the hallucinogen dimethyltryptamine (DMT). 5-HT receptor antagonists blocked mefloquine’s effects. Mefloquine had low or no affinity for dopamine D1, D2, D3, and D4.4 receptors, or dopamine and norepinephrine transporters. However, mefloquine was a very low potency antagonist at the D3 receptor and mefloquine but not chloroquine or hallucinogens blocked [3H]5-HT uptake by the 5-HT transporter. Conclusions Mefloquine but not chloroquine shares an in vitro receptor interaction profile with some hallucinogens and this neurochemistry may be relevant to the adverse neuropsychiatric effects associated with mefloquine use by a small percentage of patients. Additionally, evaluating interactions with this panel of receptors and transporters may be useful for characterizing effects of other psychotropic drugs and for avoiding psychotomimetic effects for new pharmacotherapies, including antimalarial quinolines. PMID:24488404

  2. Differentiating Siblings: The Case of Dopamine and Norepinephrine.

    PubMed

    Nakatsuka, Nako; Andrews, Anne M

    2017-02-15

    Monitoring dopamine and norepinephrine (or other structurally similar neurotransmitters) in the same brain region necessitates selective sensing. In this Viewpoint, we highlight electrochemical and optical strategies for advancing simultaneous real-time measurements of dopamine and norepinephrine transmission. The potential for DNA aptamers as recognition elements in the context of field-effect transistor sensing for selective and simultaneous neurotransmitter monitoring in vivo is also discussed.

  3. MODERATE PRENATAL ALCOHOL EXPOSURE AND SEROTONIN GENOTYPE INTERACT TO ALTER CNS SEROTONIN FUNCTION IN RHESUS MONKEYS OFFSPRING

    PubMed Central

    Schneider, Mary L.; Moore, Colleen F.; Barr, Christina S.; Larson, Julie A.; Kraemer, Gary W.

    2010-01-01

    Background Moderate prenatal alcohol exposure can contribute to neurodevelopmental impairments and disrupt several neurotransmitter systems. We examined the timing of moderate level alcohol exposure, serotonin transporter gene polymorphic region variation (rh5-HTTLPR), and levels of primary serotonin and dopamine metabolites in cerebrospinal fluid (CSF) in rhesus monkeys. Methods Thirty-two 30-month old rhesus monkeys (Macaca mulatta) from four groups of females were assessed: (1) early alcohol-exposed group (n = 9), in which mothers voluntarily consumed 0.6 g/kg/day alcohol solution on gestational days 0 – 50; (2) middle-to-late gestation alcohol-exposed group (n = 6), mothers consumed 0.6 g/kg/day alcohol solution on gestational days 50 – 135; (3) a continuous-exposure group (n = 8), mothers consumed 0.6 g/kg/day alcohol solution on gestational days 0 – 135; and (4) controls (n = 9), mothers consumed an isocaloric control solution on gestational days 0 – 50, 50 – 135, or 0 – 135. Serotonin transporter promoter region allelic variants (homozygous s/s or heterozygous s/l versus homozygous l/l) were determined. We examined CSF concentrations of the 5-HT and DA metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), respectively, at baseline and 50 hours after separation from cage-mates, when the monkeys were 30 months old. Results Early- and middle-to-late gestation-alcohol exposed monkeys carrying the short allele had lower concentrations of 5-HIAA in CSF relative to other groups. Concentrations of 5-HIAA in CSF were lower for s allele carriers and increased from baseline relative to pre-separation values, while 5-HIAA levels in l/l allele carriers were not affected by separation. Monkeys carrying the short allele had lower basal concentrations of HVA in CSF compared to monkeys homozygous for the long allele. Conclusion Carrying the s allele of the 5-HT transporter increased the probability of reduced 5-HIAA in early- and middle

  4. Development of a simple and rapid solid phase microextraction-gas chromatography-triple quadrupole mass spectrometry method for the analysis of dopamine, serotonin and norepinephrine in human urine.

    PubMed

    Naccarato, Attilio; Gionfriddo, Emanuela; Sindona, Giovanni; Tagarelli, Antonio

    2014-01-31

    The work aims at developing a simple and rapid method for the quantification of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) in human urine. The urinary levels of these biogenic amines can be correlated with several pathological conditions concerning heart disease, stress, neurological disorders and cancerous tumors. The proposed analytical approach is based on the use of solid phase microextraction (SPME) combined with gas chromatography-triple quadrupole mass spectrometry (GC-QqQ-MS) after a fast derivatization of both aliphatic amino and phenolic moieties by propyl chloroformate. The variables influencing the derivatization reaction were reliably optimized by the multivariate approach of "Experimental design". The optimal conditions were obtained by performing derivatization with 100μL of propyl chloroformate and 100μL of pyridine. The extraction ability of five commercially available SPME fibers was evaluated in univariate mode and the best results were obtained using the polyacrylate fiber. The variables affecting the efficiency of SPME analysis were again optimized by the multivariate approach of "Experimental design" and, in particular, a central composite design (CCD) was applied. The optimal values were extraction in 45min at room temperature, desorption temperature at 300°C, no addition of NaCl. Assay of derivatized analytes was performed by using a gas chromatography-triple quadrupole mass spectrometry (GC-QqQ-MS) system in selected reaction monitoring (SRM) acquisition. An evaluation of all analytical parameters demonstrates that the developed method provides satisfactory results. Indeed, very good linearities were achieved in the tested calibration range with correlation coefficient values of 0.9995, 0.9999 and 0.9997 for DA, 5-HT and NE, respectively. Accuracies and RSDs calculated for between-run and tested at concentrations of 30, 200, and 800μg L(-1) were in the range from 92.8% to 103.0%, and from 0.67 to 4.5%, respectively. Finally

  5. UWA-121, a mixed dopamine and serotonin re-uptake inhibitor, enhances L-DOPA anti-parkinsonian action without worsening dyskinesia or psychosis-like behaviours in the MPTP-lesioned common marmoset.

    PubMed

    Huot, Philippe; Johnston, Tom H; Lewis, Katie D; Koprich, James B; Reyes, M Gabriela; Fox, Susan H; Piggott, Matthew J; Brotchie, Jonathan M

    2014-07-01

    L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease (PD), but its long-term administration is complicated by wearing-off and dyskinesia. UWA-101, a dual, equipotent inhibitor of dopamine (DAT) and serotonin (SERT) transporters, has previously been shown to successfully extend duration of anti-parkinsonian benefit of L-DOPA (ON-time), without exacerbating dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. However, UWA-101 is racemic and it is unclear whether one or both enantiomers contribute to its actions, and whether a better therapeutic effect might be attained by using a single antipode. In the current study, we synthesised the two enantiomers of UWA-101, R-101 (UWA-121) and S-101 (UWA-122), characterised their pharmacological profiles and administered them to MPTP-lesioned marmosets. Parkinsonism, dyskinesia, psychosis-like behaviours and duration of ON-time were evaluated. UWA-121 is a dual DAT > SERT inhibitor, with an approximate 10:1 DAT:SERT affinity ratio (inhibitory constants (Ki) of 307 and 3830 nM, respectively). In combination with L-DOPA, UWA-121 extended duration of ON-time when compared to L-DOPA/vehicle treatment (by 40%, P < 0.01). UWA-121 also extended duration of ON-time without dyskinesia (by 215%, P < 0.05) and ON-time without psychosis-like behaviours when compared to L-DOPA/vehicle treatment (by 345%, P < 0.01). UWA-121 did not worsen the severity of dyskinesia or psychosis-like behaviours (P > 0.05). UWA-122 is a selective SERT inhibitor (Ki 120 nM, Ki at DAT > 50 μM) and, in combination with L-DOPA, had no effect on ON-time, dyskinesia or psychosis-like behaviours (P > 0.05). These data indicate that dual DAT and SERT inhibitors effectively enhance L-DOPA anti-parkinsonian action without worsening dyskinesia and that compounds with such a pharmacological profile represent promising agents against wearing-off in PD.

  6. Alterations in Brain Monoamine Neurotransmitter Release at High Pressure

    DTIC Science & Technology

    1989-01-01

    exposure results from a general imbalance of encephalopathies. Parkinson’s Syndrome, MPTP the three monoamine neurotransmitter systems toxicity . or...the [3 H]monoamines by Dopamine release, on the other hand, was reduced synaptosomes isolated from the CNS. 5-A n 4 A Pn5 p<.05 0.05 LI * 4- U) 4...Lffect of’ pressure of 3.4-miethylenledioxy-miethamiiphetamnine ( MDMA ) and re- on the release of radioaetive glycine and (IABA from spinal lated

  7. Peripheral Serotonin: a New Player in Systemic Energy Homeostasis.

    PubMed

    Namkung, Jun; Kim, Hail; Park, Sangkyu

    2015-12-01

    Whole body energy balance is achieved through the coordinated regulation of energy intake and energy expenditure in various tissues including liver, muscle and adipose tissues. A positive energy imbalance by excessive energy intake or insufficient energy expenditure results in obesity and related metabolic diseases. Although there have been many obesity treatment trials aimed at the reduction of energy intake, these strategies have achieved only limited success because of their associated adverse effects. An ancient neurotransmitter, serotonin is among those traditional pharmacological targets for anti-obesity treatment because it exhibits strong anorectic effect in the brain. However, recent studies suggest the new functions of peripheral serotonin in energy homeostasis ranging from the endocrine regulation by gut-derived serotonin to the autocrine/paracrine regulation by adipocyte-derived serotonin. Here, we discuss the role of serotonin in the regulation of energy homeostasis and introduce peripheral serotonin as a possible target for anti-obesity treatment.

  8. [Serum serotonin in patients with tension headaches].

    PubMed

    Karaulova, Iu V; Shutov, A A

    2005-01-01

    Tension headache (TH) is one of the most frequent types of idiopathic headaches. The leading role in its pathogenesis is played by depression and dysmetabolism of the neurotransmitter serotonin. The subjects were 100 patients with TH. The examination included study of headache intensity, complex psychometric testing, and immune-enzyme measurement of serotonin serum level, performed before and after treatment with the anti-depressant prodep. All the patients had moderate pain syndrome, depression, and moderate or severe anxiety, which demonstrated negative correlation with serotonin serum level. In particular, the intensity of episodic THs (n = 24) was 52 mm visual analogue scale, reactive anxiety level was as high as 51.08 +/- 4.2, the level of depression was moderate (12.9 Beck scale); serotonin blood level showed a tendency to fall (205.72 +/- 6.74 ng/ml). In 76 patients, suffering from chronic THs with a cephalgia intensity of 62 mm visual analogue scale, high indexes of reactive and personal anxiety (46.81 -/+ 2.68 and 54.2 +/- 3.64, respectively), and high depression level were associated with a prominent decrease of serotonin blood concentration (119.38 +/- 9.42 ng/ml). A course of treatment with prodep led to significant decrease of headache intensity and improved depression, while an increase of serum serotonin level was observed. Thus, serotonin serum level may be used as a marker of pain intensity and the level of depression, and an objective indicator of anti-depressive therapy.

  9. Role of serotonin in seasonal affective disorder.

    PubMed

    Gupta, A; Sharma, P K; Garg, V K; Singh, A K; Mondal, S C

    2013-01-01

    This review was prepared with an aim to show role of serotonin in seasonal affective disorder. Seasonal affective disorder, which is also called as winter depression or winter blues, is mood disorder in which persons with normal mental health throughout most of the year will show depressive symptoms in the winter or, less commonly, in the summer. Serotonin is an important endogenous neurotransmitter which also acts as neuromodulator. The least invasive, natural, and researched treatment of seasonal affective disorder is natural or otherwise is light therapy. Negative air ionization, which acts by liberating charged particles on the sleep environment, has also become effective in treatment of seasonal affective disorder.  

  10. Salvinorin A Regulates Dopamine Transporter Function Via A Kappa Opioid Receptor and ERK1/2-Dependent Mechanism

    PubMed Central

    Kivell, Bronwyn; Uzelac, Zeljko; Sundaramurthy, Santhanalakshmi; Rajamanickam, Jeyaganesh; Ewald, Amy; Chefer, Vladimir; Jaligam, Vanaja; Bolan, Elizabeth; Simonson, Bridget; Annamalai, Balasubramaniam; Mannangatti, Padmanabhan; Prisinzano, Thomas; Gomes, Ivone; Devi, Lakshmi A.; Jayanthi, Lankupalle D.; Sitte, Harald H.; Ramamoorthy, Sammanda; Shippenberg, Toni S.

    2014-01-01

    Salvinorin A (SalA), a selective κ-opioid receptor (KOR) agonist, produces dysphoria and pro-depressant like effects. These actions have been attributed to inhibition of striatal dopamine release. The dopamine transporter (DAT) regulates dopamine transmission via uptake of released neurotransmitter. KORs are apposed to DAT in dopamine nerve terminals suggesting an additional target by which SalA modulates dopamine transmission. SalA produced a concentration-dependent, nor-binaltorphimine (BNI)- and pertussis toxin-sensitive increase of ASP+ accumulation in EM4 cells coexpressing myc-KOR and YFP-DAT, using live cell imaging and the fluorescent monoamine transporter substrate, trans 4-(4-(dimethylamino)-styryl)-N-methylpyridinium) (ASP+). Other KOR agonists also increased DAT activity that was abolished by BNI pretreatment. While SalA increased DAT activity, SalA treatment decreased serotonin transporter (SERT) activity and had no effect on norepinephrine transporter (NET) activity. In striatum, SalA increased the Vmax for DAT mediated DA transport and DAT surface expression. SalA up-regulation of DAT function is mediated by KOR activation and the KOR-linked extracellular signal regulated kinase-½ (ERK1/2) pathway. Co-immunoprecipitation and BRET studies revealed that DAT and KOR exist in a complex. In live cells, DAT and KOR exhibited robust FRET signals under basal conditions. SalA exposure caused a rapid and significant increase of the FRET signal. This suggests that the formation of KOR and DAT complexes is promoted in response to KOR activation. Together, these data suggest that enhanced DA transport and decreased DA release resulting in decreased dopamine signaling may contribute to the dysphoric and pro-depressant like effects of SalA and other KOR agonists. PMID:25107591

  11. Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism.

    PubMed

    Kivell, Bronwyn; Uzelac, Zeljko; Sundaramurthy, Santhanalakshmi; Rajamanickam, Jeyaganesh; Ewald, Amy; Chefer, Vladimir; Jaligam, Vanaja; Bolan, Elizabeth; Simonson, Bridget; Annamalai, Balasubramaniam; Mannangatti, Padmanabhan; Prisinzano, Thomas E; Gomes, Ivone; Devi, Lakshmi A; Jayanthi, Lankupalle D; Sitte, Harald H; Ramamoorthy, Sammanda; Shippenberg, Toni S

    2014-11-01

    Salvinorin A (SalA), a selective κ-opioid receptor (KOR) agonist, produces dysphoria and pro-depressant like effects. These actions have been attributed to inhibition of striatal dopamine release. The dopamine transporter (DAT) regulates dopamine transmission via uptake of released neurotransmitter. KORs are apposed to DAT in dopamine nerve terminals suggesting an additional target by which SalA modulates dopamine transmission. SalA produced a concentration-dependent, nor-binaltorphimine (BNI)- and pertussis toxin-sensitive increase of ASP(+) accumulation in EM4 cells coexpressing myc-KOR and YFP-DAT, using live cell imaging and the fluorescent monoamine transporter substrate, trans 4-(4-(dimethylamino)-styryl)-N-methylpyridinium) (ASP(+)). Other KOR agonists also increased DAT activity that was abolished by BNI pretreatment. While SalA increased DAT activity, SalA treatment decreased serotonin transporter (SERT) activity and had no effect on norepinephrine transporter (NET) activity. In striatum, SalA increased the Vmax for DAT mediated DA transport and DAT surface expression. SalA up-regulation of DAT function is mediated by KOR activation and the KOR-linked extracellular signal regulated kinase-½ (ERK1/2) pathway. Co-immunoprecipitation and BRET studies revealed that DAT and KOR exist in a complex. In live cells, DAT and KOR exhibited robust FRET signals under basal conditions. SalA exposure caused a rapid and significant increase of the FRET signal. This suggests that the formation of KOR and DAT complexes is promoted in response to KOR activation. Together, these data suggest that enhanced DA transport and decreased DA release resulting in decreased dopamine signalling may contribute to the dysphoric and pro-depressant like effects of SalA and other KOR agonists.

  12. The influence of serotonin on fear learning.

    PubMed

    Hindi Attar, Catherine; Finckh, Barbara; Büchel, Christian

    2012-01-01

    Learning of associations between aversive stimuli and predictive cues is the basis of Pavlovian fear conditioning and is driven by a mismatch between expectation and outcome. To investigate whether serotonin modulates the formation of such aversive cue-outcome associations, we used functional magnetic resonance imaging (fMRI) and dietary tryptophan depletion to reduce brain serotonin (5-HT) levels in healthy human subjects. In a Pavlovian fear conditioning paradigm, 5-HT depleted subjects compared to a non-depleted control group exhibited attenuated autonomic responses to cues indicating the upcoming of an aversive event. These results were closely paralleled by reduced aversive learning signals in the amygdala and the orbitofrontal cortex, two prominent structures of the neural fear circuit. In agreement with current theories of serotonin as a motivational opponent system to dopamine in fear learning, our data provide first empirical evidence for a role of serotonin in representing formally derived learning signals for aversive events.

  13. Beta-amyloid peptides undergo regulated co-secretion with neuropeptide and catecholamine neurotransmitters.

    PubMed

    Toneff, Thomas; Funkelstein, Lydiane; Mosier, Charles; Abagyan, Armen; Ziegler, Michael; Hook, Vivian

    2013-08-01

    Beta-amyloid (Aβ) peptides are secreted from neurons, resulting in extracellular accumulation of Aβ and neurodegeneration of Alzheimer's disease. Because neuronal secretion is fundamental for the release of neurotransmitters, this study assessed the hypothesis that Aβ undergoes co-release with neurotransmitters. Model neuronal-like chromaffin cells were investigated, and results illustrate regulated, co-secretion of Aβ(1-40) and Aβ(1-42) with peptide neurotransmitters (galanin, enkephalin, and NPY) and catecholamine neurotransmitters (dopamine, norepinephrine, and epinephrine). Regulated secretion from chromaffin cells was stimulated by KCl depolarization and nicotine. Forskolin, stimulating cAMP, also induced co-secretion of Aβ peptides with peptide and catecholamine neurotransmitters. These data suggested the co-localization of Aβ with neurotransmitters in dense core secretory vesicles (DCSV) that store and secrete such chemical messengers. Indeed, Aβ was demonstrated to be present in DCSV with neuropeptide and catecholamine transmitters. Furthermore, the DCSV organelle contains APP and its processing proteases, β- and γ-secretases, that are necessary for production of Aβ. Thus, Aβ can be generated in neurotransmitter-containing DCSV. Human IMR32 neuroblastoma cells also displayed regulated secretion of Aβ(1-40) and Aβ(1-42) with the galanin neurotransmitter. These findings illustrate that Aβ peptides are present in neurotransmitter-containing DCSV, and undergo co-secretion with neuropeptide and catecholamine neurotransmitters that regulate brain functions.

  14. Construction of cell-based neurotransmitter fluorescently engineered reporters (CNiFERs) for optical detection of neurotransmitters in vivo

    PubMed Central

    Lacin, Emre; Muller, Arnaud; Fernando, Marian; Kleinfeld, David; Slesinger, Paul A

    2016-01-01

    Cell-based neurotransmitter fluorescent engineered reporters (CNiFERs) provide a new tool for neuroscientists to optically detect the release of neurotransmitters in the brain in vivo. A specific CNiFER is created from a human embryonic kidney cell that stably expresses a specific G protein-coupled receptor, which couples to Gq/11 G proteins, and a FRET-based Ca2+-detector, TN-XXL – activation of the receptor leads to an increase in the FRET signal. Because a CNiFER clone utilizes the native receptor for a particular neurotransmitter (e.g. D2R for dopamine), it has nanomolar sensitivity and a temporal response of seconds. CNiFERs are directly implanted into the brain, enabling them to sense neurotransmitter release with a spatial resolution of less than one hundred micrometers, making them ideal to measure volume transmission in vivo. CNiFERs can also be used to screen other drugs for potential cross-reactivity in vivo. We recently expanded the family of CNiFERs to include GPCRs that couple to Gi/o G proteins. CNiFERs are available for detecting acetylcholine (ACh), dopamine (DA) and norepinephrine (NE). Given that any GPCR can be used to create a novel CNiFER and that there are approximately 800 GPCRs in the human genome, we describe here the general procedure to design, realize, and test any type of CNiFER. PMID:27214050

  15. Excitatory and Inhibitory Effects of Serotonin on Sensorimotor Reactivity Measured with Acoustic Startle

    NASA Astrophysics Data System (ADS)

    Davis, Michael; Astrachan, David I.; Kass, Elizabeth

    1980-07-01

    Serotonin infused into the lateral ventricle in rats produced a dose-dependent depression of the acoustic startle reflex. When infused onto the spinal cord, serotonin produced a dose-dependent increase in startle. Thus the same neurotransmitter can modulate the same behavior in opposite ways, depending on which part of the central nervous system is involved.

  16. Imaging dopamine receptors in the human brain by position tomography

    SciTech Connect

    Wagner, H.N. Jr.; Burns, H.D.; Dannals, R.F.; Wong, D.F.; Langstrom, B.; Duelfer, T.; Frost, J.J.; Ravert, H.T.; Links, J.M.; Rosenbloom, S.B.

    1983-01-01

    Neurotransmitter receptors may be involved in a number of neuropsychiatric disease states. The ligand 3-N-(/sup 11/C)methylspiperone, which preferentially binds to dopamine receptors in vivo, was used to image the receptors by positron emission tomography scanning in baboons and in humans. This technique holds promise for noninvasive clinical studies of dopamine receptors in humans.

  17. Hypothalamic serotonin-insulin signaling cross-talk and alterations in a type 2 diabetic model.

    PubMed

    Papazoglou, Ioannis; Berthou, Flavien; Vicaire, Nicolas; Rouch, Claude; Markaki, Eirini M; Bailbe, Danielle; Portha, Bernard; Taouis, Mohammed; Gerozissis, Kyriaki

    2012-03-05

    Serotonin and insulin are key regulators of homeostatic mechanisms in the hypothalamus. However, in type 2 diabetes, the hypothalamic responsiveness to serotonin is not clearly established. We used a diabetic model, the Goto Kakizaki (GK) rats, to explore insulin receptor expression, insulin and serotonin efficiency in the hypothalamus and liver by means of Akt phosphorylation. Insulin or dexfenfluramine (stimulator of serotonin) treatment induced Akt phosphorylation in Wistar rats but not in GK rats that exhibit down-regulated insulin receptor. Studies in a neuroblastoma cell line showed that serotonin-induced Akt phosphorylation is PI3-kinase dependent. Finally, in response to food intake, hypothalamic serotonin release was reduced in GK rats, indicating impaired responsiveness of this neurotransmitter. In conclusion, hypothalamic serotonin as insulin efficiency is impaired in diabetic GK rats. The insulin-serotonin cross-talk and impairment observed is one potential key modification in the brain during the onset of diabetes.

  18. The Role of Serotonin beyond the Central Nervous System during Embryogenesis

    PubMed Central

    Lv, Junhua; Liu, Feng

    2017-01-01

    Serotonin, or 5-hydroxytryptamine (5-HT), is a well-known neurotransmitter that plays vital roles in neural activities and social behaviors. Clinically, deficiency of serotonin is linked with many psychiatric disorders. Interestingly, a large proportion of serotonin is also produced outside the central nervous system (CNS). There is increasing evidence demonstrating important roles of serotonin in the peripheral tissues. Here, we will describe the multiple biological functions of serotonin in hematopoietic system, such as development of hematopoietic stem and progenitor cells (HSPCs), differentiation of hematopoietic cells, maintenance of vascular system, and relationship with hematological diseases. The roles of serotonin in inflammatory responses mediated by hematopoietic cells as well as in liver regeneration are also discussed. Our recent understandings of the impact of serotonin on hematopoietic system, immune responses, and tissue regeneration support utilization of serotonin as a potential therapeutic target for the treatment of hematological diseases and organ repair in clinic. PMID:28348520

  19. Serotonin Transporter and Receptor Expression in Osteocytic MLO-Y4 Cells

    PubMed Central

    BLIZIOTES, M.; ESHLEMAN, A.; BURT-PICHAT, B.; ZHANG, X.-W.; HASHIMOTO, J.; WIREN, K.; CHENU, C.

    2006-01-01

    Neurotransmitter regulation of bone metabolism has been a subject of increasing interest and investigation. We reported previously that osteoblastic cells express a functional serotonin (5-HT) signal transduction system, with mechanisms for responding to and regulating uptake of 5-HT. The clonal murine osteocytic cell line, MLO-Y4, demonstrates expression of the serotonin transporter (5-HTT), and the 5-HT1A, and 5-HT2A receptors by real-time RT-PCR and immunoblot analysis. Immunohistochemistry using antibodies for the 5-HTT, and the 5-HT1A and 5-HT2A receptors reveals expression of all three proteins in both osteoblasts and osteocytes in rat tibia. 5-HTT binding sites were demonstrated in the MLO-Y4 cells with nanomolar affinity for the stable cocaine analog [125I]RTI-55. Imipramine and fluoxetine, antagonists with specificity for 5-HTT, show the highest potency to antagonize [125I]RTI-55 binding in the MLO-Y4 cells. GBR-12935, a relatively selective dopamine transporter antagonist, had a much lower potency, as did desipramine, a selective norepinephrine transporter antagonist. The maximal [3H]5-HT uptake rate in MLO-Y4 cells was 2.85 pmol/15 min/well, with a Km value of 290 nM. Imipramine and fluoxetine inhibited specific [3H]5-HT uptake with IC50 values in the nanomolar range. 5-HT rapidly stimulated PGE2 release from MLO-Y4 cells; the EC50 for 5-HT was 0.1 μM, with a 3-fold increase seen at 60 min. The rate limiting enzyme for serotonin synthesis, tryptophan hydroxylase, is expressed in MLO-Y4 cells as well as osteoblastic MC3T3-E1 cells. Thus, osteocytes, as well as osteoblasts, are capable of 5-HT synthesis, and express functional receptor and transporter components of the 5-HT signal transduction system. PMID:16884969

  20. Dirty electricity, chronic stress, neurotransmitters and disease.

    PubMed

    Milham, Samuel; Stetzer, David

    2013-12-01

    Dirty electricity, also called electrical pollution, is high-frequency voltage transients riding along the 50 or 60 Hz electricity provided by the electric utilities. It is generated by arcing, by sparking and by any device that interrupts current flow, especially switching power supplies. It has been associated with cancer, diabetes and attention deficit hyperactivity disorder in humans. Epidemiological evidence also links dirty electricity to most of the diseases of civilization including cancer, cardiovascular disease, diabetes and suicide, beginning at the turn of the twentieth century. The dirty electricity level in a public library was reduced from over 10 000 Graham/Stetzer (G/S) units to below 50 G/S units by installing plug-in capacitive filters. Before cleanup, the urinary dopamine level of only one of seven volunteers was within normal levels, while four of seven phenylethylamine levels were normal. After an initial decline, over the next 18 weeks the dopamine levels gradually increased to an average of over 215 μg/g creatinine, which is well above 170 μg/g creatinine, the high normal level for the lab. Average phenylethylamine levels also rose gradually to slightly above 70 μg/g creatinine, the high normal level for the lab. Neurotransmitters may be biomarkers for dirty electricity and other electromagnetic field exposures. We believe that dirty electricity is a chronic stressor of electrified populations and is responsible for many of their disease patterns.

  1. Analysis of 17 neurotransmitters, metabolites and precursors in zebrafish through the life cycle using ultrahigh performance liquid chromatography-tandem mass spectrometry.

    PubMed

    Santos-Fandila, A; Vázquez, E; Barranco, A; Zafra-Gómez, A; Navalón, A; Rueda, R; Ramírez, M

    2015-09-15

    An ultrahigh performance liquid chromatography-tandem mass spectrometry method for the identification and quantification of neurotransmitters, metabolites and precursors at different stages in zebrafish life was developed. Betaine, glutamine, glutamic acid, γ-aminobutyric acid, phosphocholine, glycerophosphocholine, cytidine 5'-diphosphocholine, choline, acetylcholine, dopamine, norepinephrine, serotonin, tyrosine, epinephrine, tryptophan, 5-hydroxyindolacetic acid and agmatine were selected as analytes. The method consisted of a simple deproteinization of samples using methanol and formic acid, subsequent injection onto the chromatographic equipment and quantification with a triple quadrupole mass spectrometer detector using an electrospray ionization interface in positive mode. Limits of detection ranged from 0.02 to 11ngmL(-1) and limits of quantification from 0.1 to 38ngmL(-1), depending on the analyte. The method was validated according to US Food and Drugs Administration (FDA) guideline for bioanalytical assays. Precision, expressed as relative standard deviation (%RSD), was lower than 15% in all cases, and the determination coefficient (R(2)) was equal or higher than 99.0% with a residual deviation for each calibration point lower than ±25%. Mean recoveries were between 85% and 115%. The method was applied to determine of these compounds in zebrafish from early stages of development to adulthood and showed the time-course of neurotransmitters and others neurocompounds through the life cycle. The possibility of measuring up to 17 compounds related with the main neurotransmitter systems in a simple analytical method will complement and reinforce the use of zebrafish in multiple applications in the field of neurosciences. The proposed method will facilitate future studies related with brain development.

  2. Head-to-head comparisons of carbon fiber microelectrode coatings for sensitive and selective neurotransmitter detection by voltammetry.

    PubMed

    Singh, Yogesh S; Sawarynski, Lauren E; Dabiri, Pasha D; Choi, Wonwoo R; Andrews, Anne M

    2011-09-01

    Voltammetry is widely used to investigate neurotransmission and other biological processes but is limited by poor chemical selectivity and fouling of commonly used carbon fiber microelectrodes (CFMs). We performed direct comparisons of three key coating materials purported to impart selectivity and fouling resistance to electrodes: Nafion, base-hydrolyzed cellulose acetate (BCA), and fibronectin. We systematically evaluated the impact on a range of electrode parameters. Fouling due to exposure to brain tissue was investigated using an approach that minimizes the use of animals while enabling evaluation of statistically significant populations of electrodes. We find that BCA is relatively fouling-resistant. Moreover, detection at BCA-coated CFMs can be tuned by altering hydrolysis times to minimize the impact on sensitivity losses while maintaining fouling resistance. Fibronectin coating is associated with moderate losses in sensitivity after coating and fouling. Nafion imparts increased sensitivity for dopamine and norepinephrine but not serotonin, as well as the anticipated selectivity for cationic neurotransmitters over anionic metabolites. Although Nafion has been suggested to resist fouling, both dip-coating and electrodeposition of Nafion are associated with substantial fouling, similar to levels observed at bare electrodes after exposure to brain tissue. Direct comparisons of these coatings identified unique electroanalytical properties of each that can be used to guide selection tailored to the goals and environment of specific studies.

  3. The roles of peripheral serotonin in metabolic homeostasis.

    PubMed

    El-Merahbi, Rabih; Löffler, Mona; Mayer, Alexander; Sumara, Grzegorz

    2015-07-08

    Metabolic homeostasis in the organism is assured both by the nervous system and by hormones. Among a plethora of hormones regulating metabolism, serotonin presents a number of unique features. Unlike classical hormones serotonin is produced in different anatomical locations. In brain it acts as a neurotransmitter and in the periphery it can act as a hormone, auto- and/or paracrine factor, or intracellular signaling molecule. Serotonin does not cross the blood-brain barrier; therefore the two major pools of this bioamine remain separated. Although 95% of serotonin is produced in the periphery, its functions have been ignored until recently. Here we review the impact of the peripheral serotonin on the regulation of function of the organs involved in glucose and lipid homeostasis.

  4. Effects of Postnatal Serotonin Agonism on Fear Response and Memory

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The neurotransmitter serotonin (5-HT) also acts as a neurogenic compound in the developing brain. Early administration of a 5-HT agonist could alter the development of the serotonergic circuitry, altering behaviors mediated by 5-HT signaling, such as memory, fear and aggression. White leghorn chicks...

  5. Neurotransmitters of the suprachiasmatic nuclei

    PubMed Central

    Reghunandanan, Vallath; Reghunandanan, Rajalaxmy

    2006-01-01

    There has been extensive research in the recent past looking into the molecular basis and mechanisms of the biological clock, situated in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. Neurotransmitters are a very important component of SCN function. Thorough knowledge of neurotransmitters is not only essential for the understanding of the clock but also for the successful manipulation of the clock with experimental chemicals and therapeutical drugs. This article reviews the current knowledge about neurotransmitters in the SCN, including neurotransmitters that have been identified only recently. An attempt was made to describe the neurotransmitters and hormonal/diffusible signals of the SCN efference, which are necessary for the master clock to exert its overt function. The expression of robust circadian rhythms depends on the integrity of the biological clock and on the integration of thousands of individual cellular clocks found in the clock. Neurotransmitters are required at all levels, at the input, in the clock itself, and in its efferent output for the normal function of the clock. The relationship between neurotransmitter function and gene expression is also discussed because clock gene transcription forms the molecular basis of the clock and its working. PMID:16480518

  6. Macrocyclic Gd(3+) complexes with pendant crown ethers designed for binding zwitterionic neurotransmitters.

    PubMed

    Oukhatar, Fatima; Meudal, Hervé; Landon, Céline; Logothetis, Nikos K; Platas-Iglesias, Carlos; Angelovski, Goran; Tóth, Éva

    2015-07-27

    A series of Gd(3+) complexes exhibiting a relaxometric response to zwitterionic amino acid neurotransmitters was synthesized. The design concept involves ditopic interactions 1) between a positively charged and coordinatively unsaturated Gd(3+) chelate and the carboxylate group of the neurotransmitters and 2) between an azacrown ether appended to the chelate and the amino group of the neurotransmitters. The chelates differ in the nature and length of the linker connecting the cyclen-type macrocycle that binds the Ln(3+) ion and the crown ether. The complexes are monohydrated, but they exhibit high proton relaxivities (up to 7.7 mM(-1)  s(-1) at 60 MHz, 310 K) due to slow molecular tumbling. The formation of ternary complexes with neurotransmitters was monitored by (1) H relaxometric titrations of the Gd(3+) complexes and by luminescence measurements on the Eu(3+) and Tb(3+) analogues at pH 7.4. The remarkable relaxivity decrease (≈80 %) observed on neurotransmitter binding is related to the decrease in the hydration number, as evidenced by luminescence lifetime measurements on the Eu(3+) complexes. These complexes show affinity for amino acid neurotransmitters in the millimolar range, which can be suited to imaging concentrations of synaptically released neurotransmitters. They display good selectivity over non-amino acid neurotransmitters (acetylcholine, serotonin, and noradrenaline) and hydrogenphosphate, but selectivity over hydrogencarbonate was not achieved.

  7. Determination of monoamine and amino acid neurotransmitters and their metabolites in rat brain samples by UFLC-MS/MS for the study of the sedative-hypnotic effects observed during treatment with S. chinensis.

    PubMed

    Wei, Binbin; Li, Qing; Fan, Ronghua; Su, Dan; Chen, Xiaohui; Jia, Ying; Bi, Kaishun

    2014-01-01

    Schisandra chinensis (Turcz.) Baill. has been used as a sedative and hypnotic agent in traditional Chinese medicine for centuries. The purpose of this study was to reveal the influence of insomnia on the levels of the neurotransmitters: glutamate (Glu), γ-aminobutyric acid (GABA), noradrenaline (NE), dopamine (DA), serotonin (5-HT) and their metabolites (5-HIAA, DOPAC and HVA), and to study the role of S. chinensis in the treatment of insomnia. To achieve this goal, an efficient, sensitive and selective method was developed and validated for the simultaneous determination of these five neurotransmitters and their metabolites in rat brain samples using ultra fast liquid chromatography/tandem mass spectrometry (UFLC-MS/MS). The analysis was performed on a Synergi Fusion-RP 80A ODS column (150mm×2.0mm, 4.0μm) using gradient elution, with the mobile phase consisting of acetonitrile and 0.05% formic acid in water. The method was validated using rat brain homogenate samples and showed a good linearity over a wide concentration range (r(2)>0.99) with a lower limit of quantification (LLOQ) at 4-16ngmL(-1). The intra and inter-day assay variability was less than 15% for all analytes. The results indicated that the condition of insomnia elevated GABA, NE, DA, DOPAC and HVA, and reduced 5-HT, 5-HIAA levels in rat brain. The oral administration of S. chinensis (7.5gkg(-1)day(-1), eight days) influenced insomnia by significantly increasing or reducing the levels of the neurotransmitters parameters mentioned above. These results suggested that S. chinensis could alter the levels of these brain neurotransmitters and their metabolites through its sedative-hypnotic effects.

  8. Metabolomics Approach Reveals Integrated Metabolic Network Associated with Serotonin Deficiency

    NASA Astrophysics Data System (ADS)

    Weng, Rui; Shen, Sensen; Tian, Yonglu; Burton, Casey; Xu, Xinyuan; Liu, Yi; Chang, Cuilan; Bai, Yu; Liu, Huwei

    2015-07-01

    Serotonin is an important neurotransmitter that broadly participates in various biological processes. While serotonin deficiency has been associated with multiple pathological conditions such as depression, schizophrenia, Alzheimer’s disease and Parkinson’s disease, the serotonin-dependent mechanisms remain poorly understood. This study therefore aimed to identify novel biomarkers and metabolic pathways perturbed by serotonin deficiency using metabolomics approach in order to gain new metabolic insights into the serotonin deficiency-related molecular mechanisms. Serotonin deficiency was achieved through pharmacological inhibition of tryptophan hydroxylase (Tph) using p-chlorophenylalanine (pCPA) or genetic knockout of the neuronal specific Tph2 isoform. This dual approach improved specificity for the serotonin deficiency-associated biomarkers while minimizing nonspecific effects of pCPA treatment or Tph2 knockout (Tph2-/-). Non-targeted metabolic profiling and a targeted pCPA dose-response study identified 21 biomarkers in the pCPA-treated mice while 17 metabolites in the Tph2-/- mice were found to be significantly altered compared with the control mice. These newly identified biomarkers were associated with amino acid, energy, purine, lipid and gut microflora metabolisms. Oxidative stress was also found to be significantly increased in the serotonin deficient mice. These new biomarkers and the overall metabolic pathways may provide new understanding for the serotonin deficiency-associated mechanisms under multiple pathological states.

  9. Role of Serotonin via 5-HT2B Receptors in the Reinforcing Effects of MDMA in Mice

    PubMed Central

    Doly, Stéphane; Bertran-Gonzalez, Jesus; Callebert, Jacques; Bruneau, Alexandra; Banas, Sophie Marie; Belmer, Arnauld; Boutourlinsky, Katia; Hervé, Denis; Launay, Jean-Marie; Maroteaux, Luc

    2009-01-01

    The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) reverses dopamine and serotonin transporters to produce efflux of dopamine and serotonin, respectively, in regions of the brain that have been implicated in reward. However, the role of serotonin/dopamine interactions in the behavioral effects of MDMA remains unclear. We previously showed that MDMA-induced locomotion, serotonin and dopamine release are 5-HT2B receptor-dependent. The aim of the present study was to determine the contribution of serotonin and 5-HT2B receptors to the reinforcing properties of MDMA. We show here that 5-HT2B−/− mice do not exhibit behavioral sensitization or conditioned place preference following MDMA (10 mg/kg) injections. In addition, MDMA-induced reinstatement of conditioned place preference after extinction and locomotor sensitization development are each abolished by a 5-HT2B receptor antagonist (RS127445) in wild type mice. Accordingly, MDMA-induced dopamine D1 receptor-dependent phosphorylation of extracellular regulated kinase in nucleus accumbens is abolished in mice lacking functional 5-HT2B receptors. Nevertheless, high doses (30 mg/kg) of MDMA induce dopamine-dependent but serotonin and 5-HT2B receptor-independent behavioral effects. These results underpin the importance of 5-HT2B receptors in the reinforcing properties of MDMA and illustrate the importance of dose-dependent effects of MDMA on serotonin/dopamine interactions. PMID:19956756

  10. Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

    PubMed Central

    Alex, K.D.; Pehek, E.A.

    2007-01-01

    The neurotransmitter dopamine (DA) has a long association with normal functions such as motor control, cognition, and reward, as well as a number of syndromes including drug abuse, schizophrenia, and Parkinson’s disease. Studies show that serotonin (5-HT) acts through several 5-HT receptors in the brain to modulate DA neurons in all three major dopaminergic pathways. There are at least 14 5-HT receptor subtypes, many of which have been shown to play some role in mediating 5-HT/DA interactions. Several subtypes, including the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4 receptors, act to facilitate DA release, while the 5-HT2C receptor mediates an inhibitory effect of 5-HT on DA release. Most 5-HT receptor subtypes only modulate DA release when 5-HT and/or DA neurons are stimulated, but the 5-HT2C receptor, characterized by high levels of constitutive activity, inhibits tonic as well as evoked DA release. This review summarizes the anatomical evidence for the presence of each 5-HT receptor subtype in dopaminergic regions of the brain and the neuropharmacological evidence demonstrating regulation of each DA pathway. The relevance of 5-HT receptor modulation of DA systems to the development of therapeutics used to treat schizophrenia, depression, and drug abuse is discussed. Lastly, areas are highlighted in which future research would be maximally beneficial to the treatment of these disorders. PMID:17049611

  11. Gene × environment effects of serotonin transporter, dopamine receptor D4, and monoamine oxidase A genes with contextual and parenting risk factors on symptoms of oppositional defiant disorder, anxiety, and depression in a community sample of 4-year-old children.

    PubMed

    Lavigne, John V; Herzing, Laura B K; Cook, Edwin H; Lebailly, Susan A; Gouze, Karen R; Hopkins, Joyce; Bryant, Fred B

    2013-05-01

    Genetic factors can play a key role in the multiple level of analyses approach to understanding the development of child psychopathology. The present study examined gene-environment correlations and gene × environment interactions for polymorphisms of three target genes, the serotonin transporter gene, the D4 dopamine receptor gene, and the monoamine oxidase A gene in relation to symptoms of anxiety, depression, and oppositional behavior. Saliva samples were collected from 175 non-Hispanic White, 4-year-old children. Psychosocial risk factors included socioeconomic status, life stress, caretaker depression, parental support, hostility, and scaffolding skills. In comparison with the short forms (s/s, s/l) of the serotonin transporter linked polymorphic repeat, the long form (l/l) was associated with greater increases in symptoms of oppositional defiant disorder in interaction with family stress and with greater increases in symptoms of child depression and anxiety in interaction with caretaker depression, family conflict, and socioeconomic status. In boys, low-activity monoamine oxidase A gene was associated with increases in child anxiety and depression in interaction with caretaker depression, hostility, family conflict, and family stress. The results highlight the important of gene-environment interplay in the development of symptoms of child psychopathology in young children.

  12. Treatment with Tyrosine a Neurotransmitter Precursor Reduces Environmental Stress in Humans

    DTIC Science & Technology

    1989-01-01

    brain norepinephrine and dopamine. catecholaminergic neurotransmitters. In animals, administration of tyrosine, a food constituent and precursor of the...Profile of Mood States. Stanford Sleepiness Scale) ENVIRONMENTAL STRESSORS that have been employed to evaluate a variety of psychoactive drugs foods ... tyramine . However. Plasma tyrosine levels were significantly elevated during behav- this amine is not detectable in the plasma of animals after they

  13. Snapshot of antidepressants at work: the structure of neurotransmitter transporter proteins.

    PubMed

    Cuboni, Serena; Hausch, Felix

    2014-05-12

    In the sweet spot: Cocrystal structures of engineered neurotransmitter transporters reveal the binding mode of commonly prescribed antidepressants, providing a basis for a rational drug design for this class of proteins. The picture shows the structure of the dopamine transporter of Drosophila melanogaster in complex with the antidepressant nortriptyline.

  14. Glycogen Synthase Kinase-3 is an Intermediate Modulator of Serotonin Neurotransmission

    PubMed Central

    Polter, Abigail M.; Li, Xiaohua

    2011-01-01

    Serotonin is a neurotransmitter with broad functions in brain development, neuronal activity, and behaviors; and serotonin is the prominent drug target in several major neuropsychiatric diseases. The multiple actions of serotonin are mediated by diverse serotonin receptor subtypes and associated signaling pathways. However, the key signaling components that mediate specific function of serotonin neurotransmission have not been fully identified. This review will provide evidence from biochemical, pharmacological, and animal behavioral studies showing that serotonin regulates the activation states of brain glycogen synthase kinase-3 (GSK3) via type 1 and type 2 serotonin receptors. In return, GSK3 directly interacts with serotonin receptors in a highly selective manner, with a prominent effect on modulating serotonin 1B receptor activity. Therefore, GSK3 acts as an intermediate modulator in the serotonin neurotransmission system, and balanced GSK3 activity is essential for serotonin-regulated brain function and behaviors. Particularly important, several classes of serotonin-modulating drugs, such as antidepressants and atypical antipsychotics, regulate GSK3 by inhibiting its activity in brain, which reinforces the importance of GSK3 as a potential therapeutic target in neuropsychiatric diseases associated with abnormal serotonin function. PMID:22028682

  15. Schizophrenia-like disruptions of sensory gating by serotonin receptor stimulation in rats: effect of MDMA, DOI and 8-OH-DPAT.

    PubMed

    Thwaites, Shane J; Gogos, Andrea; Van den Buuse, Maarten

    2013-11-01

    Schizophrenia pathophysiology is associated with alterations in several neurotransmitter systems, particularly dopamine, glutamate and serotonin (5-HT). Schizophrenia patients also have disruptions in sensory gating, a brain information filtering mechanism in response to repeated sensory stimuli. Dopamine and glutamate have been implicated in sensory gating; however, little is known about the contribution of serotonin. We therefore investigated the effects of several psychoactive compounds that alter serotonergic neuronal activity on event-related potentials (ERP) to paired auditory pulses. Male Sprague-Dawley rats were implanted with cortical surface electrodes to measure ERPs to 150 presentations of two 85 dB bursts of white noise, 500 ms apart (S1 and S2). Saline-treated animals suppressed the response to S2 to less than 50% of S1. In contrast, treatment with the serotonin releaser, MDMA (ecstasy; 2.0mg/kg), the 5-HT2A/2C receptor agonist, DOI (0.5mg/kg), or the 5-HT1A/7 receptor agonist, 8-OH-DPAT (0.5mg/kg), caused an increase in S2/S1 ratios. Analysis of waveform components suggested that the S2/S1 ratio disruption by MDMA was due to subtle effects on the ERPs to S1 and S2; DOI caused the disruption primarily by reducing the ERP to S1; 8-OH-DPAT-induced disruptions were due to an increase in the ERP to S2. These results show that 5-HT receptor stimulation alters S2/S1 ERP ratios in rats. These results may help to elucidate the sensory gating deficits observed in schizophrenia patients.

  16. Effects of cognitive-behavioral therapy on Eating Disorders: neurotransmitter secretory response to treatment.

    PubMed

    Brambilla, F; Dalle Grave, R; Calugi, S; Marchesini, G; Baroni, S; Marazziti, D

    2010-06-01

    The effects of cognitive-behavioral therapy (CBT) on central dopamine (DA), noradrenaline (NE) and serotonin (5-HT) secretion were studied in a group of 50 female inpatients, of which 14 suffered from anorexia nervosa restricted type (AN-R), 14 from anorexia nervosa bingeing-purging type (AN-BP), and 22 from bulimia nervosa (BN). The aim of the study was to see whether or not CBT modifies the secretion of central DA (blood homovanillic acid=HVA), NE (blood 3-methoxy-4-hydroxy-phenylglycol=MHPG) and the 5-HT transporter (as evaluated by the platelet paroxetine binding=[(3)H]-Par-binding), if the physical and psychological effects of CBT correlate with changes of the neurotransmitter secretion; and if the biological effects of CBT are linked to specific psychopathological aspect of the disorders. The treatment lasted 20 weeks. Body-mass Index, bingeing and purging, specific AN-BN psychopathological (EDE 12-OD), depression (Beck Inventory), anxiety (STAY Form-Y-1), impulsiveness (Barratt Impulsiveness Scale), self-esteem (Rosenberg Self-Biochemical Scale) and temperament (Temperament and Character Inventory, Cloninger Scale) were assessed at baseline and at the end of the treatment. CBT significantly improved the psychophysical aspects of the diseases. HVA and MHPG concentrations did not change. The [(3)H]-Par-binding parameters, the maximum binding capacity (B(max)) and dissociation constant (K(d)) values did not change in either AN-R or AN-BP patients, while the [(3)H]-Par B(max) (and not the K(d)) increased significantly in BN patients. Correlations emerged between basal and final [(3)H]-Par B(max) values and psychopathological scores, but not between CBT-induced differences between basal and final values. Our data suggest that only in BN CBT may act through changes in 5-HT system function.

  17. Serotonin-immunoreactive sensory neurons in the antenna of the cockroach Periplaneta americana.

    PubMed

    Watanabe, Hidehiro; Shimohigashi, Miki; Yokohari, Fumio

    2014-02-01

    The antennae of insects contain a vast array of sensory neurons that process olfactory, gustatory, mechanosensory, hygrosensory, and thermosensory information. Except those with multimodal functions, most sensory neurons use acetylcholine as a neurotransmitter. Using immunohistochemistry combined with retrograde staining of antennal sensory neurons in the cockroach Periplaneta americana, we found serotonin-immunoreactive sensory neurons in the antenna. These were selectively distributed in chaetic and scolopidial sensilla and in the scape, the pedicel, and first 15 segments of the flagellum. In a chaetic sensillum, A single serotonin-immunoreactive sensory neuron cohabited with up to four serotonin-negative sensory neurons. Based on their morphological features, serotonin-immunopositive and -negative sensory neurons might process mechanosensory and contact chemosensory modalities, respectively. Scolopidial sensilla constitute the chordotonal and Johnston's organs within the pedicel and process antennal vibrations. Immunoelectron microscopy clearly revealed that serotonin-immunoreactivities selectively localize to a specific type of mechanosensory neuron, called type 1 sensory neuron. In a chordotonal scolopidial sensillum, a serotonin-immunoreactive type 1 neuron always paired with a serotonin-negative type 1 neuron. Conversely, serotonin-immunopositive and -negative type 1 neurons were randomly distributed in Johnston's organ. In the deutocerebrum, serotonin-immunoreactive sensory neuron axons formed three different sensory tracts and those from distinct types of sensilla terminated in distinct brain regions. Our findings indicate that a biogenic amine, serotonin, may act as a neurotransmitter in peripheral mechanosensory neurons.

  18. Serotonin modulation of cortical neurons and networks

    PubMed Central

    Celada, Pau; Puig, M. Victoria; Artigas, Francesc

    2013-01-01

    The serotonergic pathways originating in the dorsal and median raphe nuclei (DR and MnR, respectively) are critically involved in cortical function. Serotonin (5-HT), acting on postsynaptic and presynaptic receptors, is involved in cognition, mood, impulse control and motor functions by (1) modulating the activity of different neuronal types, and (2) varying the release of other neurotransmitters, such as glutamate, GABA, acetylcholine and dopamine. Also, 5-HT seems to play an important role in cortical development. Of all cortical regions, the frontal lobe is the area most enriched in serotonergic axons and 5-HT receptors. 5-HT and selective receptor agonists modulate the excitability of cortical neurons and their discharge rate through the activation of several receptor subtypes, of which the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT3 subtypes play a major role. Little is known, however, on the role of other excitatory receptors moderately expressed in cortical areas, such as 5-HT2C, 5-HT4, 5-HT6, and 5-HT7. In vitro and in vivo studies suggest that 5-HT1A and 5-HT2A receptors are key players and exert opposite effects on the activity of pyramidal neurons in the medial prefrontal cortex (mPFC). The activation of 5-HT1A receptors in mPFC hyperpolarizes pyramidal neurons whereas that of 5-HT2A receptors results in neuronal depolarization, reduction of the afterhyperpolarization and increase of excitatory postsynaptic currents (EPSCs) and of discharge rate. 5-HT can also stimulate excitatory (5-HT2A and 5-HT3) and inhibitory (5-HT1A) receptors in GABA interneurons to modulate synaptic GABA inputs onto pyramidal neurons. Likewise, the pharmacological manipulation of various 5-HT receptors alters oscillatory activity in PFC, suggesting that 5-HT is also involved in the control of cortical network activity. A better understanding of the actions of 5-HT in PFC may help to develop treatments for mood and cognitive disorders associated with an abnormal function of the frontal lobe

  19. Serotonin modulation of cortical neurons and networks.

    PubMed

    Celada, Pau; Puig, M Victoria; Artigas, Francesc

    2013-01-01

    The serotonergic pathways originating in the dorsal and median raphe nuclei (DR and MnR, respectively) are critically involved in cortical function. Serotonin (5-HT), acting on postsynaptic and presynaptic receptors, is involved in cognition, mood, impulse control and motor functions by (1) modulating the activity of different neuronal types, and (2) varying the release of other neurotransmitters, such as glutamate, GABA, acetylcholine and dopamine. Also, 5-HT seems to play an important role in cortical development. Of all cortical regions, the frontal lobe is the area most enriched in serotonergic axons and 5-HT receptors. 5-HT and selective receptor agonists modulate the excitability of cortical neurons and their discharge rate through the activation of several receptor subtypes, of which the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT3 subtypes play a major role. Little is known, however, on the role of other excitatory receptors moderately expressed in cortical areas, such as 5-HT2C, 5-HT4, 5-HT6, and 5-HT7. In vitro and in vivo studies suggest that 5-HT1A and 5-HT2A receptors are key players and exert opposite effects on the activity of pyramidal neurons in the medial prefrontal cortex (mPFC). The activation of 5-HT1A receptors in mPFC hyperpolarizes pyramidal neurons whereas that of 5-HT2A receptors results in neuronal depolarization, reduction of the afterhyperpolarization and increase of excitatory postsynaptic currents (EPSCs) and of discharge rate. 5-HT can also stimulate excitatory (5-HT2A and 5-HT3) and inhibitory (5-HT1A) receptors in GABA interneurons to modulate synaptic GABA inputs onto pyramidal neurons. Likewise, the pharmacological manipulation of various 5-HT receptors alters oscillatory activity in PFC, suggesting that 5-HT is also involved in the control of cortical network activity. A better understanding of the actions of 5-HT in PFC may help to develop treatments for mood and cognitive disorders associated with an abnormal function of the frontal lobe.

  20. Convergent Pathways for Steroid Hormone-and Neurotransmitter-Induced Rat Sexual Behavior

    NASA Astrophysics Data System (ADS)

    Mani, S. K.; Allen, J. M. C.; Clark, J. H.; Blaustein, J. D.; O'Malley, B. W.

    1994-08-01

    Estrogen and progesterone modulate gene expression in rodents by activation of intracellular receptors in the hypothalamus, which regulate neuronal networks that control female sexual behavior. However, the neurotransmitter dopamine has been shown to activate certain steroid receptors in a ligand-independent manner. A dopamine receptor stimulant and a D_1 receptor agonist, but not a D_2 receptor agonist, mimicked the effects of progesterone in facilitating sexual behavior in female rats. The facilitatory effect of the neurotransmitter was blocked by progesterone receptor antagonists, a D_1 receptor antagonist, or antisense oligonucleotides to the progesterone receptor. The results suggest that in rodents neurotransmitters may regulate in vivo gene expression and behavior by means of cross-talk with steroid receptors in the brain.

  1. Grafted dopamine neurons: Morphology, neurochemistry, and electrophysiology.

    PubMed

    Strömberg, Ingrid; Bickford, Paula; Gerhardt, Greg A

    2010-02-09

    Grafting of dopamine-rich tissue to counteract the symptoms in Parkinson's disease became a promising tool for future treatment. This article discusses how to improve the functional outcome with respect to graft outgrowth and functions of dopamine release and electrophysiological responses to graft implantation in the host brain striatal target. It has been documented that a subpopulation of the dopamine neurons innervates the host brain in a target-specific manner, while some of the grafted dopamine neurons never project to the host striatum. Neurochemical studies have demonstrated that the graft-induced outgrowth synthesize, store, metabolize and release dopamine and possibly other neurotransmitters such as 5-HT. Furthermore, the released dopamine affects the dopamine-depleted brain in areas that are larger than the graft-derived nerve fibers reach. While stem cells will most likely be the future source of cells to be used in grafting, it is important to find the guiding cues for how to reinnervate the dopamine-depleted striatum in a proper way with respect to the dopamine subpopulations of A9 and A10 to efficiently treat the motor abnormalities seen in Parkinson's disease.

  2. Hydrophilic interaction chromatography combined with dispersive liquid-liquid microextraction as a preconcentration tool for the simultaneous determination of the panel of underivatized neurotransmitters in human urine samples.

    PubMed

    Konieczna, Lucyna; Roszkowska, Anna; Niedźwiecki, Maciej; Bączek, Tomasz

    2016-01-29

    A simple and sensitive method using dispersive liquid-liquid microextraction (DLLME) followed by liquid chromatography coupled to mass spectrometry (LC-MS) with a hydrophilic interaction chromatography (HILIC) column was developed for the simultaneous determination of 13 compounds of different polarities, comprising monoamine neurotransmitters (dopamine, norepinephrine, epinephrine and serotonin) along with their respective precursors and metabolites, in human urine samples. The microextraction procedure was based on the fast injection of a mixture of ethanol (disperser solvent) and dichloromethane (extraction solvent) into a human urine sample, forming a cloudy solution in the Eppendorf tube. After centrifugation, the sedimented phase was collected and subsequently analyzed by LC-HILIC-MS in about 12min without a derivatization step. The separation was performed on an XBridge Amide™ BEH column 3.0×100mm, 3.5mm and the mobile phase consisted of phase A: 10mM ammonium formate buffer in water pH 3.0 and phase B: 10 mM ammonium formate buffer in acetonitrile, under gradient program elution. Tyrosine, tryptophan, 5-hydroxytryptophan, dopamine, epinephrine, norepinephrine, serotonin, 3-methoxytyramine, 5-hydroxyindole-3-acetic acid, 3,4-dihydroxy-l-phenylalanine and norvaline (internal standard) were detected in the positive ionization mode. While vanillylmandelic acid, homovanillic acid, 3,4-dihydroxyphenylacetic acid and 3,4-dihydroxybenzylamine (internal standard) were detected in the negative ionization mode. Parameters influencing DLLME and LC-HILIC-MS were investigated. Under the optimum conditions, the proposed method exhibited a low detection limit (5-10ngmL(-1)), and good linearity with R between 0.9991 and 0.9998. The recoveries in human urine samples were 99.0%±3.6%. for the 13 studied biogenic amines with intra- and inter-day RSDs of 0.24-9.55% and 0.31-10.0%, respectively. The developed DLLME-LC-MS method could be successfully applied for the

  3. Common drugs inhibit human organic cation transporter 1 (OCT1)-mediated neurotransmitter uptake.

    PubMed

    Boxberger, Kelli H; Hagenbuch, Bruno; Lampe, Jed N

    2014-06-01

    The human organic cation transporter 1 (OCT1) is a polyspecific transporter involved in the uptake of positively charged and neutral small molecules in the liver. To date, few endogenous compounds have been identified as OCT1 substrates; more importantly, the effect of drugs on endogenous substrate transport has not been examined. In this study, we established monoamine neurotransmitters as substrates for OCT1, specifically characterizing serotonin transport in human embryonic kidney 293 cells. Kinetic analysis yielded a Km of 197 micomolar and a Vmax of 561 pmol/mg protein/minute for serotonin. Furthermore, we demonstrated that serotonin uptake was inhibited by diphenhydramine, fluoxetine, imatinib, and verapamil, with IC50 values in the low micromolar range. These results were recapitulated in primary human hepatocytes, suggesting that OCT1 plays a significant role in hepatic elimination of serotonin and that xenobiotics may alter the elimination of endogenous compounds as a result of interactions at the transporter level.

  4. Substrate-modulated gating dynamics in a Na+-coupled neurotransmitter transporter homologue.

    PubMed

    Zhao, Yongfang; Terry, Daniel S; Shi, Lei; Quick, Matthias; Weinstein, Harel; Blanchard, Scott C; Javitch, Jonathan A

    2011-06-02

    Neurotransmitter/Na(+) symporters (NSSs) terminate neuronal signalling by recapturing neurotransmitter released into the synapse in a co-transport (symport) mechanism driven by the Na(+) electrochemical gradient. NSSs for dopamine, noradrenaline and serotonin are targeted by the psychostimulants cocaine and amphetamine, as well as by antidepressants. The crystal structure of LeuT, a prokaryotic NSS homologue, revealed an occluded conformation in which a leucine (Leu) and two Na(+) are bound deep within the protein. This structure has been the basis for extensive structural and computational exploration of the functional mechanisms of proteins with a LeuT-like fold. Subsequently, an 'outward-open' conformation was determined in the presence of the inhibitor tryptophan, and the Na(+)-dependent formation of a dynamic outward-facing intermediate was identified using electron paramagnetic resonance spectroscopy. In addition, single-molecule fluorescence resonance energy transfer imaging has been used to reveal reversible transitions to an inward-open LeuT conformation, which involve the movement of transmembrane helix TM1a away from the transmembrane helical bundle. We investigated how substrate binding is coupled to structural transitions in LeuT during Na(+)-coupled transport. Here we report a process whereby substrate binding from the extracellular side of LeuT facilitates intracellular gate opening and substrate release at the intracellular face of the protein. In the presence of alanine, a substrate that is transported ∼10-fold faster than leucine, we observed alanine-induced dynamics in the intracellular gate region of LeuT that directly correlate with transport efficiency. Collectively, our data reveal functionally relevant and previously hidden aspects of the NSS transport mechanism that emphasize the functional importance of a second substrate (S2) binding site within the extracellular vestibule. Substrate binding in this S2 site appears to act cooperatively

  5. Effects of S-citalopram, citalopram, and R-citalopram on the firing patterns of dopamine neurons in the ventral tegmental area, N-methyl-D-aspartate receptor-mediated transmission in the medial prefrontal cortex and cognitive function in the rat.

    PubMed

    Schilström, Björn; Konradsson-Geuken, Asa; Ivanov, Vladimir; Gertow, Jens; Feltmann, Kristin; Marcus, Monica M; Jardemark, Kent; Svensson, Torgny H

    2011-05-01

    Escitalopram, the S-enantiomer of citalopram, possesses superior efficacy compared to other selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depression. Escitalopram binds to an allosteric site on the serotonin transporter, which further enhances the blockade of serotonin reuptake, whereas R-citalopram antagonizes this positive allosteric modulation. Escitalopram's effects on neurotransmitters other than serotonin, for example, dopamine and glutamate, are not well studied. Therefore, we here studied the effects of escitalopram, citalopram, and R-citalopram on dopamine cell firing in the ventral tegmental area, using single-cell recording in vivo and on NMDA receptor-mediated currents in pyramidal neurons in the medial prefrontal cortex using in vitro electrophysiology in rats. The cognitive effects of escitalopram and citalopram were also compared using the novel object recognition test. Escitalopram (40-640 μg/kg i.v.) increased both firing rate and burst firing of dopaminergic neurons, whereas citalopram (80-1280 μg/kg) had no effect on firing rate and only increased burst firing at high dosage. R-citalopram (40-640 μg/kg) had no significant effects. R-citalopram (320 μg/kg) antagonized the effects of escitalopram (320 μg/kg). A very low concentration of escitalopram (5 nM), but not citalopram (10 nM) or R-citalopram (5 nM), potentiated NMDA-induced currents in pyramidal neurons. Escitalopram's effect was antagonized by R-citalopram and blocked by the dopamine D(1) receptor antagonist SCH23390. Escitalopram, but not citalopram, improved recognition memory. Our data suggest that the excitatory effect of escitalopram on dopaminergic and NMDA receptor-mediated neurotransmission may have bearing on its cognitive-enhancing effect and superior efficacy compared to other SSRIs in major depression.

  6. Cytoplasmic permeation pathway of neurotransmitter transporters.

    PubMed

    Rudnick, Gary

    2011-09-06

    Ion-coupled solute transporters are responsible for transporting nutrients, ions, and signaling molecules across a variety of biological membranes. Recent high-resolution crystal structures of several transporters from protein families that were previously thought to be unrelated show common structural features indicating a large structural family representing transporters from all kingdoms of life. This review describes studies that led to an understanding of the conformational changes required for solute transport in this family. The first structure in this family showed the bacterial amino acid transporter LeuT, which is homologous to neurotransmitter transporters, in an extracellularly oriented conformation with a molecule of leucine occluded at the substrate site. Studies with the mammalian serotonin transporter identified positions, buried in the LeuT structure, that defined a potential pathway leading from the cytoplasm to the substrate binding site. Modeling studies utilized an inverted structural repeat within the LeuT crystal structure to predict the conformation of LeuT in which the cytoplasmic permeation pathway, consisting of positions identified in SERT, was open for diffusion of the substrate to the cytoplasm. From the difference between the model and the crystal structures, a simple "rocking bundle" mechanism was proposed, in which a four-helix bundle changed its orientation with respect to the rest of the protein to close the extracellular pathway and open the cytoplasmic one. Subsequent crystal structures from structurally related proteins provide evidence supporting this model for transport.

  7. Circulating serotonin in vertebrates.

    PubMed

    Maurer-Spurej, E

    2005-08-01

    The role of circulating serotonin is unclear and whether or not serotonin is present in the blood of non-mammalian species is not known. This study provides the first evidence for the presence of serotonin in thrombocytes of birds and three reptilian species, the endothermic leatherback sea turtle, the green sea turtle and the partially endothermic American alligator. Thrombocytes from a fresh water turtle, American bullfrog, Yellowfin tuna, and Chinook salmon did not contain serotonin. Serotonin is a vasoactive substance that regulates skin blood flow, a major mechanism for endothermic body temperature regulation, which could explain why circulating serotonin is present in warm-blooded species. The temperature sensitivity of human blood platelets with concomitant changes in serotonin content further supports a link between circulating serotonin and thermoregulation. Phylogenetic comparison of the presence of circulating serotonin indicated an evolutionary divergence within reptilian species that might coincide with the emergence of endothermy.

  8. Mimicking subsecond neurotransmitter dynamics with femtosecond laser stimulated nanosystems

    NASA Astrophysics Data System (ADS)

    Nakano, Takashi; Chin, Catherine; Myint, David Mo Aung; Tan, Eng Wui; Hale, Peter John; Krishna M., Bala Murali; Reynolds, John N. J.; Wickens, Jeff; Dani, Keshav M.

    2014-06-01

    Existing nanoscale chemical delivery systems target diseased cells over long, sustained periods of time, typically through one-time, destructive triggering. Future directions lie in the development of fast and robust techniques capable of reproducing the pulsatile chemical activity of living organisms, thereby allowing us to mimic biofunctionality. Here, we demonstrate that by applying programmed femtosecond laser pulses to robust, nanoscale liposome structures containing dopamine, we achieve sub-second, controlled release of dopamine - a key neurotransmitter of the central nervous system - thereby replicating its release profile in the brain. The fast delivery system provides a powerful new interface with neural circuits, and to the larger range of biological functions that operate on this short timescale.

  9. A dualistic conformational response to substrate binding in the human serotonin transporter reveals a high affinity state for serotonin.

    PubMed

    Bjerregaard, Henriette; Severinsen, Kasper; Said, Saida; Wiborg, Ove; Sinning, Steffen

    2015-03-20

    Serotonergic neurotransmission is modulated by the membrane-embedded serotonin transporter (SERT). SERT mediates the reuptake of serotonin into the presynaptic neurons. Conformational changes in SERT occur upon binding of ions and substrate and are crucial for translocation of serotonin across the membrane. Our understanding of these conformational changes is mainly based on crystal structures of a bacterial homolog in various conformations, derived homology models of eukaryotic neurotransmitter transporters, and substituted cysteine accessibility method of SERT. However, the dynamic changes that occur in the human SERT upon binding of ions, the translocation of substrate, and the role of cholesterol in this interplay are not fully elucidated. Here we show that serotonin induces a dualistic conformational response in SERT. We exploited the substituted cysteine scanning method under conditions that were sensitized to detect a more outward-facing conformation of SERT. We found a novel high affinity outward-facing conformational state of the human SERT induced by serotonin. The ionic requirements for this new conformational response to serotonin mirror the ionic requirements for translocation. Furthermore, we found that membrane cholesterol plays a role in the dualistic conformational response in SERT induced by serotonin. Our results indicate the existence of a subpopulation of SERT responding differently to serotonin binding than hitherto believed and that membrane cholesterol plays a role in this subpopulation of SERT.

  10. Chronoamperometry to determine differential reductions in uptake in brain synaptosomes from serotonin transporter knockout mice.

    PubMed

    Perez, Xiomara A; Andrews, Anne M

    2005-02-01

    The serotonin transporter (SERT) is a neuronal plasma membrane protein whose primary function is to take up the neurotransmitter serotonin from the extracellular space, thereby controlling the spatial and temporal aspects of serotonergic signaling in the brain. In humans, a commonly expressed genetic variant of the serotonin transporter gene results in 40% reductions in SERT expression that have been linked to increases in anxiety-related personality traits and susceptibility to stress-associated depression. Mice have been engineered to express similar reductions in SERT expression to investigate transporter-mediated control of serotonin neurotransmission and behavior. We employed carbon fiber microelectrode voltammetry (chronoamperometry) to examine serotonin clearance rates in brain liposomes (synaptosomes) prepared from mice with 50% (SERT(+/)(-)) or complete (SERT(-)(/)(-)) loss of SERT expression. Initial characterization of uptake showed that transport of serotonin was enhanced in the presence of oxygen and abolished when synaptosomes were stirred. Additionally, uptake was prevented by inclusion of the serotonin-selective reuptake inhibiting drug paroxetine in the incubation medium. Most notably, unlike prior studies using established radiochemical methods in synaptosomes, we determined 60% reductions in serotonin uptake rates in SERT(+/)(-) mice in two different brain regions-striatum and frontal cortex. Serotonin uptake was not detected in either brain region in SERT(-)(/)(-) mice. Thus, electroanalytical methods offer distinct advantages stemming from excellent temporal resolution for determining transporter kinetics. Moreover, these appear necessary for delineating moderate but biologically important changes in neurotransmitter transporter function.

  11. Excess nicotinamide increases plasma serotonin and histamine levels.

    PubMed

    Tian, Yan-Jie; Li, Da; Ma, Qiang; Gu, Xin-Yi; Guo, Ming; Lun, Yong-Zhi; Sun, Wu-Ping; Wang, Xin-Yuan; Cao, Yu; Zhou, Shi-Sheng

    2013-02-25

    Methylation, a methyl group-consuming reaction, plays a key role in the degradation (i.e., inactivation) of monoamine neurotransmitters, including catecholamines, serotonin and histamine. Without labile methyl groups, the methylation-mediated degradation cannot take place. Although high niacin (nicotinic acid and nicotinamide) intake, which is very common nowadays, is known to deplete the body's methyl-group pool, its effect on monoamine-neurotransmitter degradation is not well understood. The aim of this article was to investigate the effect of excess nicotinamide on the levels of plasma serotonin and histamine in healthy subjects. Urine and venous blood samples were collected from nine healthy male volunteers before and after oral loading with 100 mg nicotinamide. Plasma N(1)-methylnicotinamide, urinary N(1)-methyl-2-pyridone-5-carboxamide (2-Py), and plasma betaine levels were measured by using high-performance liquid chromatography (HPLC). Plasma concentrations of choline, serotonin and histamine were measured using commercial kits. The results showed that the plasma N(1)-methylnicotinamide level and the urinary excretion of 2-Py significantly increased after oral loading with 100 mg nicotinamide, which was accompanied with a decrease in the methyl-group donor betaine. Compared with those before nicotinamide load, five-hour postload plasma serotonin and histamine levels significantly increased. These results suggest that excess nicotinamide can disturb monoamine-neurotransmitter metabolism. These findings may be of significance in understanding the etiology of monoamine-related mental diseases, such as schizophrenia and autism (a neurodevelopmental disorder).

  12. Mechanism of chloride interaction with neurotransmitter:sodium symporters.

    PubMed

    Zomot, Elia; Bendahan, Annie; Quick, Matthias; Zhao, Yongfang; Javitch, Jonathan A; Kanner, Baruch I

    2007-10-11

    Neurotransmitter:sodium symporters (NSS) have a critical role in regulating neurotransmission and are targets for psychostimulants, anti-depressants and other drugs. Whereas the non-homologous glutamate transporters mediate chloride conductance, in the eukaryotic NSS chloride is transported together with the neurotransmitter. In contrast, transport by the bacterial NSS family members LeuT, Tyt1 and TnaT is chloride independent. The crystal structure of LeuT reveals an occluded binding pocket containing leucine and two sodium ions, and is highly relevant for the neurotransmitter transporters. However, the precise role of chloride in neurotransmitter transport and the location of its binding site remain elusive. Here we show that introduction of a negatively charged amino acid at or near one of the two putative sodium-binding sites of the GABA (gamma-aminobutyric acid) transporter GAT-1 from rat brain (also called SLC6A1) renders both net flux and exchange of GABA largely chloride independent. In contrast to wild-type GAT-1, a marked stimulation of the rate of net flux, but not of exchange, was observed when the internal pH was lowered. Equivalent mutations introduced in the mouse GABA transporter GAT4 (SLC6A11) and the human dopamine transporter DAT (SLC6A3) also result in chloride-independent transport, whereas the reciprocal mutations in LeuT and Tyt1 render substrate binding and/or uptake by these bacterial NSS chloride dependent. Our data indicate that the negative charge, provided either by chloride or by the transporter itself, is required during binding and translocation of the neurotransmitter, probably to counterbalance the charge of the co-transported sodium ions.

  13. Dopamine Transporter Blockade Increases LTP in the CA1 Region of the Rat Hippocampus via Activation of the D3 Dopamine Receptor

    ERIC Educational Resources Information Center

    Swant, Jarod; Wagner, John J.

    2006-01-01

    Dopamine has been demonstrated to be involved in the modulation of long-term potentiation (LTP) in the CA1 region of the hippocampus. As monoamine transporter blockade will increase the actions of endogenous monoamine neurotransmitters, the effect of a dopamine transporter (DAT) antagonist on LTP was assessed using field excitatory postsynaptic…

  14. Profiling neurotransmitter receptor expression in the Ambystoma mexicanum brain.

    PubMed

    Reyes-Ruiz, Jorge Mauricio; Limon, Agenor; Korn, Matthew J; Nakamura, Paul A; Shirkey, Nicole J; Wong, Jamie K; Miledi, Ricardo

    2013-03-22

    Ability to regenerate limbs and central nervous system (CNS) is unique to few vertebrates, most notably the axolotl (Ambystoma sp.). However, despite the fact the neurotransmitter receptors are involved in axonal regeneration, little is known regarding its expression profile. In this project, RT-PCR and qPCR were performed to gain insight into the neurotransmitter receptors present in Ambystoma. Its functional ability was studied by expressing axolotl receptors in Xenopus laevis oocytes by either injection of mRNA or by direct microtransplantation of brain membranes. Oocytes injected with axolotl mRNA expressed ionotropic receptors activated by GABA, aspartate+glycine and kainate, as well as metabotropic receptors activated by acetylcholine and glutamate. Interestingly, we did not see responses following the application of serotonin. Membranes from the axolotl brain were efficiently microtransplanted into Xenopus oocytes and two types of native GABA receptors that differed in the temporal course of their responses and affinities to GABA were observed. Results of this study are necessary for further characterization of axolotl neurotransmitter receptors and may be useful for guiding experiments aimed at understanding activity-dependant limb and CNS regeneration.

  15. A Preliminary Study of Gene Polymorphisms Involved in the Neurotransmitters Metabolism of a Homogeneous Spanish Autistic Group

    ERIC Educational Resources Information Center

    Calahorro, Fernando; Alejandre, Encarna; Anaya, Nuria; Guijarro, Teresa; Sanz, Yolanza; Romero, Auxiliadora; Tienda, Pilar; Burgos, Rafael; Gay, Eudoxia; Sanchez, Vicente; Ruiz-Rubio, Manuel

    2009-01-01

    Twin studies have shown a strong genetic component for autism. Neurotransmitters, such as serotonin and catecholamines, have been suggested to play a role in the disease since they have an essential function in synaptogenesis and brain development. In this preliminary study, polymorphism of genes implicated in the serotonergic and dopaminergic…

  16. Contributions to the field of neurotransmitters by Japanese scientists, and reflections on my own research.

    PubMed

    Otsuka, Masanori

    2007-03-01

    PART I DESCRIBES IMPORTANT CONTRIBUTIONS MADE BY SOME JAPANESE PIONEERS IN THE FIELD OF NEUROTRANSMITTERS: (their achievements in parentheses) J. Takamine (isolation and crystallization of adrenaline); K. Shimidzu (early hint for acetylcholine as a neurotransmitter); F. Kanematsu (donation of the Kanematsu Memorial Institute in Sydney); T. Hayashi (discovery of the excitatory action of glutamate and the inhibitory action of GABA); and I. Sano (discovery of a high concentration of dopamine in striatum, its reduction in a patient with Parkinson's disease and the treatment with DOPA). In Part II, I present some of my reflections on my research on neurotransmitters. The work of my colleagues and myself has made some significant contributions to the establishment of neurotransmitter roles played by GABA and substance P, the first amino acid and the first peptide neurotransmitters, respectively. By the early 1960s, 3 substances, i.e., acetylcholine, noradrenaline, and adrenaline, had been established as neurotransmitters. Now the number of neurotransmitters is believed to be as many as 50 or even more mainly due to the inclusion of several amino acids and a large number of peptide transmitters.

  17. Contributions to the field of neurotransmitters by Japanese scientists, and reflections on my own research

    PubMed Central

    Otsuka, Masanori

    2007-01-01

    Part I describes important contributions made by some Japanese pioneers in the field of neurotransmitters: (their achievements in parentheses) J. Takamine (isolation and crystallization of adrenaline); K. Shimidzu (early hint for acetylcholine as a neurotransmitter); F. Kanematsu (donation of the Kanematsu Memorial Institute in Sydney); T. Hayashi (discovery of the excitatory action of glutamate and the inhibitory action of GABA); and I. Sano (discovery of a high concentration of dopamine in striatum, its reduction in a patient with Parkinson’s disease and the treatment with DOPA). In Part II, I present some of my reflections on my research on neurotransmitters. The work of my colleagues and myself has made some significant contributions to the establishment of neurotransmitter roles played by GABA and substance P, the first amino acid and the first peptide neurotransmitters, respectively. By the early 1960s, 3 substances, i.e., acetylcholine, noradrenaline, and adrenaline, had been established as neurotransmitters. Now the number of neurotransmitters is believed to be as many as 50 or even more mainly due to the inclusion of several amino acids and a large number of peptide transmitters. PMID:24019584

  18. Immunocytochemical identification of serotonin-synthesizing neurons in the vertebrate retina: a comparative study.

    PubMed

    Wilhelm, M; Zhu, B; Gábriel, R; Straznicky, C

    1993-02-01

    Serotonin-synthesizing neurons in the retinas of goldfish, axolotl, turtle, chick, rabbit and cat were identified using double labelling with anti-serotonin and anti-phenylalanine hydroxylase antibodies. The latter antibody recognizes tryptophan 5-hydroxylase, one of the synthesizing enzymes for serotonin. Neurons labelled by both markers were considered to be serotonin-synthesizing neurons, while those only with serotonin-immunoreactivity were assumed to be serotonin-accumulating neurons. In the goldfish and chick retinas, all serotonin-immunoreactive amacrine cells (S1) were positive for phenylalanine hydroxylase. In the axolotl and turtle retinas, all the S1 amacrine cells, and only 52.8% and 40.5% of S2 amacrine cells were double-labelled. Although serotonin-immunoreactive bipolar cells were observed in the turtle and chick retinas, the synthesizing enzyme for serotonin could not be detected in these cells. In the rabbit and cat retinas, tryptophan hydroxylase could not be revealed in any cell type with immunocytochemistry. In control experiments SLI neurons in the raphe nuclei of the brain stem always exhibited PH-LI in all species examined, including mammals, indicating that our anti-PH antibody is able to recognize tryptophan hydroxylase across vertebrate classes. These results indicate that the majority of serotonin-immunoreactive amacrine cells are able to synthesize serotonin and are the source of endogenous serotonin in the non-mammalian retina, while some serotonin-immunoreactive amacrine and bipolar cells possibly only accumulate serotonin. We also suggest that serotonin may not be a primary neurotransmitter in the serotonin-accumulating bipolar and amacrine cells of the non-mammalian retina.

  19. Serotonin is critical for rewarded olfactory short-term memory in Drosophila.

    PubMed

    Sitaraman, Divya; LaFerriere, Holly; Birman, Serge; Zars, Troy

    2012-06-01

    The biogenic amines dopamine, octopamine, and serotonin are critical in establishing normal memories. A common view for the amines in insect memory performance has emerged in which dopamine and octopamine are largely responsible for aversive and appetitive memories. Examination of the function of serotonin begins to challenge the notion of one amine type per memory because altering serotonin function also reduces aversive olfactory memory and place memory levels. Could the function of serotonin be restricted to the aversive domain, suggesting a more specific dopamine/serotonin system interaction? The function of the serotonergic system in appetitive olfactory memory was examined. By targeting the tetanus toxin light chain (TNT) and the human inwardly rectifying potassium channel (Kir2.1) to the serotonin neurons with two different GAL4 driver combinations, the serotonergic system was inhibited. Additional use of the GAL80(ts1) system to control expression of transgenes to the adult stage of the life cycle addressed a potential developmental role of serotonin in appetitive memory. Reduction in appetitive olfactory memory performance in flies with these transgenic manipulations, without altering control behaviors, showed that the serotonergic system is also required for normal appetitive memory. Thus, serotonin appears to have a more general role in Drosophila memory, and implies an interaction with both the dopaminergic and octopaminergic systems.

  20. Serotonin: a never-ending story.

    PubMed

    Olivier, Berend

    2015-04-15

    The neurotransmitter serotonin is an evolutionary ancient molecule that has remarkable modulatory effects in almost all central nervous system integrative functions, such as mood, anxiety, stress, aggression, feeding, cognition and sexual behavior. After giving a short outline of the serotonergic system (anatomy, receptors, transporter) the author's contributions over the last 40 years in the role of serotonin in depression, aggression, anxiety, stress and sexual behavior is outlined. Each area delineates the work performed on animal model development, drug discovery and development. Most of the research work described has started from an industrial perspective, aimed at developing animals models for psychiatric diseases and leading to putative new innovative psychotropic drugs, like in the cases of the SSRI fluvoxamine, the serenic eltoprazine and the anxiolytic flesinoxan. Later this research work mainly focused on developing translational animal models for psychiatric diseases and implicating them in the search for mechanisms involved in normal and diseased brains and finding new concepts for appropriate drugs.

  1. Analysis of urinary neurotransmitters by capillary electrophoresis: sensitivity enhancement using field-amplified sample injection and molecular imprinted polymer solid phase extraction.

    PubMed

    Claude, Bérengère; Nehmé, Reine; Morin, Philippe

    2011-08-12

    Capillary electrophoresis (CE) has been investigated for the analysis of some neurotransmitters, dopamine (DA), 3-methoxytyramine (3-MT) and serotonin (5-hydroxytryptamine, 5-HT) at nanomolar concentrations in urine. Field-amplified sample injection (FASI) has been used to improve the sensitivity through the online pre-concentration samples. The cationic analytes were stacked at the capillary inlet between a zone of low conductivity - sample and pre-injection plug - and a zone of high conductivity - running buffer. Several FASI parameters have been optimized (ionic strength of the running buffer, concentration of the sample protonation agent, composition of the sample solvent and nature of the pre-injection plug). Best results were obtained using H(3)PO(4)-LiOH (pH 4, ionic strength of 80 mmol L(-1)) as running buffer, 100 μmol L(-1) of H(3)PO(4) in methanol-water 90/10 (v/v) as sample solvent and 100 μmol L(-1) of H(3)PO(4) in water for the pre-injection plug. In these conditions, the linearity was verified in the 50-300 nmol L(-1) concentration range for DA, 3-MT and 5-HT with a determination coefficient (r(2)) higher than 0.99. The limits of quantification (10 nmol L(-1) for DA and 3-MT, 5.9 nmol L(-1) for 5-HT) were 500 times lower than those obtained with hydrodynamic injection. However, if this method is applied to the analysis of neurotransmitters in urine, the presence of salts in the matrix greatly reduces the sensitivity of the FASI/CE-UV method.Therefore, a solid phase extraction (SPE) on a dedicated imprinted polymer (MIP) was developed to extract specific neurotransmitters, catecholamines, metanephrines and indolamines, from urine. Matrix salts were thus discarded after sample extraction on AFFINIMIP™ Catecholamine & Metanephrine (100mg) cartridge. Therefore, lower limits of quantification were determined in artificial urine (46 nmol L(-1) for DA, 11 nmol L(-1) for 3-MT and 6 nmol L(-1) for 5-HT).The application of this protocol MIP

  2. Serotonin, dopamine, noradrenaline and their metabolites: levels in the brain of the house cricket (Acheta domesticus L.) during a 24-hour period and after administration of quipazine--a 5-HT2 receptor agonist.

    PubMed

    Pyza, E; Gołembiowska, K; Antkiewicz-Michaluk, L

    1991-01-01

    1. The levels of 5-HT, DA, NA and DA metabolites (NADA, DOPAC) measured by HPLC (with electrochemical detection) in the brain of the house cricket did not change over a 24-hr period. The level of 5-HIAA, a 5-HT metabolite, was below the limit of detection. 2. The 5-HT and DOPAC levels decreased and NADA increased after quipazine injection but DA and NA levels did not change after it. 3. [3H]Ketanserin was used to identify serotonin receptors bound to sites in the house cricket brain with a KD of 5 nM and a concentration of Bmax 180 fmol/mg protein.

  3. Prenatal immune activation leads to multiple changes in basal neurotransmitter levels in the adult brain: implications for brain disorders of neurodevelopmental origin such as schizophrenia.

    PubMed

    Winter, Christine; Djodari-Irani, Anais; Sohr, Reinhard; Morgenstern, Rudolf; Feldon, Joram; Juckel, Georg; Meyer, Urs

    2009-05-01

    Maternal infection during pregnancy enhances the offspring's risk for severe neuropsychiatric disorders in later life, including schizophrenia. Recent attempts to model this association in animals provided further experimental evidence for a causal relationship between in-utero immune challenge and the postnatal emergence of a wide spectrum of behavioural, pharmacological and neuroanatomical dysfunctions implicated in schizophrenia. However, it still remains unknown whether the prenatal infection-induced changes in brain and behavioural functions may be associated with multiple changes at the neurochemical level. Here, we tested this hypothesis in a recently established mouse model of viral-like infection. Pregnant dams on gestation day 9 were exposed to viral mimetic polyriboinosinic-polyribocytidilic acid (PolyI:C, 5 mg/kg i.v.) or vehicle treatment, and basal neurotransmitter levels were then compared in the adult brains of animals born to PolyI:C- or vehicle-treated mothers by high-performance liquid chromatography on post-mortem tissue. We found that prenatal immune activation significantly increased the levels of dopamine and its major metabolites in the lateral globus pallidus and prefrontal cortex, whilst at the same time it decreased serotonin and its metabolite in the hippocampus, nucleus accumbens and lateral globus pallidus. In addition, a specific reduction of the inhibitory amino acid taurine in the hippocampus was noted in prenatally PolyI:C-exposed offspring relative to controls, whereas central glutamate and gamma-aminobutyric acid (GABA) content was largely unaffected by prenatal immune activation. Our results thus confirm that maternal immunological stimulation during early/middle pregnancy is sufficient to induce long-term changes in multiple neurotransmitter levels in the brains of adult offspring. This further supports the possibility that infection-mediated interference with early fetal brain development may predispose the developing organism

  4. Short- and long-term effects of MDMA ("ecstasy") on synaptosomal and vesicular uptake of neurotransmitters in vitro and ex vivo.

    PubMed

    Bogen, Inger Lise; Haug, Kristin Huse; Myhre, Oddvar; Fonnum, Frode

    2003-01-01

    3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a commonly abused drug which has been shown to be neurotoxic to serotonergic neurons in many species. The exact mechanism responsible for the neurotoxicity of MDMA is, however, poorly understood. In this study, the effects of MDMA on the synaptosomal and vesicular uptake of neurotransmitters were investigated. Our results show that MDMA (0.5-20 microM) reduces both synaptosomal and vesicular uptake of serotonin and dopamine in a dose dependent manner in vitro, while the uptake of glutamate and gamma-aminobutyric acid (GABA) remains unaffected. Ex vivo experiments support the importance of the monoamines, with predominant dopaminergic inhibition at short-term exposure (3 x 15 mg/kg; 2-h intervals), and exclusively serotonergic inhibition at long-term exposure (2 x 10 mg/kg per day; 4 days). This study also compares MDMA and the structurally related antidepressant paroxetine, in an attempt to reveal possible cellular mechanisms for the serotonergic toxicity of MDMA. One important difference between paroxetine and MDMA is that only MDMA has the capability of inhibiting vesicular uptake of monoamines at doses used. We suggest that inhibition of the vesicular monoamine transporter-2, and a following increase in cytoplasmatic monoamine concentrations, might be crucial for the neurotoxic effect of MDMA.

  5. Microfluidic platform for neurotransmitter sensing based on cyclic voltammetry and dielectrophoresis for in vitro experiments.

    PubMed

    Mathault, Jessy; Zamprogno, Pauline; Greener, Jesse; Miled, Amine

    2015-08-01

    This paper presents a new microfluidic platform that can simultaneously measure and locally modulate neurotransmitter concentration in a neuron network. This work focuses on the development of a first prototype including a potentiostat and electrode functionalization to detect several neurotransmitter's simultaneously. We tested dopamine as proof of concept to validate functionality. The system is based on 320 bidirectional electrode array for dielectrophoretic manipulation and cyclic voltammetry. Each electrode is connected to a mechanical multiplexer in order to reduce noise interference and fully isolate the electrode. The multiplexing rate is 476 kHz and each electrode can drive a signal with an amplitude of 60 V pp for dielectrophoretic manipulation.

  6. Rapid analysis of neurotransmitters in rat brain using ultra-fast liquid chromatography and tandem mass spectrometry: application to a comparative study in normal and insomnic rats.

    PubMed

    He, Bosai; Bi, Kaishun; Jia, Ying; Wang, Jiahong; Lv, Chunxiao; Liu, Ran; Zhao, Longshan; Xu, Huarong; Chen, Xiaohui; Li, Qing

    2013-08-01

    Neurotransmitters and their metabolites in central nervous system were known to play a significant role in sedation and hypnosis. A rapid and sensitive UFLC-MS/MS method for simultaneous determination of serotonin, 5-hydroxyindole acetic acid (5-HIAA), tryptophan (Try), dopamine (DA), norepinephrine (NE), γ-aminobutyric acid (GABA), glutamic acid (Glu) and acetylcholine (Ach) in rat brain without derivatization, ion-pairing reagent or pre-concentration was developed. Analytes and IS were separated on a Inertsil ODS-EP column (150 mm × 4.6 mm, 5 µm particles) and analyzed in a single chromatographic run in less than 9.0 min, using gradient elution with the mobile phase consisting of methanol and 0.01% acetic acid in water at a flow rate of 1.2 ml min(-1) . The detection of the analytes was performed on 4000Q UFLC-MS/MS system with turbo ion spray source in positive ion and multiple reaction monitoring mode. The developed method provided excellent linear calibration curves for the assay of analytes (R(2)  ≥ 0.9915). Limits of quantification were in the range of 1.0 ng ml(-1) to 1.0 µg ml(-1) for the analytes in rat brain. Intra- and inter-day precision and accuracy of analytes were well within acceptance criteria (15%). Mean extraction recoveries of analytes and IS from rat brain were all more than 80.0%. Furthermore, the validated method was successfully applied to comparing profiles of analytes in normal and insomnic rat brains. Results indicated that there were statistically significant differences for serotonin, 5-HIAA, DA, NE, Glu and Ach, but no significant difference for Try and GABA between two groups.

  7. A Conserved Salt Bridge between Transmembrane Segments 1 and 10 Constitutes an Extracellular Gate in the Dopamine Transporter*

    PubMed Central

    Pedersen, Anders V.; Andreassen, Thorvald F.; Loland, Claus J.

    2014-01-01

    Neurotransmitter transporters play an important role in termination of synaptic transmission by mediating reuptake of neurotransmitter, but the molecular processes behind translocation are still unclear. The crystal structures of the bacterial homologue, LeuT, provided valuable insight into the structural and dynamic requirements for substrate transport. These structures support the existence of gating domains controlling access to a central binding site. On the extracellular side, access is controlled by the “thin gate” formed by an interaction between Arg-30 and Asp-404. In the human dopamine transporter (DAT), the corresponding residues are Arg-85 and Asp-476. Here, we present results supporting the existence of a similar interaction in DAT. The DAT R85D mutant has a complete loss of function, but the additional insertion of an arginine in opposite position (R85D/D476R), causing a charge reversal, results in a rescue of binding sites for the cocaine analogue [3H]CFT. Also, the coordination of Zn2+ between introduced histidines (R85H/D476H) caused a ∼2.5-fold increase in [3H]CFT binding (Bmax). Importantly, Zn2+ also inhibited [3H]dopamine transport in R85H/D476H, suggesting that a dynamic interaction is required for the transport process. Furthermore, cysteine-reactive chemistry shows that mutation of the gating residues causes a higher proportion of transporters to reside in the outward facing conformation. Finally, we show that charge reversal of the corresponding residues (R104E/E493R) in the serotonin transporter also rescues [3H](S)-citalopram binding, suggesting a conserved feature. Taken together, these data suggest that the extracellular thin gate is present in monoamine transporters and that a dynamic interaction is required for substrate transport. PMID:25339174

  8. Mechanism for alternating access in neurotransmitter transporters.

    PubMed

    Forrest, Lucy R; Zhang, Yuan-Wei; Jacobs, Miriam T; Gesmonde, Joan; Xie, Li; Honig, Barry H; Rudnick, Gary

    2008-07-29

    Crystal structures of LeuT, a bacterial homologue of mammalian neurotransmitter transporters, show a molecule of bound substrate that is essentially exposed to the extracellular space but occluded from the cytoplasm. Thus, there must exist an alternate conformation for LeuT in which the substrate is accessible to the cytoplasm and a corresponding mechanism that switches accessibility from one side of the membrane to the other. Here, we identify the cytoplasmic accessibility pathway of the alternate conformation in a mammalian serotonin transporter (SERT) (a member of the same transporter family as LeuT). We also propose a model for the cytoplasmic-facing state that exploits the internal pseudosymmetry observed in the crystal structure. LeuT contains two structurally similar repeats (TMs1-5 and TMs 6-10) that are inverted with respect to the plane of the membrane. The conformational differences between them result in the formation of the extracellular pathway. Our model for the cytoplasm-facing state exchanges the conformations of the two repeats and thus exposes the substrate and ion-binding sites to the cytoplasm. The conformational change that connects the two states primarily involves the tilting of a 4-helix bundle composed of transmembrane helices 1, 2, 6, and 7. Switching the tilt angle of this bundle is essentially equivalent to switching the conformation of the two repeats. Extensive mutagenesis of SERT and accessibility measurements, using cysteine reagents, are accommodated by our model. These observations may be of relevance to other transporter families, many of which contain internal inverted repeats.

  9. Dopamine receptors in human gastrointestinal mucosa

    SciTech Connect

    Hernandez, D.E.; Mason, G.A.; Walker, C.H.; Valenzuela, J.E.

    1987-12-21

    Dopamine is a putative enteric neurotransmitter that has been implicated in exocrine secretory and motility functions of the gastrointestinal tract of several mammalian species including man. This study was designed to determine the presence of dopamine binding sites in human gastric and duodenal mucosa and to describe certain biochemical characteristics of these enteric receptor sites. The binding assay was performed in triplicate with tissue homogenates obtained from healthy volunteers of both sexes using /sup 3/H-dopamine as a ligand. The extent of nonspecific binding was determined in the presence of a 100-fold excess of unlabeled dopamine. Scatchard analysis performed with increasing concentrations of /sup 3/H-dopamine (20-500 nM) revealed a single class of saturable dopamine binding sites in gastric and duodenal mucosa. The results of this report demonstrate the presence of specific dopamine receptors in human gastric and duodenal mucosa. These biochemical data suggest that molecular abnormalities of these receptor sites may be operative in the pathogenesis of important gastrointestinal disorders. 33 references, 2 figures.

  10. Stereoselectivity of presynaptic autoreceptors modulating dopamine release.

    PubMed

    Arbilla, S; Langer, S Z

    1981-12-17

    The effects of the (R)- and (S)-enantiomers of sulpiride and butaclamol were studied on the spontaneous and field stimulation-evoked release of total radioactivity from slices of rabbit caudate nucleus prelabelled with [3H]dopamine. (S)-Sulpiride in concentrations ranging from 0.01--1 microM enhanced the electrically evoked release of [3H]dopamine while (R)-sulpiride was 10 times less potent than (S)-sulpiride. Exposure to (S)-butaclamol (0.01--1 microM) but not to (R)-butaclamol (0.1--10 microM) enhanced the field-stimulated release of [3H]dopamine. The facilitatory effects of (S)- and (R)-sulpiride and (S)-butaclamol on the stimulated release of the labelled neurotransmitter were observed under conditions in which these drugs did not modify the spontaneous outflow of radioactivity. Only the active enantiomers of sulpiride and butaclamol antagonized the inhibition by apomorphine (1 microM) of the stimulated release of [3H]dopamine. Our results indicate that the presynaptic inhibitory dopamine autoreceptors modulating the stimulation-evoked release of [3H]dopamine in the caudate nucleus are, like the classical postsynaptic dopamine receptors, chemically stereoselective.

  11. Is Aspartate an Excitatory Neurotransmitter?

    PubMed Central

    Herring, Bruce E.; Silm, Katlin

    2015-01-01

    Recent evidence has resurrected the idea that the amino acid aspartate, a selective NMDA receptor agonist, is a neurotransmitter. Using a mouse that lacks the glutamate-selective vesicular transporter VGLUT1, we find that glutamate alone fully accounts for the activation of NMDA receptors at excitatory synapses in the hippocampus. This excludes a role for aspartate and, by extension, a recently proposed role for the sialic acid transporter sialin in excitatory transmission. SIGNIFICANCE STATEMENT It has been proposed that the amino acid aspartate serves as a neurotransmitter. Although aspartate is a selective agonist for NMDA receptors, we find that glutamate alone fully accounts for neurotransmission at excitatory synapses in the hippocampus, excluding a role for aspartate. PMID:26180193

  12. Neurotransmitters in the vestibular system.

    PubMed

    Balaban, C D

    2016-01-01

    Neuronal networks that are linked to the peripheral vestibular system contribute to gravitoinertial sensation, balance control, eye movement control, and autonomic function. Ascending connections to the limbic system and cerebral cortex are also important for motion perception and threat recognition, and play a role in comorbid balance and anxiety disorders. The vestibular system also shows remarkable plasticity, termed vestibular compensation. Activity in these networks is regulated by an interaction between: (1) intrinsic neurotransmitters of the inner ear, vestibular nerve, and vestibular nuclei; (2) neurotransmitters associated with thalamocortical and limbic pathways that receive projections originating in the vestibular nuclei; and (3) locus coeruleus and raphe (serotonergic and nonserotonergic) projections that influence the latter components. Because the ascending vestibular interoceptive and thalamocortical pathways include networks that influence a broad range of stress responses (endocrine and autonomic), memory consolidation, and cognitive functions, common transmitter substrates provide a basis for understanding features of acute and chronic vestibular disorders.

  13. New arylpiperazinylalkyl derivatives of 8-alkoxy-purine-2,6-dione and dihydro[1,3]oxazolo[2,3-f]purinedione targeting the serotonin 5-HT1A /5-HT2A /5-HT7 and dopamine D2 receptors.

    PubMed

    Chłoń-Rzepa, Grażyna; Zagórska, Agnieszka; Bucki, Adam; Kołaczkowski, Marcin; Pawłowski, Maciej; Satała, Grzegorz; Bojarski, Andrzej J; Partyka, Anna; Wesołowska, Anna; Pękala, Elżbieta; Słoczyńska, Karolina

    2015-04-01

    To obtain potential antidepressants and/or antipsychotics, a series of new long-chain arylpiperazine derivatives of 8-alkoxy-purine-2,6-dione (10-24) and dihydro[1,3]oxazolo[2,3-f]purinedione (30-34) were synthesized and their serotonin (5-HT1A , 5-HT2A , 5-HT6 , 5-HT7 ) and dopamine (D2 ) receptor affinities were determined. The study allowed the identification of some potent 5-HT1A /5-HT7 /D2 ligands with moderate affinity for 5-HT2A sites. The binding mode of representative compounds from both chemical classes (11 and 31) in the site of 5-HT1A receptor was analyzed in computational studies. In functional in vitro studies, the selected compounds 15 and 16 showed antagonistic properties for the evaluated receptors. 8-Methoxy-7-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-1,3-dimethyl-purine-2,6-dione (15) showed a lack of activity in terms and under the conditions of the forced swim, four plate and amphetamine-induced hyperactivity tests in mice, probably as a result of its high first pass effect in the liver.

  14. Different functions for homologous serotonergic interneurons and serotonin in species-specific rhythmic behaviours.

    PubMed

    Newcomb, James M; Katz, Paul S

    2009-01-07

    Closely related species can exhibit different behaviours despite homologous neural substrates. The nudibranch molluscs Tritonia diomedea and Melibe leonina swim differently, yet their nervous systems contain homologous serotonergic neurons. In Tritonia, the dorsal swim interneurons (DSIs) are members of the swim central pattern generator (CPG) and their neurotransmitter serotonin is both necessary and sufficient to elicit a swim motor pattern. Here it is shown that the DSI homologues in Melibe, the cerebral serotonergic posterior-A neurons (CeSP-As), are extrinsic to the swim CPG, and that neither the CeSP-As nor their neurotransmitter serotonin is necessary for swim motor pattern initiation, which occurred when the CeSP-As were inactive. Furthermore, the serotonin antagonist methysergide blocked the effects of both the serotonin and CeSP-As but did not prevent the production of a swim motor pattern. However, the CeSP-As and serotonin could influence the Melibe swim circuit; depolarization of a cerebral serotonergic posterior-A was sufficient to initiate a swim motor pattern and hyperpolarization of a CeSP-A temporarily halted an ongoing swim motor pattern. Serotonin itself was sufficient to initiate a swim motor pattern or make an ongoing swim motor pattern more regular. Thus, evolution of species-specific behaviour involved alterations in the functions of identified homologous neurons and their neurotransmitter.

  15. PET evaluation of the dopamine system of the human brain

    SciTech Connect

    Volkow, N.D.; Fowler, J.S.; Gatley, S. |

    1996-07-01

    Dopamine plays a pivotal role in the regulation and control of movement, motivation and cognition. It also is closely linked to reward, reinforcement and addiction. Abnormalities in brain dopamine are associated with many neurological and psychiatric disorders including Parkinson`s disease, schizophrenia and substance abuse. This close association between dopamine and neurological and psychiatric diseases and with substance abuse make it an important topic in research in the neurosciences and an important molecular target in drug development. PET enables the direct measurement of components of the dopamine system in the living human brain. It relies on radiotracers which label dopamine receptors, dopamine transporters, precursors of dopamine or compounds which have specificity for the enzymes which degrade dopamine. Additionally, by using tracers that provide information on regional brain metabolism or blood flow as well as neurochemically specific pharmacological interventions, PET can be used to assess the functional consequences of change in brain dopamine activity. PET dopamine measurements have been used to investigate the normal human brain and its involvement in psychiatric and neurological diseases. It has also been used in psychopharmacological research to investigate dopamine drugs used in the treatment of Parkinson`s disease and of schizophrenia as well as to investigate the effects of drugs of abuse on the dopamine system. Since various functional and neurochemical parameters can be studied in the same subject, PET enables investigation of the functional integrity of the dopamine system in the human brain and investigation of the interactions of dopamine with other neurotransmitters. This paper summarizes the different tracers and experimental strategies developed to evaluate the various elements of the dopamine system in the human brain with PET and their applications to clinical research. 254 refs., 7 figs., 3 tabs.

  16. A current view of serotonin transporters

    PubMed Central

    De Felice, Louis J.

    2016-01-01

    Serotonin transporters (SERTs) are largely recognized for one aspect of their function—to transport serotonin back into the presynaptic terminal after its release. Another aspect of their function, however, may be to generate currents large enough to have physiological consequences. The standard model for electrogenic transport is the alternating access model, in which serotonin is transported with a fixed ratio of co-transported ions resulting in net charge per cycle. The alternating access model, however, cannot account for all the observed currents through SERT or other monoamine transporters.  Furthermore, SERT agonists like ecstasy or antagonists like fluoxetine generate or suppress currents that the standard model cannot support.  Here we survey evidence for a channel mode of transport in which transmitters and ions move through a pore. Available structures for dopamine and serotonin transporters, however, provide no evidence for a pore conformation, raising questions of whether the proposed channel mode actually exists or whether the structural data are perhaps missing a transient open state. PMID:27540474

  17. Plasma Dopamine-Beta-Hydroxylase as an Index of Peripheral Noradrenergic Activity

    DTIC Science & Technology

    1981-08-17

    ABSTRACT Tit le of Dissertation: Plasma Dopamine-Beta- Hydroxylase as an Index of Peripheral Noradrenergic Act iv i ty John P. A f f ron t i...Pharmacology Dopamine-Beta- Hydroxylase (DBH) (E .C . I .14.17.1) is the biosynthetic enzyme for norepinephrine and is released with the neurotransmitter dur...lu id DBH as an index of central non- adrenergic act ivi ty is addressed. PLASMA DOPAMINE-BETA- HYDROXYLASE ACTIVITY AS AN INDEX OF PERIPHERAL

  18. Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood

    PubMed Central

    Ng, Joanne; Zhen, Juan; Meyer, Esther; Erreger, Kevin; Li, Yan; Kakar, Naseebullah; Ahmad, Jamil; Thiele, Holger; Kubisch, Christian; Rider, Nicholas L.; Holmes Morton, D.; Strauss, Kevin A.; Puffenberger, Erik G.; D’Agnano, Daniela; Anikster, Yair; Carducci, Claudia; Hyland, Keith; Rotstein, Michael; Leuzzi, Vincenzo; Borck, Guntram; Reith, Maarten E. A.

    2014-01-01

    Dopamine transporter deficiency syndrome due to SLC6A3 mutations is the first inherited dopamine ‘transportopathy’ to be described, with a classical presentation of early infantile-onset progressive parkinsonism dystonia. In this study we have identified a new cohort of patients with dopamine transporter deficiency syndrome, including, most significantly, atypical presentation later in childhood with a milder disease course. We report the detailed clinical features, molecular genetic findings and in vitro functional investigations undertaken for adult and paediatric cases. Patients presenting with parkinsonism dystonia or a neurotransmitter profile characteristic of dopamine transporter deficiency syndrome were recruited for study. SLC6A3 mutational analysis was undertaken in all patients. The functional consequences of missense variants on the dopamine transporter were evaluated by determining the effect of mutant dopamine transporter on dopamine uptake, protein expression and amphetamine-mediated dopamine efflux using an in vitro cellular heterologous expression system. We identified eight new patients from five unrelated families with dopamine transporter deficiency syndrome. The median age at diagnosis was 13 years (range 1.5–34 years). Most significantly, the case series included three adolescent males with atypical dopamine transporter deficiency syndrome of juvenile onset (outside infancy) and progressive parkinsonism dystonia. The other five patients in the cohort presented with classical infantile-onset parkinsonism dystonia, with one surviving into adulthood (currently aged 34 years) and labelled as having ‘juvenile parkinsonism’. All eight patients harboured homozygous or compound heterozygous mutations in SLC6A3, of which the majority are previously unreported variants. In vitro studies of mutant dopamine transporter demonstrated multifaceted loss of dopamine transporter function. Impaired dopamine uptake was universally present, and more

  19. Serotonin receptors involved in antidepressant effects.

    PubMed

    Artigas, Francesc

    2013-01-01

    The neurotransmitter serotonin (5-hdroxytryptamine; 5-HT) has been implicated in the pathophysiology and treatment of major depression since the serendipitous discovery of antidepressant drugs in the 1950s. However, despite the generalised use of serotonin-enhancing drugs, such as the selective serotonin reuptake inhibitors (SSRIs) and the dual serotonin and norepinephrine reuptake inhibitors (SNRIs), the exact neurobiological mechanisms involved in the therapeutic action of these drugs are poorly understood. Better knowledge of these mechanisms may help to identify new therapeutic targets and to overcome the two main limitations of current treatments: reduced efficacy and slowness of action. Here I review the preclinical and clinical evidence supporting the involvement of different 5-HT receptors in the therapeutic action of antidepressant drugs. Presynaptic 5-HT(1A) and 5-HT(1B) autoreceptors play a major detrimental role in antidepressant treatments, as their activation by the excess of the active (extracellular) 5-HT fraction produced by serotonin transporter (SERT) blockade reduces presynaptic serotonergic function. Conversely, stimulation of postsynaptic 5-HT(1A) receptors in corticolimbic networks appears beneficial for the antidepressant action. The 5-HT(2) receptor family is also involved as 5-HT(2A/2C) receptor blockade improves the antidepressant action of SSRIs, and recent data suggest that 5-HT(2B) receptor activation enhances serotonergic activity. Less is known from the rest of postsynaptic 5-HT receptors. However, 5-HT(3) receptor blockade augments the 5-HT increase evoked by SERT inhibition, and 5-HT(4) receptor activation may have antidepressant effects on its own. Finally, blockade of 5-HT(6) and 5-HT(7) receptors appears also to augment the antidepressant effects of SERT inhibition.

  20. Direct affinity of dopamine to lipid membranes investigated by Nuclear Magnetic Resonance spectroscopy.

    PubMed

    Matam, Yashasvi; Ray, Bruce D; Petrache, Horia I

    2016-04-08

    Dopamine, a naturally occurring neurotransmitter, plays an important role in the brain's reward system and acts on sensory receptors in the brain. Neurotransmitters are contained in lipid membraned vesicles and are released by exocytosis. All neurotransmitters interact with transport and receptor proteins in glial cells, on neuronal dendrites, and at the axonal button, and also must interact with membrane lipids. However, the extent of direct interaction between lipid membranes in the absence of receptors and transport proteins has not been extensively investigated. In this report, we use UV and NMR spectroscopy to determine the affinity and the orientation of dopamine interacting with lipid vesicles made of either phosphatidylcholine (PC) or phosphatidylserine (PS) lipids which are primary lipid components of synaptic vesicles. We quantify the interaction of dopamine's aromatic ring with lipid membranes using our newly developed method that involves reference spectra in hydrophobic environments. Our measurements show that dopamine interacts with lipid membranes primarily through the aromatic side opposite to the hydroxyl groups, with this aromatic side penetrating deeper into the hydrophobic region of the membrane. Since dopamine's activity involves its release into extracellular space, we have used our method to also investigate dopamine's release from lipid vesicles. We find that dopamine trapped inside PC and PS vesicles is released into the external solution despite its affinity to membranes. This result suggests that dopamine's interaction with lipid membranes is complex and involves both binding as well as permeation through lipid bilayers, a combination that could be an effective trigger for apoptosis of dopamine-generating cells.

  1. Increased expression of the dopamine transporter leads to loss of dopamine neurons, oxidative stress and l-DOPA reversible motor deficits.

    PubMed

    Masoud, S T; Vecchio, L M; Bergeron, Y; Hossain, M M; Nguyen, L T; Bermejo, M K; Kile, B; Sotnikova, T D; Siesser, W B; Gainetdinov, R R; Wightman, R M; Caron, M G; Richardson, J R; Miller, G W; Ramsey, A J; Cyr, M; Salahpour, A

    2015-02-01

    The dopamine transporter is a key protein responsible for regulating dopamine homeostasis. Its function is to transport dopamine from the extracellular space into the presynaptic neuron. Studies have suggested that accumulation of dopamine in the cytosol can trigger oxidative stress and neurotoxicity. Previously, ectopic expression of the dopamine transporter was shown to cause damage in non-dopaminergic neurons due to their inability to handle cytosolic dopamine. However, it is unknown whether increasing dopamine transporter activity will be detrimental to dopamine neurons that are inherently capable of storing and degrading dopamine. To address this issue, we characterized transgenic mice that over-express the dopamine transporter selectively in dopamine neurons. We report that dopamine transporter over-expressing (DAT-tg) mice display spontaneous loss of midbrain dopamine neurons that is accompanied by increases in oxidative stress markers, 5-S-cysteinyl-dopamine and 5-S-cysteinyl-DOPAC. In addition, metabolite-to-dopamine ratios are increased and VMAT2 protein expression is decreased in the striatum of these animals. Furthermore, DAT-tg mice also show fine motor deficits on challenging beam traversal that are reversed with l-DOPA treatment. Collectively, our findings demonstrate that even in neurons that routinely handle dopamine, increased uptake of this neurotransmitter through the dopamine transporter results in oxidative damage, neuronal loss and l-DOPA reversible motor deficits. In addition, DAT over-expressing animals are highly sensitive to MPTP-induced neurotoxicity. The effects of increased dopamine uptake in these transgenic mice could shed light on the unique vulnerability of dopamine neurons in Parkinson's disease.

  2. Increased expression of the dopamine transporter leads to loss of dopamine neurons, oxidative stress and L-DOPA reversible motor deficits

    PubMed Central

    Masoud, ST; Vecchio, LM; Bergeron, Y; Hossain, MM; Nguyen, LT; Bermejo, MK; Kile, B; Sotnikova, TD; Siesser, WB; Gainetdinov, RR; Wightman, RM; Caron, MG; Richardson, JR; Miller, GW; Ramsey, AJ; Cyr, M; Salahpour, A

    2015-01-01

    The dopamine transporter is a key protein responsible for regulating dopamine homeostasis. Its function is to transport dopamine from the extracellular space into the presynaptic neuron. Studies have suggested that accumulation of dopamine in the cytosol can trigger oxidative stress and neurotoxicity. Previously, ectopic expression of the dopamine transporter was shown to cause damage in non-dopaminergic neurons due to their inability to handle cytosolic dopamine. However, it is unknown whether increasing dopamine transporter activity will be detrimental to dopamine neurons that are inherently capable of storing and degrading dopamine. To address this issue, we characterized transgenic mice that over-express the dopamine transporter selectively in dopamine neurons. We report that dopamine transporter over-expressing (DAT-tg) mice display spontaneous loss of midbrain dopamine neurons that is accompanied by increases in oxidative stress markers, 5-S-cysteinyl-dopamine and 5-S-cysteinyl-DOPAC. In addition, metabolite-to-dopamine ratios are increased and VMAT2 protein expression is decreased in the striatum of these animals. Furthermore, DAT-tg mice also show fine motor deficits on challenging beam traversal that are reversed with L-DOPA treatment. Collectively, our findings demonstrate that even in neurons that routinely handle dopamine, increased uptake of this neurotransmitter through the dopamine transporter results in oxidative damage, neuronal loss and LDOPA reversible motor deficits. In addition, DAT over-expressing animals are highly sensitive to MPTP-induced neurotoxicity. The effects of increased dopamine uptake in these transgenic mice could shed light on the unique vulnerability of dopamine neurons in Parkinson’s disease. PMID:25447236

  3. Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

    PubMed Central

    Gaskill, Peter J.; Yano, Hideaki H.; Kalpana, Ganjam V.; Javitch, Jonathan A.; Berman, Joan W.

    2014-01-01

    Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers. PMID:25268786

  4. The identification of a selective dopamine D2 partial agonist, D3 antagonist displaying high levels of brain exposure.

    PubMed

    Holmes, Ian P; Blunt, Richard J; Lorthioir, Olivier E; Blowers, Stephen M; Gribble, Andy; Payne, Andrew H; Stansfield, Ian G; Wood, Martyn; Woollard, Patrick M; Reavill, Charlie; Howes, Claire M; Micheli, Fabrizio; Di Fabio, Romano; Donati, Daniele; Terreni, Silvia; Hamprecht, Dieter; Arista, Luca; Worby, Angela; Watson, Steve P

    2010-03-15

    The identification of a highly selective D(2) partial agonist, D(3) antagonist tool molecule which demonstrates high levels of brain exposure and selectivity against an extensive range of dopamine, serotonin, adrenergic, histamine, and muscarinic receptors is described.

  5. Monitoring serotonin signaling on a subsecond time scale

    PubMed Central

    Dankoski, Elyse C.; Wightman, R. Mark

    2013-01-01

    Serotonin modulates a variety of processes throughout the brain, but it is perhaps best known for its involvement in the etiology and treatment of depressive disorders. Microdialysis studies have provided a clear picture of how ambient serotonin levels fluctuate with regard to behavioral states and pharmacological manipulation, and anatomical and electrophysiological studies describe the location and activity of serotonin and its targets. However, few techniques combine the temporal resolution, spatial precision, and chemical selectivity to directly evaluate serotonin release and uptake. Fast-scan cyclic voltammetry (FSCV) is an electrochemical method that can detect minute changes in neurotransmitter concentration on the same temporal and spatial dimensions as extrasynaptic neurotransmission. Subsecond measurements both in vivo and in brain slice preparations enable us to tease apart the processes of release and uptake. These studies have particularly highlighted the significance of regulatory mechanisms to proper functioning of the serotonin system. This article will review the findings of FSCV investigations of serotonergic neurotransmission and discuss this technique's potential in future studies of the serotonin system. PMID:23760548

  6. Biosensors for brain trauma and dual laser doppler flowmetry: enoxaparin simultaneously reduces stroke-induced dopamine and blood flow while enhancing serotonin and blood flow in motor neurons of brain, in vivo.

    PubMed

    Broderick, Patricia A; Kolodny, Edwin H

    2011-01-01

    Neuromolecular Imaging (NMI) based on adsorptive electrochemistry, combined with Dual Laser Doppler Flowmetry (LDF) is presented herein to investigate the brain neurochemistry affected by enoxaparin (Lovenox(®)), an antiplatelet/antithrombotic medication for stroke victims. NMI with miniature biosensors enables neurotransmitter and neuropeptide (NT) imaging; each NT is imaged with a response time in milliseconds. A semiderivative electronic reduction circuit images several NT's selectively and separately within a response time of minutes. Spatial resolution of NMI biosensors is in the range of nanomicrons and electrochemically-induced current ranges are in pico- and nano-amperes. Simultaneously with NMI, the LDF technology presented herein operates on line by illuminating the living brain, in this example, in dorso-striatal neuroanatomic substrates via a laser sensor with low power laser light containing optical fiber light guides. NMI biotechnology with BRODERICK PROBE(®) biosensors has a distinct advantage over conventional electrochemical methodologies both in novelty of biosensor formulations and on-line imaging capabilities in the biosensor field. NMI with unique biocompatible biosensors precisely images NT in the body, blood and brain of animals and humans using characteristic experimentally derived half-wave potentials driven by oxidative electron transfer. Enoxaparin is a first line clinical treatment prescribed to halt the progression of acute ischemic stroke (AIS). In the present studies, BRODERICK PROBE(®) laurate biosensors and LDF laser sensors are placed in dorsal striatum (DStr) dopaminergic motor neurons in basal ganglia of brain in living animals; basal ganglia influence movement disorders such as those correlated with AIS. The purpose of these studies is to understand what is happening in brain neurochemistry and cerebral blood perfusion after causal AIS by middle cerebral artery occlusion in vivo as well as to understand consequent enoxaparin

  7. Neurotransmitter Specific, Cellular-Resolution Functional Brain Mapping Using Receptor Coated Nanoparticles: Assessment of the Possibility

    PubMed Central

    Forati, Ebrahim; Sabouni, Abas; Ray, Supriyo; Head, Brian; Schoen, Christian; Sievenpiper, Dan

    2015-01-01

    Receptor coated resonant nanoparticles and quantum dots are proposed to provide a cellular-level resolution image of neural activities inside the brain. The functionalized nanoparticles and quantum dots in this approach will selectively bind to different neurotransmitters in the extra-synaptic regions of neurons. This allows us to detect neural activities in real time by monitoring the nanoparticles and quantum dots optically. Gold nanoparticles (GNPs) with two different geometries (sphere and rod) and quantum dots (QDs) with different sizes were studied along with three different neurotransmitters: dopamine, gamma-Aminobutyric acid (GABA), and glycine. The absorption/emission spectra of GNPs and QDs before and after binding of neurotransmitters and their corresponding receptors are reported. The results using QDs and nanorods with diameter 25nm and aspect rations larger than three were promising for the development of the proposed functional brain mapping approach. PMID:26717196

  8. Effect of 19 MHz RF Radiation on Neurotransmitters in Mouse Brain.

    DTIC Science & Technology

    Mice were exposed to 19 MHz radiofrequency radiation and then euthanized by microwave-heating brain inactivation. Brain levels of 5-hydroxyindole acetic acid (5HIAA), homovanillic acid (HVA), serotonin (5HT), norepinephrine (NE), and dopamine (DA) were not altered by this radiation. Brain concentration of 5HIAA, 5 HT, NE, and DA was higher when control animals were euthanized by microwave inactivation than by cervical dislocation.

  9. How Addictive Drugs Disrupt Presynaptic Dopamine Neurotransmission

    PubMed Central

    Sulzer, David

    2011-01-01

    The fundamental principle that unites addictive drugs appears to be that each enhances synaptic dopamine by means that dissociate it from normal behavioral control, so that they act to reinforce their own acquisition. This occurs via the modulation of synaptic mechanisms involved in learning, including enhanced excitation or disinhibition of dopamine neuron activity, blockade of dopamine reuptake, and altering the state of the presynaptic terminal to enhance evoked over basal transmission. Amphetamines offer an exception to such modulation in that they combine multiple effects to produce non-exocytic stimulation-independent release of neurotransmitter via reverse transport independent from normal presynaptic function. Questions on the molecular actions of addictive drugs, prominently including the actions of alcohol and solvents, remain unresolved, but their ability to co-opt normal presynaptic functions helps to explain why treatment for addiction has been challenging. PMID:21338876

  10. Dopamine D3 receptor antagonism contributes to blonanserin-induced cortical dopamine and acetylcholine efflux and cognitive improvement.

    PubMed

    Huang, Mei; Kwon, Sunoh; Oyamada, Yoshihiro; Rajagopal, Lakshmi; Miyauchi, Masanori; Meltzer, Herbert Y

    2015-11-01

    Blonanserin is a novel atypical antipsychotic drug (APD), which, unlike most atypical APDs, has a slightly higher affinity for dopamine (DA) D2 than serotonin (5-HT)2A receptors, and is an antagonist at both, as well as at D3 receptors. The effects of atypical APDs to enhance rodent cortical, hippocampal, limbic, and dorsal striatal (dSTR) DA and acetylcholine (ACh) release, contribute to their ability to improve novel object recognition (NOR) in rodents treated with sub-chronic (sc) phencyclidine (PCP) and cognitive impairment associated with schizophrenia (CIAS). Here we determined the ability of blonanserin, the D3 antagonist NGB 2904, and the typical APD, haloperidol, a D2 antagonist, to enhance neurotransmitter efflux in the medial prefrontal cortex (mPFC) and dSTR of mice, and to ameliorate the scPCP-induced deficit in NOR in rats. Blonanserin, 10mg/kg, i.p., increased DA, norepinephrine (NE), and ACh efflux in mPFC and dSTR. NGB 2904, 3mg/kg, increased DA and ACh, but not NE, efflux in mPFC, and DA, but not ACh, efflux in dSTR. Haloperidol increased DA and NE efflux in dSTR only. The selective D3 agonist PD 128907 partially blocked the blonanserin-induced cortical ACh, DA, NE and striatal DA efflux. NGB 2904, 3mg/kg, like blonanserin, 1mg/kg, and the combination of sub-effective doses of NGB 2904 and blonanserin (both 0.3mg/kg), ameliorated the scPCP-induced NOR deficit in rats. These results suggest that D3 receptor blockade may contribute to the ability of blonanserin to increase cortical DA and ACh efflux, as well as to restore NOR and improve CIAS.

  11. Dopamine pathway imbalance in mice lacking Magel2, a Prader-Willi syndrome candidate gene.

    PubMed

    Luck, Chloe; Vitaterna, Martha H; Wevrick, Rachel

    2016-08-01

    The etiology of abnormal eating behaviors, including binge-eating disorder, is poorly understood. The neural circuits modulating the activities of the neurotransmitters dopamine and serotonin are proposed to be dysfunctional in individuals suffering from eating disorders. Prader-Willi syndrome is a neurodevelopmental disorder that causes extreme food seeking and binge-eating behaviors together with reduced satiety. One of the genes implicated in Prader-Willi syndrome, Magel2, is highly expressed in the regions of the brain that control appetite. Our objective was to examine behaviors relevant to feeding and the neural circuits controlling feeding in a mouse model of Prader-Willi syndrome that lacks expression of the Magel2 gene. We performed behavioral tests related to dopaminergic function, measuring cocaine-induced hyperlocomotion, binge eating, and saccharin-induced anhedonia in Magel2-deficient mice. Next, we analyzed dopaminergic neurons in various brain regions and compared these findings between genotypes. Finally, we examined biochemical markers in the brain under standard diet, high-fat diet, and withdrawal from a high-fat diet conditions. We identified abnormal behaviors and biomarkers reflecting dopaminergic dysfunction in mice lacking Magel2. Our results provide a biological framework for clinical studies of dopaminergic function in children with Prader-Willi syndrome, and may also provide insight into binge-eating disorders that occur in the general population. (PsycINFO Database Record

  12. meso-Transdiene analogs inhibit vesicular monoamine transporter-2 function and methamphetamine-evoked dopamine release.

    PubMed

    Horton, David B; Siripurapu, Kiran B; Norrholm, Seth D; Culver, John P; Hojahmat, Marhaba; Beckmann, Joshua S; Harrod, Steven B; Deaciuc, Agripina G; Bardo, Michael T; Crooks, Peter A; Dwoskin, Linda P

    2011-03-01

    Lobeline, a nicotinic receptor antagonist and neurotransmitter transporter inhibitor, is a candidate pharmacotherapy for methamphetamine abuse. meso-Transdiene (MTD), a lobeline analog, lacks nicotinic receptor affinity, retains affinity for vesicular monoamine transporter 2 (VMAT2), and, surprisingly, has enhanced affinity for dopamine (DA) and serotonin transporters [DA transporter (DAT) and serotonin transporter (SERT), respectively]. In the current study, MTD was evaluated for its ability to decrease methamphetamine self-administration in rats relative to food-maintained responding. MTD specifically decreased methamphetamine self-administration, extending our previous work. Classical structure-activity relationships revealed that more conformationally restricted MTD analogs enhanced VMAT2 selectivity and drug likeness, whereas affinity at the dihydrotetrabenazine binding and DA uptake sites on VMAT2 was not altered. Generally, MTD analogs exhibited 50- to 1000-fold lower affinity for DAT and were equipotent or had 10-fold higher affinity for SERT, compared with MTD. Representative analogs from the series potently and competitively inhibited [(3)H]DA uptake at VMAT2. (3Z,5Z)-3,5-bis(2,4-dichlorobenzylidene)-1-methylpiperidine (UKMH-106), the 3Z,5Z-2,4-dichlorophenyl MTD analog, had improved selectivity for VMAT2 over DAT and importantly inhibited methamphetamine-evoked DA release from striatal slices. In contrast, (3Z,5E)-3,5-bis(2,4-dichlorobenzylidene)-1-methylpiperidine (UKMH-105), the 3Z,5E-geometrical isomer, inhibited DA uptake at VMAT2, but did not inhibit methamphetamine-evoked DA release. Taken together, these results suggest that these geometrical isomers interact at alternate sites on VMAT2, which are associated with distinct pharmacophores. Thus, structural modification of the MTD molecule resulted in analogs exhibiting improved drug likeness and improved selectivity for VMAT2, as well as the ability to decrease methamphetamine-evoked DA release

  13. A new balancing act: The many roles of melatonin and serotonin in plant growth and development.

    PubMed

    Erland, Lauren A E; Murch, Susan J; Reiter, Russel J; Saxena, Praveen K

    2015-01-01

    Melatonin and serotonin are indoleamines first identified as neurotransmitters in vertebrates; they have now been found to be ubiquitously present across all forms of life. Both melatonin and serotonin were discovered in plants several years after their discovery in mammals, but their presence has now been confirmed in almost all plant families. The mechanisms of action of melatonin and serotonin are still poorly defined. Melatonin and serotonin possess important roles in plant growth and development, including functions in chronoregulation and modulation of reproductive development, control of root and shoot organogenesis, maintenance of plant tissues, delay of senescence, and responses to biotic and abiotic stresses. This review focuses on the roles of melatonin and serotonin as a novel class of plant growth regulators. Their roles in reproductive and vegetative plant growth will be examined including an overview of current hypotheses and knowledge regarding their mechanisms of action in specific responses.

  14. A new balancing act: The many roles of melatonin and serotonin in plant growth and development

    PubMed Central

    Erland, Lauren A E; Murch, Susan J; Reiter, Russel J; Saxena, Praveen K

    2015-01-01

    Melatonin and serotonin are indoleamines first identified as neurotransmitters in vertebrates; they have now been found to be ubiquitously present across all forms of life. Both melatonin and serotonin were discovered in plants several years after their discovery in mammals, but their presence has now been confirmed in almost all plant families. The mechanisms of action of melatonin and serotonin are still poorly defined. Melatonin and serotonin possess important roles in plant growth and development, including functions in chronoregulation and modulation of reproductive development, control of root and shoot organogenesis, maintenance of plant tissues, delay of senescence, and responses to biotic and abiotic stresses. This review focuses on the roles of melatonin and serotonin as a novel class of plant growth regulators. Their roles in reproductive and vegetative plant growth will be examined including an overview of current hypotheses and knowledge regarding their mechanisms of action in specific responses. PMID:26418957

  15. Salvinorin A exerts opposite presynaptic controls on neurotransmitter exocytosis from mouse brain nerve terminals.

    PubMed

    Grilli, Massimo; Neri, Elisa; Zappettini, Stefania; Massa, Francesca; Bisio, Angela; Romussi, Giovanni; Marchi, Mario; Pittaluga, Anna

    2009-01-01

    We investigated the effects of salvinorin A on the basal and the 12 mM K(+)-evoked release of preloaded [(3)H]noradenaline ([(3)H]NA) and [(3)H]serotonin ([(3)H]5-HT) from mouse hippocampal nerve terminals (synaptosomes), as well as on the basal and 12mM K(+)-evoked release of preloaded [(3)H]dopamine ([(3)H]DA) from mouse striatal and prefrontal cortex (PFc) synaptosomes. Salvinorin A (0.1-1000 nM) failed to affect the basal release of amines, but inhibited the 12 mM K(+)-evoked, Ca(2+)-dependent, exocytotic-like release of [(3)H]5-HT and [(3)H]DA. At the same concentration, salvinorin A facilitated the 12 mM K(+)-evoked, Ca(2+)-dependent, exocytotic-like release of [(3)H]NA. These effects could not be observed in pertussis toxin (PTx) entrapped synaptosomes. The broad spectrum kappa-opioid receptor (KOR) antagonist norbinaltorphimine (norBNI, 1-100 nM) antagonized the inhibition of [(3)H]5-HT and [(3)H]DA exocytosis as well as the facilitation of [(3)H]NA overflow induced by 100 nM salvinorin A. The KOR agonist U69593 (1-100 nM) mimicked salvinorin A in inhibiting [(3)H]5-HT and of [(3)H]DA exocytosis, its effect being prevented by norBNI, but leaving unchanged the K(+)-evoked release of [(3)H]NA. The effects of Salvinorin A on neurotransmitter exocytosis were not prevented by the selective mu opioid (MOR) receptor antagonist CTAP (10-100 nM), whereas facilitation of [(3)H]NA exocytosis, but not inhibition of [(3)H]5-HT and [(3)H]DA K(+)-evoked release, was counteracted by the delta opioid receptor (DOR) antagonist naltrindole (1-100 nM). We conclude that salvinorin A presynaptically modulates central NA, 5-HT, and DA exocytosis evoked by a mild depolarizing stimulus by acting at presynaptic opioid receptors having different pharmacological profiles.

  16. Larvae of small white butterfly, Pieris rapae, express a novel serotonin receptor

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The biogenic amine serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter in vertebrates and invertebrates. It acts in regulation and modulation of many physiological and behavioral processes through G protein-coupled receptors. Insects express five 5-HT receptor subtypes that share high simila...

  17. Effects of Early Serotonin Programming on Fear Response, Memory and Aggression

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The neurotransmitter serotonin (5-HT) also acts as a neurogenic compound in the developing brain. Early administration of a 5-HT agonist could alter development of serotonergic circuitry, altering behaviors mediated by 5-HT signaling, including memory, fear and aggression. The present study was desi...

  18. Terahertz identification and quantification of neurotransmitter and neurotrophy mixture

    PubMed Central

    Peng, Yan; Yuan, Xiaorong; Zou, Xiang; Chen, Wanqing; Huang, Hui; Zhao, Hongwei; Song, Bo; Chen, Liang; Zhu, Yiming

    2016-01-01

    Terahertz spectroscopy has been widely used for investigating the fingerprint spectrum of different substances. For cancerous tissues, the greatest difficulty is the absorption peaks of various substances contained in tissues overlap with each other, which are hard to identify and quantitative analyze. As a result, it is very hard to measure the presence of cancer cell and then to diagnose accurately. In this paper, we select three typical neurotransmitters (γ-aminobutyric acid, L-glutamic acid, dopamine hydrochloride) and two typical metabolites (inositol and creatine) in neurons to measure their terahertz spectra with different mixture ratios. By choosing characteristic absorption peaks, removing baseline and using the least square method, we can identify the components and proportions of each mixture, where the goodness of fit to practical situation is up to 94%. These results provide important evidences for identifying nerve substances and obtaining exact quantitative analysis. PMID:27895988

  19. Effects of delayed treatment with nebracetam on neurotransmitters in brain regions after microsphere embolism in rats

    PubMed Central

    Takeo, Satoshi; Hayashi, Hideki; Miyake, Keiko; Takagi, Kaori; Tadokoro, Mina; Takagi, Norio; Oshikawa, Sayuri

    1997-01-01

    The effects of delayed treatment with nebracetam, a novel nootropic drug, on neurotransmitters of brain regions were examined in rats with microsphere embolism-induced cerebral ischaemia. Cerebral ischaemia was induced by administration of 900 microspheres (48 μm) into the internal carotid artery. The rats with stroke-like symptoms were treated p.o. with 30 mg kg−1 nebracetam twice daily. The levels of acetylcholine, dopamine, noradrenaline, 5-hydroxytryptamine (5-HT) and their metabolites in the cerebral cortex, striatum and hippocampus of animals with microsphere embolism were determined by high performance liquid chromatography (h.p.l.c.) on the 3rd and 7th days after the operation. Although the microsphere embolism induced significant changes in most of the neurotransmitters and some of their metabolites in the brain regions, the delayed treatment with nebracetam partially restored only the hippocampal 5-HT and the striatal dopamine metabolite contents on the 3rd day. The hippocampal in vivo 5-HT synthesis, but not the striatal dopamine synthesis, was attenuated in rats with microsphere embolism on the 3rd day, but was restored by treatment with nebracetam. In vivo striatal dopamine turnover rate of the rats with microsphere embolism was inhibited on the 3rd day irrespective of treatment with nebracetam. The present study provides evidence for a possible action of nebracetam on 5-HT metabolism in the ischaemic brain. PMID:9179389

  20. Sex- and SERT-mediated differences in stimulated serotonin revealed by fast microdialysis.

    PubMed

    Yang, Hongyan; Sampson, Maureen M; Senturk, Damla; Andrews, Anne M

    2015-08-19

    In vivo microdialysis is widely used to investigate how neurotransmitter levels in the brain respond to biologically relevant challenges. Here, we combined recent improvements in the temporal resolution of online sampling and analysis for serotonin with a brief high-K(+) stimulus paradigm to study the dynamics of evoked release. We observed stimulated serotonin overflow with high-K(+) pulses as short as 1 min when determined with 2-min dialysate sampling in ventral striatum. Stimulated serotonin levels in female mice during the high estrogen period of the estrous cycle were similar to serotonin levels in male mice. By contrast, stimulated serotonin overflow during the low estrogen period in female mice was increased to levels similar to those in male mice with local serotonin transporter (SERT) inhibition. Stimulated serotonin levels in mice with constitutive loss of SERT were considerably higher yet, pointing to neuroadaptive potentiation of serotonin release. When combined with brief K(+) stimulation, fast microdialysis reveals dynamic changes in extracellular serotonin levels associated with normal hormonal cycles and pharmacologic vs genetic loss of SERT function.

  1. Turn-On Near-Infrared Fluorescent Sensor for Selectively Imaging Serotonin.

    PubMed

    Hettie, Kenneth S; Glass, Timothy E

    2016-01-20

    A molecular imaging tool that provides for the direct visualization of serotonin would significantly aid in the investigation of neuropsychiatric disorders that are attributed to its neuronal dysregulation. Here, the design, synthesis, and evaluation of NeuroSensor 715 (NS715) is presented. NS715 is the first molecular sensor that exhibits a turn-on near-infrared fluorescence response toward serotonin. Density functional theory calculations facilitated the design of a fluorophore based on a coumarin-3-aldehyde scaffold that derives from an electron-rich 1,2,3,4-tetrahydroquinoxaline framework, which provides appropriate energetics to prevent the hydroxyindole moiety of serotonin from quenching its fluorescence emission. Spectroscopic studies revealed that NS715 produces an 8-fold fluorescence enhancement toward serotonin with an emission maximum at 715 nm. Accompanying binding studies indicated NS715 displays a 19-fold selective affinity for serotonin and a modest affinity for catecholamines over other primary-amine neurotransmitters. The utility of NS715 toward neuroimaging applications was validated by selectively labeling and directly imaging norepinephrine within secretory vesicles using live chromaffin cells, which serve as a model system for specialized neurons that synthesize, package, and release only a single, unique type of neurotransmitter. In addition, NS715 effectively differentiated between cell populations that express distinct neurotransmitter phenotypes.

  2. Serotonin as a Modulator of Glutamate- and GABA-Mediated Neurotransmission: Implications in Physiological Functions and in Pathology

    PubMed Central

    Ciranna, L

    2006-01-01

    The neurotransmitter serotonin (5-HT), widely distributed in the central nervous system (CNS), is involved in a large variety of physiological functions. In several brain regions 5-HT is diffusely released by volume transmission and behaves as a neuromodulator rather than as a “classical” neurotransmitter. In some cases 5-HT is co-localized in the same nerve terminal with other neurotransmitters and reciprocal interactions take place. This review will focus on the modulatory action of 5-HT on the effects of glutamate and γ-amino-butyric acid (GABA), which are the principal neurotransmitters mediating respectively excitatory and inhibitory signals in the CNS. Examples of interaction at pre-and/or post-synaptic levels will be illustrated, as well as the receptors involved and their mechanisms of action. Finally, the physiological meaning of neuromodulatory effects of 5-HT will be briefly discussed with respect to pathologies deriving from malfunctioning of serotonin system. PMID:18615128

  3. Hyperforin represents the neurotransmitter reuptake inhibiting constituent of hypericum extract.

    PubMed

    Müller, W E; Singer, A; Wonnemann, M; Hafner, U; Rolli, M; Schäfer, C

    1998-06-01

    Hydroalcoholic hypericum extract inhibits the synaptosomal uptake of serotonin, norepinephrine, and dopamine with about similar affinities and leads to a significant down-regulation of cortical beta-adrenoceptors and 5-HT2-receptors after subchronic treatment of rats. While neither hypericine nor kaempferol did show any reuptake inhibiting properties, hyperforin was identified as the unspecific reuptake inhibitor of hypericum extracts with half-maximal inhibitory concentrations for the three synaptosomal uptake systems mentioned above between 80 and 200 nmol/l. Moreover, a hyperforin-enriched (38%) CO2 extract also leads to a significant beta-receptor down-regulation after subchronic treatment. The data suggest hyperforin as the active principle of hypericum extracts in biochemical models of antidepressant activity.

  4. Activity patterns of serotonin neurons underlying cognitive flexibility

    PubMed Central

    Matias, Sara; Lottem, Eran; Dugué, Guillaume P; Mainen, Zachary F

    2017-01-01

    Serotonin is implicated in mood and affective disorders. However, growing evidence suggests that a core endogenous role is to promote flexible adaptation to changes in the causal structure of the environment, through behavioral inhibition and enhanced plasticity. We used long-term photometric recordings in mice to study a population of dorsal raphe serotonin neurons, whose activity we could link to normal reversal learning using pharmacogenetics. We found that these neurons are activated by both positive and negative prediction errors, and thus report signals similar to those proposed to promote learning in conditions of uncertainty. Furthermore, by comparing the cue responses of serotonin and dopamine neurons, we found differences in learning rates that could explain the importance of serotonin in inhibiting perseverative responding. Our findings show how the activity patterns of serotonin neurons support a role in cognitive flexibility, and suggest a revised model of dopamine–serotonin opponency with potential clinical implications. DOI: http://dx.doi.org/10.7554/eLife.20552.001 PMID:28322190

  5. Plasma HVA in Adults with Mental Retardation and Stereotyped Behavior: Biochemical Evidence for a Dopamine Deficiency Model.

    ERIC Educational Resources Information Center

    Lewis, Mark H.; And Others

    1996-01-01

    Assessment of the neurotransmitter dopamine through measurement of the dopamine metabolite homovanillic acid (HVA) in adult subjects with mental retardation and with high rates of body stereotypy (n=12), compulsive behaviors (n=9), or neither (n=12) found lowest HVA concentrations in the stereotypy group and highest in the compulsive group. (DB)

  6. A model of dopamine modulated glutamatergic synapse.

    PubMed

    Di Maio, Vito; Ventriglia, Francesco; Santillo, Silvia

    2015-10-01

    The dopamine neurotransmitter regulates important neural pathways and its action in the brain is very complex. When dopaminergic neurons make synapses on spiny neurons of the striatum nucleus, they tune the responsiveness of glutamatergic synapses by means of the dopamine D1 and D2 receptors. We studied the effect of dopamine D1 receptors on glutamatergic synapse of GABAergic spiny neurons in striatum nucleus where they are located on the neck of the same spine. The action of dopamine consists essentially in promoting the phosphorylation of AMPA and NMDA receptors thus increasing the Excitatory Post Synaptic Current peak amplitude. The consequence is a cooperative effect of glutamatergic and dopaminergic synapses for the regulation of the GABAergic neuronal code. The mechanisms by which the phosphorylation induces the increase of the EPSC amplitude still remain unclear although the lack of this regulation can be involved in several pathologies as, for example, the Parkinson's disease. We tested, by computational experiments based on our model of glutamatergic synapse, three parameters of the synaptic function that could be involved in dopamine action: (a) time binding of glutamate to receptors; (b) open probability of the receptors; and (c) single receptor conductance. For different reasons, any of the three parameters could be responsible of the increased EPSC-dopamine-dependent. Our computational results were compared and discussed with experimental results found in literature. Although for our model both the open probability and the single receptor conductance can reproduce the phosphorylation effect of dopamine, we argue that the dopamine effect consists essentially in an increase of the single receptor conductance due to a 3D rearrangement of the phosphorylated receptors.

  7. RAPID DOPAMINE TRANSMISSION WITHIN THE NUCLEUS ACCUMBENS DRAMATICALLY DIFFERS FOLLOWING MORPHINE AND OXYCODONE DELIVERY

    PubMed Central

    Mabrouk, Omar S.; Lovic, Vedran; Singer, Bryan F.; Kennedy, Robert T.; Aragona, Brandon J.

    2014-01-01

    While most drugs of abuse increase dopamine neurotransmission, rapid neurochemical measurements show that different drugs evoke distinct dopamine release patterns within the nucleus accumbens. Rapid changes in dopamine concentration following psychostimulant administration have been well studied; however, such changes have never been examined following opioid delivery. Here, we provide novel measures of rapid dopamine release following intravenous infusion of two opioids, morphine and oxycodone, in drug naïve rats using fast-scan cyclic voltammetry and rapid (1 min) microdialysis coupled with mass spectrometry. In addition to measuring rapid dopamine transmission, microdialysis HPLC-MS measures changes in GABA, glutamate, monoamines, monoamine metabolites, and several other neurotransmitters. Although both opioids increased dopamine release in the nucleus accumbens, their patterns of drug-evoked dopamine transmission differed dramatically. Oxycodone evoked a robust and stable increase in dopamine concentration and a robust increase in the frequency and amplitude of phasic dopamine release events. Conversely, morphine evoked a brief (~ 1 min) increase in dopamine that was coincident with a surge in GABA concentration and then both transmitters returned to baseline levels. Thus, by providing rapid measures of neurotransmission, this study reveals previously unknown differences in opioid-induced neurotransmitter signaling. Investigating these differences may be essential for understanding how these two drugs of abuse could differentially usurp motivational circuitry and powerfully influence behavior. PMID:25208732

  8. Stress, neurotransmitters, corticosterone and body-brain integration.

    PubMed

    Mora, Francisco; Segovia, Gregorio; Del Arco, Alberto; de Blas, Marta; Garrido, Pedro

    2012-10-02

    Stress can be defined as a brain-body reaction towards stimuli arising from the environment or from internal cues that are interpreted as a disruption of homeostasis. The organization of the response to a stressful situation involves not only the activity of different types of neurotransmitter systems in several areas of the limbic system, but also the response of neurons in these areas to several other chemicals and hormones, chiefly glucocorticoids, released from peripheral organs and glands. Thus, stress is probably the process through which body-brain integration plays a major role. Here we review first the responses to an acute stress in terms of neurotransmitters such as dopamine, acetylcholine, glutamate and GABA in areas of the brain involved in the regulation of stress responses. These areas include the prefrontal cortex, amygdala, hippocampus and nucleus accumbens and the interaction among those areas. Then, we consider the role of glucocorticoids and review some recent data about the interaction of these steroids with several neurotransmitters in those same areas of the brain. Also the actions of other substances (neuromodulators) released from peripheral organs such as the pancreas, liver or gonads (insulin, IGF-1, estrogens) are reviewed. The role of an environmental enrichment on these same responses is also discussed. Finally a section is devoted to put into perspective all these environmental-brain-body-brain interactions during stress and their consequences on aging. It is concluded that the integrative perspective framed in this review is relevant for better understanding of how the organism responds to stressful challenges and how this can be modified through different environmental conditions during the process of aging. This article is part of a Special Issue entitled: Brain Integration.

  9. Effects of central activation of serotonin 5-HT2A/2C or dopamine D2/3 receptors on the acute and repeated effects of clozapine in the conditioned avoidance response test

    PubMed Central

    Feng, Min; Gao, Jun; Sui, Nan; Li, Ming

    2014-01-01

    Rationale: Acute administration of clozapine (a gold standard of atypical antipsychotics) disrupts avoidance response in rodents, while repeated administration often causes a tolerance effect. Objective: The present study investigated the neuroanatomical basis and receptor mechanisms of acute and repeated effects of clozapine treatment in the conditioned avoidance response test in male Sprague-Dawley rats. Methods: DOI (2,5-dimethoxy-4-iodo-amphetamine, a preferential 5-HT2A/2C agonist) or quinpirole (a preferential dopamine D2/3 agonist) was microinjected into the medial prefrontal cortex (mPFC) or nucleus accumbens shell (NAs), and their effects on the acute and long-term avoidance-disruptive effect of clozapine were tested. Results: Intra-mPFC microinjection of quinpirole enhanced the acute avoidance disruptive effect of clozapine (10 mg/kg, sc), while DOI microinjections reduced it marginally. Repeated administration of clozapine (10 mg/kg, sc) daily for 5 days caused a progressive decrease in its inhibition of avoidance responding, indicating tolerance development. Intra-mPFC microinjection of DOI at 25.0 (but not 5.0) μg/side during this period completely abolished the expression of clozapine tolerance. This was indicated by the finding that clozapine-treated rats centrally infused with 25.0 μg/side DOI did not show higher levels of avoidance responses than the vehicle-treated rats in the clozapine challenge test. Microinjection of DOI into the mPFC immediately before the challenge test also decreased the expression of clozapine tolerance. Conclusions: Acute behavioral effect of clozapine can be enhanced by activation of the D2/3 receptors in the mPFC. Clozapine tolerance expression relies on the neuroplasticity initiated by its antagonist action against 5-HT2A/2C receptors in the mPFC. PMID:25288514

  10. Pituitary adenylate cyclase-activating polypeptide (PACAP) has a neuroprotective function in dopamine-based neurodegeneration in rat and snail parkinsonian models

    PubMed Central

    Kiss, Tibor; Jungling, Adel

    2017-01-01

    ABSTRACT Pituitary adenylate cyclase-activating polypeptide (PACAP) rescues dopaminergic neurons from neurodegeneration and improves motor changes induced by 6-hydroxy-dopamine (6-OHDA) in rat parkinsonian models. Recently, we investigated the molecular background of the neuroprotective effect of PACAP in dopamine (DA)-based neurodegeneration using rotenone-induced snail and 6-OHDA-induced rat models of Parkinson's disease. Behavioural activity, monoamine (DA and serotonin), metabolic enzyme (S-COMT, MB-COMT and MAO-B) and PARK7 protein concentrations were measured before and after PACAP treatment in both models. Locomotion and feeding activity were decreased in rotenone-treated snails, which corresponded well to findings obtained in 6-OHDA-induced rat experiments. PACAP was able to prevent the behavioural malfunctions caused by the toxins. Monoamine levels decreased in both models and the decreased DA level induced by toxins was attenuated by ∼50% in the PACAP-treated animals. In contrast, PACAP had no effect on the decreased serotonin (5HT) levels. S-COMT metabolic enzyme was also reduced but a protective effect of PACAP was not observed in either of the models. Following toxin treatment, a significant increase in MB-COMT was observed in both models and was restored to normal levels by PACAP. A decrease in PARK7 was also observed in both toxin-induced models; however, PACAP had a beneficial effect only on 6-OHDA-treated animals. The neuroprotective effect of PACAP in different animal models of Parkinson's disease is thus well correlated with neurotransmitter, enzyme and protein levels. The models successfully mimic several, but not all etiological properties of the disease, allowing us to study the mechanisms of neurodegeneration as well as testing new drugs. The rotenone and 6-OHDA rat and snail in vivo parkinsonian models offer an alternative method for investigation of the molecular mechanisms of neuroprotective agents, including PACAP. PMID:28067625

  11. Pituitary adenylate cyclase-activating polypeptide (PACAP) has a neuroprotective function in dopamine-based neurodegeneration in rat and snail parkinsonian models.

    PubMed

    Maasz, Gabor; Zrinyi, Zita; Reglodi, Dora; Petrovics, Dora; Rivnyak, Adam; Kiss, Tibor; Jungling, Adel; Tamas, Andrea; Pirger, Zsolt

    2017-02-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) rescues dopaminergic neurons from neurodegeneration and improves motor changes induced by 6-hydroxy-dopamine (6-OHDA) in rat parkinsonian models. Recently, we investigated the molecular background of the neuroprotective effect of PACAP in dopamine (DA)-based neurodegeneration using rotenone-induced snail and 6-OHDA-induced rat models of Parkinson's disease. Behavioural activity, monoamine (DA and serotonin), metabolic enzyme (S-COMT, MB-COMT and MAO-B) and PARK7 protein concentrations were measured before and after PACAP treatment in both models. Locomotion and feeding activity were decreased in rotenone-treated snails, which corresponded well to findings obtained in 6-OHDA-induced rat experiments. PACAP was able to prevent the behavioural malfunctions caused by the toxins. Monoamine levels decreased in both models and the decreased DA level induced by toxins was attenuated by ∼50% in the PACAP-treated animals. In contrast, PACAP had no effect on the decreased serotonin (5HT) levels. S-COMT metabolic enzyme was also reduced but a protective effect of PACAP was not observed in either of the models. Following toxin treatment, a significant increase in MB-COMT was observed in both models and was restored to normal levels by PACAP. A decrease in PARK7 was also observed in both toxin-induced models; however, PACAP had a beneficial effect only on 6-OHDA-treated animals. The neuroprotective effect of PACAP in different animal models of Parkinson's disease is thus well correlated with neurotransmitter, enzyme and protein levels. The models successfully mimic several, but not all etiological properties of the disease, allowing us to study the mechanisms of neurodegeneration as well as testing new drugs. The rotenone and 6-OHDA rat and snail in vivo parkinsonian models offer an alternative method for investigation of the molecular mechanisms of neuroprotective agents, including PACAP.

  12. Dopamine Receptors and Neurodegeneration

    PubMed Central

    Rangel-Barajas, Claudia; Coronel, Israel; Florán, Benjamín

    2015-01-01

    Dopamine (DA) is one of the major neurotransmitters and participates in a number of functions such as motor coordination, emotions, memory, reward mechanism, neuroendocrine regulation etc. DA exerts its effects through five DA receptors that are subdivided in 2 families: D1-like DA receptors (D1 and D5) and the D2-like (D2, D3 and D4). All DA receptors are widely expressed in the central nervous system (CNS) and play an important role in not only in physiological conditions but also pathological scenarios. Abnormalities in the DAergic system and its receptors in the basal ganglia structures are the basis Parkinson’s disease (PD), however DA also participates in other neurodegenerative disorders such as Huntington disease (HD) and multiple sclerosis (MS). Under pathological conditions reorganization of DAergic system has been observed and most of the times, those changes occur as a mechanism of compensation, but in some cases contributes to worsening the alterations. Here we review the changes that occur on DA transmission and DA receptors (DARs) at both levels expression and signals transduction pathways as a result of neurotoxicity, inflammation and in neurodegenerative processes. The better understanding of the role of DA receptors in neuropathological conditions is crucial for development of novel therapeutic approaches to treat alterations related to neurodegenerative diseases. PMID:26425390

  13. What Mechanisms Are Responsible for the Reuptake of Levodopa-Derived Dopamine in Parkinsonian Striatum?

    PubMed Central

    Nishijima, Haruo; Tomiyama, Masahiko

    2016-01-01

    Levodopa is the most effective medication for motor symptoms in Parkinson's disease. However, various motor and non-motor complications are associated with levodopa treatment, resulting from altered levodopa-dopamine metabolism with disease progression and long-term use of the drug. The present review emphasizes the role of monoamine transporters other than the dopamine transporter in uptake of extracellular dopamine in the dopamine-denervated striatum. When dopaminergic neurons are lost and dopamine transporters decreased, serotonin and norepinephrine transporters compensate by increasing uptake of excessive extracellular dopamine in the striatum. Organic cation transporter-3 and plasma membrane monoamine transporter, low affinity, and high capacity transporters, also potentially uptake dopamine when high-affinity transporters do not work normally. Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are often administered to patients with Parkinson's disease presenting with depression, pain or other non-motor symptoms. Thus, it is important to address the potential of these drugs to modify dopamine metabolism and uptake through blockade of the compensatory function of these transporters, which could lead to changes in motor symptoms of Parkinson's disease. PMID:28018168

  14. Mechanism of Paroxetine (Paxil) Inhibition of the Serotonin Transporter

    PubMed Central

    Davis, Bruce A.; Nagarajan, Anu; Forrest, Lucy R.; Singh, Satinder K.

    2016-01-01

    The serotonin transporter (SERT) is an integral membrane protein that exploits preexisting sodium-, chloride-, and potassium ion gradients to catalyze the thermodynamically unfavorable movement of synaptic serotonin into the presynaptic neuron. SERT has garnered significant clinical attention partly because it is the target of multiple psychoactive agents, including the antidepressant paroxetine (Paxil), the most potent selective serotonin reuptake inhibitor known. However, the binding site and orientation of paroxetine in SERT remain controversial. To provide molecular insight, we constructed SERT homology models based on the Drosophila melanogaster dopamine transporter and docked paroxetine to these models. We tested the predicted binding configurations with a combination of radioligand binding and flux assays on wild-type and mutant SERTs. Our data suggest that the orientation of paroxetine, specifically its fluorophenyl ring, in SERT’s substrate binding site directly depends on this pocket’s charge distribution, and thereby provide an avenue toward understanding and enhancing high-affinity antidepressant activity. PMID:27032980

  15. The serotonin aldehyde, 5-HIAL, oligomerizes alpha-synuclein.

    PubMed

    Jinsmaa, Yunden; Cooney, Adele; Sullivan, Patricia; Sharabi, Yehonatan; Goldstein, David S

    2015-03-17

    In Parkinson's disease (PD) alpha-synuclein oligomers are thought to be pathogenic, and 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate aldehyde intermediate in neuronal dopamine metabolism, potently oligomerizes alpha-synuclein. PD involves alpha-synuclein deposition in brainstem raphe nuclei; however, whether 5-hydroxyindoleacetaldehyde (5-HIAL), the aldehyde of serotonin, oligomerizes alpha-synuclein has been unknown. In this study we tested whether 5-HIAL oligomerizes alpha-synuclein in vitro and in PC12 cells conditionally over-expressing alpha-synuclein. Alpha-synuclein oligomers were quantified by western blotting after incubation of alpha-synuclein with serotonin and monoamine oxidase-A (MAO-A) to generate 5-HIAL or dopamine to generate DOPAL. Oligomerization of alpha-synuclein in PC12 cells over-expressing the protein was compared between vehicle-treated cells and cells incubated with levodopa to generate DOPAL or 5-hydroxytryptophan to generate 5-HIAL. Monoamine aldehyde mediation of the oligomerization was assessed using the MAO inhibitor, pargyline. Dopamine and serotonin incubated with MAO-A both strongly oligomerized alpha-synuclein (more than 10 times control); pargyline blocked the oligomerization. In synuclein overexpressing PC12 cells, levodopa and 5-hydroxytryptophan elicited pargyline-sensitive alpha-synuclein oligomerization. 5-HIAL oligomerizes alpha-synuclein both in vitro and in synuclein-overexpressing PC12 cells, in a manner similar to DOPAL. The findings may help explain loss of serotonergic neurons in PD.

  16. The Dopamine D2 Receptor Gene, Perceived Parental Support, and Adolescent Loneliness: Longitudinal Evidence for Gene-Environment Interactions

    ERIC Educational Resources Information Center

    van Roekel, Eeske; Goossens, Luc; Scholte, Ron H. J.; Engels, Rutger C. M. E.; Verhagen, Maaike

    2011-01-01

    Background: Loneliness is a common problem in adolescence. Earlier research focused on genes within the serotonin and oxytocin systems, but no studies have examined the role of dopamine-related genes in loneliness. In the present study, we focused on the dopamine D2 receptor gene (DRD2). Methods: Associations among the DRD2, sex, parental support,…

  17. Sampling phasic dopamine signaling with fast-scan cyclic voltammetry in awake, behaving rats.

    PubMed

    Fortin, S M; Cone, J J; Ng-Evans, S; McCutcheon, J E; Roitman, M F

    2015-01-05

    Fast-scan cyclic voltammetry (FSCV) is an electrochemical technique that permits the in vivo measurement of extracellular fluctuations in multiple chemical species. The technique is frequently utilized to sample sub-second (phasic) concentration changes of the neurotransmitter dopamine in awake and behaving rats. Phasic dopamine signaling is implicated in reinforcement, goal-directed behavior, and locomotion, and FSCV has been used to investigate how rapid changes in striatal dopamine concentration contribute to these and other behaviors. This unit describes the instrumentation and construction, implantation, and use of components required to sample and analyze dopamine concentration changes in awake rats with FSCV.

  18. The Role of Dopamine and Its Dysfunction as a Consequence of Oxidative Stress

    PubMed Central

    Juárez Olguín, Hugo; Calderón Guzmán, David; Hernández García, Ernestina; Barragán Mejía, Gerardo

    2016-01-01

    Dopamine is a neurotransmitter that is produced in the substantia nigra, ventral tegmental area, and hypothalamus of the brain. Dysfunction of the dopamine system has been implicated in different nervous system diseases. The level of dopamine transmission increases in response to any type of reward and by a large number of strongly additive drugs. The role of dopamine dysfunction as a consequence of oxidative stress is involved in health and disease. Introduce new potential targets for the development of therapeutic interventions based on antioxidant compounds. The present review focuses on the therapeutic potential of antioxidant compounds as a coadjuvant treatment to conventional neurological disorders is discussed. PMID:26770661

  19. Sampling phasic dopamine signaling with fast-scan cyclic voltammetry in awake behaving rats

    PubMed Central

    Fortin, SM; Cone, JJ; Ng-Evans, S; McCutcheon, JE; Roitman, MF

    2015-01-01

    Fast-scan cyclic voltammetry (FSCV) is an electrochemical technique which permits the in vivo measurement of extracellular fluctuations in multiple chemical species. The technique is frequently utilized to sample sub-second (phasic) concentration changes of the neurotransmitter dopamine in awake and behaving rats. Phasic dopamine signaling is implicated in reinforcement, goal-directed behavior, and locomotion and FSCV has been used to investigate how rapid changes in striatal dopamine concentration contribute to these and other behaviors. This unit describes the instrumentation and construction, implantation, and use of necessary components required to sample and analyze dopamine concentration changes in awake rats with FSCV. PMID:25559005

  20. Major depressive disorder and diabetes: does serotonin bridge the gap?

    PubMed

    De Long, Nicole E; Stepita, Rebecca A; Taylor, Valerie H; Holloway, Alison C

    2015-01-01

    Major depressive disorder (MDD) is one of the most common psychiatric illnesses worldwide, with reported prevalence rates ranging between 10% and 19%. Pharmacotherapy is a first-line option for the management of MDD and, as a result, the use of antidepressants has increased 4 fold in the last 20 years. Serotonin is the most commonly dysregulated neurotransmitter in the etiology of MDD and this system is the primary focus of most medications used in the treatment of illness. Although antidepressant use in adults increases the risk of developing new onset type 2 diabetes, the mechanisms underlying this association are poorly defined. This review will focus on 1) the evidence from human and animal studies suggesting a link between the use of antidepressants that target serotonin signaling (i.e., SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin antagonist and reuptake inhibitors (SARIs), and noradrenergic and specific serotonergic antidepressants (NaSSAs)) and increased risk of diabetes, and 2) the mechanisms by which alterations in serotonin signalling by antidepressants can affect glucose homeostasis.

  1. Serotonin deficiency exacerbates acetaminophen-induced liver toxicity in mice.

    PubMed

    Zhang, Jingyao; Song, Sidong; Pang, Qing; Zhang, Ruiyao; Zhou, Lei; Liu, Sushun; Meng, Fandi; Wu, Qifei; Liu, Chang

    2015-01-29

    Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-induced hepatotoxicity, as well as the role of 5-HT in the liver's response to APAP toxicity. We induced APAP hepatotoxicity in mice either sufficient of serotonin (wild-type mice and TPH1-/- plus 5- Hydroxytryptophan (5-HTP)) or lacking peripheral serotonin (Tph1-/- and wild-type mice plus p-chlorophenylalanine (PCPA)). Mice with sufficient 5-HT exposed to acetaminophen have a significantly lower mortality rate and a better outcome compared with mice deficient of 5-HT. This difference is at least partially attributable to a decreased level of inflammation, oxidative stress and endoplasmic reticulum (ER) stress, Glutathione (GSH) depletion, peroxynitrite formation, hepatocyte apoptosis, elevated hepatocyte proliferation, activation of 5-HT2B receptor, less activated c-Jun NH₂-terminal kinase (JNK) and hypoxia-inducible factor (HIF)-1α in the mice sufficient of 5-HT versus mice deficient of 5-HT. We thus propose a physiological function of serotonin that serotonin could ameliorate APAP-induced liver injury mainly through inhibiting hepatocyte apoptosis ER stress and promoting liver regeneration.

  2. The serotonin 5-HT7 receptors: two decades of research.

    PubMed

    Gellynck, Evelien; Heyninck, Karen; Andressen, Kjetil W; Haegeman, Guy; Levy, Finn Olav; Vanhoenacker, Peter; Van Craenenbroeck, Kathleen

    2013-10-01

    Like most neurotransmitters, serotonin possesses a simple structure. However, the pharmacological consequences are more complex and diverse. Serotonin is involved in numerous functions in the human body including the control of appetite, sleep, memory and learning, temperature regulation, mood, behavior, cardiovascular function, muscle contraction, endocrine regulation, and depression. Low levels of serotonin may be associated with several disorders, namely increase in aggressive and angry behaviors, clinical depression, Parkinson's disease, obsessive-compulsive disorder, eating disorders, migraine, irritable bowel syndrome, tinnitus, and bipolar disease. These effects are mediated via different serotonin (5-HT) receptors. In this review, we will focus on the last discovered member of this serotonin receptor family, the 5-HT7 receptor. This receptor belongs to the G protein-coupled receptor superfamily and was cloned two decades ago. Later, different splice variants were described but no major functional differences have been described so far. All 5-HT7 receptor variants are coupled to Gαs proteins and stimulate cAMP formation. Recently, several interacting proteins have been reported, which can influence receptor signaling and trafficking.

  3. The molecular interactions of buspirone analogues with the serotonin transporter.

    PubMed

    Jarończyk, Małgorzata; Chilmonczyk, Zdzisław; Mazurek, Aleksander P; Nowak, Gabriel; Ravna, Aina W; Kristiansen, Kurt; Sylte, Ingebrigt

    2008-10-15

    A major problem with the selective serotonin reuptake inhibitors (SSRIs) is the delayed onset of action. A reason for that may be that the initial SSRI-induced increase in serotonin levels activates somatodendritic 5-HT(1A) autoreceptors, causing a decrease in serotonin release in major forebrain areas. It has been suggested that compounds combining inhibition of the serotonin transport protein with antagonistic effects on the 5-HT(1A) receptor will shorten the onset time. The anxiolytic drug buspirone is known as 5-HT(1A) partial agonist. In the present work, we are studying the inhibition of the serotonin transporter protein by a series of buspirone analogues by molecular modelling and by experimental affinity measurements. Models of the transporter protein were constructed using the crystal structure of the Escherichia coli major facilitator family transporter-LacY and the X-ray structure of the neurotransmitter symporter family (NSS) transporter-LeuT(Aa) as templates. The buspirone analogues were docked into both SERT models and the interactions with amino acids within the protein were analyzed. Two putative binding sites were identified on the LeuT(Aa) based model, one suggested to be a high-affinity site, and the other suggested to be a low-affinity binding site. Molecular dynamic simulations of the LacY based model in complex with ligands did not induce a helical architecture of the LacY based model into an arrangement more similar to that of the LeuT(Aa) based model.

  4. [Effect of domestication of the silver fox on the main enzymes of serotonin metabolism and serotonin receptors].

    PubMed

    Popova, N K; Kulikov, A V; Avgustinovich, D F; Voĭtenko, N N; Trut, L N

    1997-03-01

    In silver foxes significant alterations in the activities of basic enzymes of neurotransmitter serotonin metabolism as well as in the densities of receptors caused by selection for the absence of the aggressive defensive reaction to man were demonstrated. In the midbrain and hypothalamus of animals selected for the absence of aggressive behavior, the activity of tryptophan hydroxylase, the key enzyme of serotonin biosynthesis, was found to be remarkably higher than in animals selected for highly aggressive behavior. Domesticated animals were characterized by low activity of the main enzyme of serotonin catabolism, monoamine oxidase type A, increased Michaelis constant km, and an unchanged maximum reaction rate (Vmax). No changes in the specific binding of [3H]-ketanserin and [3H]-8-OH-DPAT in the frontal cortex of domesticated foxes were revealed; however, in the hypothalamus, the low values of Bmax for the [3H]-8-OH-DPAT specific binding were observed, indicating the decreased density of the 5-HT1A receptors. It is assumed that the transformation of a wild aggressive animal into a domesticated one taking place during directional selection is caused by hereditary alterations favored by artificial selection in the activity of the main enzymes of serotonin metabolism and serotonin receptors.

  5. Metabolic sensing in brain dopamine systems.

    PubMed

    de Araujo, Ivan E; Ren, Xueying; Ferreira, Jozélia G

    2010-01-01

    The gustatory system allows the brain to monitor the presence of chemicals in the oral cavity and initiate appropriate responses of acceptance or rejection. Among such chemicals are the nutrients that must be rapidly recognized and ingested for immediate oxidation or storage. In the periphery, the gustatory system consists of a highly efficient sensing mechanism, where distinct cell types express receptors that bind specifically to chemicals associated with one particular taste quality. These specialized receptors connect to the brain via dedicated pathways, the stimulation of which triggers stereotypic behavioral responses as well as neurotransmitter release in brain reward dopamine systems. However, evidence also exists in favor of the concept that the critical regulators of long-term nutrient choice are physiological processes taking place after ingestion and independently of gustation. We will appraise the hypothesis that organisms can develop preferences for nutrients independently of oral taste stimulation. Of particular interest are recent findings indicating that disrupting nutrient utilization interferes with activity in brain dopamine pathways. These findings establish the metabolic fate of nutrients as previously unanticipated reward signals that regulate the reinforcing value of foods. In particular, it suggests a role for brain dopamine reward systems as metabolic sensors, allowing for signals generated by the metabolic utilization of nutrients to regulate neurotransmitter release and food reinforcement.

  6. Immunohistochemical Evaluation of Role of Serotonin in Pathogenesis of Psoriasis

    PubMed Central

    Bakry, Ola Ahmed

    2016-01-01

    Introduction Psoriasis is a common skin disorder characterized by erythaematosquamous papules and plaques. It is known to be associated with stressful and depressive disorders. Serotonin is a neurotransmitter that plays a role in the pathogenesis of inflammatory skin disorders. Aim To evaluate the role of serotonin in pathogenesis of psoriasis. Materials and Methods Using standard immunohistochemical techniques, 24 biopsies from patients with chronic plaque psoriasis were examined together with 12 biopsies from age and gender-matched healthy subjects as a control group. Results Both the percentage of positive cells (p=0.018) and H-score values (p=0.015) of serotonin expression were significantly higher in psoriasis compared to normal skin. H score of serotonin expression was significantly higher in cases with totally absent Granular Cell Layer (GCL) as opposed to those with thin/focally absent GCL (p=0.011), and in cases with moderate/strong epidermal inflammation compared to cases with mild inflammation (p=0.035). No significant correlation was detected between H score of cases and age, disease duration or Psoriasis Area and Severity Index (PASI) score. Conclusion Serotonin might play a role in development of psoriasis through its role as a growth factor promoting keratinocyte proliferation, and as mediator of inflammation and stimulant of T cell activation. It recruits T cells to sites of cutaneous inflammation and potentiate macrophage accessory function for T cell activation. Its expression is not related to the disease severity. Future large-scaled research on population of different ethnicities including other disease variants is needed. The use of serotonin receptor antagonists and serotonin reuptake inhibitors may be evaluated on wide-based studies to put the current observation into action. PMID:27891342

  7. Presence and Function of Dopamine Transporter (DAT) in Stallion Sperm: Dopamine Modulates Sperm Motility and Acrosomal Integrity

    PubMed Central

    Covarrubias, Alejandra A.; Rodríguez-Gil, Joan Enric; Ramírez-Reveco, Alfredo; Concha, Ilona I.

    2014-01-01

    Dopamine is a catecholamine with multiple physiological functions, playing a key role in nervous system; however its participation in reproductive processes and sperm physiology is controversial. High dopamine concentrations have been reported in different portions of the feminine and masculine reproductive tract, although the role fulfilled by this catecholamine in reproductive physiology is as yet unknown. We have previously shown that dopamine type 2 receptor is functional in boar sperm, suggesting that dopamine acts as a physiological modulator of sperm viability, capacitation and motility. In the present study, using immunodetection methods, we revealed the presence of several proteins important for the dopamine uptake and signalling in mammalian sperm, specifically monoamine transporters as dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters in equine sperm. We also demonstrated for the first time in equine sperm a functional dopamine transporter using 4-[4-(Dimethylamino)styryl]-N-methylpyridinium iodide (ASP+), as substrate. In addition, we also showed that dopamine (1 mM) treatment in vitro, does not affect sperm viability but decreases total and progressive sperm motility. This effect is reversed by blocking the dopamine transporter with the selective inhibitor vanoxerine (GBR12909) and non-selective inhibitors of dopamine reuptake such as nomifensine and bupropion. The effect of dopamine in sperm physiology was evaluated and we demonstrated that acrosome integrity and thyrosine phosphorylation in equine sperm is significantly reduced at high concentrations of this catecholamine. In summary, our results revealed the presence of monoamine transporter DAT, NET and SERT in equine sperm, and that the dopamine uptake by DAT can regulate sperm function, specifically acrosomal integrity and sperm motility. PMID:25402186

  8. Effects of dietary amino acids, carbohydrates, and choline on neurotransmitter synthesis

    NASA Technical Reports Server (NTRS)

    Wurtman, Richard J.

    1988-01-01

    The ability of a meal to increase or decrease brain neurotransmitter synthesis has been studied. It is concluded that brain serotonin synthesis is directly controlled by the proportions of carbohydrate to protein in meals and snacks that increase or decrease brain tryptophan levels, thereby changing the substrate saturation of tryptophan hydroxylase and the rate of serotonin synthesis. The ability of serotoninergic neurons to have their output coupled to dietary macronutrients enables them to function as sensors of peripheral metabolism, and to subserve an important role in the control of appetite. The robust and selective responses of catecholaminergic and cholinergic neurons to supplemental tyrosine and choline suggest that these compounds may become useful as a new type of drug for treating deseases or conditions in which adequate quantities of the transmitter would otherwise be unavailable.

  9. Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects: dopamine transporter occupancy as measured by PET.

    PubMed

    Appel, Lieuwe; Bergström, Mats; Buus Lassen, Jørgen; Långström, Bengt

    2014-02-01

    Tesofensine (TE) is a novel triple monoamine re-uptake inhibitor inducing a potent inhibition of the re-uptake process in the synaptic cleft of the neurotransmitters dopamine, norepinephrine, and serotonin. In recent preclinical and clinical evaluations TE showed a robust anti-obesity effect, but the specific mechanism of this triple monoamine re-uptake inhibitor still needs to be further elucidated. This positron emission tomography (PET) study, using [¹¹C]βCIT-FE, aimed to assess the degree of the dopamine transporter (DAT) occupancy, at constant TE plasma levels, following different oral, multiple doses of TE during totally 8-12 days. In addition, the relationships between DAT occupancy and TE plasma concentrations, or doses, were investigated to enable assessment of DAT occupancies in subsequent clinical trials. The results demonstrated that TE induced a dose-dependent blockade of DAT following multiple doses of 0.125-1 mg TE at anticipated steady-state conditions. The mean striatal DAT occupancy varied dose-dependently between 18% and 77%. A sigmoid E(max) model well described the relationship between striatal DAT occupancy and TE plasma concentrations or doses. It was estimated that the maximum achievable DAT occupancy was about 80% and that half of this effect was accomplished by approximately 0.25 mg TE and a plasma drug concentration of 4 ng/ml. The results indicated an important mechanism of action of TE on DAT. Further, these results suggest that the previously reported dose-dependent weight loss, in TE treated subjects, was in part mediated by an up-regulation of dopaminergic pathways due to enhanced amounts of synaptic dopamine after blockade of DAT.

  10. The neurobiology of tetrahydrobiopterin biosynthesis: a model for regulation of GTP cyclohydrolase I gene transcription within nigrostriatal dopamine neurons.

    PubMed

    Kapatos, Gregory

    2013-04-01

    Within the brain, the reduced pteridine cofactor 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) is absolutely required for the synthesis of the monoamine (MA) neurotransmitters dopamine (DA), norepinephrine, epinephrine (E), and serotonin (5-HT), the novel gaseous neurotransmitter nitric oxide and the production of yet to be identified 1-O-alkylglycerol-derived lipids. GTP cyclohydrolase I (GTPCH) catalyzes the first and limiting step in the BH4 biosynthetic pathway, which is now thought to involve up to eight different proteins supporting six alternate de novo and two alternate salvage pathways. Gene expression analysis across different regions of the human brain shows the abundance of transcripts coding for all eight of these proteins to be highly correlated with each other and to be enriched within human MA neurons. The potential for multiple routes for BH4 synthesis therefore exists within the human brain. GTPCH expression is particularly heterogeneous across different populations of human and rodent MA-containing neurons, with low expression levels and therefore BH4 being a characteristic of nigrostriatal DA (NSDA) neurons. Basic knowledge of how GCH1 gene transcription is controlled within NSDA neurons may explain the distinctive susceptibility of these neurons to human genetic mutations that result in BH4 deficiency. A model for cyclic adenosine monophosphate-dependent GCH1 transcription is described that involves a unique combination of DNA regulatory sequences and transcription factors. This model proposes that low levels of GCH1 transcription within NSDA neurons are driven by their distinctive physiology, suggesting that pharmacological manipulation of GCH1 gene transcription can be used to modify BH4 levels and therefore DA synthesis in the basal ganglia.

  11. Melatonin Supports CYP2D-Mediated Serotonin Synthesis in the Brain.

    PubMed

    Haduch, Anna; Bromek, Ewa; Wójcikowski, Jacek; Gołembiowska, Krystyna; Daniel, Władysława A

    2016-03-01

    Melatonin is used in the therapy of sleep and mood disorders and as a neuroprotective agent. The aim of our study was to demonstrate that melatonin supported (via its deacetylation to 5-methoxytryptamine) CYP2D-mediated synthesis of serotonin from 5-methoxytryptamine. We measured serotonin tissue content in some brain regions (the cortex, hippocampus, nucleus accumbens, striatum, thalamus, hypothalamus, brain stem, medulla oblongata, and cerebellum) (model A), as well as its extracellular concentration in the striatum using an in vivo microdialysis (model B) after melatonin injection (100 mg/kg i.p.) to male Wistar rats. Melatonin increased the tissue concentration of serotonin in the brain structures studied of naïve, sham-operated, or serotonergic neurotoxin (5,7-dihydroxytryptamine)-lesioned rats (model A). Intracerebroventricular quinine (a CYP2D inhibitor) prevented the melatonin-induced increase in serotonin concentration. In the presence of pargyline (a monoaminoxidase inhibitor), the effect of melatonin was not visible in the majority of the brain structures studied but could be seen in all of them in 5,7-dihydroxytryptamine-lesioned animals when serotonin storage and synthesis via a classic tryptophan pathway was diminished. Melatonin alone did not significantly increase extracellular serotonin concentration in the striatum of naïve rats but raised its content in pargyline-pretreated animals (model B). The CYP2D inhibitor propafenone given intrastructurally prevented the melatonin-induced increase in striatal serotonin in those animals. The obtained results indicate that melatonin supports CYP2D-catalyzed serotonin synthesis from 5-methoxytryptamine in the brain in vivo, which closes the serotonin-melatonin-serotonin biochemical cycle. The metabolism of exogenous melatonin to the neurotransmitter serotonin may be regarded as a newly recognized additional component of its pharmacological action.

  12. SEROTONIN BINDING TO PREPARATIONS FROM RAT BRAIN,

    DTIC Science & Technology

    BRAIN , SEROTONIN, SEROTONIN, OXIDOREDUCTASES, LYSERGIC ACIDS, RESERPINE, CHLORPROMAZINE, ACETYLCHOLINE, FATTY ACIDS, NOREPINEPHRINE, LEARNING, PERMEABILITY, MITOCHONDRIA, MORPHOLOGY(BIOLOGY), DRUGS, PHYSIOLOGY.

  13. Antidepressant binding site in a bacterial homologue of neurotransmitter transporters.

    PubMed

    Singh, Satinder K; Yamashita, Atsuko; Gouaux, Eric

    2007-08-23

    Sodium-coupled transporters are ubiquitous pumps that harness pre-existing sodium gradients to catalyse the thermodynamically unfavourable uptake of essential nutrients, neurotransmitters and inorganic ions across the lipid bilayer. Dysfunction of these integral membrane proteins has been implicated in glucose/galactose malabsorption, congenital hypothyroidism, Bartter's syndrome, epilepsy, depression, autism and obsessive-compulsive disorder. Sodium-coupled transporters are blocked by a number of therapeutically important compounds, including diuretics, anticonvulsants and antidepressants, many of which have also become indispensable tools in biochemical experiments designed to probe antagonist binding sites and to elucidate transport mechanisms. Steady-state kinetic data have revealed that both competitive and noncompetitive modes of inhibition exist. Antagonist dissociation experiments on the serotonin transporter (SERT) have also unveiled the existence of a low-affinity allosteric site that slows the dissociation of inhibitors from a separate high-affinity site. Despite these strides, atomic-level insights into inhibitor action have remained elusive. Here we screen a panel of molecules for their ability to inhibit LeuT, a prokaryotic homologue of mammalian neurotransmitter sodium symporters, and show that the tricyclic antidepressant (TCA) clomipramine noncompetitively inhibits substrate uptake. Cocrystal structures show that clomipramine, along with two other TCAs, binds in an extracellular-facing vestibule about 11 A above the substrate and two sodium ions, apparently stabilizing the extracellular gate in a closed conformation. Off-rate assays establish that clomipramine reduces the rate at which leucine dissociates from LeuT and reinforce our contention that this TCA inhibits LeuT by slowing substrate release. Our results represent a molecular view into noncompetitive inhibition of a sodium-coupled transporter and define principles for the rational design of

  14. Antidepressant Binding Site in a Bacterial Homologue of Neurotransmitter Transporters

    SciTech Connect

    Singh,S.; Yamashita, A.; Gouaux, E.

    2007-01-01

    Sodium-coupled transporters are ubiquitous pumps that harness pre-existing sodium gradients to catalyse the thermodynamically unfavourable uptake of essential nutrients, neurotransmitters and inorganic ions across the lipid bilayer. Dysfunction of these integral membrane proteins has been implicated in glucose/galactose malabsorption, congenital hypothyroidism, Bartter's syndrome, epilepsy, depression, autism and obsessive-compulsive disorder. Sodium-coupled transporters are blocked by a number of therapeutically important compounds, including diuretics, anticonvulsants and antidepressants, many of which have also become indispensable tools in biochemical experiments designed to probe antagonist binding sites and to elucidate transport mechanisms. Steady-state kinetic data have revealed that both competitive and noncompetitive modes of inhibition exist. Antagonist dissociation experiments on the serotonin transporter (SERT) have also unveiled the existence of a low-affinity allosteric site that slows the dissociation of inhibitors from a separate high-affinity site. Despite these strides, atomic-level insights into inhibitor action have remained elusive. Here we screen a panel of molecules for their ability to inhibit LeuT, a prokaryotic homologue of mammalian neurotransmitter sodium symporters, and show that the tricyclic antidepressant (TCA) clomipramine noncompetitively inhibits substrate uptake. Cocrystal structures show that clomipramine, along with two other TCAs, binds in an extracellular-facing vestibule about 11 {angstrom} above the substrate and two sodium ions, apparently stabilizing the extracellular gate in a closed conformation. Off-rate assays establish that clomipramine reduces the rate at which leucine dissociates from LeuT and reinforce our contention that this TCA inhibits LeuT by slowing substrate release. Our results represent a molecular view into noncompetitive inhibition of a sodium-coupled transporter and define principles for the rational

  15. Serotonin mediated immunoregulation and neural functions: Complicity in the aetiology of autism spectrum disorders.

    PubMed

    Jaiswal, Preeti; Mohanakumar, Kochupurackal P; Rajamma, Usha

    2015-08-01

    Serotonergic system has long been implicated in the aetiology of autism spectrum disorders (ASD), since platelet hyperserotonemia is consistently observed in a subset of autistic patients, who respond well to selective serotonin reuptake inhibitors. Apart from being a neurotransmitter, serotonin functions as a neurotrophic factor directing brain development and as an immunoregulator modulating immune responses. Serotonin transporter (SERT) regulates serotonin level in lymphoid tissues to ensure its proper functioning in innate and adaptive responses. Immunological molecules such as cytokines in turn regulate the transcription and activity of SERT. Dysregulation of serotonergic system could trigger signalling cascades that affect normal neural-immune interactions culminating in neurodevelopmental and neural connectivity defects precipitating behavioural abnormalities, or the disease phenotypes. Therefore, we suggest that a better understanding of the cross talk between serotonergic genes, immune systems and serotonergic neurotransmission will open wider avenues to develop pharmacological leads for addressing the core ASD behavioural deficits.

  16. Administration of caffeine inhibited adenosine receptor agonist-induced decreases in motor performance, thermoregulation, and brain neurotransmitter release in exercising rats.

    PubMed

    Zheng, Xinyan; Hasegawa, Hiroshi

    2016-01-01

    We examined the effects of an adenosine receptor agonist on caffeine-induced changes in thermoregulation, neurotransmitter release in the preoptic area and anterior hypothalamus, and endurance exercise performance in rats. One hour before the start of exercise, rats were intraperitoneally injected with either saline alone (SAL), 10 mg kg(-1) caffeine and saline (CAF), a non-selective adenosine receptor agonist (5'-N-ethylcarboxamidoadenosine [NECA]: 0.5 mg kg(-1)) and saline (NECA), or the combination of caffeine and NECA (CAF+NECA). Rats ran until fatigue on the treadmill with a 5% grade at a speed of 18 m min(-1) at 23 °C. Compared to the SAL group, the run time to fatigue (RTTF) was significantly increased by 52% following caffeine administration and significantly decreased by 65% following NECA injection (SAL: 91 ± 14.1 min; CAF: 137 ± 25.8 min; NECA: 31 ± 13.7 min; CAF+NECA: 85 ± 11.8 min; p<0.05). NECA decreased the core body temperature (Tcore), oxygen consumption, which is an index of heat production, tail skin temperature, which is an index of heat loss, and extracellular dopamine (DA) release at rest and during exercise. Furthermore, caffeine injection inhibited the NECA-induced decreases in the RTTF, Tcore, heat production, heat loss, and extracellular DA release. Neither caffeine nor NECA affected extracellular noradrenaline or serotonin release. These results support the findings of previous studies showing improved endurance performance and overrides in body limitations after caffeine administration, and imply that the ergogenic effects of caffeine may be associated with the adenosine receptor blockade-induced increases in brain DA release.

  17. Selective Serotonin Reuptake Inhibitors (SSRIs)

    MedlinePlus

    ... dangerous reactions when combined with certain medications or herbal supplements. Serotonin syndrome. Rarely, an antidepressant can cause high ... antidepressants, certain pain or headache medications, and the herbal supplement St. John's wort. Signs and symptoms of serotonin ...

  18. Homeostatic mechanisms in dopamine synthesis and release: a mathematical model

    PubMed Central

    Best, Janet A; Nijhout, H Frederik; Reed, Michael C

    2009-01-01

    Background Dopamine is a catecholamine that is used as a neurotransmitter both in the periphery and in the central nervous system. Dysfunction in various dopaminergic systems is known to be associated with various disorders, including schizophrenia, Parkinson's disease, and Tourette's syndrome. Furthermore, microdialysis studies have shown that addictive drugs increase extracellular dopamine and brain imaging has shown a correlation between euphoria and psycho-stimulant-induced increases in extracellular dopamine [1]. These consequences of dopamine dysfunction indicate the importance of maintaining dopamine functionality through homeostatic mechanisms that have been attributed to the delicate balance between synthesis, storage, release, metabolism, and reuptake. Methods We construct a mathematical model of dopamine synthesis, release, and reuptake and use it to study homeostasis in single dopaminergic neuron terminals. We investigate the substrate inhibition of tyrosine hydroxylase by tyrosine, the consequences of the rapid uptake of extracellular dopamine by the dopamine transporters, and the effects of the autoreceoptors on dopaminergic function. The main focus is to understand the regulation and control of synthesis and release and to explicate and interpret experimental findings. Results We show that the substrate inhibition of tyrosine hydroxylase by tyrosine stabilizes cytosolic and vesicular dopamine against changes in tyrosine availability due to meals. We find that the autoreceptors dampen the fluctuations in extracellular dopamine caused by changes in tyrosine hydroxylase expression and changes in the rate of firing. We show that short bursts of action potentials create significant dopamine signals against the background of tonic firing. We explain the observed time courses of extracellular dopamine responses to stimulation in wild type mice and mice that have genetically altered dopamine transporter densities and the observed half-lives of extracellular

  19. Waterborne lead affects circadian variations of brain neurotransmitters in fathead minnows

    SciTech Connect

    Spieler, R.E.; Russo, A.C.; Weber, D.N.

    1995-09-01

    Lead is a potent neurotoxin affecting brain levels of a number of vertebrate neurotransmitters. Reports on these effects are, however, not consistent either among or within species. For example, with lead-intoxicated rats there are reports of decreased acetylcholine (ACh) release and decreased ACh brain levels as well as reports of increased levels or no change in levels. Also, with rats there are reports of increased levels, decreased levels, or no change in brain catecholamines, with lead producing similar changes in both norephinephrine (NE) and dopamine (DA) in some cases and differences in response between the two in others. Although most early reports dealt with whole brain levels, reports on neurotransmitter levels in specific brain regions can be equally conflicting. Similar sorts of discrepancies exist among studies with fishes. Much of the variation among studies on lead effects on neurotransmitters is, no doubt, due to differences among the studies in variables such as: species, age, dosage and duration, route of administration. However, lead can apparently affect circadian locomotor rhythms of both rats and fishes. Therefore, another possible cause for the variation among studies is that there is an interaction among dosage, sampling time and endogenous rhythms. A lead-produced phase shift or disruption in endogenous neurotransmitter rhythms could in turn elicit a host of varying results and interpretations depending on the circadian time of sampling. We elected to examine this possibility in the fathead minnow, Pimephales promelas, a freshwater species widely used for toxicity studies. 15 refs., 3 figs.

  20. Serotonin produces monoamine oxidase-dependent oxidative stress in human heart valves

    PubMed Central

    Miller, Jordan D.; Chu, Yi; Heistad, Donald D.

    2009-01-01

    Heart valve disease and pulmonary hypertension, in patients with carcinoid tumors and people who used the fenfluramine-phentermine combination for weight control, have been associated with high levels of serotonin in blood. The mechanism by which serotonin induces valvular changes is not well understood. We recently reported that increased oxidative stress is associated with valvular changes in aortic valve stenosis in humans and mice. In this study, we tested the hypothesis that serotonin induces oxidative stress in human heart valves, and examined mechanisms by which serotonin may increase reactive oxygen species. Superoxide (O2·−) was measured in heart valves from explanted human hearts that were not used for transplantation. O2·− levels (lucigenin-enhanced chemoluminescence) were increased in homogenates of cardiac valves and blood vessels after incubation with serotonin. A nonspecific inhibitor of flavin-oxidases (diphenyliodonium), or inhibitors of monoamine oxidase [MAO (tranylcypromine and clorgyline)], prevented the serotonin-induced increase in O2·−. Dopamine, another MAO substrate that is increased in patients with carcinoid syndrome, also increased O2·− levels in heart valves, and this effect was attenuated by clorgyline. Apocynin [an inhibitor of NAD(P)H oxidase] did not prevent increases in O2·− during serotonin treatment. Addition of serotonin to recombinant human MAO-A generated O2·−, and this effect was prevented by an MAO inhibitor. In conclusion, we have identified a novel mechanism whereby MAO-A can contribute to increased oxidative stress in human heart valves and pulmonary artery exposed to serotonin and dopamine. PMID:19666839

  1. Immunohistological localization of serotonin in the CNS and feeding system of the stable fly stomoxys calcitrans L. (Diptera: muscidae)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Serotonin, or 5-hydroxytryptamine (5-HT), plays critical roles as a neurotransmitter and neuromodulator that control or modulate many behaviors in insects, such as feeding. Neurons immunoreactive (IR)to 5-HT were detected in the central nervous system (CNS) of the larval and adult stages of the stab...

  2. Rationality and emotionality: serotonin transporter genotype influences reasoning bias.

    PubMed

    Stollstorff, Melanie; Bean, Stephanie E; Anderson, Lindsay M; Devaney, Joseph M; Vaidya, Chandan J

    2013-04-01

    Reasoning often occurs under emotionally charged, opinion-laden circumstances. The belief-bias effect indexes the extent to which reasoning is based upon beliefs rather than logical structure. We examined whether emotional content increases this effect, particularly for adults genetically predisposed to be more emotionally reactive. SS/SL(G) carriers of the serotonin transporter genotype (5-HTTLPR) were less accurate selectively for evaluating emotional relational reasoning problems with belief-logic conflict relative to L(A)L(A) carriers. Trait anxiety was positively associated with emotional belief-bias, and the 5-HTTLPR genotype significantly accounted for the variance in this association. Thus, deductive reasoning, a higher cognitive ability, is sensitive to differences in emotionality rooted in serotonin neurotransmitter function.

  3. Validation of an ELISA for urinary dopamine: applications in monitoring treatment of dopamine-related disorders.

    PubMed

    Nichkova, Mikaela; Wynveen, Paul M; Marc, David T; Huisman, Han; Kellermann, Gottfried H

    2013-06-01

    Dopamine is a catecholamine that serves as a neurotransmitter in the central and peripheral nervous system. Non-invasive, reliable, and high-throughput techniques for its quantification are needed to assess dysfunctions of the dopaminergic system and monitor therapies. We developed and validated a competitive ELISA for direct determination of dopamine in urine samples. The method provides high specificity, good accuracy, and precision (average inter-assay variation < 12%). The analysis is not affected by general urinary components and structurally related drugs and metabolites. The correlation between ELISA and LC-MS/MS analyses was very good (r = 0.986, n = 28). The reference range was 64-261 μg/g Cr (n = 64). Week-to-week biological variations of second morning urinary dopamine under free-living conditions were 23.9% for within- and 35.5% for between-subject variation (n = 10). The assay is applied in monitoring Parkinson's disease patients under different treatments. Urinary dopamine levels significantly increase in a dose-dependent manner for Parkinson's disease patients under l-DOPA treatment. The present ELISA provides a cost-effective alternative to chromatographic methods to monitor patients receiving dopamine restoring treatment to ensure appropriate dosing and clinical efficacy. The method can be used in pathological research for the assessment of possible peripheral biological markers for disorders related to the dopaminergic system.

  4. Molecular model of the neural dopamine transporter

    NASA A