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Sample records for neurotransmitters serotonin dopamine

  1. The association between the serotonin and dopamine neurotransmitters and personality traits.

    PubMed

    Delvecchio, G; Bellani, M; Altamura, A C; Brambilla, P

    2016-04-01

    Evidence from previous studies has reported that complex traits, including psychiatric disorders, are moderately to highly heritable. Moreover, it has also been shown that specific personality traits may increase the risk to develop mental illnesses. Therefore the focus of the research shifted towards the identification of the biological mechanisms underpinning these traits by exploring the effects of a constellation of genetic polymorphisms in healthy subjects. Indeed, studying the effect of genetic variants in normal personality provides a unique means for identifying candidate genes which may increase the risk for psychiatric disorders. In this review, we discuss the impact of two of the most frequently studied genetic polymorphisms on personality in healthy subjects, the 5-HTT polymorphism of the serotonin transporter and the DRD2/DRD4 polymorphisms of the D2/D4 dopamine's receptors. The main aims are: (a) to highlight that the study of candidate genes provides a fruitful ground for the identification of the biological underpinnings of personality without, though, reaching a general consensus about the strength of this relationship; and (b) to outline that the research in personality genetics should be expanded to provide a clearer picture of the heritability of personality traits. PMID:26750396

  2. Modulation of midbrain dopamine neurotransmission by serotonin, a versatile interaction between neurotransmitters and significance for antipsychotic drug action.

    PubMed

    Olijslagers, J E; Werkman, T R; McCreary, A C; Kruse, C G; Wadman, W J

    2006-01-01

    Schizophrenia has been associated with a dysfunction of brain dopamine (DA). This, so called, DA hypothesis has been refined as new insights into the pathophysiology of schizophrenia have emerged. Currently, dysfunction of prefrontocortical glutamatergic and GABAergic projections and dysfunction of serotonin (5-HT) systems are also thought to play a role in the pathophysiology of schizophrenia. Refinements of the DA hypothesis have lead to the emergence of new pharmacological targets for antipsychotic drug development. It was shown that effective antipsychotic drugs with a low liability for inducing extra-pyramidal side-effects have affinities for a range of neurotransmitter receptors in addition to DA receptors, suggesting that a combination of neurotransmitter receptor affinities may be favorable for treatment outcome.This review focuses on the interaction between DA and 5-HT, as most antipsychotics display affinity for 5-HT receptors. We will discuss DA/5-HT interactions at the level of receptors and G protein-coupled potassium channels and consequences for induction of depolarization blockade with specific attention to DA neurons in the ventral tegmental area (VTA) and the substantia nigra zona compacta (SN), neurons implicated in treatment efficacy and the side-effects of schizophrenia, respectively. Moreover, it has been reported that electrophysiological interactions between DA and 5-HT show subtle, but important, differences between the SN and the VTA which could explain (in part) the effectiveness and lower propensity to induce side-effects of the newer atypical antipsychotic drugs. In that respect the functional implications of DA/5-HT interactions for schizophrenia will be discussed.

  3. Synapsins differentially control dopamine and serotonin release.

    PubMed

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

    2010-07-21

    Synapsins are a family of synaptic vesicle proteins that are important for neurotransmitter release. Here we have used triple knock-out (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

  4. 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. PMID:26721607

  5. 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.

  6. The microwave spectrum of neurotransmitter serotonin.

    PubMed

    Cabezas, Carlos; Varela, Marcelino; Peña, Isabel; López, Juan C; Alonso, José L

    2012-10-21

    A laser ablation device in combination with a molecular beam Fourier-transform microwave spectrometer has allowed the observation of the rotational spectrum of serotonin for the first time. Three conformers of the neurotransmitter have been detected and characterized in the 4-10 GHz frequency range. The complicated hyperfine structure arising from the presence of two (14)N nuclei has been fully resolved for all conformers and used for their identification. Nuclear quadrupole coupling constants of the nitrogen atom of the side chain have been used to determine the orientation of the amino group probing the existence of N-Hπ interactions involving the amino group and the pyrrole unit in the Gauche-Phenyl conformer (GPh) or the phenyl unit in the Gauche-Pyrrole (GPy) ones.

  7. 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

  8. Optogenetic control of serotonin and dopamine release in Drosophila larvae.

    PubMed

    Xiao, Ning; Privman, Eve; Venton, B Jill

    2014-08-20

    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.

  9. 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.

  10. 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.

  11. Differential Contributions of Dopamine and Serotonin to Orbitofrontal Cortex Function in the Marmoset

    PubMed Central

    Walker, S.C.; Robbins, T.W.

    2009-01-01

    We have shown previously that the inhibitory control functions of the orbitofrontal cortex (OFC) are disrupted by serotonin, but not dopamine depletions. However, both dopamine and serotonin terminals and receptors are present within the OFC and thus the aim of the present study was to determine the differential contributions of these neurotransmitters to orbitofrontal function. OFC and dopamine are involved in the process by which neutral stimuli take on reinforcing properties, by virtue of their prior association with reward, and guide behavior. Thus, we compared the performance of marmosets with dopaminergic or serotoninergic OFC depletions on a test of conditioned reinforcement. To further our understanding of serotonin in behavioral flexibility, the effect of these depletions was also compared on the extinction of a visual discrimination. Monkeys with serotonin depletions of the OFC displayed stimulus-bound responding on both tests of conditioned reinforcement and discrimination extinction suggesting that orbitofrontal serotonin plays a specific role in preventing competing, task irrelevant, salient stimuli from biasing responding. In contrast, monkeys with dopamine depletion were insensitive to conditioned reinforcers and displayed persistent responding in the absence of reward in extinction, a pattern of deficits that may reflect basic deficits in the associative processing of reward. PMID:18723695

  12. 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.

  13. Serotonin, serotonin 5-HT(1A) receptors and dopamine in blood peripheral lymphocytes of major depression patients.

    PubMed

    Fajardo, O; Galeno, J; Urbina, M; Carreira, I; Lima, L

    2003-09-01

    There are increasing evidences of cell markers present in the immune and the nervous systems. These include neurotransmitter receptors and transporters. Serotonin receptor subtypes are related to depression and also have been shown to be present in certain cells of the immune system. In the present report, we determined the presence of 5-HT(1A) receptors by the binding of the selective agonist 8-hydroxy-2-(di-n-propyl-amino)tetralin in lymphocytes of peripheral blood isolated by Ficoll/Hypaque gradients from controls and depressed patients. The capacity of these receptors was around 24 fmol/10(6) cells in both groups of subjects, without significant difference among them. The affinity was in the nM range and either differ between controls and patients. Serotonin, 5-hydroxyindoleacetic acid, dopamine and 3,4-dihydroxyphenylacetic acid were determined by HPLC with electrochemical detector. There were no significant differences between controls and major depression patients in the values obtained for rich and poor platelet plasma or in the isolated cells. However, there was a reduction in serotonin turnover rate indicated by an increase in the ratio serotonin/5-hydroxyindoleacetic acid, but not in that of dopamine, in lymphocytes of major depression patients. Thus, there is a serotonergic dysfunction in immune circulating cells of major depression patients, without changes in the number of 5-HT(1A) receptors, although the coupling of these receptors to transduction mechanisms could be affected and may be related to the alteration of 5-HT turnover rate.

  14. 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

  15. 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

  16. The neurotransmitters serotonin and glutamate accelerate the heart rate of the mosquito Anopheles gambiae.

    PubMed

    Hillyer, Julián F; Estévez-Lao, Tania Y; Mirzai, Homa E

    2015-10-01

    Serotonin and glutamate are neurotransmitters that in insects are involved in diverse physiological processes. Both serotonin and glutamate have been shown to modulate the physiology of the dorsal vessel of some insects, yet until the present study, their activity in mosquitoes remained unknown. To test whether serotonin or glutamate regulate dorsal vessel physiology in the African malaria mosquito, Anopheles gambiae, live mosquitoes were restrained, and a video of the contracting heart (the abdominal portion of the dorsal vessel) was acquired. These adult female mosquitoes were then injected with various amounts of serotonin, glutamate, or a control vehicle solution, and additional videos were acquired at 2 and 10 min post-treatment. Comparison of the videos taken before and after treatment revealed that serotonin accelerates the frequency of heart contractions, with the cardioacceleration being significantly more pronounced when the wave-like contractions of cardiac muscle propagate in the anterograde direction (toward the head). Comparison of the videos taken before and after treatment with glutamate revealed that this molecule is also cardioacceleratory. However, unlike serotonin, the activity of glutamate does not depend on whether the contractions propagate in the anterograde or the retrograde (toward the posterior of the abdomen) directions. Serotonin or glutamate induces a minor change or no change in the percentage of contractions and the percentage of the time that the heart contracts in the anterograde or the retrograde directions. In summary, this study shows that the neurotransmitters serotonin and glutamate increase the heart contraction rate of mosquitoes. PMID:26099947

  17. The neurotransmitters serotonin and glutamate accelerate the heart rate of the mosquito Anopheles gambiae.

    PubMed

    Hillyer, Julián F; Estévez-Lao, Tania Y; Mirzai, Homa E

    2015-10-01

    Serotonin and glutamate are neurotransmitters that in insects are involved in diverse physiological processes. Both serotonin and glutamate have been shown to modulate the physiology of the dorsal vessel of some insects, yet until the present study, their activity in mosquitoes remained unknown. To test whether serotonin or glutamate regulate dorsal vessel physiology in the African malaria mosquito, Anopheles gambiae, live mosquitoes were restrained, and a video of the contracting heart (the abdominal portion of the dorsal vessel) was acquired. These adult female mosquitoes were then injected with various amounts of serotonin, glutamate, or a control vehicle solution, and additional videos were acquired at 2 and 10 min post-treatment. Comparison of the videos taken before and after treatment revealed that serotonin accelerates the frequency of heart contractions, with the cardioacceleration being significantly more pronounced when the wave-like contractions of cardiac muscle propagate in the anterograde direction (toward the head). Comparison of the videos taken before and after treatment with glutamate revealed that this molecule is also cardioacceleratory. However, unlike serotonin, the activity of glutamate does not depend on whether the contractions propagate in the anterograde or the retrograde (toward the posterior of the abdomen) directions. Serotonin or glutamate induces a minor change or no change in the percentage of contractions and the percentage of the time that the heart contracts in the anterograde or the retrograde directions. In summary, this study shows that the neurotransmitters serotonin and glutamate increase the heart contraction rate of mosquitoes.

  18. Depression of Serotonin Synaptic Transmission by the Dopamine Precursor L-DOPA.

    PubMed

    Gantz, Stephanie C; Levitt, Erica S; Llamosas, Nerea; Neve, Kim A; Williams, John T

    2015-08-11

    Imbalance between the dopamine and serotonin (5-HT) neurotransmitter systems has been implicated in the comorbidity of Parkinson's disease (PD) and psychiatric disorders. L-DOPA, the leading treatment of PD, facilitates the production and release of dopamine. This study assessed the action of L-DOPA on monoamine synaptic transmission in mouse brain slices. Application of L-DOPA augmented the D2-receptor-mediated inhibitory postsynaptic current (IPSC) in dopamine neurons of the substantia nigra. This augmentation was largely due to dopamine release from 5-HT terminals. Selective optogenetic stimulation of 5-HT terminals evoked dopamine release, producing D2-receptor-mediated IPSCs following treatment with L-DOPA. In the dorsal raphe, L-DOPA produced a long-lasting depression of the 5-HT1A-receptor-mediated IPSC in 5-HT neurons. When D2 receptors were expressed in the dorsal raphe, application of L-DOPA resulted in a D2-receptor-mediated IPSC. Thus, treatment with L-DOPA caused ectopic dopamine release from 5-HT terminals and a loss of 5-HT-mediated synaptic transmission. PMID:26235617

  19. Striatal serotonin depletion facilitates rat egocentric learning via dopamine modulation.

    PubMed

    Anguiano-Rodríguez, Patricia B; Gaytán-Tocavén, Lorena; Olvera-Cortés, María Esther

    2007-02-01

    Egocentric spatial learning has been defined as the ability to navigate in an environment using only proprioceptive information, thereby performing a motor response based on one's own movement. This form of learning has been associated with the neural memory system, including the striatum body. Cerebral serotonin depletion induces better performance, both in tasks with strong egocentric components and in egocentric navigation in the Morris' maze. Based on this, we propose that the striatal serotonergic depletion must facilitate egocentric learning. Fifteen female Sprague Dawley rats weighing 250-350 g and maintained under standard conditions were chronically implanted with infusion cannulas for bilateral application of drugs into the striatum. The animals were evaluated for egocentric navigation using the Morris' maze, under different conditions: saline solution infusion, serotonin depletion by infusion of 5,7-Dihydroxytryptamine (25 microg of free base solved in 2.5 microl of ascorbic acid 1% in saline solution), infusion of mixed dopamine D(1) and D(2) receptor antagonists (0.5 microl/min during 5 min of mixed spiperone 20 microM and SCH23390 10 microM), or serotonin depletion and dopamine blockade simultaneously. Striatal serotonin depletion facilitated egocentric learning, which was demonstrated as shorter escape latencies and the display of a defined sequence of movements for reaching the platform. The facilitation was not observed under condition of simultaneous dopamine blockade. Striatal serotonin depletion produced a dopamine-dependent facilitation of egocentric learning. A role for serotonin in the inhibition of striatal-mediated learning strategies is proposed. PMID:17126827

  20. 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.

  1. 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

  2. Evaluation of Tetrahydrobiopterin Therapy with Large Neutral Amino Acid Supplementation in Phenylketonuria: Effects on Potential Peripheral Biomarkers, Melatonin and Dopamine, for Brain Monoamine Neurotransmitters

    PubMed Central

    Yano, Shoji; Moseley, Kathryn; Fu, Xiaowei; Azen, Colleen

    2016-01-01

    Background Phenylketonuria (PKU) is due to a defective hepatic enzyme, phenylalanine (Phe) hydroxylase. Transport of the precursor amino acids from blood into the brain for serotonin and dopamine synthesis is reported to be inhibited by high blood Phe concentrations. Deficiencies of serotonin and dopamine are involved in neurocognitive dysfunction in PKU. Objective (1) To evaluate the effects of sapropterin (BH4) and concurrent use of large neutral amino acids (LNAA) on the peripheral biomarkers, melatonin and dopamine with the hypothesis they reflect brain serotonin and dopamine metabolism. (2) To evaluate synergistic effects with BH4 and LNAA. (3) To determine the effects of blood Phe concentrations on the peripheral biomarkers concentrations. Methods Nine adults with PKU completed our study consisting of four 4-week phases: (1) LNAA supplementation, (2) Washout, (3) BH4 therapy, and (4) LNAA with BH4 therapy. An overnight protocol measured plasma amino acids, serum melatonin, and 6-sulfatoxymelatonin and dopamine in first void urine after each phase. Results (1) Three out of nine subjects responded to BH4. A significant increase of serum melatonin levels was observed in BH4 responders with decreased blood Phe concentration. No significant change in melatonin, dopamine or Phe levels was observed with BH4 in the subjects as a whole. (2) Synergistic effects with BH4 and LNAA were observed in serum melatonin in BH4 responders. (3) The relationship between serum melatonin and Phe showed a significant negative slope (p = 0.0005) with a trend toward differing slopes among individual subjects (p = 0.066). There was also a negative association overall between blood Phe and urine 6-sulfatoxymelatonin and dopamine (P = 0.040 and 0.047). Conclusion Blood Phe concentrations affected peripheral monoamine neurotransmitter biomarker concentrations differently in each individual with PKU. Melatonin levels increased with BH4 therapy only when blood Phe decreased. Monitoring

  3. 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...

  4. 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.

  5. Highly selective determination of dopamine in the presence of ascorbic acid and serotonin at glassy carbon electrodes modified with carbon nanotubes dispersed in polyethylenimine.

    PubMed

    Rodríguez, Marcela C; Rubianes, María D; Rivas, Gustavo A

    2008-11-01

    We report the highly selective and sensitive voltammetric dopamine quantification in the presence of ascorbic acid and serotonin by using glassy carbon electrodes modified with a dispersion of multi-wall carbon nanotubes (MWCNT) in polyethylenimine, PEI (GCE/MWCNT-PEI). The electrocatalytic activity of the MWCNT deposited on the glassy carbon electrode has allowed an important decrease in the overvoltages for the oxidation of ascorbic acid and dopamine, making possible a clear definition of dopamine, serotonin and ascorbic acid oxidation processes. The sensitivities for dopamine in the presence and absence of 1.0 mM ascorbic acid and serotonin were (2.18 +/- 0.03) x 10(5) microAM(-1) (r = 0.9998); and (2.10 +/- 0.07) x 10(5) miroAM(-1) (r=0.9985), respectively, demonstrating the excellent performance of the GCE/MWCNT-PEI. The detection limit for dopamine in the mixture was 9.2 x 10(-7) M. The R. S. D. for the determination of 50 microM dopamine using four different electrodes was 3.9% when modified with the same MWCNT/PEI dispersion, and 4.6% when using four different dispersions. The modified electrode has been successfully applied for recovery assays of dopamine in human blood serum. Therefore, the new sensor represents an interesting and promising alternative for the electrochemical quantification of neurotransmitters and other analytes of clinical interest.

  6. Neurotransmitter and psychostimulant recognition by the dopamine transporter.

    PubMed

    Wang, Kevin H; Penmatsa, Aravind; Gouaux, Eric

    2015-05-21

    Na(+)/Cl(-)-coupled biogenic amine transporters are the primary targets of therapeutic and abused drugs, ranging from antidepressants to the psychostimulants cocaine and amphetamines, and to their cognate substrates. Here we determine X-ray crystal structures of the Drosophila melanogaster dopamine transporter (dDAT) bound to its substrate dopamine, a substrate analogue 3,4-dichlorophenethylamine, the psychostimulants d-amphetamine and methamphetamine, or to cocaine and cocaine analogues. All ligands bind to the central binding site, located approximately halfway across the membrane bilayer, in close proximity to bound sodium and chloride ions. The central binding site recognizes three chemically distinct classes of ligands via conformational changes that accommodate varying sizes and shapes, thus illustrating molecular principles that distinguish substrates from inhibitors in biogenic amine transporters.

  7. Neurotransmitter and psychostimulant recognition by the dopamine transporter

    PubMed Central

    Wang, Kevin H.; Penmatsa, Aravind; Gouaux, Eric

    2015-01-01

    Na+/Cl−-coupled biogenic amine transporters are the primary targets of therapeutic and abused drugs, ranging from antidepressants to the psychostimulants cocaine and amphetamines, and to their cognate substrates. Here we determine x-ray crystal structures of the Drosophila melanogaster dopamine transporter (dDAT) bound to its substrate dopamine (DA), a substrate analogue 3,4-dichlorophenethylamine, the psychostimulants D-amphetamine, methamphetamine, or to cocaine and cocaine analogues. All ligands bind to the central binding site, located approximately halfway across the membrane bilayer, in close proximity to bound sodium and chloride ions. The central binding site recognizes three chemically distinct classes of ligands via conformational changes that accommodate varying sizes and shapes, thus illustrating molecular principles that distinguish substrates from inhibitors in biogenic amine transporters. PMID:25970245

  8. Reduced cocaine-induced serotonin, but not dopamine and noradrenaline, release in rats with a genetic deletion of serotonin transporters.

    PubMed

    Verheij, Michel M M; Karel, Peter; Cools, Alexander R; Homberg, Judith R

    2014-11-01

    It has recently been proposed that the increased reinforcing properties of cocaine and ecstasy observed in rats with a genetic deletion of serotonin transporters are the result of a reduction in the psychostimulant-induced release of serotonin. Here we provide the neurochemical evidence in favor of this hypothesis and show that changes in synaptic levels of dopamine or noradrenaline are not very likely to play an important role in the previously reported enhanced psychostimulant intake of these serotonin transporter knockout rats. The results may very well explain why human subjects displaying a reduced expression of serotonin transporters have an increased risk to develop addiction. PMID:25261262

  9. 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

  10. Dispensable, redundant, complementary, and cooperative roles of dopamine, octopamine, and serotonin in Drosophila melanogaster.

    PubMed

    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

  11. 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.

  12. 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.

  13. Suppression of serum gonadal steroids in rats by chronic treatment with dopamine and serotonin reuptake inhibitors.

    PubMed

    Rehavi, M; Attali, G; Gil-Ad, I; Weizman, A

    2000-05-01

    The impact of chronic administration (3 weeks) of dopamine and serotonin reuptake inhibitors on serum gonadal steroid hormones and prolactin was studied in intact male and female rats. Both the dopamine and the serotonin reuptake inhibitors lowered serum estradiol and progesterone levels in the female rats. The dopamine transporter blockers suppressed testosterone serum levels in the male rats, whereas serotonin reuptake inhibitors induced only a non-significant reduction (30%) of this hormone. In contrast to the decrease in gonadal steroids, none of the serotonin or the dopamine reuptake blockers altered prolactin serum levels in either the male or female rats. It seems that the effect of these agents on ovarian and testicular hormones is related to the impact of the monoamine reuptake inhibitors on the hypothalamic-pituitary-gonadal axis.

  14. Prepuberal subchronic methylphenidate and atomoxetine induce different long-term effects on adult behaviour and forebrain dopamine, norepinephrine and serotonin in Naples high-excitability rats.

    PubMed

    Ruocco, L A; Carnevale, U A Gironi; Treno, C; Sadile, A G; Melisi, D; Arra, C; Ibba, M; Schirru, C; Carboni, E

    2010-06-26

    The psychostimulant methylphenidate and the non-stimulant atomoxetine are two approved drugs for attention-deficit hyperactivity disorder (ADHD) therapy. The aim of this study was to investigate the long-term effects of prepuberal subchronic methylphenidate and atomoxetine on adult behaviour and the forebrain neurotransmitter and metabolite content of Naples High-Excitability (NHE) rats, a genetic model for the mesocortical variant of ADHD. Male NHE rats were given a daily intraperitoneal injection (1.0mg/kg) of methylphenidate, atomoxetine or vehicle from postnatal day 29 to 42. At postnatal day 70-75, rats were exposed to spatial novelty in the Làt and radial (Olton) mazes. Behavioural analysis for indices of horizontal, vertical, non-selective (NSA) and selective spatial attention (SSA) indicated that only methylphenidate significantly reduced horizontal activity to a different extent, i.e., 39 and 16% respectively. Moreover methylphenidate increased NSA as assessed by higher leaning duration. The high-performance liquid chromatography (HPLC) tissue content assessment of dopamine, norepinephrine, serotonin and relative metabolites in the prefrontal cortex (PFC), cortical motor area (MC), dorsal striatum (DS), ventral striatum (VS), hippocampus and mesencephalon indicated that methylphenidate decreased (i) dopamine, DOPAC, norepinephrine, MHPG, 5-HT and 5-HIAA in the PFC, (ii) dopamine, DOPAC, HVA, serotonin, 5-HIAA in the DS, (iii) dopamine, DOPAC, HVA and MHPG (but increased norepinephrine) in the VS and (iv) norepinephrine, MHPG, serotonin and 5-HIAA in the hippocampus. Atomoxetine increased dopamine and decreased MHPG in the PFC. Like methylphenidate, atomoxetine decreased dopamine, DOPAC, HVA, serotonin and 5-HIAA in the DS, but decreased MHPG in the VS. These results suggest that methylphenidate determined long-term effects on behavioural and neurochemical parameters, whereas atomoxetine affected only the latter.

  15. Variation of the genes encoding the human glutamate EAAT2, serotonin and dopamine transporters and Susceptibility to idiopathic generalized epilepsy.

    PubMed

    Sander, T; Berlin, W; Ostapowicz, A; Samochowiec, J; Gscheidel, N; Hoehe, M R

    2000-08-01

    Several interacting genetic factors are likely to be involved in the epileptogenesis of idiopathic generalized epilepsies (IGE). Neurotransmitter transporters play a central role in the fine tuning of neurotransmission by removal of released neurotransmitters from the synaptic cleft. The present association study tested the hypotheses that variation of the genes encoding neurotransmitter transporters confers susceptibility to IGE. The genotypes of 133 German IGE subjects and 223 ethnically matched controls were assessed for DNA polymorphisms of genes encoding the glutamate (EAAT2), the serotonin (SERT), and dopamine (DAT) transporters. To increase genetic homogeneity, a subgroup of 76 patients with idiopathic absence epilepsy (IAE) was analyzed separately. We found no evidence for an allelic association of either the silent G603A substitution polymorphism in exon 5 of the EAAT2 gene or the regulatory promoter polymorphism of the SERT gene with either IGE or IAE. The frequency of the nine-copy allele of the 40 base pair repeat polymorphism in the 3' un pop popd region of the DAT gene was significantly increased in the IGE patients (chi2 = 4.11, degrees of freedom (d.f.) = 1, P = 0.043) and, in particular, in the IAE patients (chi2 = 7.81, d.f. = 1, P = 0.005) compared with the controls. The present findings strengthen previous evidence that genetic variation of the DAT gene modulates neuronal network excitability and contributes to the epileptogenesis of IAE.

  16. 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

  17. Comonitoring of adenosine and dopamine using the Wireless Instantaneous Neurotransmitter Concentration System: proof of principle

    PubMed Central

    Shon, Young-Min; Chang, Su-Youne; Tye, Susannah J.; Kimble, Christopher J.; Bennet, Kevin E.; Blaha, Charles D.; Lee, Kendall H.

    2010-01-01

    Object The authors of previous studies have demonstrated that local adenosine efflux may contribute to the therapeutic mechanism of action of thalamic deep brain stimulation (DBS) for essential tremor. Real-time monitoring of the neurochemical output of DBS-targeted regions may thus advance functional neurosurgical procedures by identifying candidate neurotransmitters and neuromodulators involved in the physiological effects of DBS. This would in turn permit the development of a method of chemically guided placement of DBS electrodes in vivo. Designed in compliance with FDA-recognized standards for medical electrical device safety, the authors report on the utility of the Wireless Instantaneous Neurotransmitter Concentration System (WINCS) for real-time comonitoring of electrical stimulation–evoked adenosine and dopamine efflux in vivo, utilizing fast-scan cyclic voltammetry (FSCV) at a polyacrylonitrile-based (T-650) carbon fiber microelectrode (CFM). Methods The WINCS was used for FSCV, which consisted of a triangle wave scanned between −0.4 and +1.5 V at a rate of 400 V/second and applied at 10 Hz. All voltages applied to the CFM were with respect to an Ag/AgCl reference electrode. The CFM was constructed by aspirating a single T-650 carbon fiber (r = 2.5 μm) into a glass capillary and pulling to a microscopic tip using a pipette puller. The exposed carbon fiber (the sensing region) extended beyond the glass insulation by ∼ 50 μm. Proof of principle tests included in vitro measurements of adenosine and dopamine, as well as in vivo measurements in urethane-anesthetized rats by monitoring adenosine and dopamine efflux in the dorsomedial caudate putamen evoked by high-frequency electrical stimulation of the ventral tegmental area and substantia nigra. Results The WINCS provided reliable, high-fidelity measurements of adenosine efflux. Peak oxidative currents appeared at +1.5 V and at +1.0 V for adenosine, separate from the peak oxidative current at +0.6 V

  18. Neurotransmitters in hiccups.

    PubMed

    Nausheen, Fauzia; Mohsin, Hina; Lakhan, Shaheen E

    2016-01-01

    Hiccups are the sudden involuntary contractions of the diaphragm and intercostal muscles. They are generally benign and self-limited, however, in some cases they are chronic and debilitating. There are approximately 4000 admissions for hiccups each year in the United States. The hiccup reflex arc is composed of three components: (1) an afferent limb including the phrenic, vagus, and sympathetic nerves, (2) the central processing unit in the midbrain, and (3) the efferent limb carrying motor fibers to the diaphragm and intercostal muscles. Hiccups may be idiopathic, organic, psychogenic, or medication-induced. Data obtained largely from case studies of hiccups either induced by or treated with medications have led to hypotheses on the neurotransmitters involved. The central neurotransmitters implicated in hiccups include GABA, dopamine, and serotonin, while the peripheral neurotransmitters are epinephrine, norepinephrine, acetylcholine, and histamine. Further studies are needed to characterize the nature of neurotransmitters at each anatomical level of the reflex arc to better target hiccups pharmacologically. PMID:27588250

  19. 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

  20. 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.

  1. 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.

  2. Understanding the redox coupling between quantum dots and the neurotransmitter dopamine in hybrid self-assemblies

    NASA Astrophysics Data System (ADS)

    Ji, Xin; Makarov, Nikolay S.; Wang, Wentao; Palui, Goutam; Robel, Istvan; Mattoussi, Hedi

    2015-03-01

    Interactions between luminescent fluorophores and redox active molecules often involve complex charge transfer processes, and have great ramifications in biology. Dopamine is a redox active neurotransmitter involved in a range of brain activities. We used steady-state and time-resolved fluorescence along with transient absorption bleach measurements, to probe the effects of changing the QD size and valence on the rate of photoluminescence quenching in QD-dopamine conjugates, when the pH of the medium was varied. In particular, we measured substantially larger quenching efficiencies, combined with more pronounced shortening in the PL lifetime decay when smaller size QDs and/or alkaline pH were used. Moreover, we found that changes in the nanocrystal size alter both the electron and hole relaxation of photoexcited QDs but with very different extents. For instance, a more pronounced change in the hole relaxation was recorded in alkaline buffers and for green-emitting QDs compared to their red-emitting counterparts. We attributed these results to the more favorable electron transfer pathway from the reduced form of the complex to the valence band of the QD. This process benefits from the combination of lower oxidation potential and larger energy mismatch in alkaline buffers and for green-emitting QDs. In comparison, the effects on the rate of electron transfer from excited QDs to dopamine are less affected by QD size. These findings provide new insights into the mechanisms that drive charge transfer interactions and the ensuing quenching of QD emission in such assemblies.

  3. Ovarian hormones differentially influence immunoreactivity for dopamine beta- hydroxylase, choline acetyltransferase, and serotonin in the dorsolateral prefrontal cortex of adult rhesus monkeys.

    PubMed

    Kritzer, M F; Kohama, S G

    1999-07-01

    Recent studies have shown that ovariectomy reduces, and subsequent hormone replacement restores the density of axons immunoreactive for tyrosine hydroxylase in the dorsolateral prefrontal cortex of adult female rhesus monkeys. The present study indicates that three additional extrathalamic frontal lobe afferents are also sensitive to changes in the ovarian hormone environment. Specifically, the combination of hormone manipulation with qualitative and quantitative analysis of immunocytochemistry for dopamine beta-hydroxylase, choline acetyltransferase, and serotonin in the primate prefrontal cortex revealed quantitative responses in both cholinergic and monoaminergic axons to changing ovarian hormone levels. However, whereas ovariectomy produced a modest net decrease in the density of fibers immunoreactive for choline acetyltransferase, this same treatment markedly increased the density of axons immunoreactive for dopamine beta-hydroxylase and for serotonin. Further, the effects of ovariectomy on these afferent systems were differentially attenuated by estrogen verses estrogen plus progesterone hormone replacement. Estrogen was as effective as estrogen plus progesterone in stimulating normal prefrontal immunoreactivity for choline acetyltransferase and dopamine beta-hydroxylase. The dual replacement of estrogen plus progesterone, however, was a much more potent influence than estrogen alone for serotonin immunoreactivity. Thus, ovarian hormones appear to provide stimulation that differentially affects each of four chemically identified extrathalamic prefrontal afferent systems examined to date, and may have roles in maintaining the normal balance and functional interactions between these neurotransmitter systems.

  4. 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

  5. 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

  6. The clozapine metabolite N-desmethylclozapine displays variable activity in diverse functional assays at human dopamine D₂ and serotonin 5-HT₁A receptors.

    PubMed

    Heusler, Peter; Bruins Slot, Liesbeth; Tourette, Amélie; Tardif, Stéphanie; Cussac, Didier

    2011-11-01

    N-desmethylclozapine (NDMC or norclozapine) is the major active metabolite of the antipsychotic clozapine in humans. The activity of NDMC differs from clozapine at a number of neurotransmitter receptors, probably influencing the pharmacological effects of clozapine treatment. Here, we tested the properties of NDMC in comparison with clozapine at recombinant human dopamine D(2) and serotonin 5-HT(1A) receptors, using a panel of functional assays implicating diverse signalling pathways. At dopamine D(2) receptors, NDMC as well as clozapine did not display agonist activity in measures of G protein activation by [(35)S]GTPγS binding and in the sensitive Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) phosphorylation assay. In contrast, there were weak partial agonist actions of NDMC (but not of clozapine) for dopamine D(2)-dependent activation of Ca(2+) liberation via coexpressed chimeric Gα(q/o) proteins and for G protein-coupled inward rectifier potassium channel (GIRK) current induction in Xenopus oocytes. Intriguingly, GIRK currents induced by NDMC via dopamine D(2) receptors showed a rapid and transient time course, strikingly different from currents recorded with other receptor agonists. At serotonin 5-HT(1A) receptors, NDMC was a more efficacious partial agonist than clozapine for [(35)S]GTPγS binding, ERK1/2 phosphorylation and GIRK activation. Respective low and moderate partial agonist properties of NDMC at dopamine D(2) and serotonin 5-HT(1A) receptors thus differentiate the metabolite from its parent drug and may contribute to the overall effects of clozapine pharmacotherapy.

  7. 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

  8. The Roles of Dopamine and Serotonin in Decision Making: Evidence from Pharmacological Experiments in Humans

    PubMed Central

    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

  9. Genetics of monoamine neurotransmitter disorders

    PubMed Central

    2015-01-01

    The monoamine neurotransmitter disorders are a heterogeneous group of inherited neurological disorders involving defects in the metabolism of dopamine, norepinephrine, epinephrine and serotonin. The inheritance of these disorders is mostly autosomal recessive. The neurological symptoms are primarily attributable to cerebral deficiency of dopamine, serotonin or both. The clinical presentations were highly variable and substantial overlaps exist. Evidently, laboratory investigations are crucial for accurate diagnosis. Measurement of neurotransmitter metabolites in cerebral spinal fluid (CSF) is the key to delineate the metabolic defects. Adjuvant investigations including plasma phenylalanine, urine pterins, urine 3-O-methyldopa (3-OMD) and serum prolactin are also helpful to establish the diagnosis. Genetic analyses are pivotally important to confirm the diagnosis which allows specific treatments, proper genetic counselling, prognosis prediction, assessment of recurrent risk in the family as well as prenatal diagnosis. Early diagnosis with appropriate treatment is associated with remarkable response and favourable clinical outcome in several disorders in this group. PMID:26835371

  10. Serotonin, noradrenaline, dopamine metabolites in transcendental meditation-technique.

    PubMed

    Bujatti, M; Riederer, P

    1976-01-01

    The highly significant increase of 5-HIAA (5-hydroxyindole-3-acetic acid) in Transcendental Meditation technique suggests systemic serotonin as "rest and fulfillment hormone" of deactivation-relaxation. Furthermore 5-HT (5-hydroxytryptamine, serotonin) is considered to be the EC-cell (enterochromaffine-cell) hormone requested by Fujita and Kobayashi and its role for EEG synchronisation via area postrema chemoreceptor as anti arousal agent is being discussed. The significant decrease of the catecholamine metabolite VMA (vanillic-mandelic acid) in meditators, that is associated with a reciprocal increase of 5-HIAA supports as a feedback necessity the "rest and fulfillment response" versus "fight and flight". As the adreno medullary tissue serves for hormonal reinforcement of orthosympathetic activity, the Enterochromaffine Cell System (having taken the form of distinct organs in some species as octopus and discoglossus) is suggested to serve via serotonin for humoral reinforcement of parasympathetic activity in deep relaxation.

  11. 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. PMID:26113399

  12. Effects of Dopamine and Serotonin Systems on Modulating Neural Oscillations in Hippocampus-Prefrontal Cortex Pathway in Rats.

    PubMed

    Xu, Xiaxia; Zheng, Chenguang; An, Lei; Wang, Rubin; Zhang, Tao

    2016-07-01

    Theta and gamma oscillations are believed to play an important role in cognition and memory, and their phase coupling facilitates the information transmission in hippocampal-cortex network. In a rat model of chronic stress, the phase coupling of both theta and gamma oscillations between ventral hippocampal CA1 (vCA1) and medial prefrontal cortex (mPFC) was found to be disrupted, which was associated with the impaired synaptic plasticity in the pathway. However, little was known about the mechanisms underlying the process. In order to address this issue, both dopamine and serotonin as monoaminergic neurotransmitters were involved in this study, since they were crucial factors in pathological basis of depressive disorder. Local field potentials (LFPs) were recorded simultaneously at both vCA1 and mPFC regions under anesthesia, before and after the injection of dopamine D1 receptor antagonist and 5-HT1A receptor agonist, respectively. The results showed that the blockage of D1 receptor could lead to depression-like decrement on theta phase coupling. In addition, the activation of 5-HT1A receptor enhanced vCA1-mPFC coupling on gamma oscillations, and attenuated CA1 theta-fast gamma cross frequency coupling. These data suggest that the theta phase coupling between vCA1 and mPFC may be modulated by dopamine system that is an underlying mechanism of the cognitive dysfunction in depression. Besides, the serotonergic system is probably involved in the regulation of gamma oscillations coupling in vCA1-mPFC network. PMID:26969669

  13. Focus on: neurotransmitter systems.

    PubMed

    Valenzuela, C Fernando; Puglia, Michael P; Zucca, Stefano

    2011-01-01

    Neurotransmitter systems have been long recognized as important targets of the developmental actions of alcohol (i.e., ethanol). Short- and long-term effects of ethanol on amino acid (e.g., γ-aminobutyric acid and glutamate) and biogenic amine (e.g., serotonin and dopamine) neurotransmitters have been demonstrated in animal models of fetal alcohol spectrum disorders (FASD). Researchers have detected ethanol effects after exposure during developmental periods equivalent to the first, second, and third trimesters of human pregnancy. Results support the recommendation that pregnant women should abstain from drinking-even small quantities-as effects of ethanol on neurotransmitter systems have been detected at low levels of exposure. Recent studies have elucidated new mechanisms and/or consequences of the actions of ethanol on amino acid and biogenic amine neuro-transmitter systems. Alterations in these neurotransmitter systems could, in part, be responsible for many of the conditions associated with FASD, including (1) learning, memory, and attention deficits; (2) motor coordination impairments; (3) abnormal responsiveness to stress; and (4) increased susceptibility to neuropsychiatric disorders, such as substance abuse and depression, and also neurological disorders, such as epilepsy and sudden infant death syndrome. However, future research is needed to conclusively establish a causal relationship between these conditions and developmental dysfunctions in neurotransmitter systems.

  14. Serotonin and dopamine independently regulate pituitary beta-endorphin release in vivo.

    PubMed

    Sapun-Malcolm, D; Farah, J M; Mueller, G P

    1986-01-01

    Serotonin and dopamine neurons have been shown to exert a stimulatory and inhibitory control, respectively, over pituitary release of beta-endorphin-like immunoreactivity (beta-END-LI). In the present study we sought to determine whether an interaction exists between these two reciprocal mechanisms regulating beta-END-LI in the rat. The intraperitoneal (i.p.) administration of 5 mg/kg quipazine, a serotonin receptor agonist, or 2.5 mg/kg haloperidol, a dopamine receptor antagonist, each elevated circulating levels by beta-END-LI 5-fold over control levels by 30 min post-injection. Pretreatment (1 h) with 5 mg/kg, i.p., cinanserin, a serotonin receptor antagonist, completely blocked the quipazine-induced rise in beta-END-LI without affecting the elevated levels of beta-END-LI in haloperidol-treated animals. Conversely, pretreatment (2 h) with 1 mg/kg, i.p., bromocriptine, a dopamine receptor agonist, had no effect on quipazine-induced release of beta-END-LI but did completely prevent the rise in plasma beta-END-LI due to haloperidol treatment. Gel filtration chromatography revealed that quipazine and haloperidol treatments elevated plasma levels of both beta-END-size immunoreactivity and beta-lipotropin (beta-LPH)-sized immunoreactivity though to different relative degrees. However, since circulating levels of beta-LPH serve as a marker for anterior lobe (AL) beta-END-LI secretion, serotonin and dopamine appear to exert stimulatory and inhibitory control, respectively, over AL beta-END-LI release. Further, the quipazine-induced rise in total plasma beta-END-LI primarily resembled beta-LPH in size and was blocked by cinanserin but not bromocriptine pretreatment. And conversely, bromocriptine but not cinanserin prevented the haloperidol-induced rise in circulating beta-END-LI.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. 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…

  16. Radioenzymatic analysis of neurotransmitters

    SciTech Connect

    Philips, S.R.

    1987-08-17

    Since the late 1960's, radioenzymatic assays have gradually come to replace the less sensitive and less specific spectrofluorometric and bioassay procedures previously used to determine many of the neurotransmitters. These assays provide the means to measure picogram quantities of most of these substances, and have enabled determinations to be made in very small volumes of body fluids, in brain perfusates and individual brain nuclei, and in large individual cells of some simple animals. This paper reviews briefly some of the radioenzymatic techniques presently available for assaying norepinephrine (NE), epinephrine (E), dopamine (DA), serotonin, and the trace amines octopamine (OA), phenylethanolamine (PEOHA), phenylethylamine (PEA), tyramine (TA) and tryptamine (T).

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

    PubMed

    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

    2015-07-20

    An aversion to harming others is a core component of human morality and is disturbed in antisocial behavior. Deficient harm aversion may underlie instrumental and reactive aggression, which both feature in psychopathy. Past work has highlighted monoaminergic influences on aggression, 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. 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, 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

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

    PubMed

    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

    2015-07-20

    An aversion to harming others is a core component of human morality and is disturbed in antisocial behavior. Deficient harm aversion may underlie instrumental and reactive aggression, which both feature in psychopathy. Past work has highlighted monoaminergic influences on aggression, 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. 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, 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.

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

    PubMed

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

    2016-10-01

    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 3 rhesus macaques. We found that animals had slower reaction times (RTs) on escitalopram than on GBR-12909 or saline. However, they were also least accurate on escitalopram. Animals were faster, although nonsignificantly, 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 RTs the animals were less impulsive on escitalopram. However, the decreased accuracy of the monkeys shows that they were not able to make use of their slower response times to make more accurate decisions. Therefore, impulsivity was reduced on escitalopram, but at the expense of a slower information-processing rate in the perceptual inference task. (PsycINFO Database Record

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

    PubMed

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

    2016-10-01

    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 3 rhesus macaques. We found that animals had slower reaction times (RTs) on escitalopram than on GBR-12909 or saline. However, they were also least accurate on escitalopram. Animals were faster, although nonsignificantly, 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 RTs the animals were less impulsive on escitalopram. However, the decreased accuracy of the monkeys shows that they were not able to make use of their slower response times to make more accurate decisions. Therefore, impulsivity was reduced on escitalopram, but at the expense of a slower information-processing rate in the perceptual inference task. (PsycINFO Database Record PMID:27513807

  1. 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

  2. Serotonin as a facilitatory neurotransmitter in the anticonvulsant activity of methaqualone.

    PubMed

    Leadbetter, M I; Parmar, S S

    1989-07-01

    The neuromodulatory role of serotonin in the anticonvulsant activity of methaqualone was investigated. A dose-dependent increase in the ability of methaqualone to provide protection against pentylenetetrazol (90 mg/kg SC)-induced convulsions in mice was observed. The ED50 value for the anticonvulsant activity of methaqualone was calculated and found to be 60 mg/kg, IP. Pretreatment of mice with 5-hydroxytryptophan (100 mg/kg, IP, 2 hr) and p-chlorophenylalanine (300 mg/kg, IP, 2 hr), causing an increase in brain serotonin levels, resulted in a 60% and 80% increase, respectively, in the anticonvulsant activity of methaqualone. Similar pretreatment with p-chlorophenylalanine (300 mg/kg, IP, 48 hr), causing a lowering of brain serotonin, and methysergide (10 mg/kg, IP, 0.5 hr), causing blockade of brain serotonin receptors, resulted in a 40% and 20% decrease, respectively, in the ability of methaqualone to provide protection against pentylenetetrazol-induced convulsions. These results suggest a facilitatory role of serotonin in the anticonvulsant activity of methaqualone.

  3. [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

  4. 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.

  5. 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.

  6. Induction of depressive-like behavior by intranigral 6-OHDA is directly correlated with deficits in striatal dopamine and hippocampal serotonin.

    PubMed

    Santiago, Ronise M; Barbiero, Janaína; Gradowski, Raisa W; Bochen, Suelen; Lima, Marcelo M S; Da Cunha, Cláudio; Andreatini, Roberto; Vital, Maria A B F

    2014-02-01

    Among the non-motor phenomena of Parkinson's disease (PD) are depressive symptoms, with a prevalence of 40-70%. The reason for this high prevalence is not yet clear. The basal ganglia receives dopamine (DA) inputs from the substantia nigra pars compacta (SNpc), which is known to be impaired in PD patients. The neurotransmitter deficiency hypothesis of PD considers that low serotonin (5-hydroxytryptamine [5-HT]) activity in the brain in PD patients is a risk factor for depression. We investigated whether DA depletion promoted by the neurotoxin 6-hydroxydopamine (6-OHDA) is able to induce depressive-like behavior and neurotransmitter alterations that are similar to those observed in PD. To test this hypothesis, we performed intranigral injections of 6-OHDA in male Wistar rats and conducted motor behavior, depressive-like behavior, histological, and neurochemical tests. After the motor recovery period, 6-OHDA was able to produce anhedonia and behavioral despair 7, 14, and 21 days after neurotoxin infusion. These altered behavioral responses were accompanied by reductions of striatal DA. Additionally, decreases in hippocampal 5-HT content were detected in the 6-OHDA group. Notably, correlations were found between 5-HT and DA levels and swimming, immobility, and sucrose preference. Our results indicate that 6-OHDA produced depressive-like behavior accompanied by striatal DA and hippocampal 5-HT reductions. Moreover, DA and 5-HT levels were strongly correlated with "emotional" impairments, suggesting the important participation of these neurotransmitters in anhedonia and behavioral despair after 6-OHDA-induced nigral lesions.

  7. 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.

  8. 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.

  9. Amisulpride-induced acute akathisia in OCD: an example of dysfunctional dopamine-serotonin interactions?

    PubMed

    Ersche, Karen D; Cumming, Paul; Craig, Kevin J; Müller, Ulrich; Fineberg, Naomi A; Bullmore, Edward T; Robbins, Trevor W

    2012-06-01

    We report about a clinical observation in a well-characterized group of patients with obsessive-compulsive disorder (OCD) during an experimental medicine study in which a single dose of amisulpride (a selective D₂/₃ antagonist) was administered. Almost half of the OCD patients, in particular those with less severe obsessive-compulsive symptoms, experienced acute akathisia in response to the amisulpride challenge. This unexpectedly high incidence of akathisia in the selective serotonin reuptake inhibitor (SSRI)-treated patients with OCD suggests that individual differences in dopamine-serotonin interactions underlie the clinical heterogeneity of OCD, and may thus explain the insufficiency of SSRI monotherapy in those patients not experiencing a satisfactory outcome in symptom reduction. We further speculate about the neuropathology possibly underlying this clinical observation and outline a testable hypothesis for future molecular imaging studies.

  10. 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

  11. Alterations in brain dopamine and serotonin metabolism during the development of tolerance to human beta-endorphin in rats.

    PubMed

    Van Loon, G R; De Souza, E B; Kim, C

    1978-12-01

    Repeated intracisternal injections of human beta-endorphin lead to development of tolerance with respect to the catalepsy, analgesia, and hypothermia which are seen following a single injection. The initial injection of beta-endorphin results in increases in the dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in neostriatum, as well as increases in the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in hypothalamus and brainstem and a decrease in 5-HIAA in hippocampus. In the present study, we report changes in metabolism of dopamine and serotonin in specific brain areas during the development of tolerance to beta-endorphin. Thus, the development of tolerance to beta-endorphin with respect to catalepsy, analgesia, and hypothermia may be mediated by development of tolerance to the effects of beta-endorphin on brain dopamine and serotonin release.

  12. Changes in sensitivity of brain dopamine and serotonin receptors during long-term treatment with carbidine

    SciTech Connect

    Zharkovskii, A.M.; Allikmets, L.K.; Chereshka, K.S.; Zharkovskaya, T.A.

    1986-04-01

    The authors study the state of the dopamine and serotonin receptors of the brain during chronic administration of carbidine to animals. Parts of the brain from two rats were pooled and binding of tritium-spiperone and tritium-LSD was determined. Statistical analysis of the data for apomorphine sterotypy was carried out and the Student's test was used for analysis of the remaining data. It is shown that after discontinuation of carbidine binding of tritium-spiperone and tritium-LSD in the cortex was reduced.

  13. Influence of enkephalin on K+-evoked efflux of putative neurotransmitters in rat brain. Selective inhibition of acetylcholine and dopamine release.

    PubMed

    Subramanian, N; Mitznegg, P; Sprügel, W; Domschke, W; Domschke, S; Wünsch, E; Demling, L

    1977-09-01

    In rat brain slices preincubated with various radiolabelled putative neurotransmitters, methionine-enkephalin diminished the potassium-evoked release of dopamine and acetylcholine. The effect was antagonised by naloxone. The potassium-induced effux of three other neurotransmitters, histamine, 5-hydroxy-tryptamine and gamma-aminobutyric acid, were unaffected by methionine-enkephalin. A probable physiological function for the endogenous ligands in specifically affecting the catecholaminergic and cholinergic transmission is suggested.

  14. L-DOPA elicits non-vesicular releases of serotonin and dopamine in hemiparkinsonian rats in vivo.

    PubMed

    Miguelez, Cristina; Navailles, Sylvia; Delaville, Claire; Marquis, Loïse; Lagière, Mélanie; Benazzouz, Abdelhamid; Ugedo, Luisa; De Deurwaerdère, Philippe

    2016-08-01

    The control of the secretory activity of serotonergic neurons has been pointed out to reduce motor and non-motor side effects of the antiparkinsonian drug L-DOPA. This strategy deserves further investigation because it is presently unclear whether L-DOPA promotes a non-vesicular release of dopamine and serotonin from serotonergic neurons. To get a full neurochemical picture compatible with the existence of such a mechanism, we combined multisite intracerebral microdialysis, post mortem tissue measurement and single unit extracellular recordings in the dorsal raphe nucleus from hemiparkinsonian rats. L-DOPA (3-100mg/kg, ip.) non-homogeneously decreased extracellular serotonin levels in the striatum, substantia nigra pars reticulata, hippocampus and prefrontal cortex and homogenously serotonin tissue content in the striatum, cortex and cerebellum. L-DOPA (12mg/kg) did not modify the firing rate or pattern of serotonergic-like neurons recorded in the dorsal raphe nucleus. When focusing on serotonin release in the prefrontal cortex and the hippocampus, we found that L-DOPA (12 or 100mg/kg) enhanced serotonin extracellular levels in both regions upon Ca(2+) removal. Concomitantly, L-DOPA-stimulated dopamine release partly persisted in the absence of Ca(2+) in a region-dependent manner. Local application of the serotonin reuptake inhibitor citalopram (1µM) blunted the responses to L-DOPA (3-12mg/kg), measured as extracellular dopamine levels, most prominently in the hippocampus. These data stress that L-DOPA, already at low to moderate doses, promotes non-vesicular releases of serotonin and dopamine in a region-dependent manner. PMID:27234917

  15. 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. PMID:25752199

  16. 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.

  17. Correlation between acidic phospholipids and serotonin and between lysolecithin and dopamine in ganglia of the marine mussel, Mytilus edulis.

    PubMed

    Haley, J E; Stefano, G B; Catapane, E J

    1978-02-15

    These studies have demonstrated a positive correlation between the acidic phospholipids and the serotonin content and between the lysolecithin and the dopamine content in the cerebral, pedal and visceral ganglia of Mytilus edulis. These relationships were further supported by experiments utilizing 6-hydroxydopamine and 5,6-dihydroxytryptamine. PMID:624353

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

    PubMed Central

    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.

    2011-01-01

    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. PMID:21969584

  19. 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

  20. Genetic Susceptibility and Neurotransmitters in Tourette Syndrome

    PubMed Central

    Paschou, Peristera; Fernandez, Thomas V.; Sharp, Frank; Heiman, Gary A.; Hoekstra, Pieter J.

    2015-01-01

    Family studies have consistently shown that Tourette syndrome (TS) is a familial disorder and twin studies have clearly indicated a genetic contribution in the etiology of TS. Whereas early segregation studies of TS suggested a single-gene autosomal dominant disorder, later studies have pointed to more complex models including additive and multifactorial inheritance and likely interaction with genetic factors. While the exact cellular and molecular base of TS is as yet elusive, neuroanatomical and neurophysiological studies have pointed to the involvement of cortico-striato-thalamocortical circuits and abnormalities in dopamine, glutamate, gamma-aminobutyric acid, and serotonin neurotransmitter systems, with the most consistent evidence being available for involvement of dopamine-related abnormalities, that is, a reduction in tonic extracellular dopamine levels along with hyperresponsive spike-dependent dopamine release, following stimulation. Genetic and gene expression findings are very much supportive of involvement of these neurotransmitter systems. Moreover, intriguingly, genetic work on a two-generation pedigree has opened new research pointing to a role for histamine, a so far rather neglected neurotransmitter, with the potential of the development of new treatment options. Future studies should be aimed at directly linking neurotransmitter-related genetic and gene expression findings to imaging studies (imaging genetics), which enables a better understanding of the pathways and mechanisms through which the dynamic interplay of genes, brain, and environment shapes the TS phenotype. PMID:24295621

  1. 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

  2. [Spatial memory and regulation of brain adenylyl cyclase by serotonin and dopamine in rat with streptozotocin diabetes].

    PubMed

    Sukhov, I B; Chistyakova, O V; Shipilov, V N; Doilnitsyn, A M; Shpakov, A O

    2015-03-01

    The most common complication of diabetes mellitus of the type 1 (DM1) is a cognitive deficiency, which develops as a result of neurodegenerative changes in the brain. The aim of this work was to study the learning and spatial memory in rats with streptozotocin DM1 with different duration (1.5 and 6 months), as well as the activity of adenylyl cyclase signaling system (ACSS) sensitive to agonists of the serotonin and the dopamine receptors in the brain of diabetic rats. Our experiments demonstrated that rats with 1.5-months DM1 has no changes in spatial memory which were evaluated in a Morris water maze whereas in rats with 6-months DM1 the spatial memory and learning ability were decreased. The alterations of the regulation of adenylyl cyclase by agonists of types 1 and 6 serotonin receptors and type 2 dopamine receptors were found in both the 1.5- and 6-months DM1 which indicates their importance in the development of cognitive deficiency. Abnormalities in the. brain ACSS can be considered as key factors in the etiology and pathogenesis of cognitive dysfunctions in DM1. Hypothesized that cognitive deficiency occurs only in the later stages of DM1 due to alterations in the serotonin and dopamine signaling systems of the brain.

  3. Carbon nanofiber multiplexed array and Wireless Instantaneous Neurotransmitter Concentration Sensor for simultaneous detection of dissolved oxygen and dopamine

    PubMed Central

    Marsh, Michael P.; Koehne, Jessica E.; Andrews, Russell J.; Meyyappan, M.; Bennet, Kevin E.; Lee, Kendall H.

    2014-01-01

    Purpose While the mechanism of Deep Brain Stimulation (DBS) remains poorly understood, previous studies have shown that it evokes release of neurochemicals and induces activation of functional magnetic resonance imaging (fMRI) blood oxygen level-dependent signal in distinct areas of the brain. Therefore, the main purpose of this paper is to demonstrate the capabilities of the Wireless Instantaneous Neurotransmitter Concentration Sensor system (WINCS) in conjunction with a carbon nanofiber (CNF) multiplexed array electrode as a powerful tool for elucidating the mechanism of DBS through the simultaneous detection of multiple bioactive-molecules. Methods Patterned CNF nanoelectrode arrays were prepared on a 4-inch silicon wafer where each device consists of 3 × 3 electrode pads, 200 μm square, that contain CNFs spaced at 1μm intervals. The multiplexed carbon nanofiber CNF electrodes were integrated with WINCS to detect mixtures of dopamine (DA) and oxygen (O2) using fast scan cyclic voltammetry (FSCV) in vitro. Results First, simultaneous detection of O2 at two spatially different locations, 200 um apart, was demonstrated. Second, simultaneous detection of both O2 and DA at two spatially different locations, using two different decoupled waveforms was demonstrated. Third, controlled studies demonstrated that the waveform must be interleaved to avoid electrode crosstalk artifacts in the acquired data. Conclusions Multiplexed CNF nanoelectrode arrays for electrochemical detection of neurotransmitters show promise for the detection of multiple analytes with the application of time independent decoupled waveforms. Electrochemistry on CNF electrodes may be helpful in elucidating the mechanism of DBS, and may also provide the precision and sensitivity required for future applications in feedback modulated DBS neural control systems. PMID:24688800

  4. Dopamine D4 receptor and serotonin transporter gene effects on the longitudinal development of infant temperament.

    PubMed

    Holmboe, K; Nemoda, Z; Fearon, R M P; Sasvari-Szekely, M; Johnson, M H

    2011-07-01

    Existing studies of the effect on infant temperament of the 48 base pair variable number of tandem repeats polymorphism in exon 3 of the dopamine D4 receptor gene, DRD4 VNTR, and the serotonin transporter-linked polymorphic region, 5-HTTLPR, have provided contradictory results, and age seems to be an important factor. The present study investigated the effect of these two polymorphisms on the stability of infant temperament between 4 and 9 months of age. Furthermore, the effect of a recently discovered single nucleotide polymorphism which modulates the 5-HTTLPR (rs25531) was investigated in relation to infant temperament. The study sample consisted of 90 infants, who were assessed by parental report at the two ages under consideration using the Revised Infant Behavior Questionnaire. It was found that infants carrying the 7-repeat allele of the DRD4 VNTR had higher levels of Negative Affect. Furthermore, there was an interaction between DRD4 VNTR and 5-HTTLPR genotype such that infants with the DRD4 VNTR 7-repeat allele and the highest expressing 5-HTTLPR genotype (L(A) L(A) ) had the highest level of Negative Affect. These effects were largely driven by scores on the Falling Reactivity scale. Genetic effects were stable across age. The results emphasize the need for developmental studies of genetic effects on temperament.

  5. 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

  6. Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder.

    PubMed

    Howell, Leonard L; 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

  7. 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.

  8. 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.

  9. 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 these

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

    PubMed Central

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

    2008-01-01

    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 ofthese 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 KO mice and wildtype littermates were studied in the forced swim test (FST), the tail suspension test (TST) and for sucrose consumption. In order to dissociate general activity from the potential antidepressant effects three types of behavior were assessed in the FST: immobility, climbing and swimming. In confirmation of previous reports, both DAT KO and NET KO mice exhibited less immobility than wildtype littermates while SERT KO mice did not. Effects of DAT deletion were not simply due to 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, while swimming was almost eliminated in DAT -/-mice, while 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 forced swim test results in antidepressant animal models, while 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 TST, 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 these effects of

  11. D1-type dopamine receptors inhibit growth cone motility in cultured retina neurons: evidence that neurotransmitters act as morphogenic growth regulators in the developing central nervous system.

    PubMed Central

    Lankford, K L; DeMello, F G; Klein, W L

    1988-01-01

    Precedent exists for the early development and subsequent down-regulation of neurotransmitter receptor systems in the vertebrate central nervous system, but the function of such embryonic receptors has not been established. Here we show that stimulation of early-developing dopamine receptors in avian retina cells greatly inhibits the motility of neuronal growth cones. Neurons from embryonic chicken retinas were cultured in low-density monolayers, and their growth cones were observed with phase-contrast or video-enhanced-contrast-differential-interference-contrast (VEC-DIC) microscopy. Approximately 25% of the neurons responded to micromolar dopamine with a rapid reduction in filopodial activity followed by a flattening of growth cones and retraction of neurites. The response occurred at all ages examined (embryonic day-8 retinal neurons cultured on polylysine-coated coverslips for 1-7 days), although neurite retraction was greatest in younger cultures. Effects of dopamine on growth cone function could be reversed by haloperidol or (+)-SCH 23390, whereas forskolin elicited a response similar to dopamine; these data show the response was receptor-mediated, acting through a D1-type system, and are consistent with the use of cAMP as a second messenger. The experiments provide strong support for the hypothesis that neurotransmitters, besides mediating transynaptic signaling in the adult, may have a role in neuronal differentiation as growth regulators. Images PMID:3380807

  12. D1-type dopamine receptors inhibit growth cone motility in cultured retina neurons: evidence that neurotransmitters act as morphogenic growth regulators in the developing central nervous system.

    PubMed Central

    Lankford, K L; DeMello, F G; Klein, W L

    1988-01-01

    Precedent exists for the early development and subsequent down-regulation of neurotransmitter receptor systems in the vertebrate central nervous system, but the function of such embryonic receptors has not been established. Here we show that stimulation of early-developing dopamine receptors in avian retina cells greatly inhibits the motility of neuronal growth cones. Neurons from embryonic chicken retinas were cultured in low-density monolayers, and their growth cones were observed with phase-contrast or video-enhanced-contrast-differential-interference-contrast (VEC-DIC) microscopy. Approximately 25% of the neurons responded to micromolar dopamine with a rapid reduction in filopodial activity followed by a flattening of growth cones and retraction of neurites. The response occurred at all ages examined (embryonic day-8 retinal neurons cultured on polylysine-coated coverslips for 1-7 days), although neurite retraction was greatest in younger cultures. Effects of dopamine on growth cone function could be reversed by haloperidol or (+)-SCH 23390, whereas forskolin elicited a response similar to dopamine; these data show the response was receptor-mediated, acting through a D1-type system, and are consistent with the use of cAMP as a second messenger. The experiments provide strong support for the hypothesis that neurotransmitters, besides mediating transynaptic signaling in the adult, may have a role in neuronal differentiation as growth regulators. Images PMID:3357895

  13. Characterization of the effects of serotonin on the release of (/sup 3/H)dopamine from rat nucleus accumbens and striatal slices

    SciTech Connect

    Nurse, B.; Russell, V.A.; Taljaard, J.J.

    1988-05-01

    The effect of serotonin agonists on the depolarization (K+)-induced, calcium-dependent, release of (/sup 3/H)dopamine (DA) from rat nucleus accumbens and striatal slices was investigated. Serotonin enhanced basal /sup 3/H overflow and reduced K+-induced release of (/sup 3/H)DA from nucleus accumbens slices. The effect of serotonin on basal /sup 3/H overflow was not altered by the serotonin antagonist, methysergide, or the serotonin re-uptake blocker, chlorimipramine, but was reversed by the DA re-uptake carrier inhibitors nomifensine and benztropine. With the effect on basal overflow blocked, serotonin did not modulate K+-induced release of (/sup 3/H)DA in the nucleus accumbens or striatum. The serotonin agonists, quipazine (in the presence of nomifensine) and 5-methoxytryptamine, did not significantly affect K+-induced release of (/sup 3/H)DA in the nucleus accumbens. This study does not support suggestions that serotonin receptors inhibit the depolarization-induced release of dopamine in the nucleus accumbens or striatum of the rat brain. The present results do not preclude the possibility that serotonin may affect the mesolimbic reward system at a site which is post-synaptic to dopaminergic terminals in the nucleus accumbens.

  14. The pediatric neurotransmitter disorders.

    PubMed

    Pearl, Phillip L; Taylor, Jacob L; Trzcinski, Stacey; Sokohl, Alex

    2007-05-01

    The pediatric neurotransmitter disorders represent an enlarging group of neurological syndromes characterized by abnormalities of neurotransmitter synthesis and breakdown. The disorders of dopamine and serotonin synthesis are aromatic amino acid decarboxylase deficiency, tyrosine hydroxylase deficiency, and disorders of tetrahydrobiopterin synthesis. Amino acid decarboxylase, tyrosine hydroxylase, sepiapterin reductase, and guanosine triphosphate cyclohydrolase (Segawa disease) deficiencies do not feature elevated serum phenylalanine and require cerebrospinal fluid analysis for diagnosis. Segawa disease is characterized by dramatic and lifelong responsiveness to levodopa. Glycine encephalopathy is typically manifested by refractory neonatal seizures secondary to a defect of the glycine degradative pathway. gamma-amino butyric acid (GABA) metabolism is associated with several disorders, including glutamic acid decarboxylase deficiency with nonsyndromic cleft lip/ palate, GABA-transaminase deficiency, and succinic semialdehyde dehydrogenase deficiency. The latter is characterized by elevated gamma-hydroxybutyric acid and includes a wide range of neuropsychiatric symptoms as well as epilepsy. Pyridoxine-dependent seizures have now been associated with deficiency of alpha-aminoadipic semialdehyde dehydrogenase, as well as a new variant requiring therapy with pyridoxal-5-phosphate, the biologically active form of pyridoxine.

  15. 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. PMID:25342005

  16. 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.

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

    PubMed

    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.

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

    PubMed

    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

  19. Role of aminergic (serotonin and dopamine) systems in the embryogenesis and different embryonic behaviors of the pond snail, Lymnaea stagnalis.

    PubMed

    Filla, Adrienn; Hiripi, László; Elekes, Károly

    2009-01-01

    A detailed biochemical and pharmacological analysis of the dopaminergic (DAergic) and serotonergic (5-HTergic) systems was performed during the embryogenesis of Lymnaea stagnalis, to monitor their role in development and different behaviors. The dopamine (DA) level and the synthesizing decarboxylase enzyme activity showed a continuous increase, whereas the serotonin (5-HT) concentration remained low until late postmetamorphic development, when they all showed a rapid and significant increase. Application of monoamine precursors increased, whereas enzyme inhibitors and neurotoxins reduced monoamine levels; all treatments resulting in a prolongation of embryogenesis. Following, p-chlorphenylalanine (pCPA) and 3-hydroxybenzylhydrazine (Nsd-1015) treatments, no 5-HT immunoreactivity could be detected in the embryonic nervous system. These findings suggest that changes of monoamine levels in either (negative or positive) direction cause slowing of embryogenesis. Embryonic rotation and radula protrusion rate was enhanced following both serotonin and dopamine application, whereas frequency of gliding was increased by serotonin treatment. These results clearly indicate the involvement of 5-HT and DA in the regulation of a broad range of embryonic behaviors. Pharmacological characterization of a 5-HT receptor associated with the L. stagnalis embryonic behaviors studied revealed that a mammalian 5-HT(1)-like receptor type is involved in the 5-HTergic regulation of locomotion activity.

  20. 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

  1. Highly sensitive isotope-dilution liquid-chromatography-electrospray ionization-tandem-mass spectrometry approach to study the drug-mediated modulation of dopamine and serotonin levels in Caenorhabditis elegans.

    PubMed

    Schumacher, Fabian; Chakraborty, Sudipta; Kleuser, Burkhard; Gulbins, Erich; Schwerdtle, Tanja; Aschner, Michael; Bornhorst, Julia

    2015-11-01

    Dopamine (DA) and serotonin (SRT) are monoamine neurotransmitters that play a key role in regulating the central and peripheral nervous system. Their impaired metabolism has been implicated in several neurological disorders, such as Parkinson's disease and depression. Consequently, it is imperative to monitor changes in levels of these low-abundant neurotransmitters and their role in mediating disease. For the first time, a rapid, specific and sensitive isotope-dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of DA and SRT in the nematode Caenorhabditis elegans (C. elegans). This model organism offers a unique approach for studying the effect of various drugs and environmental conditions on neurotransmitter levels, given by the conserved DA and SRT biology, including synaptic release, trafficking and formation. We introduce a novel sample preparation protocol incorporating the usage of sodium thiosulfate in perchloric acid as extraction medium that assures high recovery of the relatively unstable neurotransmitters monitored. Moreover, the use of both deuterated internal standards and the multiple reaction monitoring (MRM) technique allows for unequivocal quantification. Thereby, to the best of our knowledge, we achieve a detection sensitivity that clearly exceeds those of published DA and SRT quantification methods in various matrices. We are the first to show that exposure of C. elegans to the monoamine oxidase B (MAO-B) inhibitor selegiline or the catechol-O-methyltransferase (COMT) inhibitor tolcapone, in order to block DA and SRT degradation, resulted in accumulation of the respective neurotransmitter. Assessment of a behavioral output of the dopaminergic system (basal slowing response) corroborated the analytical LC-MS/MS data. Thus, utilization of the C. elegans model system in conjunction with our analytical method is well-suited to investigate drug-mediated modulation of the DA and

  2. Highly sensitive isotope-dilution liquid-chromatography-electrospray ionization-tandem-mass spectrometry approach to study the drug-mediated modulation of dopamine and serotonin levels in Caenorhabditis elegans.

    PubMed

    Schumacher, Fabian; Chakraborty, Sudipta; Kleuser, Burkhard; Gulbins, Erich; Schwerdtle, Tanja; Aschner, Michael; Bornhorst, Julia

    2015-11-01

    Dopamine (DA) and serotonin (SRT) are monoamine neurotransmitters that play a key role in regulating the central and peripheral nervous system. Their impaired metabolism has been implicated in several neurological disorders, such as Parkinson's disease and depression. Consequently, it is imperative to monitor changes in levels of these low-abundant neurotransmitters and their role in mediating disease. For the first time, a rapid, specific and sensitive isotope-dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of DA and SRT in the nematode Caenorhabditis elegans (C. elegans). This model organism offers a unique approach for studying the effect of various drugs and environmental conditions on neurotransmitter levels, given by the conserved DA and SRT biology, including synaptic release, trafficking and formation. We introduce a novel sample preparation protocol incorporating the usage of sodium thiosulfate in perchloric acid as extraction medium that assures high recovery of the relatively unstable neurotransmitters monitored. Moreover, the use of both deuterated internal standards and the multiple reaction monitoring (MRM) technique allows for unequivocal quantification. Thereby, to the best of our knowledge, we achieve a detection sensitivity that clearly exceeds those of published DA and SRT quantification methods in various matrices. We are the first to show that exposure of C. elegans to the monoamine oxidase B (MAO-B) inhibitor selegiline or the catechol-O-methyltransferase (COMT) inhibitor tolcapone, in order to block DA and SRT degradation, resulted in accumulation of the respective neurotransmitter. Assessment of a behavioral output of the dopaminergic system (basal slowing response) corroborated the analytical LC-MS/MS data. Thus, utilization of the C. elegans model system in conjunction with our analytical method is well-suited to investigate drug-mediated modulation of the DA and

  3. Oxidatively Generated DNA Damage Following Cu(II)-Catalysis of Dopamine and Related Catecholamine Neurotransmitters and Neurotoxins: Role of Reactive Oxygen Species1

    PubMed Central

    Spencer, Wendy A.; Jeyabalan, Jeyaprakash; Kichambre, Sunita; Gupta, Ramesh C.

    2012-01-01

    There is increasing evidence supporting a causal role of oxidatively damaged DNA in neurodegeneration during the natural aging process and neurodegenerative diseases such as Parkinson’s and Alzheimer’s. The presence of redox-active catecholamine neurotransmitters coupled with the localization of catalytic copper to DNA suggests a plausible role for these agents in the induction of oxidatively generated DNA damage. In this study we have investigated the role of Cu(II)-catalyzed oxidation of several catecholamine neurotransmitters and related neurotoxins to induce oxidatively generated DNA damage. Auto-oxidation of all catechol neurotransmitters and related congeners tested resulted in the formation of nearly a dozen oxidation DNA products resulting in a decomposition pattern that was essentially identical for all agents tested. The presence of Cu(II), and to a lesser extent Fe(III), had no effect on the decomposition pattern but substantially enhanced the DNA product levels by up to 75 fold, with dopamine producing the highest levels of unidentified oxidation DNA products (383 ± 46 adducts/106 nucleotides), comparable to 8-oxo-7,8-dihydro-2′-deoxyguanosine levels under the same conditions (122 ± 19 adducts/106 nucleotides). The addition of sodium azide, 2,2,6,6-tetramethyl-4-piperidone, tiron, catalase, bathocuproine or methional to the dopamine/Cu(II) reaction mixture resulted in a substantial decrease (>90%) in oxidation DNA product levels, indicating a role of singlet oxygen, superoxide, H2O2, Cu(I) and Cu(I)OOH in their formation. While the addition of N-tert-butyl-α-phenylnitrone significantly decreased (67%) dopamine-mediated oxidatively damaged DNA, three other hydroxyl radical scavengers, ascorbic acid, sodium benzoate and mannitol, had little to no effect on these oxidation DNA product levels, suggesting that free hydroxyl radicals may have limited involvement in this dopamine/Cu(II)-mediated oxidatively generated DNA damage. These studies suggest

  4. Oxidatively generated DNA damage after Cu(II) catalysis of dopamine and related catecholamine neurotransmitters and neurotoxins: Role of reactive oxygen species.

    PubMed

    Spencer, Wendy A; Jeyabalan, Jeyaprakash; Kichambre, Sunita; Gupta, Ramesh C

    2011-01-01

    There is increasing evidence supporting a causal role for oxidatively damaged DNA in neurodegeneration during the natural aging process and in neurodegenerative diseases such as Parkinson and Alzheimer. The presence of redox-active catecholamine neurotransmitters coupled with the localization of catalytic copper to DNA suggests a plausible role for these agents in the induction of oxidatively generated DNA damage. In this study we have investigated the role of Cu(II)-catalyzed oxidation of several catecholamine neurotransmitters and related neurotoxins in inducing oxidatively generated DNA damage. Autoxidation of all catechol neurotransmitters and related congeners tested resulted in the formation of nearly a dozen oxidation DNA products resulting in a decomposition pattern that was essentially identical for all agents tested. The presence of Cu(II), and to a lesser extent Fe(III), had no effect on the decomposition pattern but substantially enhanced the DNA product levels by up to 75-fold, with dopamine producing the highest levels of unidentified oxidation DNA products (383±46 adducts/10(6) nucleotides), nearly 3-fold greater than 8-oxo-7,8-dihydro-2'-deoxyguanosine (122±19 adducts/10(6) nucleotides) under the same conditions. The addition of sodium azide, 2,2,6,6-tetramethyl-4-piperidone, tiron, catalase, bathocuproine, or methional to the dopamine/Cu(II) reaction mixture resulted in a substantial decrease (>90%) in oxidation DNA product levels, indicating a role for singlet oxygen, superoxide, H(2)O(2), Cu(I), and Cu(I)OOH in their formation. Whereas the addition of N-tert-butyl-α-phenylnitrone significantly decreased (67%) dopamine-mediated oxidatively damaged DNA, three other hydroxyl radical scavengers, ascorbic acid, sodium benzoate, and mannitol, had little to no effect on these oxidation DNA product levels, suggesting that free hydroxyl radicals may have limited involvement in this dopamine/Cu(II)-mediated oxidatively generated DNA damage. These

  5. 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.

  6. 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. PMID:22105846

  7. The roles of dopamine and serotonin, and of their receptors, in regulating sleep and waking.

    PubMed

    Monti, Jaime M; Jantos, Héctor

    2008-01-01

    Based on electrophysiological, neurochemical and neuropharmacological approaches, it is currently accepted that serotonin (5-HT) and dopamine (DA) function to promote waking (W) and to inhibit slow wave sleep (SWS) and/or rapid-eye-movement sleep (REMS). Serotonergic neurons of the dorsal raphe nucleus (DRN) fire at a steady rate during W, decrease their firing during SWS and virtually cease activity during REMS. On the other hand, DA cells in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc) do not change their mean firing rate across the sleep-wake cycle. It has been proposed that DA cells in the midbrain show a change in temporal pattern rather than firing rate during the sleep-wake cycle. Available evidence tends to indicate that during W and REMS an increase of burst firing activity of DA neurons occurs together with an enhanced release of DA in the VTA, the nucleus accumbens and several forebrain structures. Recently, DA neurons were characterised in the ventral periaqueductal grey matter (VPAG) that express Fos protein during W. Lesioning of these cells resulted in an increase of SWS and REMS, which led to the proposal that VPAG DA neurons may play a role in the promotion of W. Systemic injection of full agonists at postsynaptic 5-HT(1A) (8-OH-DPAT, flesinoxan), 5-HT(1B) (CGS 12066B, CP-94,253), 5-HT(2A/2C) (DOI, DOM) and 5-HT(3) (m-chlorophenylbiguanide) receptors increases W and reduces SWS and REMS. On the other hand, microdialysis perfusion or direct infusion of 8-OH-DPAT or flesinoxan into the DRN, where somatodendritic 5-HT(1A) receptors are located, significantly increases REMS. Systemic administration of the selective DA D(1) receptor agonist SKF 38393 induces behavioural arousal together with an increase of W and a reduction of sleep. On the other hand, injection of a DA D(2) receptor agonist (apomorphine, bromocriptine, quinpirole) gives rise to biphasic effects, such that low doses reduce W and augment SWS and REMS

  8. 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.

  9. Methamphetamine-induced hyperthermia and lethal toxicity: role of the dopamine and serotonin transporters.

    PubMed

    Numachi, Yohtaro; Ohara, Arihisa; Yamashita, Motoyasu; Fukushima, Setsu; Kobayashi, Hideaki; Hata, Harumi; Watanabe, Hidekazu; Hall, F Scott; Lesch, Klaus-Peter; Murphy, Dennis L; Uhl, George R; Sora, Ichiro

    2007-10-31

    We examined the hyperthermic and lethal toxic effects of methamphetamine in dopamine transporter (DAT) and/or serotonin transporter (SERT) knockout (KO) mice. Methamphetamine (45 mg/kg) caused significant hyperthermia even in the mice with a single DAT gene copy and no SERT copies (DAT+/- SERT-/- mice). Mice with no DAT copies and a single SERT gene copy (DAT-/- SERT+/- mice) showed significant but reduced hyperthermia when compared to wild-type mice after methamphetamine. Surprisingly, DAT/SERT double KO mice exhibited a paradoxical hypothermia after methamphetamine. These results demonstrate that methamphetamine exerts a hyperthermic effect via DAT, or via SERT, in the absence of DAT. The selective norepinephrine transporter blocker (20 mg/kg nisoxetine) caused hyperthermia in DAT/SERT double KO mice, suggesting that the norepinephrine system is not responsible for methamphetamine-induced paradoxical hypothermia in the double KO mice. DAT gene deletion in mice strikingly increased LD50 of methamphetamine by 1.7-1.8 times that of wild-type mice, suggesting that the lethal toxic effect of methamphetamine is mainly dependent on DAT. Moreover, dissociation between hyperthermic and lethal toxic effects of methamphetamine in DAT single KO mice and DAT/SERT double KO mice suggest that hyperthermia is not a prerequisite for methamphetamine-induced lethality. Methamphetamine (45 mg/kg) significantly increased mRNA of interleukin-1beta, which is the major endogenous pyrogen, in the hypothalamus of wild-type mice but not in DAT/SERT double KO mice, which provides a partial mechanism of methamphetamine-induced paradoxical hypothermia. These results suggest that DAT and SERT are key molecules for hyperthermic and lethal toxic effects of methamphetamine.

  10. Running wheel exercise ameliorates methamphetamine-induced damage to dopamine and serotonin terminals.

    PubMed

    O'Dell, Steven J; Galvez, Bryan A; Ball, Alexander J; Marshall, John F

    2012-01-01

    Repeated administration of methamphetamine (mAMPH) to rodents in a single-day "binge" produces long-lasting damage to dopaminergic and serotonergic terminals. Because previous research has demonstrated that physical activity can ameliorate nigrostriatal injury, this study investigated whether voluntary exercise in rats can alter the monoaminergic damage resulting from a neurotoxic mAMPH binge. Adult male rats were allowed constant access to running wheels or kept in nonwheel cages for three weeks, then given a binge dosing regimen of mAMPH or saline. The rats were returned to their original environments for three additional weeks post-mAMPH. [(125) I]RTI-55 binding and autoradiography was used to quantify dopamine transporters (DAT), and radioimmunocytochemistry was used to quantify striatal tyrosine hydroxylase (TH). Binge mAMPH treatment significantly reduced striatal DAT and TH in a regionally specific pattern; with greatest effects in ventral caudate-putamen (CP) and relative sparing of the nucleus accumbens septi (NAc). The effects of mAMPH on striatal DAT and TH were ameliorated in the running, compared to the sedentary, animals. Also, mAMPH was found to reduce [(125) I]RTI-55 binding to serotonin transporters (SERT) in frontoparietal cortex, and this too was significantly attenuated by exercise. Additional correlational analyses showed that the post-mAMPH running of individual animals predicted the amelioration of striatal DAT and TH as well as frontoparietal SERT. Overall, voluntary exercise significantly diminished mAMPH-induced forebrain monoaminergic damage. The significant correlations between post-mAMPH exercise and markers of monoaminergic terminal integrity provide novel evidence that voluntary exercise may exert beneficial effects on behavior in recovering mAMPH addicts.

  11. Serotonin and dopamine receptors in motivational and cognitive disturbances of schizophrenia.

    PubMed

    Sumiyoshi, Tomiki; Kunugi, Hiroshi; Nakagome, Kazuyuki

    2014-01-01

    Negative symptoms (e.g., decreased spontaneity, social withdrawal, blunt affect) and disturbances of cognitive function (e.g., several types of memory, attention, processing speed, executive function, fluency) provide a major determinant of long-term outcome in patients with schizophrenia. Specifically, motivation deficits, a type of negative symptoms, have been attracting interest as (1) a moderator of cognitive performance in schizophrenia and related disorders, and (2) a modulating factor of cognitive enhancers/remediation. These considerations suggest the need to clarify neurobiological substrates regulating motivation. Genetic studies indicate a role for the monoamine systems in motivation and key cognitive domains. For example, polymorphism of genes encoding catecholamine-O-methyltransferase, an enzyme catabolizing dopamine (DA), affects performance on tests of working memory and executive function in a phenotype (schizophrenia vs. healthy controls)-dependent fashion. On the other hand, motivation to maximize rewards has been shown to be influenced by other genes encoding DA-related substrates, such as DARPP-32 and DA-D2 receptors. Serotonin (5-HT) receptors may also play a significant role in cognitive and motivational disabilities in psychoses and mood disorders. For example, mutant mice over-expressing D2 receptors in the striatum, an animal model of schizophrenia, exhibit both decreased willingness to work for reward and up-regulation of 5-HT2C receptors. Taken together, genetic predisposition related to 5-HT receptors may mediate the diversity of incentive motivation that is impaired in patients receiving biological and/or psychosocial treatments. Thus, research into genetic and neurobiological measures of motivation, in association with 5-HT receptors, is likely to facilitate intervention into patients seeking better social consequences. PMID:25538549

  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. 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. PMID:24959862

  14. 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.

  15. Alcohol misuse in emerging adulthood: Association of dopamine and serotonin receptor genes with impulsivity-related cognition.

    PubMed

    Leamy, Talia E; Connor, Jason P; Voisey, Joanne; Young, Ross McD; Gullo, Matthew J

    2016-12-01

    Impulsivity predicts alcohol misuse and risk for alcohol use disorder. Cognition mediates much of this association. Genes also account for a large amount of variance in alcohol misuse, with dopamine and serotonin receptor genes of particular interest, because of their role in motivated behavior. The precise psychological mechanisms through which such genes confer risk is unclear. Trait impulsivity conveys risk for alcohol misuse by influencing two distinct domains of cognition: beliefs about the reinforcing effects of alcohol consumption (positive alcohol expectancy) and the perceived ability to resist it (drinking refusal self-efficacy). This study investigated the effect of the dopamine-related polymorphism in the DRD2/ANKK1 gene (rs1800497) and a serotonin-related polymorphism in the HTR2A gene (rs6313) on associations between impulsivity, cognition, and alcohol misuse in 120 emerging adults (18-21years). HTR2A predicted lower positive alcohol expectancy, higher refusal self-efficacy, and lower alcohol misuse. However, neither polymorphism moderated the linkages between impulsivity, cognition, and alcohol misuse. This is the first report of an association between HTR2A and alcohol-related cognition. Theoretically-driven biopsychosocial models have potential to elucidate the specific cognitive mechanisms through which distal risk factors like genes and temperament affect alcohol misuse in emerging adulthood. PMID:27399274

  16. Reelin influences the expression and function of dopamine D2 and serotonin 5-HT2A receptors: a comparative study.

    PubMed

    Varela, M J; Lage, S; Caruncho, H J; Cadavid, M I; Loza, M I; Brea, J

    2015-04-01

    Reelin is an extracellular matrix protein that plays a critical role in neuronal guidance during brain neurodevelopment and in synaptic plasticity in adults and has been associated with schizophrenia. Reelin mRNA and protein levels are reduced in various structures of post-mortem schizophrenic brains, in a similar way to those found in heterozygous reeler mice (HRM). Reelin is involved in protein expression in dendritic spines that are the major location where synaptic connections are established. Thus, we hypothesized that a genetic deficit in reelin would affect the expression and function of dopamine D2 and serotonin 5-HT2A receptors that are associated with the action of current antipsychotic drugs. In this study, D2 and 5-HT2A receptor expression and function were quantitated by using radioligand binding studies in the frontal cortex and striatum of HRM and wild-type mice (WTM). We observed increased expression (p<0.05) in striatum membranes and decreased expression (p<0.05) in frontal cortex membranes for both dopamine D2 and serotonin 5-HT2A receptors from HRM compared to WTM. Our results show parallel alterations of D2 and 5-HT2A receptors that are compatible with a possible hetero-oligomeric nature of these receptors. These changes are similar to changes described in schizophrenic patients and provide further support for the suitability of using HRM as a model for studying this disease and the effects of antipsychotic drugs. PMID:25637489

  17. Effects of combined dopamine and serotonin transporter inhibitors on cocaine self-administration in rhesus monkeys.

    PubMed

    Howell, Leonard L; Carroll, F Ivy; Votaw, John R; Goodman, Mark M; Kimmel, Heather L

    2007-02-01

    Dopamine transporter (DAT) inhibitors may represent a promising class of drugs in the development of cocaine pharmacotherapies. In the present study, the effects of pretreatments with the selective DAT inhibitor 3beta-(4-chlorophenyl)tropane-2beta-[3-(4'-methylphenyl)isoxazol-5-yl] hydrochloride (RTI-336) (0.3-1.7 mg/kg) were characterized in rhesus monkeys trained to self-administer cocaine (0.1 and 0.3 mg/kg/injection) under a multiple second-order schedule of i.v. drug or food delivery. In addition, RTI-336 (0.01-1.0 mg/kg/injection) was substituted for cocaine to characterize its reinforcing effects. Last, the dose of RTI-336 that reduced cocaine-maintained behavior by 50% (ED(50)) was coadministered with the selective serotonin transporter (SERT) inhibitors fluoxetine (3.0 mg/kg) and citalopram (3.0 mg/kg) to characterize their combined effects on cocaine self-administration. PET neuroimaging with the selective DAT ligand [(18)F]8-(2-[(18)F]fluoroethyl)-2beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane quantified DAT occupancy at behaviorally relevant doses of RTI-336. Pretreatments of RTI-336 produced dose-related reductions in cocaine self-administration, and the ED(50) dose resulted in approximately 90% DAT occupancy. RTI-336 was reliably self-administered, but responding maintained by RTI-336 was lower than responding maintained by cocaine. Doses of RTI-336 that maintained peak rates of responding resulted in approximately 62% DAT occupancy. Co-administration of the ED(50) dose of RTI-336 in combination with either SERT inhibitor completely suppressed cocaine self-administration without affecting DAT occupancy. Hence, at comparable levels of DAT occupancy, coadministration of SERT inhibitors with RTI-336 produced more robust reductions in cocaine self-administration compared with RTI-336 alone. Collectively, the results indicate that combined inhibition of DAT and SERT warrants consideration as a viable approach in the development of cocaine medications

  18. Effect of environmental enrichment on dopamine and serotonin transporters and glutamate neurotransmission in medial prefrontal and orbitofrontal cortex.

    PubMed

    Darna, Mahesh; Beckmann, Joshua S; Gipson, Cassandra D; Bardo, Michael T; Dwoskin, Linda P

    2015-03-01

    Recent studies have reported that rats raised in an enriched condition (EC) have decreased dopamine transporter (DAT) function and expression in medial prefrontal cortex (mPFC), as well as increased d-amphetamine-induced glutamate release in nucleus accumbens compared to rats raised in an isolated condition (IC). In these previous studies, DAT function and expression were evaluated using mPFC pooled from four rats for each condition to obtain kinetic parameters due to sparse DAT expression in mPFC. In contrast, accumbal glutamate release was determined using individual rats. The current study extends the previous work and reports on the optimization of DAT and serotonin transporter (SERT) functional assays, as well as cell surface expression assays using both mPFC and orbitofrontal cortex (OFC) from individual EC or IC rats. In addition, the effect of d-amphetamine on glutamate release in mPFC and OFC of EC and IC rats was determined using in vivo microdialysis. Results show that environmental enrichment decreased maximal transport velocity (Vmax) for [(3)H]dopamine uptake in mPFC, but increased Vmax for [(3)H]dopamine uptake in OFC. Corresponding changes in DAT cell surface expression were not found. In contrast, Vmax for [(3)H]serotonin uptake and cellular localization of SERT in mPFC and OFC were not different between EC and IC rats. Further, acute d-amphetamine (2mg/kg, s.c.) increased extracellular glutamate concentrations in mPFC of EC rats only and in OFC of IC rats only. Overall, these results suggest that enrichment produces long-lasting alterations in mPFC and OFC DAT function via a trafficking-independent mechanism, as well as differential glutamate release in mPFC and OFC. Rearing-induced modulation of DAT function and glutamate release in prefrontal cortical subregions may contribute to the known protective effects of enrichment on drug abuse vulnerability.

  19. Discrete regional distribution of biochemical markers for the dopamine, noradrenaline, serotonin, GABA and acetylcholine systems in the monkey brain (Cebus Apella). Effects of stress.

    PubMed

    Häggström, J E; Sjöquist, B; Eckernäs, S A; Ingvast, A; Gunne, L M

    1984-01-01

    Brains from Cebus Apella monkeys have been mapped biochemically using a cryo-section technique which enables exact micro-dissectioning of tissue. Two neurotransmitters; noradrenaline (NA) and gamma-amino-butyric acid (GABA) were measured by gas chromatography-masspectrometry technique. In addition biochemical markers reflecting metabolic activity in the dopamine (homovanillic acid, HVA, 3, 4-dihydroxyphenylacetic acid, DOPAC), serotonin (5-hydroxyindoleacetic acid, 5-HIAA), noradrenaline (4-hydroxy-3-methoxy-phenylglycol, HMPG), acetylcholine (choline acetyltransferase, CAT) and GABA (glutamic acid decarboxylase, GAD) transmitter systems were assayed. The distribution of these transmitter markers roughly corresponded to earlier studies in other non-human primates, whereas similar studies on the human brain generally show lower concentrations and enzyme activities. One monkey exposed to severe stress immediately before death deviated from the normal animals with regard to HVA, 5-HIAA, GAD and GABA. For the study of neuroleptic drugs, and notably their neurological side-effects, Cebus Apella monkeys have turned out to be particularly useful. In our laboratory we have employed this species of monkey to develop a model for acute dystonia and tardive dyskinesia (Gunne and Barany 1976, 1979, Barany et al. 1979). As a first step in the topological mapping of brain neuro-chemistry in these animals we here present data from normal monkeys, not treated with neuroleptics. During the ongoing project there was an unplanned "stress experiment" in one monkey, which had a nightly fight with a cage partner and had to be sacrificed the morning after due to severe wounds. The present communication describes a method for obtaining well-defined samples from monkey brains and presents the data on homovanillic acid (HVA), 3.4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NA), 4-hydroxy-3-methoxy-phenyl glycol (HMPG), choline acetyltransferase (Ch

  20. Quantification of the neurotransmitters melatonin and N-acetyl-serotonin in human serum by supercritical fluid chromatography coupled with tandem mass spectrometry.

    PubMed

    Wolrab, Denise; Frühauf, Peter; Gerner, Christopher

    2016-09-21

    The aim of this study was developing a supercritical fluid chromatography tandem mass spectrometry (SFC-MS/MS) method and an ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method, for the analysis of N-acetyl-serotonin (NAS) and melatonin (Mel) in human serum, and to compare the performance of these methods. Deuterated isotopologues of the neurotransmitters were synthesized and evaluated for suitability as internal standards in sample preparation. Liquid-liquid extraction was selected as sample preparation procedure. With chloroform, the best extraction solvent tested, an extraction yield of 48 ± 2% for N-acetyl-serotonin and 101 ± 10% for melatonin was achieved. SFC separation was accomplished within 3 min on a BEH stationary phase, employing isocratic elution with 90% carbon dioxide and 0.1% formic acid as well as 0.05% ammonium formate in methanol. For the 4 min UHPLC gradient separation with 0.1% formic acid in water and methanol, respectively, a Kinetex XB-C18 was used as stationary phase. Both chromatographic techniques were optimized regarding mobile phase composition, additives to the mobile phase and column temperature. Multiple reaction monitoring (MRM) analysis was used for quantification of the metabolites. Both methods were validated regarding retention time stability, LOD, LOQ, repeatability and reproducibility of quantification, process efficiency, extraction recovery and matrix effects. LOD and LOQ were 0.017 and 0.05 pg μL(-1) for NAS and 0.006 and 0.018 pg μL(-1) for Mel in SFC-MS/MS compared to 0.028 and 0.1 pg μL(-1) for NAS and 0.006 and 0.017 pg μL(-1) for Mel in UHPLC-MS/MS. PMID:27590559

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

    PubMed Central

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

    2013-01-01

    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. PMID:23228495

  2. Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain.

    PubMed

    Borg, J; Cervenka, S; Kuja-Halkola, R; Matheson, G J; Jönsson, E G; Lichtenstein, P; Henningsson, S; Ichimiya, T; Larsson, H; Stenkrona, P; Halldin, C; Farde, L

    2016-08-01

    The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about the regulation of receptor and transporter density levels. This lack of knowledge obscures interpretation of differences in protein availability reported in psychiatric patients. In this study, we used positron emission tomography (PET) in a twin design to estimate the relative contribution of genetic and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [(11)C]raclopride binding to the D2- and D3-dopamine receptor and [(11)C]WAY100635 binding to the serotonin 5-HT1A receptor. Heritability, shared environmental effects and individual-specific non-shared effects were estimated for regional D2/3 and 5-HT1A receptor availability in projection areas. We found a major contribution of genetic factors (0.67) on individual variability in striatal D2/3 receptor binding and a major contribution of environmental factors (pairwise shared and unique individual; 0.70-0.75) on neocortical 5-HT1A receptor binding. Our findings indicate that individual variation in neuroreceptor availability in the adult brain is the end point of a nature-nurture interplay, and call for increased efforts to identify not only the genetic but also the environmental factors that influence neurotransmission in health and disease. PMID:26821979

  3. The antidepressant-like pharmacological profile of Yuanzhi-1, a novel serotonin, norepinephrine and dopamine reuptake inhibitor.

    PubMed

    Jin, Zeng-liang; Gao, Nana; Li, Xiao-rong; Tang, Yu; Xiong, Jie; Chen, Hong-xia; Xue, Rui; Li, Yun-Feng

    2015-04-01

    Triple reuptake inhibitors that block dopamine transporters (DATs), norepinephrine transporters (NETs), and serotonin transporters (SERTs) are being developed as a new class of antidepressants that might have better efficacy and fewer side effects than traditional antidepressants. In this study, we performed in vitro binding and uptake assays as well as in vivo behavioural tests to assess the pharmacological properties and antidepressant-like efficacy of Yuanzhi-1. In vitro, Yuanzhi-1 had a high affinity for SERTs, NETs, and DATs prepared from rat brain tissue (Ki=3.95, 4.52 and 0.87nM, respectively) and recombinant cells (Ki=2.87, 6.86 and 1.03nM, respectively). Moreover, Yuanzhi-1 potently inhibited the uptake of serotonin (5-hydroxytryptamine; 5-HT), norepinephrine (NE) and dopamine (DA) into rat brain synaptosomes (Ki=2.12, 4.85 and 1.08nM, respectively) and recombinant cells (Ki=1.65, 5.32 and 0.68nM, respectively). In vivo, Yuanzhi-1 decreased immobility in a dose-dependent manner, which was shown among rats via the forced-swim test (FST) and mice via the tail-suspension test (TST). The results observed in the behavioural tests did not appear to result from the stimulation of locomotor activity. Repeated Yuanzhi-1 treatment (2.5, 5 or 10mg/kg) significantly reversed depression-like behaviours in chronically stressed rats, including reduced sucrose preference, decreased locomotor activity, and prolonged time to begin eating. Furthermore, in vivo microdialysis studies showed that 5- and 10-mg/kg administrations of Yuanzhi-1 significantly increased the extracellular concentrations of 5-HT, NE and DA in the frontal cortices of freely moving rats. Therefore, Yuanzhi-1 might represent a novel triple reuptake inhibitor and possess antidepressant-like activity. PMID:25638027

  4. Dopamine and serotonin signaling during two sensitive developmental periods differentially impact adult aggressive and affective behaviors in mice

    PubMed Central

    Yu, Qinghui; Teixeira, Cátia M.; Mahadevia, Darshini; Huang, Yung-Yu; Balsam, Daniel; Mann, J John; Gingrich, Jay A; Ansorge, Mark S.

    2014-01-01

    Pharmacologic blockade of monoamine oxidase A (MAOA) or serotonin transporter (5-HTT) has antidepressant and anxiolytic efficacy in adulthood. Yet, genetically conferred MAOA or 5-HTT hypo-activity is associated with altered aggression and increased anxiety/depression. Here we test the hypothesis that increased monoamine signaling during development causes these paradoxical aggressive and affective phenotypes. We find that pharmacologic MAOA blockade during early postnatal development (P2-P21) but not during peri-adolescence (P22-41) increases anxiety- and depression-like behavior in adult (> P90) mice, mimicking the effect of P2-21 5-HTT inhibition. Moreover, MAOA blockade during peri-adolescence, but not P2-21 or P182-201, increases adult aggressive behavior, and 5-HTT blockade from P22-P41 reduced adult aggression. Blockade of the dopamine transporter, but not the norepinephrine transporter, during P22-41 also increases adult aggressive behavior. Thus, P2-21 is a sensitive period during which 5-HT modulates adult anxiety/depression-like behavior, and P22-41 is a sensitive period during which DA and 5-HT bi-directionally modulate adult aggression. Permanently altered DAergic function as a consequence of increased P22-P41 monoamine signaling might underlie altered aggression. In support of this hypothesis, we find altered aggression correlating positively with locomotor response to amphetamine challenge in adulthood. Proving that altered DA function and aggression are causally linked, we demonstrate that optogenetic activation of VTA DAergic neurons increases aggression. It therefore appears that genetic and pharmacologic factors impacting dopamine and serotonin signaling during sensitive developmental periods can modulate adult monoaminergic function and thereby alter risk for aggressive and emotional dysfunction. PMID:24589889

  5. GTP cyclohydrolase I deficiency, a new enzyme defect causing hyperphenylalaninemia with neopterin, biopterin, dopamine, and serotonin deficiencies and muscular hypotonia.

    PubMed

    Niederwieser, A; Blau, N; Wang, M; Joller, P; Atarés, M; Cardesa-Garcia, J

    1984-02-01

    A 4-year-old patient is described with hyperphenylalaninemia, severe retardation in development, severe muscular hypotonia of the trunk and hypertonia of the extremities, convulsions, and frequent episodes of hyperthermia without infections. Urinary excretion of neopterin, biopterin, pterin, isoxanthopterin, dopamine, and serotonin was very low, although the relative proportions of pterins were normal. In lumbar cerebrospinal fluid, homovanillic acid, 5-hydroxyindoleacetic acid, neopterin and biopterin were low. Oral administration of L-erythro tetrahydrobiopterin normalized the elevated serum phenylalanine within 4 h, serum tyrosine was increased briefly and serum alanine and glutamic acid for a longer time. Urinary dopamine and serotonin excretion were also increased. Administration of an equivalent dose of D-erythro tetrahydroneopterin was ineffective and demonstrated that this compound is not a cofactor in vivo and cannot be transformed into an active cofactor. GTP cyclohydrolase I activity was not detectable in liver biopsies from the patient. The presence of an endogenous inhibitor in the patient's liver was excluded. This is the first case of a new variant of hyperphenylalaninemia in which the formation of dihydroneopterin triphosphate and its pterin metabolites in liver is markedly diminished. Normal activities of xanthine oxidase and sulfite oxidase were apparent since uric acid levels were normal and no increase in hypoxanthine, xanthine, and S-sulfocysteine concentrations could be observed in urine. It is concluded that the molybdenum cofactor of these enzymes may not be derived from dihydroneopterin triphosphate in man. Also, since no gross abnormalities in the patient's immune system could be found, it seems unlikely that dihydroneopterin triphosphate metabolites, such as neopterin, participate actively in immunological processes, as postulated by others. See Note added in proof. PMID:6734669

  6. The role of neurotransmitters in alcohol dependence: animal research.

    PubMed

    De Witte, P

    1996-03-01

    Animal studies have demonstrated that alcohol changes neurotransmitter concentrations in the brain. These changes in levels of dopamine, serotonin, gamma-aminobutyric acid (GABA), endogenous opioid peptides, and noradrenaline are associated with activation of reward centres in the brain. It is this property of alcohol that is believed to be responsible for the reinforcing effect of alcohol consumption in rats. One class of neurotransmitters, the endogenous opioid peptides, are believed to play an important role in alcohol reinforcement. This view is supported by the reduced preference for alcohol consumption found in rats given an opiate agonist. The widely distributed inhibitory neurotransmitter GABA is also believed to play a fundamental role in mediating the effects of alcohol. A better understanding of the mechanisms that support alcohol dependence in animals offers hope for the development of pharmacological interventions to block these mechanisms, an approach that is now being explored in humans.

  7. Polyethylenimine carbon nanotube fiber electrodes for enhanced detection of neurotransmitters.

    PubMed

    Zestos, Alexander G; Jacobs, Christopher B; Trikantzopoulos, Elefterios; Ross, Ashley E; Venton, B Jill

    2014-09-01

    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

  8. Effects of p-Aminosalicylic acid on the Neurotoxicity of Manganese and Levels of Dopamine and Serotonin in the Nervous System and Innervated Organs of Crassostrea virginica.

    PubMed

    King, Candice; Myrthil, Marie; Carroll, Margaret A; Catapane, Edward J

    2008-01-01

    Manganese is a neurotoxin causing Manganism in individuals chronically exposed to elevated levels in their environment. Toxic manganese exposure causes mental and emotional disturbances, and a movement disorder similar to Idiopathic Parkinsons Disease. Manganese interferes with dopamine neurons involved in control of body movements. Recently, p-aminosalicylic acid (PAS) is being used to alleviate symptoms of Manganism, but its mechanism of action is unknown. The eastern oyster, Crassostrea virginica, possesses a dopaminergic innervation of its gill. Oysters exposed to manganese have reduced levels of dopamine in the cerebral ganglia, visceral ganglia and gill, but not of norepinephrine, octopamine or serotonin. Those results are consistent with reported mechanisms of action of manganese in human and mammalian systems. In this study we determined the effects of PAS treatments on dopamine and serotonin levels in oysters exposed to manganese. Adult C. virginica were exposed to 500 µM and 1 mM of manganese with and without 500 µM and 1 mM of PAS by removing one shell and maintaining the animals in individual containers of aerated artificial sea water at 18° C for 3 days. Control animals were similarly treated without manganese or PAS. Dopamine and serotonin levels were measured by HPLC with fluorescence detection. PAS protected the ganglia and gill against the effects of 500 µM manganese, but not against the 1 mM manganese treatments. Serotonin levels were not affected by the treatments. The study demonstrates PAS can protect against reductions in dopamine levels caused by neurotoxic manganese exposure, but is concentration dependent. These findings may provide insights into the actions of PAS in therapeutic treatments of Manganism.

  9. Effects of p-Aminosalicylic acid on the Neurotoxicity of Manganese and Levels of Dopamine and Serotonin in the Nervous System and Innervated Organs of Crassostrea virginica.

    PubMed

    King, Candice; Myrthil, Marie; Carroll, Margaret A; Catapane, Edward J

    2008-01-01

    Manganese is a neurotoxin causing Manganism in individuals chronically exposed to elevated levels in their environment. Toxic manganese exposure causes mental and emotional disturbances, and a movement disorder similar to Idiopathic Parkinsons Disease. Manganese interferes with dopamine neurons involved in control of body movements. Recently, p-aminosalicylic acid (PAS) is being used to alleviate symptoms of Manganism, but its mechanism of action is unknown. The eastern oyster, Crassostrea virginica, possesses a dopaminergic innervation of its gill. Oysters exposed to manganese have reduced levels of dopamine in the cerebral ganglia, visceral ganglia and gill, but not of norepinephrine, octopamine or serotonin. Those results are consistent with reported mechanisms of action of manganese in human and mammalian systems. In this study we determined the effects of PAS treatments on dopamine and serotonin levels in oysters exposed to manganese. Adult C. virginica were exposed to 500 µM and 1 mM of manganese with and without 500 µM and 1 mM of PAS by removing one shell and maintaining the animals in individual containers of aerated artificial sea water at 18° C for 3 days. Control animals were similarly treated without manganese or PAS. Dopamine and serotonin levels were measured by HPLC with fluorescence detection. PAS protected the ganglia and gill against the effects of 500 µM manganese, but not against the 1 mM manganese treatments. Serotonin levels were not affected by the treatments. The study demonstrates PAS can protect against reductions in dopamine levels caused by neurotoxic manganese exposure, but is concentration dependent. These findings may provide insights into the actions of PAS in therapeutic treatments of Manganism. PMID:21841974

  10. Effects of p-Aminosalicylic acid on the Neurotoxicity of Manganese and Levels of Dopamine and Serotonin in the Nervous System and Innervated Organs of Crassostrea virginica

    PubMed Central

    King, Candice; Myrthil, Marie; Carroll, Margaret A; Catapane, Edward J.

    2011-01-01

    Manganese is a neurotoxin causing Manganism in individuals chronically exposed to elevated levels in their environment. Toxic manganese exposure causes mental and emotional disturbances, and a movement disorder similar to Idiopathic Parkinsons Disease. Manganese interferes with dopamine neurons involved in control of body movements. Recently, p-aminosalicylic acid (PAS) is being used to alleviate symptoms of Manganism, but its mechanism of action is unknown. The eastern oyster, Crassostrea virginica, possesses a dopaminergic innervation of its gill. Oysters exposed to manganese have reduced levels of dopamine in the cerebral ganglia, visceral ganglia and gill, but not of norepinephrine, octopamine or serotonin. Those results are consistent with reported mechanisms of action of manganese in human and mammalian systems. In this study we determined the effects of PAS treatments on dopamine and serotonin levels in oysters exposed to manganese. Adult C. virginica were exposed to 500 µM and 1 mM of manganese with and without 500 µM and 1 mM of PAS by removing one shell and maintaining the animals in individual containers of aerated artificial sea water at 18° C for 3 days. Control animals were similarly treated without manganese or PAS. Dopamine and serotonin levels were measured by HPLC with fluorescence detection. PAS protected the ganglia and gill against the effects of 500 µM manganese, but not against the 1 mM manganese treatments. Serotonin levels were not affected by the treatments. The study demonstrates PAS can protect against reductions in dopamine levels caused by neurotoxic manganese exposure, but is concentration dependent. These findings may provide insights into the actions of PAS in therapeutic treatments of Manganism. PMID:21841974

  11. 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…

  12. 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.

  13. 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. PMID:27272046

  14. 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.

  15. 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.

  16. 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

  17. 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.

  18. WINCS-BASED WIRELESS ELECTROCHEMICAL MONITORING OF SEROTONIN (5-HT) USING FAST-SCAN CYCLIC VOLTAMMETRY: PROOF OF PRINCIPLE

    PubMed Central

    Griessenauer, Christoph J.; Chang, Su-Youne; Tye, Susannah J.; Kimble, Christopher J.; Bennet, Kevin E.; Garris, Paul A.; Lee, Kendall H.

    2010-01-01

    Object We previously reported the development of a Wireless Instantaneous Neurotransmitter Concentration System (WINCS) for measuring dopamine and suggested that this technology may be useful for evaluating deep brain stimulation (DBS)-related neuromodulatory effects on neurotransmitter systems. WINCS supports fast-scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM) for real-time, spatially resolved neurotransmitter measurements. The FSCV parameters used to establish WINCS dopamine measurements are not suitable for serotonin, a neurotransmitter implicated in depression, because they lead to CFM fouling and a loss of sensitivity. Here, we incorporate into WINCS a previously described N-shaped waveform applied at a high scan rate to establish wireless serotonin monitoring. Methods FSCV optimized for the detection of serotonin consisted of an N-shaped waveform scanned linearly from a resting potential of, in V, +0.2 to +1.0, then to −0.1 and back to +0.2 at a rate of 1000 V/s. Proof of principle tests included flow injection analysis and electrically evoked serotonin release in the dorsal raphe nucleus of rat brain slices. Results Flow cell injection analysis demonstrated that the N waveform applied at a scan rate of 1000 V/s significantly reduced serotonin fouling of the CFM, relative to that observed with FSCV parameters for dopamine. In brain slices, WINCS reliably detected sub-second serotonin release in the dorsal raphe nucleus evoked by local high-frequency stimulation. Conclusion WINCS supported high-fidelity wireless serotonin monitoring by FSCV at a CFM. In the future such measurements of serotonin in large animal models and in humans may help to establish the mechanism of DBS for psychiatric disease. PMID:20415521

  19. 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.

  20. Simultaneous Determination of Dopamine, Serotonin and Ascorbic Acid at a Glassy Carbon Electrode Modified with Carbon-Spheres

    PubMed Central

    Zhou, Jianqing; Sheng, Meili; Jiang, Xueyue; Wu, Guozhi; Gao, Feng

    2013-01-01

    A novel glassy carbon electrode (GCE) modified with carbon-spheres has been fabricated through a simple casting procedure. The modified GCE displays high selectivity and excellent electrochemical catalytic activities towards dopamine (DA), serotonin (5-HT), and ascorbic acid (AA). In the co-existence system, the peak separations between AA and DA, DA and 5-HT, and AA and 5-HT are large up to 230, 180, and 410 mV, respectively. Differential pulse voltammetry (DPV) has been employed to simultaneously detect DA, 5-HT, and AA, and the linear calibration curves for DA, 5-HT, and AA are obtained in the range of 20.0–150.0 μM, 40.0–750.0 μM and 300.0–2,000.0 μM with detection limits (S/N = 3) of 2.0 μM, 0.7 μM and 0.6 μM, respectively. The proposed electrode has been applied to detect DA, 5-HT, and AA in real samples using standard addition method with satisfactory results. PMID:24135993

  1. Drosophila Vesicular Monoamine Transporter Mutants Can Adapt to Reduced or Eliminated Vesicular Stores of Dopamine and Serotonin

    PubMed Central

    Simon, Anne F.; Daniels, Richard; Romero-Calderón, Rafael; Grygoruk, Anna; Chang, Hui-Yun; Najibi, Rod; Shamouelian, David; Salazar, Evelyn; Solomon, Mordecai; Ackerson, Larry C.; Maidment, Nigel T.; DiAntonio, Aaron; Krantz, David E.

    2009-01-01

    Physiologic and pathogenic changes in amine release induce dramatic behavioral changes, but the underlying cellular mechanisms remain unclear. To investigate these adaptive processes, we have characterized mutations in the Drosophila vesicular monoamine transporter (dVMAT), which is required for the vesicular storage of dopamine, serotonin, and octopamine. dVMAT mutant larvae show reduced locomotion and decreased electrical activity in motoneurons innervating the neuromuscular junction (NMJ) implicating central amines in the regulation of these activities. A parallel increase in evoked glutamate release by the motoneuron is consistent with a homeostatic adaptation at the NMJ. Despite the importance of aminergic signaling for regulating locomotion and other behaviors, adult dVMAT homozygous null mutants survive under conditions of low population density, thus allowing a phenotypic characterization of adult behavior. Homozygous mutant females are sterile and show defects in both egg retention and development; males also show reduced fertility. Homozygotes show an increased attraction to light but are mildly impaired in geotaxis and escape behaviors. In contrast, heterozygous mutants show an exaggerated escape response. Both hetero- and homozygous mutants demonstrate an altered behavioral response to cocaine. dVMAT mutants define potentially adaptive responses to reduced or eliminated aminergic signaling and will be useful to identify the underlying molecular mechanisms. PMID:19033154

  2. Drosophila vesicular monoamine transporter mutants can adapt to reduced or eliminated vesicular stores of dopamine and serotonin.

    PubMed

    Simon, Anne F; Daniels, Richard; Romero-Calderón, Rafael; Grygoruk, Anna; Chang, Hui-Yun; Najibi, Rod; Shamouelian, David; Salazar, Evelyn; Solomon, Mordecai; Ackerson, Larry C; Maidment, Nigel T; Diantonio, Aaron; Krantz, David E

    2009-02-01

    Physiologic and pathogenic changes in amine release induce dramatic behavioral changes, but the underlying cellular mechanisms remain unclear. To investigate these adaptive processes, we have characterized mutations in the Drosophila vesicular monoamine transporter (dVMAT), which is required for the vesicular storage of dopamine, serotonin, and octopamine. dVMAT mutant larvae show reduced locomotion and decreased electrical activity in motoneurons innervating the neuromuscular junction (NMJ) implicating central amines in the regulation of these activities. A parallel increase in evoked glutamate release by the motoneuron is consistent with a homeostatic adaptation at the NMJ. Despite the importance of aminergic signaling for regulating locomotion and other behaviors, adult dVMAT homozygous null mutants survive under conditions of low population density, thus allowing a phenotypic characterization of adult behavior. Homozygous mutant females are sterile and show defects in both egg retention and development; males also show reduced fertility. Homozygotes show an increased attraction to light but are mildly impaired in geotaxis and escape behaviors. In contrast, heterozygous mutants show an exaggerated escape response. Both hetero- and homozygous mutants demonstrate an altered behavioral response to cocaine. dVMAT mutants define potentially adaptive responses to reduced or eliminated aminergic signaling and will be useful to identify the underlying molecular mechanisms. PMID:19033154

  3. 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.

  4. 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.

    PubMed

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

    2015-12-28

    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.

  5. The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue.

    PubMed

    Brisch, Ralf; Saniotis, Arthur; Wolf, Rainer; Bielau, Hendrik; Bernstein, Hans-Gert; Steiner, Johann; Bogerts, Bernhard; Braun, Katharina; Braun, Anna Katharina; Jankowski, Zbigniew; Kumaratilake, Jaliya; Kumaritlake, Jaliya; Henneberg, Maciej; Gos, Tomasz

    2014-01-01

    Dopamine is an inhibitory neurotransmitter involved in the pathology of schizophrenia. The revised dopamine hypothesis states that dopamine abnormalities in the mesolimbic and prefrontal brain regions exist in schizophrenia. However, recent research has indicated that glutamate, GABA, acetylcholine, and serotonin alterations are also involved in the pathology of schizophrenia. This review provides an in-depth analysis of dopamine in animal models of schizophrenia and also focuses on dopamine and cognition. Furthermore, this review provides not only an overview of dopamine receptors and the antipsychotic effects of treatments targeting them but also an outline of dopamine and its interaction with other neurochemical models of schizophrenia. The roles of dopamine in the evolution of the human brain and human mental abilities, which are affected in schizophrenia patients, are also discussed.

  6. The Role of Dopamine in Schizophrenia from a Neurobiological and Evolutionary Perspective: Old Fashioned, but Still in Vogue

    PubMed Central

    Brisch, Ralf; Saniotis, Arthur; Wolf, Rainer; Bielau, Hendrik; Bernstein, Hans-Gert; Steiner, Johann; Bogerts, Bernhard; Braun, Katharina; Jankowski, Zbigniew; Kumaratilake, Jaliya; Henneberg, Maciej; Gos, Tomasz

    2014-01-01

    Dopamine is an inhibitory neurotransmitter involved in the pathology of schizophrenia. The revised dopamine hypothesis states that dopamine abnormalities in the mesolimbic and prefrontal brain regions exist in schizophrenia. However, recent research has indicated that glutamate, GABA, acetylcholine, and serotonin alterations are also involved in the pathology of schizophrenia. This review provides an in-depth analysis of dopamine in animal models of schizophrenia and also focuses on dopamine and cognition. Furthermore, this review provides not only an overview of dopamine receptors and the antipsychotic effects of treatments targeting them but also an outline of dopamine and its interaction with other neurochemical models of schizophrenia. The roles of dopamine in the evolution of the human brain and human mental abilities, which are affected in schizophrenia patients, are also discussed. PMID:24904434

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

    PubMed

    Cataldo, L R; Mizgier, M L; Busso, D; Olmos, P; Galgani, J E; Valenzuela, R; Mezzano, D; 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.

  8. 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

  9. Neonatal Parathion Exposure Disrupts Serotonin and Dopamine Synaptic Function in Rat Brain Regions

    PubMed Central

    Slotkin, Theodore A.; Wrench, Nicola; Ryde, Ian T.; Lassiter, T. Leon; Levin, Edward D.; Seidler, Frederic J.

    2009-01-01

    The consequences of exposure to developmental neurotoxicants are influenced by environmental factors. In the present study, we examined the role of dietary fat intake. We administered parathion to neonatal rats and then evaluated whether a high-fat diet begun in adulthood could modulate the persistent effects on 5HT and DA systems. Neonatal rats received parathion on postnatal days 1-4 at 0.1 or 0.2 mg/kg/day, straddling the cholinesterase inhibition threshold. In adulthood, half the animals in each exposure group were given a high-fat diet for 8 weeks. We assessed 5HT and DA concentrations and turnover in brain regions containing their respective cell bodies and projections. In addition, we monitored 5HT1A and 5HT2 receptor binding and the concentration of 5HT presynaptic transporters. Neonatal parathion exposure evoked widespread increases in neurotransmitter turnover, indicative of presynaptic hyperactivity, further augmented by 5HT receptor upregulation. In control rats, consumption of a high-fat diet recapitulated many of the changes seen with neonatal parathion exposure; the effects represented convergent mechanisms, since the high-fat diet often obtunded further increases caused by parathion. Neonatal parathion exposure causes lasting hyperactivity of 5HT and DA systems accompanied by 5HT receptor upregulation, consistent with “miswiring” of neuronal projections. A high-fat diet obtunds the effect of parathion, in part by eliciting similar changes itself. Thus, dietary factors may produce similar synaptic changes as do developmental neurotoxicants, potentially contributing to the increasing incidence in neurodevelopmental disorders. PMID:19616088

  10. Behavioral deficits in rats following acute administration of glimepiride: Relationship with brain serotonin and dopamine.

    PubMed

    Sheikh, Shehnaz Abdul; Ikram, Huma; Haleem, Darakhshan Jabeen

    2015-07-01

    A considerable body of literature suggests that depression and diabetes mellitus are co-morbid. The present study was designed to test any possible behavioral deficits and/or neurochemical changes in the brain as induced by the anti-diabetic drugs. Twenty-four rats were divided into four groups: (i) saline (ii) glimepiride (2.5mg/kg)- (iii) glimepiride (5.0mg/kg)- and (iv) glimepiride (10 mg/kg) injected animals. Behavioral activities in Skinner's box, open field and elevated plus maze were monitored 20, 35 and 45 minutes post injection respectively. Animals were decapitated 60 minutes post injection to collect brain samples. Samples were kept at -70°C until neurochemical analysis by HPLC-EC. Results from the present study show decreased time spent in the open arm of the elevated plus maze (p<0.05) at all the three doses. A decrease in the HVA (Homovanillic acid) levels at all three doses (p<0.01) was also observed along with decreased 5-HT (5-Hydroxytryptamine) (p<0.05 at 5.0 and 10mg/kg) and 5-HIAA (5-Hydroxyindoleacetic acid) (p<0.05 at all three doses) levels. Since a decrease in 5-HT metabolism can induce depression-like effects, the present study therefore suggests that the occurrence of depression in diabetic patients is due to the use of glimipride. Effects of long-term administration of smaller doses of glimipride are to be explored further to monitor tolerance in glimipride-induced deficits of serotonin. The finding may help to explore the cause of depression in diabetics for improving pharmacotherapy in diabetes. PMID:26142509

  11. 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.

  12. 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. PMID:26711020

  13. 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. PMID:26116760

  14. Regional and laminar distribution of the dopamine and serotonin innervation in the macaque cerebral cortex: a radioautographic study

    SciTech Connect

    Berger, B.; Trottier, S.; Verney, C.; Gaspar, P.; Alvarez, C.

    1988-07-01

    The regional density and laminar distribution of dopamine (DA) and serotonin (5-HT) afferents were investigated in the cerebral cortex of cynomolgus monkeys using a radioautographic technique that is based on the high affinity uptake capacity of these aminergic neurons. Large vibratome sections, 50 micron thick, were incubated with (3H) DA (0.2 microM) and desipramine (5 microM) or with unlabeled norepinephrine (5 microM) and (3H) 5-HT (0.6 microM), which allowed for the specific labeling of the DA and 5-HT innervations, respectively. After fixation, these sections were dried, defatted, and radioautographed by dipping. Semiquantitative data on the DA innervation also were provided by counting (3H) DA-labeled axonal varicosities in radioautographs from 4-micron-thick sections of the slices obtained after epon embedding. The DA innervation was widespread and differed in density and laminar distribution in the agranular and granular cortices. DA afferents were densest in the anterior cingulate (area 24) and the motor areas (areas 4, 6, and supplementary motor area (SMA)). In the latter they displayed a trilaminar pattern of distribution, predominating in layers I, IIIa, and V-VI, with characteristic cluster-like formations in layer IIIa, especially in the medial part of motor areas. In the granular prefrontal (areas 46, 9, 10, 11, 12), parietal (areas 1, 2, 3, 5, 7), temporal (areas 21, 22), and posterior cingulate (area 23) cortices, DA afferents were less dense and showed a bilaminar pattern of distribution, predominating in the depth of layer I and in layers V-VI; density in layers II, III, and IV was only 20% of that in layer I. The lowest density was in the visual cortex, particularly in area 17, where the DA afferents were almost restricted to layer I.

  15. Running Reduces Uncontrollable Stress-Evoked Serotonin and Potentiates Stress-Evoked Dopamine Concentrations in the Rat Dorsal Striatum.

    PubMed

    Clark, Peter J; Amat, Jose; McConnell, Sara O; Ghasem, Parsa R; Greenwood, Benjamin N; Maier, Steven F; Fleshner, Monika

    2015-01-01

    Accumulating evidence from both the human and animal literature indicates that exercise reduces the negative consequences of stress. The neurobiological etiology for this stress protection, however, is not completely understood. Our lab reported that voluntary wheel running protects rats from expressing depression-like instrumental learning deficits on the shuttle box escape task after exposure to unpredictable and inescapable tail shocks (uncontrollable stress). Impaired escape behavior is a result of stress-sensitized serotonin (5-HT) neuron activity in the dorsal raphe (DRN) and subsequent excessive release of 5-HT into the dorsal striatum following exposure to a comparatively mild stressor. However, the possible mechanisms by which exercise prevents stress-induced escape deficits are not well characterized. The purpose of this experiment was to test the hypothesis that exercise blunts the stress-evoked release of 5-HT in the dorsal striatum. Changes to dopamine (DA) levels were also examined, since striatal DA signaling is critical for instrumental learning and can be influenced by changes to 5-HT activity. Adult male F344 rats, housed with or without running wheels for 6 weeks, were either exposed to tail shock or remained undisturbed in laboratory cages. Twenty-four hours later, microdialysis was performed in the medial (DMS) and lateral (DLS) dorsal striatum to collect extracellular 5-HT and DA before, during, and following 2 mild foot shocks. We report wheel running prevents foot shock-induced elevation of extracellular 5-HT and potentiates DA concentrations in both the DMS and DLS approximately 24 h following exposure to uncontrollable stress. These data may provide a possible mechanism by which exercise prevents depression-like instrumental learning deficits following exposure to acute stress. PMID:26555633

  16. 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.

  17. 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.

  18. Running Reduces Uncontrollable Stress-Evoked Serotonin and Potentiates Stress-Evoked Dopamine Concentrations in the Rat Dorsal Striatum

    PubMed Central

    Clark, Peter J.; Amat, Jose; McConnell, Sara O.; Ghasem, Parsa R.; Greenwood, Benjamin N.; Maier, Steven F.; Fleshner, Monika

    2015-01-01

    Accumulating evidence from both the human and animal literature indicates that exercise reduces the negative consequences of stress. The neurobiological etiology for this stress protection, however, is not completely understood. Our lab reported that voluntary wheel running protects rats from expressing depression-like instrumental learning deficits on the shuttle box escape task after exposure to unpredictable and inescapable tail shocks (uncontrollable stress). Impaired escape behavior is a result of stress-sensitized serotonin (5-HT) neuron activity in the dorsal raphe (DRN) and subsequent excessive release of 5-HT into the dorsal striatum following exposure to a comparatively mild stressor. However, the possible mechanisms by which exercise prevents stress-induced escape deficits are not well characterized. The purpose of this experiment was to test the hypothesis that exercise blunts the stress-evoked release of 5-HT in the dorsal striatum. Changes to dopamine (DA) levels were also examined, since striatal DA signaling is critical for instrumental learning and can be influenced by changes to 5-HT activity. Adult male F344 rats, housed with or without running wheels for 6 weeks, were either exposed to tail shock or remained undisturbed in laboratory cages. Twenty-four hours later, microdialysis was performed in the medial (DMS) and lateral (DLS) dorsal striatum to collect extracellular 5-HT and DA before, during, and following 2 mild foot shocks. We report wheel running prevents foot shock-induced elevation of extracellular 5-HT and potentiates DA concentrations in both the DMS and DLS approximately 24 h following exposure to uncontrollable stress. These data may provide a possible mechanism by which exercise prevents depression-like instrumental learning deficits following exposure to acute stress. PMID:26555633

  19. Characterization of typical and atypical antipsychotic drugs based on in vivo occupancy of serotonin2 and dopamine2 receptors.

    PubMed

    Stockmeier, C A; DiCarlo, J J; Zhang, Y; Thompson, P; Meltzer, H Y

    1993-09-01

    Atypical antipsychotic drugs related to clozapine may be distinguishable from typical antipsychotic drugs by having a greater potency in vitro at serotonin2 (5-HT2) receptors relative to dopamine2 (D2) receptors. The in vivo potencies of 10 typical and 10 putative atypical antipsychotic drugs in occupying D2 and 5-HT2 receptors in rat brain are reported here. There is no significant difference in the average potency of the two groups of antipsychotic drugs in preventing the in vivo binding of N-[3H] methylspiperone to 5-HT2 receptors in the cortex. However, the average potency of the atypical antipsychotic drugs is about 8-fold less than typical antipsychotic drugs in preventing N-[3H] methylspiperone binding to D2 receptors in the striatum. Thus, all of the atypical antipsychotic drugs that are clozapine-like have a greater relative affinity in vivo for the 5-HT2 than the D2 receptor. As a group, the typical antipsychotic drugs tend to be equipotent at both receptors. The average relative potency of the group of typical antipsychotic drugs at 5-HT2 vs. D2 receptors is essentially equal when examined in vivo vs. in vitro. Atypical antipsychotic drugs are slightly but significantly more potent in vivo at D2 receptors in the olfactory tubercle than the striatum. For only the typical antipsychotic drugs, the in vivo and in vitro potencies in occupying D2 receptors are correlated with their average clinical dosage. Thus, the relative in vivo potency of clozapine-related drugs at 5-HT2 vs. D2 receptors may help identify these compounds as atypical antipsychotic drugs.

  20. 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.

  1. Orquestic regulation of neurotransmitters on reward-seeking behavior.

    PubMed

    Arias-Carrión, Oscar; Caraza-Santiago, Xanic; Salgado-Licona, Sergio; Salama, Mohamed; Machado, Sergio; Nardi, Antonio Egidio; Menéndez-González, Manuel; Murillo-Rodríguez, Eric

    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

  2. Orquestic regulation of neurotransmitters on reward-seeking behavior.

    PubMed

    Arias-Carrión, Oscar; Caraza-Santiago, Xanic; Salgado-Licona, Sergio; Salama, Mohamed; Machado, Sergio; Nardi, Antonio Egidio; Menéndez-González, Manuel; Murillo-Rodríguez, Eric

    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.

  3. 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

  4. Pharmacological profiles in rats of novel antipsychotics with combined dopamine D2/serotonin 5-HT1A activity: comparison with typical and atypical conventional antipsychotics.

    PubMed

    Bardin, Laurent; Auclair, Agnès; Kleven, Mark S; Prinssen, Eric P M; Koek, Wouter; Newman-Tancredi, Adrian; Depoortère, Ronan

    2007-03-01

    Combining antagonist/partial agonist activity at dopamine D2 and agonist activity at serotonin 5-HT1A receptors is one of the approaches that has recently been chosen to develop new generation antipsychotics, including bifeprunox, SSR181507 and SLV313. There have been, however, few comparative data on their pharmacological profiles. Here, we have directly compared a wide array of these novel dopamine D2/5-HT1A and conventional antipsychotics in rat models predictive of antipsychotic activity. Potency of antipsychotics to antagonize conditioned avoidance, methylphenidate-induced behaviour and D-amphetamine-induced hyperlocomotion correlated with their affinity at dopamine D2 receptors. Potency against ketamine-induced hyperlocomotion was independent of affinity at dopamine D2 or 5-HT1A receptors. Propensity to induce catalepsy, predictive of occurrence of extrapyramidal side effects, was inversely related to affinity at 5-HT1A receptors. As a result, preferential D2/5-HT1A antipsychotics displayed a large separation between doses producing 'antipsychotic-like' vs. cataleptogenic actions. These data support the contention that 5-HT1A receptor activation greatly reduces or prevents the cataleptogenic potential of novel antipsychotics. They also emphasize that interactions at 5-HT1A and D2 receptors, and the nature of effects (antagonism or partial agonism) at the latter has a profound influence on pharmacological activities, and is likely to affect therapeutic profiles.

  5. 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.

  6. 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. PMID:20012186

  7. 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.

  8. 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

  9. 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. PMID:22015808

  10. Treatment of congenital neurotransmitter deficiencies by intracerebral ventricular injection of an adeno-associated virus serotype 9 vector.

    PubMed

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

    2014-03-01

    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 (Ddc(KI) 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 Ddc(KI) 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 Ddc(KI) mice and normalized their hindlimb clasping and cardiovascular dysfunctions. The behavioral abnormalities of the Ddc(KI) mice were partially corrected, and the treated Ddc(KI) 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

  11. 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

  12. Monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate "agonist" medications for cocaine dependence: studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys.

    PubMed

    Negus, S S; Mello, N K; Blough, B E; Baumann, M H; Rothman, R B

    2007-02-01

    Monoamine releasers constitute one class of drugs under investigation as candidate medications for the treatment of cocaine abuse. Promising preclinical and clinical results have been obtained with amphetamine, which has high selectivity for releasing dopamine/norepinephrine versus serotonin. However, use of amphetamine as a pharmacotherapy is complicated by its high abuse potential. Recent preclinical studies suggest that nonselective monoamine releasers or serotonin-selective releasers have lower abuse liability and may warrant evaluation as alternatives to amphetamine. To address this issue, the present study evaluated the effects of five monoamine releasers in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys. The releasers varied along a continuum from dopamine/norepinephrine-selective to serotonin-selective [m-fluoroamphetamine (PAL-353), methamphetamine, m-methylamphetamine (PAL-314), 1-napthyl-2-aminopropane (PAL-287), fenfluramine]. In drug discrimination studies, rhesus monkeys were trained to discriminate saline from cocaine (0.4 mg/kg i.m.) in a two-key, food-reinforced drug discrimination procedure. Substitution for cocaine was positively associated with selectivity for dopamine/norepinephrine versus serotonin release. In drug self-administration studies, rhesus monkeys responded for cocaine (0.01 and 0.032 mg/kg/injection) and food (1-g pellets) under a second-order fixed-ratio 2 (variable-ratio 16:S) schedule. In general, monoamine releasers produced dose-dependent and sustained decreases in cocaine self-administration. However, the dopamine/norepinephrine-selective releasers decreased cocaine self-administration with minimal effects on food-maintained responding, whereas the more serotonin-selective releasers produced nonselective reductions in both cocaine- and food-maintained responding. These results are consistent with the conclusion that dopamine/norepinephrine-selective releasers retain cocaine-like abuse

  13. 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

  14. 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.

  15. Toxic effects of methoxychlor in rat striatum: modifications in several neurotransmitters.

    PubMed

    Lafuente, A; Cabaleiro, T; Caride, A; Gutiérrez, A; Esquifino, A I

    2007-06-01

    Neurotoxic effects of methoxychlor (MTX) are poorly understood at present. This study was undertaken to evaluate the possible effects of MTX in norepinephrine, dopamine and amino acid contents and serotonin turnover in rat striatum. For this purpose, adult male Sprague-Dawley rats were administered 25 mg/kg/day of MTX in sesame oil or vehicle only for 30 days. The neurotransmitters of interest were measured in the striatum by HPLC. MTX decreased norepinephrine and 5-hydroxyindole acetic acid (5-HIAA) content and serotonin turnover (measured as 5-HIAA/serotonin ratio), and increased glutamate and GABA concentrations. However, the content of serotonin, aspartate, glutamine and taurine was not modified by MTX exposure. These data suggest that MTX exposure inhibits norepinephrine synthesis and serotonin metabolism. The inhibitory effect on norepinephrine could be explained, at least in part, by the increase of both GABA and glutamate contents. Further studies are needed to understand the effects of MTX on serotonin. Also a disruptive effect of MTX on the metabolisms of glutamate, aspartate, glutamine and GABA emerges.

  16. Dopaminergic agents: influence on serotonin in the molluscan nervous system.

    PubMed

    Stefano, G B; Catapane, E; Aiello, E

    1976-10-29

    Treatment of the mussel Mytilus edulis with 6-hydroxydopamine or with alpha-methyl-p-tyrosine decreased dopamine and increased serotonin in the nervous system. Treatment with dopamine decreased serotonin concentrations and prevented the effect of 6-hydroxydopamine. The serotonin concentration appears to be determined in part by the concentration of dopamine. PMID:973139

  17. Decreased cerebral spinal fluid neurotransmitter levels in Smith-Lemli-Opitz syndrome.

    PubMed

    Sparks, S E; Wassif, C A; Goodwin, H; Conley, S K; Lanham, D C; Kratz, L E; Hyland, K; Gropman, A; Tierney, E; Porter, F D

    2014-05-01

    Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple congenital anomaly syndrome with cognitive impairment and a distinct behavioral phenotype that includes autistic features. SLOS is caused by a defect in 3β-hydroxysterol Δ(7)-reductase which leads to decreased cholesterol levels and elevated cholesterol precursors, specifically 7- and 8-dehydrocholesterol. However, the pathological processes contributing to the neurological abnormalities in SLOS have not been defined. In view of prior data suggesting defects in SLOS in vesicular release and given the association of altered serotonin metabolism with autism, we were interested in measuring neurotransmitter metabolite levels in SLOS to assess their potential to be used as biomarkers in therapeutic trials. We measured cerebral spinal fluid levels of serotonin and dopamine metabolites, 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) respectively, in 21 SLOS subjects. Results were correlated with the SLOS anatomical severity score, Aberrant Behavior Checklist scores and concurrent sterol biochemistry. Cerebral spinal fluid (CSF) levels of both 5HIAA and HVA were significantly reduced in SLOS subjects. In individual patients, the levels of both 5HIAA and HVA were reduced to a similar degree. CSF neurotransmitter metabolite levels did not correlate with either CSF sterols or behavioral measures. This is the first study demonstrating decreased levels of CSF neurotransmitter metabolites in SLOS. We propose that decreased levels of neurotransmitters in SLOS are caused by a sterol-related defect in synaptic vesicle formation and that CSF 5HIAA and HVA will be useful biomarkers in development of future therapeutic trials.

  18. 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.

  19. 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 Central

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

    2015-01-01

    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. PMID:26233799

  20. 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

  1. Could Dopamine Agonists Aid in Drug Development for Anorexia Nervosa?

    PubMed Central

    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. PMID:25988121

  2. 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

  3. 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.

  4. Basic advances in serotonin pharmacology.

    PubMed

    Fuller, R W

    1992-10-01

    Several advances in serotonin pharmacology have implications for psychiatry. The introduction of selective inhibitors of serotonin uptake into clinical use has established more firmly the relevance of brain serotonin neurons to depressive illness and is permitting an exploration of other therapeutic consequences of amplifying serotonergic function. A recent major advance in basic pharmacology has been the definition and characterization of multiple serotonin receptor subtypes in brain. Highly selective agonists and antagonists at these receptor subtypes are being developed as candidate drugs for therapy and as pharmacologic probes for assessing functionality of brain serotonin neurons in disease. Improved pharmacologic specificity will provide better tools for eliciting measurable responses mediated by brain serotonin receptors and for imaging key presynaptic and postsynaptic constituents of serotonin neuronal systems. Advances in serotonin pharmacology should therefore expand our understanding of serotonin's roles as a brain neurotransmitter in health and disease and lead to improved therapeutic agents.

  5. Extremely Low Frequency Magnetic Field Modulates the Level of Neurotransmitters

    PubMed Central

    Chung, Yoon Hee; Lee, Young Joo; Lee, Ho Sung; Chung, Su Jin; Lim, Cheol Hee; Oh, Keon Woong; Sohn, Uy Dong

    2015-01-01

    This study was aimed to observe that extremely low frequency magnetic field (ELF-MF) may be relevant to changes of major neurotransmitters in rat brain. After the exposure to ELF-MF (60 Hz, 2.0 mT) for 2 or 5 days, we measured the levels of biogenic amines and their metabolites, amino acid neurotransmitters and nitric oxide (NO) in the cortex, striatum, thalamus, cerebellum and hippocampus. The exposure of ELF-MF for 2 or 5 days produced significant differences in norepinephrine and vanillyl mandelic acid in the striatum, thalamus, cerebellum and hippocampus. Significant increases in the levels of serotonin and 5-hydroxyindoleacetic acid were also observed in the striatum, thalamus or hippocampus. ELF-MF significantly increased the concentration of dopamine in the thalamus. ELF-MF tended to increase the levels of amino acid neurotransmitters such as glutamine, glycine and γ -aminobutyric acid in the striatum and thalamus, whereas it decreased the levels in the cortex, cerebellum and hippocampus. ELF-MF significantly increased NO concentration in the striatum, thalamus and hippocampus. The present study has demonstrated that exposure to ELF-MFs may evoke the changes in the levels of biogenic amines, amino acid and NO in the brain although the extent and property vary with the brain areas. However, the mechanisms remain further to be characterized. PMID:25605992

  6. Extremely low frequency magnetic field modulates the level of neurotransmitters.

    PubMed

    Chung, Yoon Hee; Lee, Young Joo; Lee, Ho Sung; Chung, Su Jin; Lim, Cheol Hee; Oh, Keon Woong; Sohn, Uy Dong; Park, Eon Sub; Jeong, Ji Hoon

    2015-01-01

    This study was aimed to observe that extremely low frequency magnetic field (ELF-MF) may be relevant to changes of major neurotransmitters in rat brain. After the exposure to ELF-MF (60 Hz, 2.0 mT) for 2 or 5 days, we measured the levels of biogenic amines and their metabolites, amino acid neurotransmitters and nitric oxide (NO) in the cortex, striatum, thalamus, cerebellum and hippocampus. The exposure of ELF-MF for 2 or 5 days produced significant differences in norepinephrine and vanillyl mandelic acid in the striatum, thalamus, cerebellum and hippocampus. Significant increases in the levels of serotonin and 5-hydroxyindoleacetic acid were also observed in the striatum, thalamus or hippocampus. ELF-MF significantly increased the concentration of dopamine in the thalamus. ELF-MF tended to increase the levels of amino acid neurotransmitters such as glutamine, glycine and γ -aminobutyric acid in the striatum and thalamus, whereas it decreased the levels in the cortex, cerebellum and hippocampus. ELF-MF significantly increased NO concentration in the striatum, thalamus and hippocampus. The present study has demonstrated that exposure to ELF-MFs may evoke the changes in the levels of biogenic amines, amino acid and NO in the brain although the extent and property vary with the brain areas. However, the mechanisms remain further to be characterized.

  7. Neurotransmitters in the human and nonhuman primate basal ganglia.

    PubMed

    Haber, S N

    1986-01-01

    In recent years, a number of new molecules, particularly peptides, have been identified as putative neurotransmitters. The basal ganglia, is especially rich in a number of classical transmitter molecules, amino acids and neuropeptides considered to function in neurotransmission. These include: the well-described terminal fields in the striatum which originate from the brain stem and contain the monoamines, dopamine and serotonin; amino acid containing axons projecting from the cortex and thalamus; striatal cholinergic and peptide-positive interneurons; and amino acid and peptide containing projection neurons to the globus pallidus and substantia nigra. Two amino acids, glutamate and aspartate, are considered to provide excitatory input to the striatum while gamma aminobutyric acid is thought to mediate inhibitory output. Neuropeptides which are richly concentrated in the basal ganglia include, enkephalin, dynorphin, substance P, somatostatin, neuropeptide Y and cholincystokinease. Changes in many of these peptide levels have recently been associated with a number of basal ganglia disorders.

  8. SLC18: Vesicular neurotransmitter transporters for monoamines and acetylcholine.

    PubMed

    Lawal, Hakeem O; Krantz, David E

    2013-01-01

    The exocytotic release of neurotransmitters requires active transport into synaptic vesicles and other types of secretory vesicles. Members of the SLC18 family perform this function for acetylcholine (SLC18A3, the vesicular acetylcholine transporter or VAChT) and monoamines such as dopamine and serotonin (SLC18A1 and 2, the vesicular monoamine transporters VMAT1 and 2, respectively). To date, no specific diseases have been attributed to a mutation in an SLC18 family member; however, polymorphisms in SLC18A1 and SLC18A2 may confer risk for some neuropsychiatric disorders. Additional members of this family include SLC18A4, expressed in insects, and SLC18B1, the function of which is not known. SLC18 is part of the Drug:H(+) Antiporter-1 Family (DHA1, TCID 2.A.1.2) within the Major Facilitator Superfamily (MFS, TCID 2.A.1).

  9. SLC18: Vesicular neurotransmitter transporters for monoamines and acetylcholine ☆

    PubMed Central

    Lawal, Hakeem O.; Krantz, David E.

    2012-01-01

    The exocytotic release of neurotransmitters requires active transport into synaptic vesicles and other types of secretory vesicles. Members of the SLC18 family perform this function for acetylcholine (SLC18A3, the vesicular acetylcholine transporter or VAChT) and monoamines such as dopamine and serotonin (SLC18A1 and 2, the vesicular monoamine transporters VMAT1 and 2, respectively). To date, no specific diseases have been attributed to a mutation in an SLC18 family member; however, polymorphisms in SLC18A1 and SLC18A2 may confer risk for some neuropsychiatric disorders. Additional members of this family include SLC18A4, expressed in insects, and SLC18B1, the function of which is not known. SLC18 is part of the Drug:H+ Antiporter-1 Family (DHA1, TCID 2.A.1.2) within the Major Facilitator Superfamily (MFS, TCID 2.A.1). PMID:23506877

  10. 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.

  11. Functional mechanisms of neurotransmitter transporters regulated by lipid-protein interactions of their terminal loops

    PubMed Central

    Khelashvili, George; Weinstein, Harel

    2015-01-01

    The physiological functions of neurotransmitter:sodium symporters (NSS) in reuptake of neurotransmitters from the synapse into the presynaptic nerve have been shown to be complemented by their involvement, together with non-plasma membrane neurotransmitter transporters, in the reverse transport of substrate (efflux) in response to psychostimulants. Recent experimental evidence implicates highly anionic phosphatidylinositol 4,5-biphosphate (PIP2) lipids in such functions of the serotonin (SERT) and dopamine (DAT) transporters. Thus, for both SERT and DAT, neurotransmitter efflux has been shown to be strongly regulated by the presence of PIP2 lipids in the plasma membrane, and the electrostatic interaction of the N-terminal region of DAT with the negatively charged PIP2 lipids. We examine the experimentally established phenotypes in a structural context obtained from computational modeling based on recent crystallographic data. The results are shown to set the stage for a mechanistic understanding of physiological actions of neurotransmitter transporters in the NSS family of membrane proteins. PMID:25847498

  12. Brain-derived neurotrophic factor and neurotrophin-3 activate striatal dopamine and serotonin metabolism and related behaviors: interactions with amphetamine.

    PubMed

    Martin-Iverson, M T; Todd, K G; Altar, C A

    1994-03-01

    To investigate behavioral and neurochemical effects of neurotrophic factors in vivo, rats received continuous 14 d infusions of either brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or vehicle unilaterally into the substantia nigra. BDNF and NT-3 decreased body weights, an effect that was sustained over the infusion period. BDNF elevated daytime and nocturnal locomotion compared with infusions of vehicle or NT-3. At 2 weeks, a systemic injection of amphetamine (1.5 mg/kg, s.c.) increased the frequencies and durations of rotations contraversive to the side of BDNF and NT-3 infusions. Both factors attenuated amphetamine-induced locomotion without affecting amphetamine-induced stereotyped behaviors such as sniffing, head movements, and snout contact with cage surfaces. Only BDNF induced backward walking, and this response was augmented by amphetamine. BDNF, but not NT-3, increased dopamine turnover in the striatum ipsilateral to the infusion relative to the contralateral striatum. Both trophic factors decreased dopamine turnover in the infused substantia nigra relative to the contralateral hemisphere and increased 5-HT turnover in the striatum of both sides. Contraversive rotations were positively correlated with dopamine content decreases and 5-HT turnover increases in the striatum ipsilateral to the infused substantia nigra. Backward walking was positively correlated with increased dopamine and 5-HT turnover in the striatum of the infused hemisphere. Supranigral infusions of BDNF and NT-3 alter circadian rhythms, spontaneous motor activity, body weights, and amphetamine-induced behaviors including locomotion and contraversive rotations. These behavioral effects of the neurotrophins are consistent with a concomitant activation of dopamine and 5-HT systems in vivo.

  13. 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.

  14. 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.

  15. Chronic Effect of Aspartame on Ionic Homeostasis and Monoamine Neurotransmitters in the Rat Brain.

    PubMed

    Abhilash, M; Alex, Manju; Mathews, Varghese V; Nair, R Harikumaran

    2014-05-28

    Aspartame is one of the most widely used artificial sweeteners globally. Data concerning acute neurotoxicity of aspartame is controversial, and knowledge on its chronic effect is limited. In the current study, we investigated the chronic effects of aspartame on ionic homeostasis and regional monoamine neurotransmitter concentrations in the brain. Our results showed that aspartame at high dose caused a disturbance in ionic homeostasis and induced apoptosis in the brain. We also investigated the effects of aspartame on brain regional monoamine synthesis, and the results revealed that there was a significant decrease of dopamine in corpus striatum and cerebral cortex and of serotonin in corpus striatum. Moreover, aspartame treatment significantly alters the tyrosine hydroxylase activity and amino acids levels in the brain. Our data suggest that chronic use of aspartame may affect electrolyte homeostasis and monoamine neurotransmitter synthesis dose dependently, and this might have a possible effect on cognitive functions.

  16. Antipsychotics differ in their ability to internalise human dopamine D2S and human serotonin 5-HT1A receptors in HEK293 cells.

    PubMed

    Heusler, Peter; Newman-Tancredi, Adrian; Loock, Timothé; Cussac, Didier

    2008-02-26

    Antipsychotic drugs act preferentially via dopamine D(2) receptor blockade, but interaction with serotonin 5-HT(1A) receptors has attracted interest as additional target for antipsychotic treatment. As receptor internalisation is considered crucial for drug action, we tested the propensity of antipsychotics to internalise human (h)D(2S) receptors and h5-HT(1A) receptors. Agonist-induced internalisation of hemaglutinin (HA)-tagged hD(2S) and HA-h5-HT(1A) receptors expressed in HEK293 cells was increased by coexpression of G-protein coupled receptor kinase 2 and beta-arrestin2. At the HA-hD(2S) receptor, dopamine, quinpirole and bromocriptine behaved as full agonists, while S(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(-)-3PPP] and sarizotan were partial agonists. The typical antipsychotic, haloperidol, and the atypical compounds, olanzapine, nemonapride, ziprasidone and clozapine did not internalise HA-hD(2S) receptors, whereas aripiprazole potently internalised these receptors (>50% relative efficacy). Among antipsychotics with combined D(2)/5-HT(1A) properties, bifeprunox and (3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo-[3.2.1]octane-3-methanamine (SSR181507) partially internalised HA-hD(2S) receptors, piperazine, 1-(2,3-dihydro-1,4-benzodioxin-5-yl)-4-[[5-(4-fluorophenyl)-3-pyridinyl]methyl (SLV313) and N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine (F15063) were inactive. At the HA-h5-HT(1A) receptor, serotonin, (+)-8-hydroxy-2-(di-n-propylamino)tetralin [(+)-8-OH-DPAT] and sarizotan were full agonists, buspirone acted as partial agonist. (-)-Pindolol showed little activity and no internalising properties were manifested for the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY100635). Most antipsychotics induced HA-h5-HT(1A) receptor internalisation, with an efficacy rank order: nemonapride>F15063>SSR181507

  17. 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.

  18. Carbon nanopipette electrodes for dopamine detection in Drosophila

    PubMed Central

    Rees, Hillary R.; Anderson, Sean E.; Privman, Eve; Bau, Haim H.; Venton, B. Jill

    2015-01-01

    Small, robust, sensitive electrodes are desired for in vivo neurotransmitter measurements. Carbon nanopipettes have been previously manufactured and used for single cell drug delivery and electrophysiological measurements. Here, a modified fabrication procedure was developed to produce batches of solid carbon nanopipette electrodes (CNPEs) with ~250 nm diameter tips, and controllable lengths of exposed carbon, ranging from 5 μm to 175 μm. The electrochemical properties of CNPEs were characterized with fast-scan cyclic voltammetry (FSCV) for the first time. CNPEs were used to detect the electroactive neurotransmitters dopamine, serotonin, and octopamine. CNPEs were significantly more sensitive for serotonin detection than traditional carbon fiber microelectrodes (CFMEs). Similar to CFMEs, CNPEs have a linear response for dopamine concentrations ranging from 0.1 to 10 μM and a LOD of 25 ± 5 nM. Recordings with CNPEs were stable for over 3 hours when the applied triangle waveform was scanned between −0.4 and 1.3 V vs. Ag/AgCl/Cl− at 400 V/s. CNPEs were used to detect endogenous dopamine release in Drosophila larvae using optogenetics, which verified the utility of CNPEs for in vivo neuroscience studies. CNPEs are advantageous because they are an order of magnitude smaller in diameter than typical CFMEs and have a sharp, tunable geometry that facilitates penetration and implantation for localized measurements in distinct regions of small organisms, such as the Drosophila brain. PMID:25711512

  19. Carbon nanopipette electrodes for dopamine detection in Drosophila.

    PubMed

    Rees, Hillary R; Anderson, Sean E; Privman, Eve; Bau, Haim H; Venton, B Jill

    2015-04-01

    Small, robust, sensitive electrodes are desired for in vivo neurotransmitter measurements. Carbon nanopipettes have been previously manufactured and used for single-cell drug delivery and electrophysiological measurements. Here, a modified fabrication procedure was developed to produce batches of solid carbon nanopipette electrodes (CNPEs) with ∼250 nm diameter tips, and controllable lengths of exposed carbon, ranging from 5 to 175 μm. The electrochemical properties of CNPEs were characterized with fast-scan cyclic voltammetry (FSCV) for the first time. CNPEs were used to detect the electroactive neurotransmitters dopamine, serotonin, and octopamine. CNPEs were significantly more sensitive for serotonin detection than traditional carbon-fiber microelectrodes (CFMEs). Similar to CFMEs, CNPEs have a linear response for dopamine concentrations ranging from 0.1 to 10 μM and a limit of detection of 25 ± 5 nM. Recordings with CNPEs were stable for over 3 h when the applied triangle waveform was scanned between -0.4 and +1.3 V vs Ag/AgCl/Cl(-) at 400 V/s. CNPEs were used to detect endogenous dopamine release in Drosophila larvae using optogenetics, which verified the utility of CNPEs for in vivo neuroscience studies. CNPEs are advantageous because they are 1 order of magnitude smaller in diameter than typical CFMEs and have a sharp, tunable geometry that facilitates penetration and implantation for localized measurements in distinct regions of small organisms, such as the Drosophila brain.

  20. 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. PMID:25304540

  1. 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.

  2. Neurotransmitter transporters in schistosomes: structure, function and prospects for drug discovery.

    PubMed

    Ribeiro, Paula; Patocka, Nicholas

    2013-12-01

    Neurotransmitter transporters (NTTs) play a fundamental role in the control of neurotransmitter signaling and homeostasis. Sodium symporters of the plasma membrane mediate the cellular uptake of neurotransmitter from the synaptic cleft, whereas proton-driven vesicular transporters sequester the neurotransmitter into synaptic vesicles for subsequent release. Together these transporters control how much transmitter is released and how long it remains in the synaptic cleft, thereby regulating the intensity and duration of signaling. NTTs have been the subject of much research in mammals and there is growing interest in their activities among invertebrates as well. In this review we will focus our attention on NTTs of the parasitic flatworm Schistosoma mansoni. Bloodflukes of the genus Schistosoma are the causative agents of human schistosomiasis, a devastating disease that afflicts over 200 million people worldwide. Schistosomes have a well-developed nervous system and a rich diversity of neurotransmitters, including many of the small-molecule ("classical") neurotransmitters that normally employ NTTs in their mechanism of signaling. Recent advances in schistosome genomics have unveiled numerous NTTs in this parasite, some of which have now been cloned and characterized in vitro. Moreover new genetic and pharmacological evidence suggests that NTTs are required for proper control of neuromuscular signaling and movement of the worm. Among these carriers are proteins that have been successfully targeted for drug discovery in other organisms, in particular sodium symporters for biogenic amine neurotransmitters such as serotonin and dopamine. Our goal in this chapter is to review the current status of research on schistosome NTTs, with emphasis on biogenic amine sodium symporters, and to evaluate their potential for anti-schistosomal drug targeting. Through this discussion we hope to draw attention to this important superfamily of parasite proteins and to identify new

  3. Comparison of noradrenaline, dopamine and serotonin in mediating the tachycardic and thermogenic effects of methamphetamine in the ventral medial prefrontal cortex.

    PubMed

    Hassan, S F; Zumut, S; Burke, P G; McMullan, S; Cornish, J L; Goodchild, A K

    2015-06-01

    Methamphetamine (METH) is a psychostimulant that disrupts monoaminergic neurotransmission to evoke profound behavioral and physiological effects. Rapidly distributing to forebrain regions to increase synaptic concentrations of three monoamines (dopamine (DA), serotonin (5-HT) and noradrenaline (NA)), the medial prefrontal cortex (mPFC) is important in METH-altered behavioral and psychological profiles. Activation of the ventral mPFC can modify physiological variables, however, METH-evoked autonomic changes from this region are unknown. Therefore, the aim of this study was to characterize the respiratory, metabolic and cardiovascular effects of microinjection of METH, DA, 5-HT and NA into the ventral mPFC in urethane-anesthetized Sprague-Dawley rats. METH and NA microinjection evoked dose-related increases in heart rate, interscapular brown adipose tissue temperature and expired CO2, a pattern of response characteristic of non-shivering thermogenesis. NA and 5-HT microinjection elicited pressor and depressor responses, respectively, with matching baroreflex adjustments in sympathetic nerve activity while METH and DA evoked no change in vasomotor outflow. Low doses of METH and DA may evoke respiratory depression. These data suggest that METH's actions in the ventral mPFC, likely via adrenergic receptors, evoke non-shivering thermogenesis which may contribute to the increased body temperature and tachycardia seen in those that abuse METH. PMID:25813709

  4. 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.

  5. Adrenocortical reactivity and central serotonin and dopamine turnover in young chicks from a high and low feather-pecking line of laying hens.

    PubMed

    van Hierden, Yvonne M; Korte, S Mechiel; Ruesink, E Wim; van Reenen, Cornelis G; Engel, Bas; Korte-Bouws, Gerdien A H; Koolhaas, Jaap M; Blokhuis, Harry J

    2002-04-15

    Feather pecking in domestic fowl is a behavioral abnormality that consists of mild or injurious pecking at feathers of conspecifics. Previously, it was shown that chicks from a high feather-pecking (HFP) and low feather-pecking (LFP) line of laying hens already differ in their propensity to feather peck at 14 and 28 days of age. As a first step in investigating a possible relationship between the development of feather pecking and physiological and neurobiological characteristics of laying hens, two subsequent experiments were carried out. Firstly, we investigated the development of adrenocortical (re)activity in HFP and LFP chicks during the first 8 weeks of life. Secondly, we studied dopamine (DA) and serotonin (5-HT) turnover in the brain of 28-day-old HFP and LFP chicks. In both experiments, chicks were exposed to manual restraint (placing the chicks on its side for 5 min). Plasma corticosterone levels were lower (baseline on Days 3 and 56; restraint-induced on Days 3, 14 and 28) in HFP chicks. Both brain DA and 5-HT turnover were lower in the HFP chicks, as well. Possible consequences for the observed differences in (stress) physiology and neurobiology between the two lines in relation to the feather pecking are discussed. PMID:12020730

  6. 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. PMID:24872521

  7. 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.

  8. Changes in the levels, expression, and possible roles of serotonin and dopamine during embryonic development in the giant freshwater prawn, Macrobrachium rosenbergii.

    PubMed

    Tinikul, Yotsawan; Poljaroen, Jaruwan; Tinikul, Ruchanok; Sobhon, Prasert

    2016-01-01

    We investigated the changes in the levels of serotonin (5-HT) and dopamine (DA), and their possible roles during embryonic development of the freshwater prawn, Macrobrachium rosenbergii. The 5-HT and DA concentrations were quantified using high performance liquid chromatography with electrochemical detection (HPLC-ECD). The levels of 5-HT and DA gradually increased from early developing embryos to late developing embryos. The 5-HT concentrations gradually increased from the pale yellow egg to orange egg stages, and reaching a maximum at the black egg stage. DA concentrations were much lower in the early embryos than those of 5-HT (P<0.05), and gradually increased to reach the highest level at the black egg stage. Immunohistochemically, 5-HT was firstly detected in the early embryonic stages, whereas DA developed later than 5-HT. Functionally, 5-HT-treated female prawns at doses of 2.5×10(-5), 2.5×10(-6) and 2.5×10(-7)mol/prawn, produced embryos with significantly shortened lengths of early embryonic stages, whereas DA-treated prawns at all three doses, exerted its effects by significantly lengthening the period of mid-embryonic stage onwards. These results suggest significant involvement of 5-HT and DA in embryonic developmental processes of this species.

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

    PubMed

    Pehek, E A; Hernan, A E

    2015-04-01

    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 (PFC) 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 ventral tegmental area (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 of the rat. Infusions of a combination of a N-methyl-d-aspartic acid (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] (2.5mg/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.

  10. The effects of child maltreatment and polymorphisms of the serotonin transporter and dopamine D4 receptor genes on infant attachment and intervention efficacy.

    PubMed

    Cicchetti, Dante; Rogosch, Fred A; Toth, Sheree L

    2011-05-01

    This investigation examined the extent to which polymorphisms of the serotonin transporter linked promoter region (5-HTTLPR) and the dopamine receptor D4 (DRD4) genes differentially influenced the development of attachment security and disorganization in maltreated and nonmaltreated infants at age 13 months, and the extent to which the efficacy of preventive interventions to promote attachment security were influenced by genetic variation. The sample consisted of 106 infants from maltreating families, participating in a randomized control trial evaluating the efficacy of two interventions, child-parent psychotherapy and psychoeducational parenting intervention, and 47 infants from nonmaltreating families. DNA samples were genotyped for polymorphisms of 5-HTTLPR, DRD4 exon III variable number tandem repeat, and DRD4-521. Attachment organization at age 1 and at age 2 was assessed with the Strange Situation for all participants, prior to and following the completion of the interventions. High rates of disorganized attachment were observed in the maltreatment compared to the nonmaltreatment group, and both interventions resulted in increased rates of attachment security at age 2. Genetic variation did not influence improvement in attachment organization among maltreated infants. Among maltreated infants, genetic variation had minimal effect on attachment organization. In contrast, among nonmaltreated infants, 5-HTTLPR and DRD4 polymorphisms influenced attachment security and disorganization at age 2 and the stability of attachment disorganization over time.

  11. 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. PMID:26845201

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

    PubMed

    Pehek, E A; Hernan, A E

    2015-04-01

    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 (PFC) 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 ventral tegmental area (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 of the rat. Infusions of a combination of a N-methyl-d-aspartic acid (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] (2.5mg/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

  13. Development of 3-Phenyltropane Analogs with High Affinity for the Dopamine and Serotonin Transporters and Low Affinity for the Norepinephrine Transporter

    PubMed Central

    Jin, Chunyang; Navarro, Hernán A.; Carroll, F. Ivy

    2010-01-01

    Previous studies showed that the mixed monoamine transporter inhibitor (6, RTI-112) reduced cocaine self-administration at a high level of serotonin transporter (5-HTT) occupancy with no detectable dopamine transporter (DAT) occupancy. In this study, a series of 3β-(substituted phenyl)tropane-2β-carboxylic acid methyl esters 7a-g, 3β-(4-methoxyphenyl)tropane-2β-carboxylic acid esters 8a-j, and 3β-(4-methoxyphenyl)-2β-[3-(4′-methylphenyl)isoxazol-5-yl]tropane (9) were synthesized and evaluated for their monoamine transporter binding affinities to identify potent and selective compounds for both the DAT and 5-HTT relative to the norepinephrine transporter (NET). A number of compounds showed high binding affinities for both the DAT and 5-HTT and low affinity for the NET. 3β-(4-Methoxyphenyl)tropane-2β-carboxylic acid 2-(3-iodo-4-aminophenyl)ethyl ester (8i) with an IC50 value of 2.5 nM for the DAT and Ki values of 3.5 nM and 2040 nM for the 5-HTT and NET, respectively, is the most potent and selective compound for the DAT and 5-HTT relative to the NET in this study. PMID:19053748

  14. 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

  15. Neurotransmitter receptor density changes in Pitx3ak mice--a model relevant to Parkinson's disease.

    PubMed

    Cremer, J N; Amunts, K; Graw, J; Piel, M; Rösch, F; Zilles, K

    2015-01-29

    Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by alterations of nigrostriatal dopaminergic neurotransmission. Compared to the wealth of data on the impairment of the dopamine system, relatively limited evidence is available concerning the role of major non-dopaminergic neurotransmitter systems in PD. Therefore, we comprehensively investigated the density and distribution of neurotransmitter receptors for glutamate, GABA, acetylcholine, adrenaline, serotonin, dopamine and adenosine in brains of homozygous aphakia mice being characterized by mutations affecting the Pitx3 gene. This genetic model exhibits crucial hallmarks of PD on the neuropathological, symptomatic and pharmacological level. Quantitative receptor autoradiography was used to characterize 19 different receptor binding sites in eleven brain regions in order to understand receptor changes on a systemic level. We demonstrated striking differential changes of neurotransmitter receptor densities for numerous receptor types and brain regions, respectively. Most prominent, a strong up-regulation of GABA receptors and associated benzodiazepine binding sites in different brain regions and concomitant down-regulations of striatal nicotinic acetylcholine and serotonergic receptor densities were found. Furthermore, the densities of glutamatergic kainate, muscarinic acetylcholine, adrenergic α1 and dopaminergic D2/D3 receptors were differentially altered. These results present novel insights into the expression of neurotransmitter receptors in Pitx3(ak) mice supporting findings on PD pathology in patients and indicating on the possible underlying mechanisms. The data suggest Pitx3(ak) mice as an appropriate new model to investigate the role of neurotransmitter receptors in PD. Our study highlights the relevance of non-dopaminergic systems in PD and for the understanding of its molecular pathology. PMID:25451278

  16. Neurotransmitter, opiodergic system, steroid-hormone interaction and involvement in the replacement therapy of sexual disorders.

    PubMed

    Frajese, G; Lazzari, R; Magnani, A; Moretti, C; Sforza, V; Nerozzi, D

    1990-11-20

    Dopamine (DA) and serotonin (5-HT) are the neurotransmitters most directly involved in sexual activity. DA plays a stimulatory role while 5-HT has an inhibitory effect. The two monoaminergic systems modulate the secretion of many hormones (GnRH, LH, testosterone, prolactin and endorphins) involved in sexual functional capacity. Furthermore, hormones influence synthesis and storage of brain neurotransmitters. Impotence can often be associated to clinical depression and altered neurotransmitter function. Moreover, stress represents an unbalance between various neurotransmitter systems and can induce impotence especially when disorders of the endorphinic system are present. Replacement therapy is based upon the understanding of these basic concepts. Impotence due to an underlying depressive illness must be treated with dopaminergic antidepressant drugs; while in stressful conditions a good response to the naloxone test is the preliminary criterion to subsequent naltrexone treatment. When a hormonal deficiency has been proved, the hormone replacement therapy is of course highly effective (gonadotropins in hypogonadotropic syndromes, testosterone in aging, etc.). Finally, idiopathic impotence could be treated by DA agonist and/or 5-HT antagonist drugs either alone or better yet in association with psychotherapy.

  17. Neurotransmitter, opiodergic system, steroid-hormone interaction and involvement in the replacement therapy of sexual disorders.

    PubMed

    Frajese, G; Lazzari, R; Magnani, A; Moretti, C; Sforza, V; Nerozzi, D

    1990-11-20

    Dopamine (DA) and serotonin (5-HT) are the neurotransmitters most directly involved in sexual activity. DA plays a stimulatory role while 5-HT has an inhibitory effect. The two monoaminergic systems modulate the secretion of many hormones (GnRH, LH, testosterone, prolactin and endorphins) involved in sexual functional capacity. Furthermore, hormones influence synthesis and storage of brain neurotransmitters. Impotence can often be associated to clinical depression and altered neurotransmitter function. Moreover, stress represents an unbalance between various neurotransmitter systems and can induce impotence especially when disorders of the endorphinic system are present. Replacement therapy is based upon the understanding of these basic concepts. Impotence due to an underlying depressive illness must be treated with dopaminergic antidepressant drugs; while in stressful conditions a good response to the naloxone test is the preliminary criterion to subsequent naltrexone treatment. When a hormonal deficiency has been proved, the hormone replacement therapy is of course highly effective (gonadotropins in hypogonadotropic syndromes, testosterone in aging, etc.). Finally, idiopathic impotence could be treated by DA agonist and/or 5-HT antagonist drugs either alone or better yet in association with psychotherapy. PMID:1979499

  18. Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters.

    PubMed

    Bermingham, Daniel P; Blakely, Randy D

    2016-10-01

    Modulation of neurotransmission by the monoamines dopamine (DA), norepinephrine (NE), and serotonin (5-HT) is critical for normal nervous system function. Precise temporal and spatial control of this signaling in mediated in large part by the actions of monoamine transporters (DAT, NET, and SERT, respectively). These transporters act to recapture their respective neurotransmitters after release, and disruption of clearance and reuptake has significant effects on physiology and behavior and has been linked to a number of neuropsychiatric disorders. To ensure adequate and dynamic control of these transporters, multiple modes of control have evolved to regulate their activity and trafficking. Central to many of these modes of control are the actions of protein kinases, whose actions can be direct or indirectly mediated by kinase-modulated protein interactions. Here, we summarize the current state of our understanding of how protein kinases regulate monoamine transporters through changes in activity, trafficking, phosphorylation state, and interacting partners. We highlight genetic, biochemical, and pharmacological evidence for kinase-linked control of DAT, NET, and SERT and, where applicable, provide evidence for endogenous activators of these pathways. We hope our discussion can lead to a more nuanced and integrated understanding of how neurotransmitter transporters are controlled and may contribute to disorders that feature perturbed monoamine signaling, with an ultimate goal of developing better therapeutic strategies. PMID:27591044

  19. The Fluorescence Methods to Study Neurotransmitters (Biomediators) in Plant Cells.

    PubMed

    Roshchina, Victoria V

    2016-05-01

    Fluorescence as a parameter for analysis of intracellular binding and localization of neurotransmitters also named biomediators (acetylcholine and biogenic amines such as catecholamines, serotonin, histamine) as well as their receptors in plant cells has been estimated basing on several world publications and own experiments of the author. The subjects of the consideration were 1. application of reagents forming fluorescent products (for catecholamines - glyoxylic acid, for histamine - formaldehyde or ortho-phthalic aldehyde) to show the presence and binding of the compounds in cells, 2. binding of their fluorescent agonists and antagonists with cell, 3. effects of the compounds, their agonists and antagonists on autofluorescence, 4. action of external factors on the accumulation of the compounds in cells. How neurotransmitters can bind to certain cellular compartments has been shown on intact individual cells (vegetative microspores, pollens, secretory cells) and isolated organelles. The staining with reagents on biogenic amines leads to the appearance blue or blue-green emission on the surface and excretions of intact cells as well in some DNA-containing organelles within cells. The difference between autofluorescence and histochemically induced fluorescence may reflect the occurrence and amount of biogenic amines in the cells studied. Ozone and salinity as external factors can regulate the emission of intact cells related to biogenic amines. After the treatment of isolated cellular organelles with glyoxylic acid blue emission with maximum 460-475 nm was seen in nuclei and chloroplasts (in control variants in this spectral region the noticeable emission was absent) and very expressive fluorescence (more than twenty times as compared to control) in the vacuoles. After exposure to ortho-phthalic aldehyde blue emission was more noticeable in nuclei and chloroplasts. Fluorescent agonists (muscarine, 6,7-diOHATN, BODIPY-dopamine or BODIPY-5HT) or antagonists (d

  20. 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.

  1. Plasma neurotransmitters and cortisol in chronic illness: role of stress.

    PubMed

    Lechin, F; van der Dijs, B; Lechin, A; Orozco, B; Lechin, M; Báez, S; Rada, I; León, G; Acosta, E

    1994-01-01

    We routinely measured plasma neurotransmitters and hormone levels in order to investigate the role of stress on many types of diseases. In this study, we present results obtained from patients with severe chronic diseases. The study sample consisted of 88 patients (asthmatics, ulcerative colitis, Crohn's disease, chronic active hepatitis, chronic relapsing hepatitis, multiple sclerosis, trigeminal neuralgia, systemic lupus erithematous, and rheumatoid arthritis), and their respective controls. Noradrenaline (NA), adrenaline (Ad), dopamine (DA), platelet-serotonin (pS), free-serotonin (fS), growth hormone (GH) and cortisol (CRT) were determined during both exacerbation and improvement periods. A profile compatible with uncoping stress disorder (raised NA-Ad-DA + fS + CRT as well as low pS and NA/Ad ratio) was found during exacerbation periods when compared with improvement, as seen in controls. However, during improvement periods the neurochemical profile remained significantly different from that of normal controls. The neurochemical plus hormonal plasma profiles registered in chronic illness, both during exacerbation and improvement periods, strongly suggest that an uncoping stress mechanism underlies diseases of these patients. PMID:7996062

  2. The elevation of immunoreactive beta-endorphin in old male rats is related to alterations in dopamine and serotonin.

    PubMed

    Forman, L J; Cavalieri, T; Estilow, S; Tatarian, G T

    1990-01-01

    The concentration of immunoreactive beta-endorphin (IR-BE) in the anterior pituitary (AP) and the neurointermediate lobe of the pituitary (NIL) was elevated in old as compared to young male rats. Treatment of old male rats with the dopamine precursor, L-DOPA, did not affect the concentration of IR-BE in the AP and produced a significant reduction in the concentration of IR-BE in the NIL. By contrast, administration of the serotonergic neurotoxin, p-CPA, significantly diminished the concentration of IR-BE in the AP of old male rats, while the concentration of IR-BE in the NIL remained unchanged. Hypothalamic IR-BE was decreased in old male rats and was not influenced by administration of L-DOPA or p-CPA. Chromatographic analysis indicated that in the AP of old animals the amount of beta-endorphin relative to beta-lipotropin was increased and was diminished slightly by the treatments. Alterations in IR-BE in the NIL and hypothalamus were represented solely by beta-endorphin. These data suggest that in old male rats, a decrease in dopaminergic activity contributes to the increase in IR-BE levels in the NIL, and an increase in serotonergic function, at least in part, is responsible for the elevation in the level of IR-BE in the AP.

  3. Synthesis of 8-thiabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters.

    PubMed

    Pham-Huu, Duy-Phong; Deschamps, Jeffrey R; Liu, Shanghao; Madras, Bertha K; Meltzer, Peter C

    2007-01-15

    Cocaine is a potent stimulant of the central nervous system. Its reinforcing and stimulant properties have been associated with inhibition of the dopamine transporter (DAT) on presynaptic neurons. In the search for medications for cocaine abuse, we have prepared 2-carbomethoxy-3-aryl-8-thiabicyclo[3.2.1]octane analogues of cocaine. We report that this class of compounds provides potent and selective inhibitors of the DAT and SERT. The selectivity resulted from reduced activity at the SERT. The 3beta-(3,4-dichlorophenyl) analogue inhibits the DAT and SERT with a potency of IC(50)=5.7 nM and 8.0 nM, respectively. The 3-(3,4-dichlorophenyl)-2,3-unsaturated analogue inhibits the DAT potently (IC(50)=4.5 nM) and selectively (>800-fold vs SERT). Biological enantioselectivity of DAT inhibition was limited for both the 3-aryl-2,3-unsaturated and the 3alpha-aryl analogues (2-fold), but more robust (>10-fold) for the 3beta-aryl analogues. The (1R)-configuration provided the eutomers. PMID:17070057

  4. Synthesis of 8-thiabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters.

    PubMed

    Pham-Huu, Duy-Phong; Deschamps, Jeffrey R; Liu, Shanghao; Madras, Bertha K; Meltzer, Peter C

    2007-01-15

    Cocaine is a potent stimulant of the central nervous system. Its reinforcing and stimulant properties have been associated with inhibition of the dopamine transporter (DAT) on presynaptic neurons. In the search for medications for cocaine abuse, we have prepared 2-carbomethoxy-3-aryl-8-thiabicyclo[3.2.1]octane analogues of cocaine. We report that this class of compounds provides potent and selective inhibitors of the DAT and SERT. The selectivity resulted from reduced activity at the SERT. The 3beta-(3,4-dichlorophenyl) analogue inhibits the DAT and SERT with a potency of IC(50)=5.7 nM and 8.0 nM, respectively. The 3-(3,4-dichlorophenyl)-2,3-unsaturated analogue inhibits the DAT potently (IC(50)=4.5 nM) and selectively (>800-fold vs SERT). Biological enantioselectivity of DAT inhibition was limited for both the 3-aryl-2,3-unsaturated and the 3alpha-aryl analogues (2-fold), but more robust (>10-fold) for the 3beta-aryl analogues. The (1R)-configuration provided the eutomers.

  5. 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.

  6. 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.

  7. Dose-related effects of clozapine and risperidone on the pattern of brain regional serotonin and dopamine metabolism and on tests related to extrapyramidal functions in rats.

    PubMed

    Batool, Farhat; Hasnat, Ambreen; Haleem, Muhammad Abdul; Haleem, Darakhshan Jabeen

    2010-06-01

    The present study was designed to evaluate the behavioral and neurochemical profiles of clozapine and risperidone in rats in a dose-dependent manner. Animals injected intraperitoneally (i.p.) with clozapine (2.5, 5.0 and 10.0 mg kg-1) or risperidone (1.0, 2.5 and 5.0 mg kg-1) were sacrificed 1 h later to collect brain samples. Hypolocomotive effects (home cage activity and catalepsy) were successively monitored in each animal after the drug or saline administration. Both drugs significantly (p < 0.01) decreased locomotor activity at high doses and in a dose-dependent manner. Maximum (100%) cataleptic potential was achieved at a high dose (5.0 mg kg-1) of risperidone. Neurochemical estimations were carried out by HPLC with electrochemical detection. Both drugs, at all doses, significantly (p < 0.01) increased the concentration of homovanillic acid (HVA), a metabolite of dopamine (DA), in the striatum. Dihydroxyphenylacetic acid (DOPAC) levels increased in the striatum and decreased in the rest of the brain, particularly in clozapine-injected rats. 5-Hydroxyindoleacetic acid (5-HIAA), the predominant metabolite of serotonin, significantly (p < 0.01) decreased in the striatum. 5-Hydroxytryptamine (5-HT) was significantly (p < 0.01) increased by risperidone and decreased by clozapine in the rest of the brain. Striatal tryptophan (TRP) was significantly (p < 0.01) decreased by risperidone and increased in the rest of the brain. The striatal HVA/DA ratio increased and the 5-HT turnover rate remained unchanged in the rest of the brain. Results suggest that the affinity of the two drugs towards D2/5-HT1A receptors interaction is involved in lower incidence of extrapyramidal side effects. Role of 5-HT1A receptors in the treatment of schizophrenia is discussed. PMID:21134850

  8. 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. PMID:25446572

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

    PubMed

    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

    2013-02-28

    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. 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. Twenty-seven individuals recovered (REC) from eating disorders (EDs) (7 AN-BN, 11 AN, 9 BN) and nine control women (CW) were analyzed for correlations between [(11)C]McN5652 and [(11)C]raclopride binding. There was a significant positive correlation between [(11)C]McN5652 binding potential (BP(non displaceable(ND))) and [(11)C]Raclopride BP(ND) for the dorsal caudate, antero-ventral striatum (AVS), middle caudate, and ventral and dorsal putamen. No significant correlations were found in CW. [(11)C]Raclopride BP(ND), but not [(11)C]McN5652 BP(ND), was significantly related to HA in REC EDs. A linear regression analysis showed that the interaction between [(11)C]McN5652 BP(ND) and [(11)C]raclopride BP(ND) in the dorsal putamen significantly predicted HA. This is the first study using PET and the radioligands [(11)C]McN5652 and [(11)C]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.

  10. SK3 K+ channel-deficient mice have enhanced dopamine and serotonin release and altered emotional behaviors.

    PubMed

    Jacobsen, J P R; Weikop, P; Hansen, H H; Mikkelsen, J D; Redrobe, J P; Holst, D; Bond, C T; Adelman, J P; Christophersen, P; Mirza, N R

    2008-11-01

    SK3 K(+) channels influence neuronal excitability and are present in 5-hydroxytryptamine (5-HT) and dopamine (DA) nuclei in the brain stem. We therefore hypothesized that SK3 channels affect 5-HT and DA neurotransmission and associated behaviors. To explore this, we used doxycycline-induced conditional SK3-deficient (T/T) mice. In microdialysis, T/T mice had elevated baseline levels of striatal extracellular DA and the metabolites dihydroxyphenylacetic acid and homovanillic acid. While baseline hippocampal extracellular 5-HT was unchanged in T/T mice, the 5-HT response to the 5-HT transporter inhibitor citalopram was enhanced. Furthermore, baseline levels of the 5-HT metabolite 5-hydroxyindoleacetic acid were elevated in T/T mice. T/T mice performed equally to wild type (WT) in most sensory and motor tests, indicating that SK3 deficiency does not lead to gross impairments. In the forced swim and tail suspension tests, the T/T mice displayed reduced immobility compared with WT, indicative of an antidepressant-like phenotype. Female T/T mice were more anxious in the zero maze. In contrast, anxiety-like behaviors in the open-field and four-plate tests were unchanged in T/T mice of both sexes. Home cage diurnal activity was also unchanged in T/T mice. However, SK3 deficiency had a complex effect on activity responses to novelty: T/T mice showed decreased, increased or unchanged activity responses to novelty, depending on sex and context. In summary, we report that SK3 deficiency leads to enhanced DA and 5-HT neurotransmission accompanied by distinct alterations in emotional behaviors. PMID:18616612

  11. 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.

  12. Benefits of Neuronal Preferential Systemic Gene Therapy for Neurotransmitter Deficiency.

    PubMed

    Lee, Ni-Chung; Muramatsu, Shin-Ichi; Chien, Yin-Hsiu; Liu, Wen-Shin; Wang, Wei-Hua; Cheng, Chia-Hao; Hu, Meng-Kai; Chen, Pin-Wen; Tzen, Kai-Yuan; Byrne, Barry J; Hwu, Wuh-Liang

    2015-10-01

    Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disease that impairs synthesis of dopamine and serotonin. Children with AADC deficiency exhibit severe motor, behavioral, and autonomic dysfunctions. We previously generated an IVS6+4A>T knock-in mouse model of AADC deficiency (Ddc(KI) mice) and showed that gene therapy at the neonatal stage can rescue this phenotype. In the present study, we extended this treatment to systemic therapy on young mice. After intraperitoneal injection of AADC viral vectors into 7-day-old Ddc(KI) mice, the treated mice exhibited improvements in weight gain, survival, motor function, autonomic function, and behavior. The yfAAV9/3-Syn-I-mAADC-treated mice showed greater neuronal transduction and higher brain dopamine levels than AAV9-CMV-hAADC-treated mice, whereas AAV9-CMV-hAADC-treated mice exhibited hyperactivity. Therefore, neurotransmitter-deficient animals can be rescued at a young age using systemic gene therapy, although a vector for preferential neuronal expression may be necessary to avoid hyperactivity caused by this treatment. PMID:26137853

  13. Benefits of Neuronal Preferential Systemic Gene Therapy for Neurotransmitter Deficiency.

    PubMed

    Lee, Ni-Chung; Muramatsu, Shin-Ichi; Chien, Yin-Hsiu; Liu, Wen-Shin; Wang, Wei-Hua; Cheng, Chia-Hao; Hu, Meng-Kai; Chen, Pin-Wen; Tzen, Kai-Yuan; Byrne, Barry J; Hwu, Wuh-Liang

    2015-10-01

    Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disease that impairs synthesis of dopamine and serotonin. Children with AADC deficiency exhibit severe motor, behavioral, and autonomic dysfunctions. We previously generated an IVS6+4A>T knock-in mouse model of AADC deficiency (Ddc(KI) mice) and showed that gene therapy at the neonatal stage can rescue this phenotype. In the present study, we extended this treatment to systemic therapy on young mice. After intraperitoneal injection of AADC viral vectors into 7-day-old Ddc(KI) mice, the treated mice exhibited improvements in weight gain, survival, motor function, autonomic function, and behavior. The yfAAV9/3-Syn-I-mAADC-treated mice showed greater neuronal transduction and higher brain dopamine levels than AAV9-CMV-hAADC-treated mice, whereas AAV9-CMV-hAADC-treated mice exhibited hyperactivity. Therefore, neurotransmitter-deficient animals can be rescued at a young age using systemic gene therapy, although a vector for preferential neuronal expression may be necessary to avoid hyperactivity caused by this treatment.

  14. Benefits of Neuronal Preferential Systemic Gene Therapy for Neurotransmitter Deficiency

    PubMed Central

    Lee, Ni-Chung; Muramatsu, Shin-Ichi; Chien, Yin-Hsiu; Liu, Wen-Shin; Wang, Wei-Hua; Cheng, Chia-Hao; Hu, Meng-Kai; Chen, Pin-Wen; Tzen, Kai-Yuan; Byrne, Barry J; Hwu, Wuh-Liang

    2015-01-01

    Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disease that impairs synthesis of dopamine and serotonin. Children with AADC deficiency exhibit severe motor, behavioral, and autonomic dysfunctions. We previously generated an IVS6+4A>T knock-in mouse model of AADC deficiency (DdcKI mice) and showed that gene therapy at the neonatal stage can rescue this phenotype. In the present study, we extended this treatment to systemic therapy on young mice. After intraperitoneal injection of AADC viral vectors into 7-day-old DdcKI mice, the treated mice exhibited improvements in weight gain, survival, motor function, autonomic function, and behavior. The yfAAV9/3-Syn-I-mAADC-treated mice showed greater neuronal transduction and higher brain dopamine levels than AAV9-CMV-hAADC-treated mice, whereas AAV9-CMV-hAADC-treated mice exhibited hyperactivity. Therefore, neurotransmitter-deficient animals can be rescued at a young age using systemic gene therapy, although a vector for preferential neuronal expression may be necessary to avoid hyperactivity caused by this treatment. PMID:26137853

  15. Impact of High Fat Diet-induced Obesity on the Plasma Levels of Monoamine Neurotransmitters in C57BL/6 Mice

    PubMed Central

    Kim, Minjeong; Bae, SeungJin; Lim, Kyung-Min

    2013-01-01

    Obesity is one of the most serious health problems in developed countries. It negatively affects diverse aspects of human wellbeing. Of these, a relationship between obesity and depression is widely recognized but biomarkers for assessment of obesityassociated mood changes in animal obesity models are rarely known. Here we explored the link between obesity and the plasma levels of monoamine neurotransmitters involved in mood control using a sensitive UPLC/MSMS technique in high fat diet (HFD)- induced obesity model in male C57BL/6 mice to explore the potential utility of plasma tests for obesity-associated mood change. HFD (60% of total calories, 8 weeks) induced significantly higher weight gains in body (+37.8%) and fat tissue (+306%) in male C57BL/6 mice. Bioanalysis of serotonin, dopamine and norepinephrine in plasma at 8 weeks of HFD revealed that serotonin decreased significantly in the obese mice when compared to normal diet-fed mice (2.7 ± 0.6 vs 4.3 ± 2.0 ng/ml, N=8). Notably, a negative correlation was found between the levels of serotonin and body weight gains. Furthermore, principal component analysis (PCA) with the individual levels of neurotransmitters revealed that plasma levels of dopamine and serotonin could apparently differentiate the obese mice from lean ones. Our study demonstrated that blood plasma levels of neurotransmitters can be employed to evaluate the mood changes associated with obesity and more importantly, provided an important clue for understanding of the relationship between obesity and mood disorders. PMID:24404339

  16. Occupancy of dopamine D2 and D3 and serotonin 5-HT1A receptors by the novel antipsychotic drug candidate, cariprazine (RGH-188), in monkey brain measured using positron emission tomography

    PubMed Central

    Seneca, Nicholas; Finnema, Sjoerd J.; Laszlovszky, István; Kiss, Béla; Horváth, Attila; Pásztor, Gabriella; Kapás, Margó; Gyertyán, István; Farkas, Sándor; Innis, Robert B.; Halldin, Christer

    2011-01-01

    Rationale Cariprazine is a novel antipsychotic drug candidate that exhibits high selectivity and affinity to dopamine D3 and D2 receptors and moderate affinity to serotonin 5-HT1A receptors. Targeting receptors other than D2 may provide a therapeutic benefit for both positive and negative symptoms associated with schizophrenia. Positron emission tomography (PET) can be used as a tool in drug development to assess the in vivo distribution and pharmacological properties of a drug. Objectives The objective of this study was to determine dopamine D2/D3 and serotonin 5-HT1A receptor occupancy in monkey brain after the administration of cariprazine. Methods We examined three monkeys using the following PET radioligands: [11C]MNPA (an agonist at D2 and D3 receptors), [11C]raclopride (an antagonist at D2 and D3 receptors), and [11C]WAY-100635 (an antagonist at 5-HT1A receptors). During each experimental day, the first PET measurement was a baseline study, the second after a low dose of cariprazine, and the third after the administration of a high dose. Results We found that cariprazine occupied D2/D3 receptors in a dose-dependent and saturable manner, with the lowest dose occupying ~5% of receptors and the highest dose showing more than 90% occupancy. 5-HT1A receptor occupancy was considerably lower compared with D2/D3 occupancy at the same doses, with a maximal value of ~30% for the raphe nuclei. Conclusions We conclude that cariprazine binds preferentially to dopamine D2/D3 rather than to serotonin 5-HT1A receptors in monkey brain. These findings can be used to guide the selection of cariprazine dosing in humans. PMID:21625907

  17. Neurotransmitter precursors and brain function.

    PubMed

    Conlay, L A; Zeisel, S H

    1982-04-01

    Brain function can be affected by the availability of dietary precursors of neurotransmitters. This occurs because the rate-limiting synthetic enzymes are not "saturated" with substrate under normal circumstances. Tyrosine affects catecholaminergic neurons that fire rapidly, whether in the brain stem to decrease blood pressure in hypertension or in the adrenal gland to increase blood pressure in hypotension, and has been used in the treatment of Parkinson's disease and depression. Choline forms acetylcholine and has been used successfully in the treatment of tardive dyskinesia and memory disorders. Tryptophan, which forms serotonin, has been used for chronic pain therapy, sleep disorders, depression, and appetite control. Although these substances may lack the potency of traditionally used agonists, they offer an increase in specificity because the enzymes necessary to convert them to neurotransmitters are found only in neurons. Precursors are also "physiological"; they are consumed as foods and, therefore, should be relatively safe therapeutic agents. PMID:6124895

  18. 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)

  19. Dopamine function in Lesch-Nyhan disease.

    PubMed

    Nyhan, W L

    2000-06-01

    Lesch-Nyhan disease is a disorder of purine metabolism resulting from mutations in the gene for hypoxanthine guanine phosphoribosyl transferase on the X chromosome. It is characterized by hyperuricemia and all of its consequences, as in gout; but in addition, patients have impressive disease of the central nervous system. This includes spasticity, involuntary movements, and retardation of motor development. The behavioral phenotype is best remembered by self-injurious biting behavior with attendant destruction of tissue. The connection between aberrant metabolism of purines and these neurologic and behavioral features of the disease is not clear. Increasing evidence points to imbalance of neurotransmitters. There is increased excretion of the serotonin metabolite 5-hydroxyindoleacetic acid in the urine. There are decreased quantities and activities of a number of dopaminergic functions. Positron emission tomography scanning has indicated deficiency in the dopamine transporter.

  20. 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

  1. [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.

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

    PubMed Central

    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

  3. 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. PMID:24796848

  4. The appetite regulatory effect of guggulsterones in rats: a repertoire of plasma hormones and neurotransmitters.

    PubMed

    Mithila, M V; Khanum, Farhath

    2014-09-01

    Guggulsterone or guggulipid is a steroidal constituent present in the neutral fraction of gum resin of Commiphora mukul, commonly known as guggul. The traditional uses of guggul-resin extract are well documented in the Ayurveda-where it is prescribed to treat a variety of ailments including lipid-related disorders such as obesity and arteriosclerosis. The hypolipidemic activity of the extracts known since ancient times can be traced to the two closely related steroidal ketones, E-guggulsterone and Z-guggulsterone. In this study, we have investigated the dose dependent (100, 200, 400 mg/kg body weight) effect of guggulsterones on appetite regulating hormones [ghrelin, leptin, cholecystokinin (CCK)] and neurotransmitters (serotonin and dopamine), which play a major role in the energy homeostasis and thus influence obesity related factors. We have also studied its effect on food intake, body weight and plasma triglycerides and glucose in rats. Guggulsterones at the dose of 400 mg/kg body weight was able to significantly reduce food intake and limit body weight gain over a period of 15 days. It also significantly decreased the plasma ghrelin, glucose, triglyceride levels and increased plasma leptin, serotonin, dopamine levels, but did not show much effect on CCK levels. PMID:25025986

  5. 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

  6. Neurotransmitter and their metabolite concentrations in different areas of the HPRT knockout mouse brain.

    PubMed

    Tschirner, Sarah K; Gutzki, Frank; Schneider, Erich H; Seifert, Roland; Kaever, Volkhard

    2016-06-15

    Lesch-Nyhan syndrome (LNS) is characterized by uric acid overproduction and severe neurobehavioral symptoms, such as recurrent self-mutilative behavior. To learn more about the pathophysiology of the disease, we quantified neurotransmitters and their metabolites in the cerebral hemisphere, cerebellum and the medulla oblongata of HPRT knockout mice, an animal model for LNS, in comparison to the corresponding wild-type. Our analyses included l-glutamate, 4-aminobutanoic acid (GABA), acetylcholine, serotonin, 5-hydroxyindoleacetic acid (5-HIAA), norepinephrine, l-normetanephrine, epinephrine and l-metanephrine and were conducted via high performance liquid chromatography (HPLC) coupled to tandem mass spectrometry (MS/MS). Among these neurotransmitter systems, we did not find any abnormalities in the HPRT knockout mouse brains. On one side, this might indicate that HPRT deficiency most severely affects dopamine signaling, while brain functioning based on other neurotransmitters is more or less spared. On the other hand, our findings may reflect a compensating mechanism for impaired purine salvage that protects the brain in HPRT-deficient mice but not in LNS patients. PMID:27206901

  7. [Neurophysiological and neurotransmitter mechanisms of behavior inhibition in normal and pathological conditions].

    PubMed

    Shul'gina, G I

    2010-01-01

    The data concerning neurophysiological and neurotransmitter mechanisms of two principal kinds of inhibition of behavior is carried out: the inborn genetically determined inhibition and that developed in the course of training. On the basis of the experiments performed by the author and the literature on general neurophysiology the conclusion is made that development of inhibition of behavior during training (i.e. internal inhibition, including "latent inhibition") is determined by the relative strengthening of inhibitory hyperpolarization processes either locally (in a conditioned stimulus analyzer) or globally in the brain cortex and other brain structures during intensification of the inhibitory state (profound inhibition of a reflex and sleep). The main neurotransmitter in development of internal inhibition is gamma-aminobutyric acid. Inhibition of behavior without preliminary training arises either during the action of superstrong stimuli, (exceeding the maximum value inhibition) or during interaction of two and more active systems. A stronger one of these two systems suppresses another one (external inhibition, dominant inhibition, "freezing", "prepulse inhibition", etc.). These kinds of inhibition develop on the background of EEG activation, which suggests participation in their realization of reticular structures and corresponding neurotransmitters (acetylcholine, noradrenalin, dopamine and serotonin). Behavior pathology causes a break of the balanced interaction between the excitation and inhibition in the central nervous system. This affects both genetically determined forms of behavior inhibition and the learned internal inhibition.

  8. Decoding dopamine signaling.

    PubMed

    Bibb, James A

    2005-07-29

    Dopamine is a key neurotransmitter that is important for many physiological functions including motor control, mood, and the reward pathway. In this issue of Cell, the laboratories of Marc Caron and Li-Huei Tsai identify two very different molecules--beta-arrestin 2 and Par-4, respectively--that unexpectedly are involved in dopamine signaling via the D2 receptor. These two new signaling pathways mediate the actions of dopamine on behavior and facilitate crosstalk between different signaling pathways that are activated by binding of dopamine to the D2 receptor.

  9. 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.

  10. [Serotonin and its immune and physiological effects].

    PubMed

    Sepiashvili, R I; Balmasova, I P; Staurina, L N

    2013-01-01

    Now that the neurotransmitter serotonin modulates the immune system cells, and its main sources for antigenpresenting cells and lymphocytes are enterochromaffin cells of the gut, peripheral nerves, platelets and mast cells in case of inflammation. Immune cells uptake serotonin because they express receptors for this monoamine and intracellular serotonin transporters. The dendritic cells have a mechanism to transfer serotonin to T lymphocytes during antigen presentation. The macrophages and T cells have the ability to serotonin synthesis. Serotonin can influence mobility and proliferation of lymphocytes, phagocytosis, cytolytic properties, synthesis of chemokines and cytokines. Diversity of immunomodulating effects of serotonin is determined by heterogeneity of serotoninergic receptors. Immunomodulating action of serotonin is evidence of the close relationship between nervous and immune systems.

  11. Sensitive determination of neurotransmitters in urine by microchip electrophoresis with multiple-concentration approaches combining field-amplified and reversed-field stacking.

    PubMed

    Zhang, Yan; Zhang, Yi; Wang, Guan; Chen, Wujuan; Li, Yi; Zhang, Yating; He, Pingang; Wang, Qingjiang

    2016-07-01

    Microchip electrophoresis (MCE) is particularly attractive as it provides high sensitivity and selectivity, short analysis time and low sample consumption. An on-line preconcentration strategy combining field-amplified stacking (FASS) and reversed-field stacking (RFS) was developed for efficient and sensitive analysis of neurotransmitters in real urine samples by MCE with laser induced fluorescence (LIF) detection. In this study, the multiple-preconcentration strategy greatly improves the sensitivity enhancement and surpass other conventional analytical methods for neurotransmitters detection. Under optimal conditions, the separation of three neurotransmitters (dopamine, norepinephrine and serotonin), was achieved within 3min with limits of detection (S/N=3) of 1.69, 2.35, and 2.73nM, respectively. The detection sensitivities were improved by 201-, 182-, and 292-fold enhancement, for the three neurotransmitters respectively. Other evaluation parameters such as linear correlation coefficients were considered as satisfactory. A real urine sample was analyzed with recoveries of 101.8-106.4%. The proposed FASS-RFS-MCE method was characterized in terms of precision, linearity, accuracy and successfully applied for rapid and sensitive determination of three neurotransmitters in human urine. PMID:27187932

  12. Sensitive determination of neurotransmitters in urine by microchip electrophoresis with multiple-concentration approaches combining field-amplified and reversed-field stacking.

    PubMed

    Zhang, Yan; Zhang, Yi; Wang, Guan; Chen, Wujuan; Li, Yi; Zhang, Yating; He, Pingang; Wang, Qingjiang

    2016-07-01

    Microchip electrophoresis (MCE) is particularly attractive as it provides high sensitivity and selectivity, short analysis time and low sample consumption. An on-line preconcentration strategy combining field-amplified stacking (FASS) and reversed-field stacking (RFS) was developed for efficient and sensitive analysis of neurotransmitters in real urine samples by MCE with laser induced fluorescence (LIF) detection. In this study, the multiple-preconcentration strategy greatly improves the sensitivity enhancement and surpass other conventional analytical methods for neurotransmitters detection. Under optimal conditions, the separation of three neurotransmitters (dopamine, norepinephrine and serotonin), was achieved within 3min with limits of detection (S/N=3) of 1.69, 2.35, and 2.73nM, respectively. The detection sensitivities were improved by 201-, 182-, and 292-fold enhancement, for the three neurotransmitters respectively. Other evaluation parameters such as linear correlation coefficients were considered as satisfactory. A real urine sample was analyzed with recoveries of 101.8-106.4%. The proposed FASS-RFS-MCE method was characterized in terms of precision, linearity, accuracy and successfully applied for rapid and sensitive determination of three neurotransmitters in human urine.

  13. Effects of HIV/TAT protein expression and chronic selegiline treatment on spatial memory, reversal learning and neurotransmitter levels in mice.

    PubMed

    Kesby, James P; Markou, Athina; Semenova, Svetlana

    2016-09-15

    Neurotoxic viral protein TAT may contribute to deficits in dopaminergic and cognitive function in individuals infected with human immunodeficiency virus. Transgenic mice with brain-specific doxycycline-induced TAT expression (TAT+, TAT- control) show impaired cognition. However, previously reported TAT-induced deficits in reversal learning may be compromised by initial learning deficits. We investigated the effects of TAT expression on memory retention/recall and reversal learning, and neurotransmitter function. We also investigated if TAT-induced effects can be reversed by improving dopamine function with selegiline, a monoamine oxidase inhibitor. Mice were tested in the Barnes maze and TAT expression was induced after the task acquisition. Selegiline treatment continued throughout behavioral testing. Dopamine, serotonin and glutamate tissue levels in the prefrontal/orbitofrontal cortex, hippocampus and caudate putamen were measured using high performance liquid chromatography. Neither TAT expression nor selegiline altered memory retention. On day 2 of reversal learning testing, TAT+ mice made fewer errors and used more efficient search strategies than TAT- mice. TAT expression decreased dopamine turnover in the caudate putamen, increased serotonin turnover in the hippocampus and tended to increase the conversion of glutamate to glutamine in all regions. Selegiline decreased dopamine and serotonin metabolism in all regions and increased glutamate levels in the caudate putamen. In the absence of impaired learning, TAT expression does not impair spatial memory retention/recall, and actually facilitates reversal learning. Selegiline-induced increases in dopamine metabolism did not affect cognitive function. These findings suggest that TAT-induced alterations in glutamate signaling, but not alterations in monoamine metabolism, may underlie the facilitation of reversal learning. PMID:27211061

  14. Effects of HIV/TAT protein expression and chronic selegiline treatment on spatial memory, reversal learning and neurotransmitter levels in mice.

    PubMed

    Kesby, James P; Markou, Athina; Semenova, Svetlana

    2016-09-15

    Neurotoxic viral protein TAT may contribute to deficits in dopaminergic and cognitive function in individuals infected with human immunodeficiency virus. Transgenic mice with brain-specific doxycycline-induced TAT expression (TAT+, TAT- control) show impaired cognition. However, previously reported TAT-induced deficits in reversal learning may be compromised by initial learning deficits. We investigated the effects of TAT expression on memory retention/recall and reversal learning, and neurotransmitter function. We also investigated if TAT-induced effects can be reversed by improving dopamine function with selegiline, a monoamine oxidase inhibitor. Mice were tested in the Barnes maze and TAT expression was induced after the task acquisition. Selegiline treatment continued throughout behavioral testing. Dopamine, serotonin and glutamate tissue levels in the prefrontal/orbitofrontal cortex, hippocampus and caudate putamen were measured using high performance liquid chromatography. Neither TAT expression nor selegiline altered memory retention. On day 2 of reversal learning testing, TAT+ mice made fewer errors and used more efficient search strategies than TAT- mice. TAT expression decreased dopamine turnover in the caudate putamen, increased serotonin turnover in the hippocampus and tended to increase the conversion of glutamate to glutamine in all regions. Selegiline decreased dopamine and serotonin metabolism in all regions and increased glutamate levels in the caudate putamen. In the absence of impaired learning, TAT expression does not impair spatial memory retention/recall, and actually facilitates reversal learning. Selegiline-induced increases in dopamine metabolism did not affect cognitive function. These findings suggest that TAT-induced alterations in glutamate signaling, but not alterations in monoamine metabolism, may underlie the facilitation of reversal learning.

  15. The Sea Urchin Embryo, an Invertebrate Model for Mammalian Developmental Neurotoxicity, Reveals Multiple Neurotransmitter Mechanisms for Effects of Chlorpyrifos: Therapeutic Interventions and a Comparison with the Monoamine Depleter, Reserpine

    PubMed Central

    Buznikov, Gennady A.; Nikitina, Lyudmila A.; Rakić, Ljubiša M.; Miloševi, Ivan; Bezuglov, Vladimir V.; Lauder, Jean M.; Slotkin, Theodore A.

    2007-01-01

    Lower organisms show promise for the screening of neurotoxicants that might target mammalian brain development. Sea urchins use neurotransmitters as embryonic growth regulatory signals, so that adverse effects on neural substrates for mammalian brain development can be studied in this simple organism. We compared the effects of the organophosphate insecticide, chlorpyrifos in sea urchin embryos with those of the monoamine depleter, reserpine, so as to investigate multiple neurotransmitter mechanisms involved in developmental toxicity and to evaluate different therapeutic interventions corresponding to each neurotransmitter system. Whereas reserpine interfered with all stages of embryonic development, the effects of chlorpyrifos did not emerge until the mid-blastula stage. After that point, the effects of the two agents were similar. Treatment with membrane permeable analogs of the monoamine neurotransmitters, serotonin and dopamine, prevented the adverse effects of either chlorpyrifos or reserpine, despite the fact that chlorpyrifos works simultaneously through actions on acetylcholine, monoamines and other neurotransmitter pathways. This suggests that different neurotransmitters, converging on the same downstream signaling events, could work together or in parallel to offset the developmental disruption caused by exposure to disparate agents. We tested this hypothesis by evaluating membrane permeable analogs of acetylcholine and cannabinoids, both of which proved effective against chlorpyrifos- or reserpine-induced teratogenesis. Invertebrate test systems can provide both a screening procedure for mammalian neuroteratogenesis and may uncover novel mechanisms underlying developmental vulnerability as well as possible therapeutic approaches to prevent teratogenesis. PMID:17720543

  16. Serotonin and cancer: what is the link?

    PubMed

    Sarrouilhe, D; Clarhaut, J; Defamie, N; Mesnil, M

    2015-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine that acts as a neurotransmitter in the central nervous system, local mediator in the gut and vasoactive agent in the blood. Serotonin exerts its multiple, sometimes opposing actions through interaction with a multiplicity of receptors coupled to various signalling pathways. In addition to its well-known functions, serotonin has been shown to be a mitogenic factor for a wide range of normal and tumoral cells. Serotonin exhibits a growth stimulatory effect in aggressive cancers and carcinoids more often through 5- HT1 and 5-HT2 receptors. In contrast, low doses of serotonin can inhibit tumour growth via the decrease of blood supply to the tumour, suggesting that the role of serotonin on tumour growth is concentration-dependent. Data are also available on serotonin involvement in cancer cell migration, metastatic processes and as a mediator of angiogenesis. Moreover, the progression of some tumours is accompanied by a dysregulation of the pattern of serotonin receptor expressions. Serum serotonin level was found to be suitable for prognosis evaluation of urothelial carcinoma in the urinary bladder, adenocarcinoma of the prostate and renal cell carcinoma. In some cases, antagonists of serotonin receptors, inhibitors of selective serotonin transporter and of serotonin synthesis have been successfully used to prevent cancer cell growth. This review revaluates serotonin involvement in several types of cancer and at different stages of their progression. PMID:25601469

  17. Central PGE2 exhibits anxiolytic-like activity via EP1 and EP4 receptors in a manner dependent on serotonin 5-HT1A, dopamine D1 and GABAA receptors.

    PubMed

    Suzuki, Chihiro; Miyamoto, Chihiro; Furuyashiki, Tomoyuki; Narumiya, Shuh; Ohinata, Kousaku

    2011-07-21

    We found that centrally administered prostaglandin (PG) E(2) exhibited anxiolytic-like activity in the elevated plus-maze and open field test in mice. Agonists selective for EP(1) and EP(4) receptors, among four receptor subtypes for PGE(2), mimicked the anxiolytic-like activity of PGE(2). The anxiolytic-like activity of PGE(2) was blocked by an EP(1) or EP(4) antagonist, as well as in EP(4) but not EP(1) knockout mice. Central activation of either EP(1) or EP(4) receptors resulted in anxiolytic-like activity. The PGE(2)-induced anxiolytic-like activity was inhibited by antagonists for serotonin 5-HT(1A), dopamine D(1) and GABA(A) receptors. Taken together, PGE(2) exhibits anxiolytic-like activity via EP(1) and EP(4) receptors, with downstream involvement of 5-HT(1A), D(1) and GABA(A) receptor systems.

  18. 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

  19. Effects of repeated doses of aspartame on serotonin and its metabolite in various regions of the mouse brain.

    PubMed

    Sharma, R P; Coulombe, R A

    1987-08-01

    Following a finding that single doses (approximating to average intakes and to potential 'over-use') of aspartame administered orally to mice caused significant increases in norepinephrine and dopamine concentrations in various brain regions, the effect of repeated exposure to aspartame was studied. Male CD-1 mice were given a daily oral dose of 0, 13, 133 or 650 mg/kg for 30 days and 1 day after the last dose the animals were decapitated and their brain regions were quickly isolated. Analyses of the different regions for catecholamine and indoleamine neurotransmitters and their major metabolites indicated that the increases in adrenergic chemicals observed shortly after a single exposure were not apparent after repeated dosing. In contrast, concentrations of serotonin and its metabolite, 5-hydroxyindoleacetic acid, were decreased in several regions. An increased supply of phenylalanine may be responsible for a decrease in tryptophan uptake by the brain tissue or for a depression in tryptophan conversion to serotonin.

  20. 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.

  1. 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.

  2. 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. PMID:25595338

  3. 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.

  4. Synaptic Neurotransmitter-Gated Receptors

    PubMed Central

    Smart, Trevor G.; Paoletti, Pierre

    2012-01-01

    Since the discovery of the major excitatory and inhibitory neurotransmitters and their receptors in the brain, many have deliberated over their likely structures and how these may relate to function. This was initially satisfied by the determination of the first amino acid sequences of the Cys-loop receptors that recognized acetylcholine, serotonin, GABA, and glycine, followed later by similar determinations for the glutamate receptors, comprising non-NMDA and NMDA subtypes. The last decade has seen a rapid advance resulting in the first structures of Cys-loop receptors, related bacterial and molluscan homologs, and glutamate receptors, determined down to atomic resolution. This now provides a basis for determining not just the complete structures of these important receptor classes, but also for understanding how various domains and residues interact during agonist binding, receptor activation, and channel opening, including allosteric modulation. This article reviews our current understanding of these mechanisms for the Cys-loop and glutamate receptor families. PMID:22233560

  5. Effects of chronic delta-9-tetrahydrocannabinol (THC) administration on neurotransmitter concentrations and receptor binding in the rat brain.

    PubMed

    Ali, S F; Newport, G D; Scallet, A C; Gee, K W; Paule, M G; Brown, R M; Slikker, W

    1989-01-01

    THC is the major psychoactive constituent of marijuana and is also known as an hallucinogenic compound. Numerous reports have shown that large doses of THC produce significant alterations in various neurotransmitter systems. The present study was designed to determine whether chronic exposure to THC produces significant alterations in selected neurotransmitter systems (dopamine, serotonin, acetylcholine, GABAergic, benzodiazepine, and opiate) in the rat brain. In Experiment 1, male Sprague-Dawley rats were gavaged with vehicle, 10 or 20 mg THC/kg body weight daily, 5 days/week for 90 days. Animals were killed either 24 hours or two months after the last dose. Brains were dissected into different regions for neurochemical analyses. Two months after the cessation of chronic administration, there was a significant decrease in GABA receptor binding in the hippocampus of animals in the high dose group. However, no other significant changes were found in neurotransmitter receptor binding characteristics in the hippocampus or in neurotransmitter concentrations in the caudate nucleus, hypothalamus or septum after chronic THC administration. In an attempt to replicate the GABA receptor binding changes and also to determine the [35S]TBPS binding in hippocampus, we designed Experiment 2. In this experiment, we dosed the animals by gavage with 0, 5, 10 or 20 mg THC/kg daily, 5 days/week or with 20 mg THC/kg Monday through Thursday and 60 mg/kg on Friday for 90 days. Results from this experiment failed to replicate the dose-dependent effect of THC on GABA receptor binding in hippocampus. Modulation of [35S]TBPS binding by GABA or 3 alpha-OH-DHP or inhibition by cold TBPS in frontal cortex did not show any significant dose-related effects. Results from these experiments suggest that chronic exposure to THC does not produce significant alterations in catecholamine or indoleamine neurotransmitter systems or in opiate or GABA receptor systems in the rat brain.

  6. 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

  7. Serotonin 2A Receptors Differentially Contribute to Abuse-Related Effects of Cocaine and Cocaine-Induced Nigrostriatal and Mesolimbic Dopamine Overflow in Nonhuman Primates

    PubMed Central

    Murnane, Kevin S.; Winschel, Jake; Schmidt, Karl T.; Stewart, LaShaya M.; Rose, Samuel J.; Cheng, Kejun; Rice, Kenner C.

    2013-01-01

    Two of the most commonly used procedures to study the abuse-related effects of drugs in laboratory animals are intravenous drug self-administration and reinstatement of extinguished behavior previously maintained by drug delivery. Intravenous self-administration is widely accepted to model ongoing drug-taking behavior, whereas reinstatement procedures are accepted to model relapse to drug taking following abstinence. Previous studies indicate that 5-HT2A receptor antagonists attenuate the reinstatement of cocaine-maintained behavior but not cocaine self-administration in rodents. Although the abuse-related effects of cocaine have been closely linked to brain dopamine systems, no previous study has determined whether this dissociation is related to differential regulation of dopamine neurotransmission. To elucidate the neuropharmacological and neuroanatomical mechanisms underlying this phenomenon, we evaluated the effects of the selective 5-HT2A receptor antagonist M100907 on intravenous cocaine self-administration and drug- and cue-primed reinstatement in rhesus macaques (Macaca mulatta). In separate subjects, we evaluated the role of 5-HT2A receptors in cocaine-induced dopamine overflow in the nucleus accumbens (n = 4) and the caudate nucleus (n = 5) using in vivo microdialysis. Consistent with previous studies, M100907 (0.3 mg/kg, i.m.) significantly attenuated drug- and cue-induced reinstatement but had no significant effects on cocaine self-administration across a range of maintenance doses. Importantly, M100907 (0.3 mg/kg, i.m.) attenuated cocaine-induced (1.0 mg/kg, i.v.) dopamine overflow in the caudate nucleus but not in the nucleus accumbens. These data suggest that important abuse-related effects of cocaine are mediated by distinct striatal dopamine projection pathways. PMID:23946394

  8. Serotonin 2A receptors differentially contribute to abuse-related effects of cocaine and cocaine-induced nigrostriatal and mesolimbic dopamine overflow in nonhuman primates.

    PubMed

    Murnane, Kevin S; Winschel, Jake; Schmidt, Karl T; Stewart, LaShaya M; Rose, Samuel J; Cheng, Kejun; Rice, Kenner C; Howell, Leonard L

    2013-08-14

    Two of the most commonly used procedures to study the abuse-related effects of drugs in laboratory animals are intravenous drug self-administration and reinstatement of extinguished behavior previously maintained by drug delivery. Intravenous self-administration is widely accepted to model ongoing drug-taking behavior, whereas reinstatement procedures are accepted to model relapse to drug taking following abstinence. Previous studies indicate that 5-HT2A receptor antagonists attenuate the reinstatement of cocaine-maintained behavior but not cocaine self-administration in rodents. Although the abuse-related effects of cocaine have been closely linked to brain dopamine systems, no previous study has determined whether this dissociation is related to differential regulation of dopamine neurotransmission. To elucidate the neuropharmacological and neuroanatomical mechanisms underlying this phenomenon, we evaluated the effects of the selective 5-HT2A receptor antagonist M100907 on intravenous cocaine self-administration and drug- and cue-primed reinstatement in rhesus macaques (Macaca mulatta). In separate subjects, we evaluated the role of 5-HT2A receptors in cocaine-induced dopamine overflow in the nucleus accumbens (n = 4) and the caudate nucleus (n = 5) using in vivo microdialysis. Consistent with previous studies, M100907 (0.3 mg/kg, i.m.) significantly attenuated drug- and cue-induced reinstatement but had no significant effects on cocaine self-administration across a range of maintenance doses. Importantly, M100907 (0.3 mg/kg, i.m.) attenuated cocaine-induced (1.0 mg/kg, i.v.) dopamine overflow in the caudate nucleus but not in the nucleus accumbens. These data suggest that important abuse-related effects of cocaine are mediated by distinct striatal dopamine projection pathways. PMID:23946394

  9. 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.

  10. Chronic social isolation affects thigmotaxis and whole-brain serotonin levels in adult zebrafish.

    PubMed

    Shams, Soaleha; Chatterjee, Diptendu; Gerlai, Robert

    2015-10-01

    The popularity of the zebrafish has been growing in behavioral brain research. Previously utilized mainly in developmental biology and genetics, the zebrafish has turned out to possess a complex behavioral repertoire. For example, it is a highly social species, and individuals form tight groups, a behavior called shoaling. Social isolation induced changes in brain function and behavior have been demonstrated in a variety of laboratory organisms. However, despite its highly social nature, the zebrafish has rarely been utilized in this research area. Here, we investigate the effects of chronic social isolation (lasting 90 days) on locomotor activity and anxiety-related behaviors in an open tank. We also examine the effect of chronic social isolation on levels of whole-brain serotonin and dopamine and their metabolites. We found that long-term social deprivation surprisingly decreased anxiety-related behavious during open-tank testing but had no effect on locomotor activity. We also found that serotonin levels, decreased significantly in socially isolated fish, but levels of dopamine and metabolites of these neurotransmitters 5HIAA and DOPAC, respectively, remained unchanged. Our results imply that the standard high density housing employed in most zebrafish laboratories may not be the optimal way to keep these fish, and open a new avenue towards the analysis of the biological mechanisms of social behavior and of social deprivation induced changes in brain function using this simple vertebrate model organism.

  11. Neurotransmitter imaging in living cells based on native fluorescence detection

    SciTech Connect

    Tan, W.; Yeung, E.S. |; Parpura, V.; Haydon, P.G.

    1995-08-01

    A UV laser-based optical microscope and CCD detection system with high sensitivity has been developed to image neurotransmitters in living cells. We demonstrate the detection of serotonin that has been taken up into individual living glial cells (astrocytes) based on its native fluorescence. We found that the fluorescence intensity of astrocytes increased by up to 10 times after serotonin uptake. The temporal resolution of this detection system at 10{sup -4} M serotonin is as fast as 50 ms, and the spatial resolution is diffraction limited. This UV laser microscope imaging system shows promise for studies of spatial-temporal dynamics of neurotransmitter levels in living neurons and glia. 19 refs., 5 figs., 1 tab.

  12. 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.

  13. Colocalization of serotonin and GABA in retinal neurons of Ichthyophis kohtaoensis (amphibia; Gymnophiona).

    PubMed

    Dünker, N

    1998-01-01

    Ichthyophis kohtaoensis, a member of the limbless Gymnophiona, has a specialized subterranean burrowing mode of life and a predominantly olfactory-guided orientation. The only visually guided behavior seems to be negative phototaxis. As these animals possess extremely small eyes (only 540 microm in diameter in adults), functional investigations of single retinal cells by electrophysiological methods have so far failed. Therefore, the content and distribution of retinal transmitters have been investigated as indications of a functioning sense organ in an animal that is supposed to be blind. Previous immunohistochemical investigation of the retinal transmitter system revealed immunoreactivity for gamma-aminobutyric acid (GABA), serotonin, dopamine and tyrosine hydroxylase, the rate-limiting enzyme in the catecholamine synthetic pathway. The present studies have been performed in order to determine a possible colocalization of serotonin and GABA in retinal neurons of the caecilian retina. Therefore retinal cryostat sections of various developmental stages have been investigated by the indirect fluorescence method. In single-label preparations, serotonin is localized to cells in the inner nuclear layer and the ganglion cell layer. GABA immunocytochemistry labels a variety of cell types in the inner nuclear layer as well as cell bodies in the ganglion cell layer. In double-label preparations, some of the serotonergic cells are found to express GABA immunoreactivity and some GABAergic neurons also label for serotonin immunocytochemistry. Thus, despite the fact that caecilians mainly rely on olfaction and are believed to have a reduced visual system, their retina exhibits a surprisingly "normal" distribution of neurotransmitters and neuromodulators, also typical of other anamniotes with a well-developed visual system, including the partial colocalization of serotonin and GABA at all developmental stages of I. kohtaoensis. These results indicate that a functional system

  14. 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.

  15. 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. PMID:26459186

  16. 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.

  17. 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. PMID:24854234

  18. 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

  19. Reprint of: Effects of the antidepressant venlafaxine on fish brain serotonin and predation behavior.

    PubMed

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

    2014-06-01

    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

  20. 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

  1. 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

  2. N1-methyl-2-125I-lysergic acid diethylamide, a preferred ligand for in vitro and in vivo characterization of serotonin receptors.

    PubMed

    Hoffman, B J; Scheffel, U; Lever, J R; Karpa, M D; Hartig, P R

    1987-01-01

    Methylation of 2-125I-lysergic acid diethylamide (125I-LSD) at the N1 position produces a new derivative, N1-methyl-2-125I-lysergic acid diethylamide (125I-MIL), with improved selectivity and higher affinity for serotonin 5-HT2 receptors. In rat frontal cortex homogenates, specific binding of 125I-MIL represents 80-90% of total binding, and the apparent dissociation constant (KD) for serotonin 5-HT2 receptors is 0.14 nM (using 2 mg of tissue/ml). 125I-MIL also displays a high affinity for serotonin 5-HT1C receptors, with an apparent dissociation constant of 0.41 nM at this site. 125I-MIL exhibits at least 60-fold higher affinity for serotonin 5-HT2 receptors than for other classes of neurotransmitter receptors, with the dopamine D2 receptor as its most potent secondary binding site. Studies of the association and dissociation kinetics of 125I-MIL reveal a strong temperature dependence, with very slow association and dissociation rates at 0 degree C. Autoradiographic experiments confirm the improved specificity of 125I-MIL. Selective labeling of serotonin receptors was observed in all brain areas examined. In vivo binding studies in mice indicate that 125I-MIL is the best serotonin receptor label yet described, with the highest frontal cortex to cerebellum ratio of any serotonergic radioligand. 125I-MIL is a promising ligand for both in vitro and in vivo labeling of serotonin receptors in the mammalian brain.

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

    DOE PAGES

    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 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

  4. 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.

  5. 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

    2016-01-01

    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. PMID:26639609

  6. 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.

  7. Serotonin syndrome

    MedlinePlus

    ... Increased body temperature Loss of coordination Nausea Overactive reflexes Rapid changes in blood pressure Vomiting ... as confusion or hypomania Muscle spasms (myoclonus) Overactive reflexes ( ... Tremor Uncoordinated movements (ataxia) Serotonin syndrome ...

  8. Simultaneous quantification of monoamine neurotransmitters and their biogenic metabolites intracellularly and extracellularly in primary neuronal cell cultures and in sub-regions of guinea pig brain.

    PubMed

    Schou-Pedersen, Anne Marie V; Hansen, Stine N; Tveden-Nyborg, Pernille; Lykkesfeldt, Jens

    2016-08-15

    In the present paper, we describe a validated chromatographic method for the simultaneous quantification of monoamine neurotransmitters and their biogenic metabolites intracellularly and extracellularly in primary neuronal cell culture and in sub-regions of the guinea pig brain. Electrochemical detection provided limits of quantifications (LOQs) between 3.6 and 12nM. Within the linear range, obtained recoveries were from 90.9±9.9 to 120±14% and intra-day and inter-day precisions found to be less than 5.5% and 12%, respectively. The analytical method was applicable for quantification of intracellular and extracellular amounts of monoamine neurotransmitters and their metabolites in guinea pig frontal cortex and hippocampal primary neuronal cell cultures. Noradrenaline, dopamine and serotonin were found to be in a range from 0.31 to 1.7pmol per 2 million cells intracellularly, but only the biogenic metabolites could be detected extracellularly. Distinct differences in monoamine concentrations were observed when comparing concentrations in guinea pig frontal cortex and cerebellum tissue with higher amounts of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid in frontal cortex, as compared to cerebellum. The chemical turnover in frontal cortex tissue of guinea pig was for serotonin successfully predicted from the turnover observed in the frontal cortex cell culture. In conclusion, the present analytical method shows high precision, accuracy and sensitivity and is broadly applicable to monoamine measurements in cell cultures as well as brain biopsies from animal models used in preclinical neurochemistry.

  9. Serotonin Syndrome

    PubMed Central

    Volpi-Abadie, Jacqueline; Kaye, Adam M.; Kaye, Alan David

    2013-01-01

    Background Serotonin syndrome is a potentially life-threatening syndrome that is precipitated by the use of serotonergic drugs and overactivation of both the peripheral and central postsynaptic 5HT-1A and, most notably, 5HT-2A receptors. This syndrome consists of a combination of mental status changes, neuromuscular hyperactivity, and autonomic hyperactivity. Serotonin syndrome can occur via the therapeutic use of serotonergic drugs alone, an intentional overdose of serotonergic drugs, or classically, as a result of a complex drug interaction between two serotonergic drugs that work by different mechanisms. A multitude of drug combinations can result in serotonin syndrome. Methods This review describes the presentation and management of serotonin syndrome and discusses the drugs and interactions that can precipitate this syndrome with the goal of making physicians more alert and aware of this potentially fatal yet preventable syndrome. Conclusion Many commonly used medications have proven to be the culprits of serotonin syndrome. Proper education and awareness about serotonin syndrome will improve the accuracy of diagnosis and promote the institution of the appropriate treatment that may prevent significant morbidity and mortality. PMID:24358002

  10. 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. PMID:26921458

  11. 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.

  12. Neurotransmitter and imaging studies in anorexia nervosa: new targets for treatment.

    PubMed

    Barbarich, Nicole C; Kaye, Walter H; Jimerson, David

    2003-02-01

    Anorexia and Bulimia Nervosa are disorders of unknown etiology that invariably begin during adolescence and near in time to puberty in young women. These disorders are associated with aberrant eating behaviors, body image distortions, impulse and mood disturbances, as well as characteristic temperament and personality traits. It is well known that malnutrition produces changes in neuroendocrine function. More recently, disturbances in neuronal systems have been found to play a role in the modulation of feeding, mood, and impulse control. These neuronal systems include neuropeptides (CRH, opioids, neuropeptide-Y (NPY) and peptide YY (PYY), vasopressin and oxytocin, CCK, and leptin) and monoamines (serotonin, dopamine, norepinephrine). Disturbances of most of these neuronal systems have been found when people are ill with an eating disorder, but it was not certain whether they were a cause or consequence of symptoms. In order to address these questions, a growing number of studies have investigated whether neuromodulatory disturbances persist after recovery. Studies from several centers tend to show altered serotonin activity persists after prolonged normalization of weight, nutrition, and menstrual function, as do anxiety, obsessionality, and perfectionism. While there are fewer data, there may be persistent alterations of dopamine or some neuropeptides in some subjects in a recovered state. The inaccessibility of the central nervous system has made it difficult to understand brain and behavior. In the past decade, new tools, such as brain imaging, have offered the possibility of better characterization of complex neuronal function and behavior. Such studies have tended to consistently find that alterations of brain regions, such as the temporal lobe, occur in people who are ill with anorexia nervosa and appear to persist after some degree of weight gain and recovery. New imaging technology, that marries Positron Emission Tomography (PET) imaging with selective

  13. Dopamine dysfunction in borderline personality disorder: a hypothesis.

    PubMed

    Friedel, Robert O

    2004-06-01

    Research on the biological basis of borderline personality disorder (BPD) has focused primarily on the serotonin model of impulsive aggression. However, there is evidence that dopamine (DA) dysfunction may also be associated with BPD. Pertinent research and review articles, identified by Medline searches of relevant topics, books, references from bibliographies, and conference proceedings from 1975 to 2003, were reviewed. Evidence of DA dysfunction in BPD derives from the efficacy of traditional and atypical antipsychotic agents in BPD, and from provocative challenges with amphetamine and methylphenidate of subjects with the disorder. In addition, human and animal studies indicate that DA activity plays an important role in emotion information processing, impulse control, and cognition. The results of this review suggest that DA dysfunction is associated with three dimensions of BPD, that is, emotional dysregulation, impulsivity, and cognitive-perceptual impairment. The main limitation of this hypothesis is that the evidence reviewed is circumstantial. There is no study that directly demonstrates DA dysfunction in BPD. In addition, the therapeutic effects of antipsychotic agents observed in BPD may be mediated by non-DA mechanisms of action. If the stated hypothesis is correct, DA dysfunction in BPD may result from genetic, developmental, or environmental factors directly affecting specific DA pathways. Alternatively, DA dysfunction in BPD may be a compensatory response to alterations in the primary neural systems that control emotion, impulse control, and cognition, and that are mediated by the brain's main neurotransmitters, glutamate, and GABA, or in one or more other neuromodulatory pathways such as serotonin, acetylcholine, and norepinephrine.

  14. 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

  15. 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.

  16. Protective Effect of Spermidine Against Excitotoxic Neuronal Death Induced by Quinolinic Acid in Rats: Possible Neurotransmitters and Neuroinflammatory Mechanism.

    PubMed

    Jamwal, Sumit; Singh, Shamsher; Kaur, Navneet; Kumar, Puneet

    2015-08-01

    Huntington disease is hyperkinetic movement disorder characterized by selective and immense degradation of GABAergic medium spiny neurons in striatum. Quinolinic acid (QA)-induced neurotoxicity involves a cascade of events such as excitotoxicity, ATP depletion, oxidative stress, neuroinflammation, as well as selective GABAergic neuronal loss. Therefore, we investigated spermidine, an endogenous molecule with free radical scavenging, anti-inflammatory, and N-methyl-D-aspartate receptor antagonistic properties, for its beneficial potential if any, in QA-induced Huntington's like symptoms in rats. Rats were administered with QA (200 nmol/2 µl saline) bilaterally on 0 day. Spermidine (5 and 10 mg/kg, p.o.) was administered for 21 days once a day. Behavioral parameters (body weight, locomotor activity, grip strength, and narrow beam walk) observations were done on 1st, 7th, 14th, and 21st day after QA treatment. On 21st day, animals were sacrificed and rat striatum was isolated for biochemical (LPO, GSH, Nitrite), neuroinflammation (TNF-α, IL-1β, and IL-6), and neurochemical analysis (GABA, glutamate, dopamine, norepinephrine, serotonin, DOPAC, HVA, 5-HIAA, adenosine, adenine, hypoxanthine, and inosine). QA treatment significantly altered body weight, locomotor activity, motor coordination, oxidative defense (increased LPO, nitrite, and decreased GSH), pro-inflammatory levels (TNF-α, IL-6 and IL-1β), GABA, glutamate, catecholamines level (norepinephrine, dopamine, and serotonin and their metabolites), and purines level (adenosine, inosine, and hypoxanthine). Spermidine (5 and 10 mg/kg, p.o.) significantly attenuated these alterations in body weight, motor impairments, oxidative stress, neuroinflammatory markers, GABA, glutamate, catecholamines, adenosine, and their metabolites levels in striatum. The neuroprotective effect of spermidine against QA-induced excitotoxic cell death is attributed to its antioxidant, N-methyl-D-aspartate receptor antagonistic, anti

  17. Pyrrolo[1,3]benzothiazepine-based serotonin and dopamine receptor antagonists. Molecular modeling, further structure-activity relationship studies, and identification of novel atypical antipsychotic agents.

    PubMed

    Campiani, Giuseppe; Butini, Stefania; Fattorusso, Caterina; Catalanotti, Bruno; Gemma, Sandra; Nacci, Vito; Morelli, Elena; Cagnotto, Alfredo; Mereghetti, Ilario; Mennini, Tiziana; Carli, Miriana; Minetti, Patrizia; Di Cesare, M Assunta; Mastroianni, Domenico; Scafetta, Nazzareno; Galletti, Bruno; Stasi, M Antonietta; Castorina, Massimo; Pacifici, Licia; Vertechy, Mario; Di Serio, Stefano; Ghirardi, Orlando; Tinti, Ornella; Carminati, Paolo

    2004-01-01

    Recently we reported the pharmacological characterization of the 9,10-dihydropyrrolo[1,3]benzothiazepine derivative (S)-(+)-8 as a novel atypical antipsychotic agent. This compound had an optimum pK(i) 5-HT(2A)/D(2) ratio of 1.21 (pK(i) 5-HT(2A) = 8.83; pK(i) D(2) = 7.79). The lower D(2) receptor affinity of (S)-(+)-8 compared to its enantiomer was explained by the difficulty in reaching the conformation required to optimally fulfill the D(2) pharmacophore. With the aim of finding novel atypical antipsychotics we further investigated the core structure of (S)-(+)-8, synthesizing analogues with specific substituents; the structure-activity relationship (SAR) study was also expanded with the design and synthesis of other analogues characterized by a pyrrolo[2,1-b][1,3]benzothiazepine skeleton, substituted on the benzo-fused ring or on the pyrrole system. On the 9,10-dihydro analogues the substituents introduced on the pyrrole ring were detrimental to affinity for dopamine and for 5-HT(2A) receptors, but the introduction of a double bond at C-9/10 on the structure of (S)-(+)-8 led to a potent D(2)/5-HT(2A) receptor ligand with a typical binding profile (9f, pK(i) 5-HT(2A)/D(2) ratio of 1.01, log Y = 8.43). Then, to reduce D(2) receptor affinity and restore atypicality on unsaturated analogues, we exploited the effect of specific substitutions on the tricyclic system of 9f. Through a molecular modeling approach we generated a novel series of potential atypical antipsychotic agents, with optimized 5HT(2A)/D(2) receptor affinity ratios and that were easier to synthesize and purify than the reference compound (S)-(+)-8. A number of SAR trends were identified, and among the analogues synthesized and tested in binding assays, 9d and 9m were identified as the most interesting, giving atypical log Y scores respectively 4.98 and 3.18 (pK(i) 5-HT(2A)/D(2) ratios of 1.20 and 1.30, respectively). They had a multireceptor affinity profile and could be promising atypical agents

  18. Integrated Carbon Nanostructures for Detection of Neurotransmitters.

    PubMed

    Sainio, Sami; Palomäki, Tommi; Tujunen, Noora; Protopopova, Vera; Koehne, Jessica; Kordas, Krisztian; Koskinen, Jari; Meyyappan, M; Laurila, Tomi

    2015-10-01

    Carbon-based materials, such as diamond-like carbon (DLC), carbon nanofibers (CNFs), and carbon nanotubes (CNTs), are inherently interesting for neurotransmitter detection due to their good biocompatibility, low cost and relatively simple synthesis. In this paper, we report on new carbon-hybrid materials, where either CNTs or CNFs are directly grown on top of tetrahedral amorphous carbon (ta-C). We show that these hybrid materials have electrochemical properties that not only combine the best characteristics of the individual "building blocks" but their synergy makes the electrode performance superior compared to conventional carbon based electrodes. By combining ta-C with CNTs, we were able to realize electrode materials that show wide and stable water window, almost reversible electron transfer properties and high sensitivity and selectivity for detecting dopamine in the presence of ascorbic acid. Furthermore, the sensitivity of ta-C + CNF hybrids towards dopamine as well as glutamate has been found excellent paving the road for actual in vivo measurements. The wide and stable water window of these sensors enables detection of other neurotransmitters besides DA as well as capability of withstanding higher potentials without suffering from oxygen and hydrogen evolution. PMID:26093378

  19. 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. PMID:26712377

  20. Polyphosphoinositide metabolism in rat brain: effects of neuropeptides, neurotransmitters and cyclic nucleotides.

    PubMed

    Jolles, J; van Dongen, C J; ten Haaf, J; Gispen, W H

    1982-01-01

    This study describes effects of various peptides, neurotransmitters and cyclic nucleotides on brain polyphosphoinositide metabolism in vitro. The interconversion of the polyanionic inositol phospholipids was studied by incubation of a lysed crude mitochondrial/synaptosomal fraction with [gamma-32P]-ATP. The reference peptide ACTH1-24 stimulated the formation of radiolabelled phosphatidylinositol 4,5-diphosphate (TPI) and inhibited that of phosphatidic acid (PA). Substance P inhibited both TPI and PA labelling, whereas beta-endorphin inhibited that of PA without any effect on TPI. Morphine had no effect at any concentration tested, whereas high concentrations of naloxone inhibited the labelling of both PA and TPI. Naloxone did not counteract the effects of ACTH1-24. The other peptides tested (lysine 8-vasopressin and angiotensin II) were without any effect. Under the conditions used, adrenaline, noradrenaline and acetylcholine did not affect the labelling of the (poly)phosphoinositides. Both dopamine and serotonin, however, dose-dependently inhibited the formation of radiolabelled TPI and PA. Low concentrations of cAMP stimulated TPI, but higher concentrations had an overall inhibitory effect on the labelling of TPI, PA and especially phosphatidylinositol 4-phosphate (DPI). The cyclic nucleotide did not mediate or counteract the effects of ACTH, and cGMP was without any effect. These results are discussed in the light of current ideas on the mechanism of action of neuropeptides.

  1. 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

  2. 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

  3. 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

  4. The antimalarial drug quinine interferes with serotonin biosynthesis and action.

    PubMed

    Islahudin, Farida; Tindall, Sarah M; Mellor, Ian R; Swift, Karen; Christensen, Hans E M; Fone, Kevin C F; Pleass, Richard J; Ting, Kang-Nee; Avery, Simon V

    2014-01-01

    The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor of the neurotransmitter serotonin (5-HT), here we test the hypothesis that quinine disrupts serotonin function. Quinine inhibited serotonin-induced proliferation of yeast as well as human (SHSY5Y) cells. One possible cause of this effect is through inhibition of 5-HT receptor activation by quinine, as we observed here. Furthermore, cells exhibited marked decreases in serotonin production during incubation with quinine. By assaying activity and kinetics of the rate-limiting enzyme for serotonin biosynthesis, tryptophan hydroxylase (TPH2), we showed that quinine competitively inhibits TPH2 in the presence of the substrate tryptophan. The study shows that quinine disrupts both serotonin biosynthesis and function, giving important new insight to the action of quinine on mammalian cells.

  5. 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

  6. 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.  

  7. Radical scavenging reactivity of catecholamine neurotransmitters and the inhibition effect for DNA cleavage.

    PubMed

    Kawashima, Tomonori; Ohkubo, Kei; Fukuzumi, Shunichi

    2010-01-14

    Neurotransmitters such as catecholamines (dopamine, L-dopa, epinephrine, norepinephrine) have phenol structure and scavenge reactive oxygen species (ROS) by hydrogen atom transfer (HAT) to ROS. Radical scavenging reactivity of neurotransmitters with galvinoxyl radical (GO*) and cumyloxyl radical (RO*) in acetonitrile at 298 K was determined by the UV-vis spectral change. The UV-vis spectral change for HAT from catecholamine neurotransmitters to GO* was measured by a photodiode array spectrophotometer, whereas HAT to much more reactive cumylperoxyl radical, which was produced by photoirradiation of dicumyl peroxide, was measured by laser flash photolysis. The second-order rate constants (k(GO)) were determined from the slopes of linear plots of the pseudo-first-order rate constants vs concentrations of neurotransmitters. The k(GO) value of hydrogen transfer from dopamine to GO* was determined to be 23 M(-1) s(-1), which is the largest among examined catecholamine neurotransmitters. This value is comparable to the value of a well-known antioxidant: (+)-catechine (27 M(-1) s(-1)). The k(GO) value of hydrogen transfer from dopamine to GO* increased in the presence of Mg(2+) with increasing concentration of Mg(2+). Such enhancement of the radical scavenging reactivity may result from the metal ion-promoted electron transfer from dopamine to the galvinoxyl radical. Inhibition of DNA cleavage with neurotransmitters was also examined using agarose gel electrophoresis of an aqueous solution containing pBR322 DNA, NADH, and catecholamine neurotransmitters under photoirradiation. DNA cleavage was significantly inhibited by the presence of catecholamine neurotransmitters that can scavenge hydroperoxyl radicals produced under photoirradiation of an aerated aqueous solution of NADH. The inhibition effect of dopamine on DNA cleavage was enhanced by the presence of Mg(2+) because of the enhancement of the radical scavenging reactivity. PMID:19938853

  8. Genes Affecting Sensitivity to Serotonin in Caenorhabditis Elegans

    PubMed Central

    Schafer, W. R.; Sanchez, B. M.; Kenyon, C. J.

    1996-01-01

    Regulating the response of a postsynaptic cell to neurotransmitter is an important mechanism for controlling synaptic strength, a process critical to learning. We have begun to define and characterize genes that may control sensitivity to the neurotransmitter serotonin in the nematode Caenorhabditis elegans by identifying serotonin-hypersensitive mutants. We reported previously that mutations in the gene unc-2, which encodes a putative calcium channel subunit, result in hypersensitivity to serotonin. Here we report that mutants defective in the unc-36 gene, which encodes a homologue of a calcium channel auxiliary subunit, are also serotonin-hypersensitive. Moreover, the unc-36 gene appears to be required in the same cells as unc-2 for control of the same behaviors. Mutations in several other genes, including unc-8, unc-10, unc-20, unc-35, unc-75, unc-77, and snt-1 also result in hypersensitivity to serotonin. Several of these mutations have previously been shown to confer resistance to acetylcholinesterase inhibitors, suggesting that they may affect acetylcholine release. Moreover, we found that mutations that decrease acetylcholine synthesis cause defective egg-laying and serotonin hypersensitivity. Thus, acetylcholine appears to negatively regulate the response to serotonin and may participate in the process of serotonin desensitization. PMID:8807295

  9. Neurotransmitters in rats fed fumonisin B1.

    PubMed

    Porter, J K; Voss, K A; Chamberlain, W J; Bacon, C W; Norred, W P

    1993-03-01

    Fumonisin B1, a toxin produced by Fusarium moniliforme, has been associated with a neurotoxic syndrome in horses known as equine leukoencephlomalacia. Previous investigations showed that F. moniliforme cultured on corn and incorporated into rat chow increased brain 5-hydroxyindoleacetic acid (5HIAA) and 5HIAA: serotonin (5HT) ratios in these animals. Therefore, this study was undertaken to determine whether fumonisin B1 would produce related neurochemical effects in the brain and pineal gland of male and female rats. Rats were fed fumonisin B1 at 15, 50, and 150 ppm for 4 weeks. No differences occurred in brain concentrations of norepinephrine, dopamine, 3,4-dihydroxyphenylacetic acid, 3-methoxytyramine, homovanillic acid, 5HT, 5HIAA, and the 5HIAA to 5HT ratios in either male or female rats, nor where there differences between the sexes. When compared across sexes, the norepinephrine to dopamine ratios were decreased (P < 0.05) in the 150-ppm-treated animals. This may suggest a fumonisin B1-induced imbalance in brain norepinephrine and/or dopamine. No differences were observed in pineal norepinephrine, 5HT, 5HIAA, and the 5HIAA to 5HT ratios. Since fumonisin B1 failed to duplicate the effects of the F. moniliforme-induced imbalances in 5HT and 5HIAA metabolism in the brains of rats, other mycotoxins from F. moniliforme may be responsible for these effects.

  10. Oestradiol modulation of serotonin reuptake transporter and serotonin metabolism in the brain of monkeys.

    PubMed

    Sánchez, M G; Morissette, M; Di Paolo, T

    2013-06-01

    Serotonin (5-hydroxytryptamine; 5-HT) is an important brain neurotransmitter that is implicated in mental and neurodegenerative diseases and is modulated by ovarian hormones. Nevertheless, the effect of oestrogens on 5-HT neurotransmission in the primate caudate nucleus, putamen and nucleus accumbens, which are major components of the basal ganglia, and the anterior cerebral cortex, mainly the frontal and cingulate gyrus, is not well documented. The present study evaluated 5-HT reuptake transporter (SERT) and 5-HT metabolism in these brain regions in response to 1-month treatment with 17β-oestradiol in short-term (1 month) ovariectomised (OVX) monkeys (Macaca fascicularis). SERT-specific binding was measured by autoradiography using the radioligand [³H]citalopram. Biogenic amine concentrations were quantified by high-performance liquid chromatography. 17β-Oestradiol increased SERT in the superior frontal cortex and in the anterior cingulate cortex, in the nucleus accumbens, and in subregions of the caudate nucleus of OVX monkeys. 17β-Oestradiol left [³H]citalopram-specific binding unchanged in the putamen, as well as the dorsal and medial raphe nucleus. 17β-Oestradiol treatment decreased striatal concentrations of the precursor of 5-HT, 5-hydroxytryptophan, and increased 5-HT, dopamine and 3-methoxytyramine concentrations in the nucleus accumbens, caudate nucleus and putamen, whereas the concentrations of the metabolites 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid and homovanillic acid remained unchanged. No effect of 17β-oestradiol treatment was observed for biogenic amine concentrations in the cortical regions. A significant positive correlation was observed between [³H]citalopram-specific binding and 5-HT concentrations in the caudate nucleus, putamen and nucleus accumbens, suggesting their link. These results have translational value for women with low oestrogen, such as those in surgical menopause or perimenopause. PMID:23414342

  11. Structural specificity of serotonin effect on human erythrocyte fragility.

    PubMed

    Gilboa-Garber, N; Kirstein-Segal, R

    1998-08-01

    Serotonin, a neurotransmitter and vasoconstrictor, affects various cell properties. We have analyzed the importance of its structural components for its extensive effect on human erythrocyte fragility, using its O- and N-linked derivatives and related compounds. The results presented in this communication indicate that the amino group, free of adjacent negative charges, and the hydroxyl group are indispensable for the serotonin-induced increase in red blood cell fragility. PMID:9758719

  12. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action.

    PubMed

    Vollenweider, F X; Vollenweider-Scherpenhuyzen, M F; Bäbler, A; Vogel, H; Hell, D

    1998-12-01

    Psilocybin, an indoleamine hallucinogen, produces a psychosis-like syndrome in humans that resembles first episodes of schizophrenia. In healthy human volunteers, the psychotomimetic effects of psilocybin were blocked dose-dependently by the serotonin-2A antagonist ketanserin or the atypical antipsychotic risperidone, but were increased by the dopamine antagonist and typical antipsychotic haloperidol. These data are consistent with animal studies and provide the first evidence in humans that psilocybin-induced psychosis is due to serotonin-2A receptor activation, independently of dopamine stimulation. Thus, serotonin-2A overactivity may be involved in the pathophysiology of schizophrenia and serotonin-2A antagonism may contribute to therapeutic effects of antipsychotics.

  13. Expression of serotonin receptor genes in cranial ganglia.

    PubMed

    Maeda, Naohiro; Ohmoto, Makoto; Yamamoto, Kurumi; Kurokawa, Azusa; Narukawa, Masataka; Ishimaru, Yoshiro; Misaka, Takumi; Matsumoto, Ichiro; Abe, Keiko

    2016-03-23

    Taste cells release neurotransmitters to gustatory neurons to transmit chemical information they received. Sweet, umami, and bitter taste cells use ATP as a neurotransmitter. However, ATP release from sour taste cells has not been observed so far. Instead, they release serotonin when they are activated by sour/acid stimuli. Thus it is still controversial whether sour taste cells use ATP, serotonin, or both. By reverse transcription-polymerase chain reaction and subsequent in situ hybridization (ISH) analyses, we revealed that of 14 serotonin receptor genes only 5-HT3A and 5-HT3B showed significant/clear signals in a subset of neurons of cranial sensory ganglia in which gustatory neurons reside. Double-fluorescent labeling analyses of ISH for serotonin receptor genes with wheat germ agglutinin (WGA) in cranial sensory ganglia of pkd1l3-WGA mice whose sour neural pathway is visualized by the distribution of WGA originating from sour taste cells in the posterior region of the tongue revealed that WGA-positive cranial sensory neurons rarely express either of serotonin receptor gene. These results suggest that serotonin receptors expressed in cranial sensory neurons do not play any role as neurotransmitter receptor from sour taste cells. PMID:26854841

  14. Serotonin enhances solitariness in phase transition of the migratory locust

    PubMed Central

    Guo, Xiaojiao; Ma, Zongyuan; Kang, Le

    2013-01-01

    The behavioral plasticity of locusts is a striking trait presented during the reversible phase transition between solitary and gregarious individuals. However, the results of serotonin as a neurotransmitter from the migratory locust Locusta migratoria in phase transition showed an alternative profile compared to the results from the desert locust Schistocerca gregaria. In this study, we investigated the roles of serotonin in the brain during the phase change of the migratory locust. During the isolation of gregarious nymphs, the concentration of serotonin in the brain increased significantly, whereas serotonin receptors (i.e., 5-HT1, 5-HT2, and 5-HT7) we identified here showed invariable expression patterns. Pharmacological intervention showed that serotonin injection in the brain of gregarious nymphs did not induced the behavioral change toward solitariness, but injection of this chemical in isolated gregarious nymphs accelerated the behavioral change from gregarious to solitary phase. During the crowding of solitary nymphs, the concentration of serotonin in the brain remained unchanged, whereas 5-HT2 increased after 1 h of crowding and maintained stable expression level thereafter. Activation of serotonin-5-HT2 signaling with a pharmaceutical agonist inhibited the gregariousness of solitary nymphs in crowding treatment. These results indicate that the fluctuations of serotonin content and 5-HT2 expression are results of locust phase change. Overall, this study demonstrates that serotonin enhances the solitariness of the gregarious locusts. Serotonin may regulate the withdrawal-like behavioral pattern displayed during locust phase change and this mechanism is conserved in different locust species. PMID:24109441

  15. Prostaglandin synthesis inhibitors reduce Cannabis and restraint stress induced increase in rat brain serotonin concentrations.

    PubMed

    Bhattacharya, S K; Bhattacharya, D

    1983-01-01

    Cannabis resin (CI) produced a dose-related increase in rat brain serotonin concentrations, whereas restraint stress produced maximal rise of the neurotransmitter concentrations at 1 h, followed by a tendency to normalise by 4 h. The prostaglandin (PG) synthesis inhibitors, diclofenac and paracetamol, antagonized CI and restraint stress induced rise in serotonin concentrations. The findings lend credence to earlier reports that PG synthesis inhibitors antagonize serotonin-mediated neuropharmacological actions of CI and restraint stress in rats.

  16. 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.

  17. Serotonin-immunoreactive neural system and contractile system in the hydroid Cladonema (Cnidaria, Hydrozoa).

    PubMed

    Mayorova, T D; Kosevich, I A

    2013-12-01

    Serotonin is a widespread neurotransmitter which is present in almost all animal phyla including lower metazoans such as Cnidaria. Serotonin detected in the polyps of several cnidarian species participates in the functioning of a neural system. It was suggested that serotonin coordinates polyp behavior. For example, serotonin may be involved in muscle contraction and/or cnidocyte discharge. However, the role of serotonin in cnidarians is not revealed completely yet. The aim of this study was to investigate the neural system of Cladonema radiatum polyps. We detected the net of serotonin-positive processes within the whole hydranth body using anti-serotonin antibodies. The hypostome and tentacles had denser neural net in comparison with the gastric region. Electron microscopy revealed muscle processes throughout the hydranth body. Neural processes with specific vesicles and neurotubules in their cytoplasm were also shown at an ultrastructural level. This work demonstrates the structure of serotonin-positive neural system and smooth muscle layer in C. radiatum hydranths.

  18. 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.

  19. The roles of peripheral serotonin in metabolic homeostasis.

    PubMed

    El-Merahbi, Rabih; Löffler, Mona; Mayer, Alexander; Sumara, Grzegorz

    2015-07-01

    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.

  20. Sensing small neurotransmitter-enzyme interaction with nanoporous gated ion-sensitive field effect transistors.

    PubMed

    Kisner, Alexandre; Stockmann, Regina; Jansen, Michael; Yegin, Ugur; Offenhäusser, Andreas; Kubota, Lauro Tatsuo; Mourzina, Yulia

    2012-01-15

    Ion-sensitive field effect transistors with gates having a high density of nanopores were fabricated and employed to sense the neurotransmitter dopamine with high selectivity and detectability at micromolar range. The nanoporous structure of the gates was produced by applying a relatively simple anodizing process, which yielded a porous alumina layer with pores exhibiting a mean diameter ranging from 20 to 35 nm. Gate-source voltages of the transistors demonstrated a pH-dependence that was linear over a wide range and could be understood as changes in surface charges during protonation and deprotonation. The large surface area provided by the pores allowed the physical immobilization of tyrosinase, which is an enzyme that oxidizes dopamine, on the gates of the transistors, and thus, changes the acid-base behavior on their surfaces. Concentration-dependent dopamine interacting with immobilized tyrosinase showed a linear dependence into a physiological range of interest for dopamine concentration in the changes of gate-source voltages. In comparison with previous approaches, a response time relatively fast for detecting dopamine was obtained. Additionally, selectivity assays for other neurotransmitters that are abundantly found in the brain were examined. These results demonstrate that the nanoporous structure of ion-sensitive field effect transistors can easily be used to immobilize specific enzyme that can readily and selectively detect small neurotransmitter molecule based on its acid-base interaction with the receptor. Therefore, it could serve as a technology platform for molecular studies of neurotransmitter-enzyme binding and drugs screening.

  1. Neurotransmitter Switching? No Surprise

    PubMed Central

    Spitzer, Nicholas C.

    2015-01-01

    Among the many forms of brain plasticity, changes in synaptic strength and changes in synapse number are particularly prominent. However, evidence for neurotransmitter respecification or switching has been accumulating steadily, both in the developing nervous system and in the adult brain, with observations of transmitter addition, loss, or replacement of one transmitter with another. Natural stimuli can drive these changes in transmitter identity, with matching changes in postsynaptic transmitter receptors. Strikingly, they often convert the synapse from excitatory to inhibitory or vice versa, providing a basis for changes in behavior in those cases in which it has been examined. Progress has been made in identifying the factors that induce transmitter switching and in understanding the molecular mechanisms by which it is achieved. There are many intriguing questions to be addressed. PMID:26050033

  2. 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...

  3. Increased brain serotonin turnover in panic disorder patients in the absence of a panic attack: reduction by a selective serotonin reuptake inhibitor.

    PubMed

    Esler, Murray; Lambert, Elisabeth; Alvarenga, Marlies; Socratous, Florentia; Richards, Jeff; Barton, David; Pier, Ciaran; Brenchley, Celia; Dawood, Tye; Hastings, Jacqueline; Guo, Ling; Haikerwal, Deepak; Kaye, David; Jennings, Garry; Kalff, Victor; Kelly, Michael; Wiesner, Glen; Lambert, Gavin

    2007-08-01

    Since the brain neurotransmitter changes characterising panic disorder remain uncertain, we quantified brain noradrenaline and serotonin turnover in patients with panic disorder, in the absence of a panic attack. Thirty-four untreated patients with panic disorder and 24 matched healthy volunteers were studied. A novel method utilising internal jugular venous sampling, with thermodilution measurement of jugular blood flow, was used to directly quantify brain monoamine turnover, by measuring the overflow of noradrenaline and serotonin metabolites from the brain. Radiographic depiction of brain venous sinuses allowed differential venous sampling from cortical and subcortical regions. The relation of brain serotonin turnover to serotonin transporter genotype and panic disorder severity were evaluated, and the influence of an SSRI drug, citalopram, on serotonin turnover investigated. Brain noradrenaline turnover in panic disorder patients was similar to that in healthy subjects. In contrast, brain serotonin turnover, estimated from jugular venous overflow of the metabolite, 5-hydroxyindole acetic acid, was increased approximately 4-fold in subcortical brain regions and in the cerebral cortex (P < 0.01). Serotonin turnover was highest in patients with the most severe disease, was unrelated to serotonin transporter genotype, and was reduced by citalopram (P < 0.01). Normal brain noradrenaline turnover in panic disorder patients argues against primary importance of the locus coeruleus in this condition. The marked increase in serotonin turnover, in the absence of a panic attack, possibly represents an important underlying neurotransmitter substrate for the disorder, although this point remains uncertain. Support for this interpretation comes from the direct relationship which existed between serotonin turnover and illness severity, and the finding that SSRI administration reduced serotonin turnover. Serotonin transporter genotyping suggested that increased whole brain

  4. Androgen inhibits neurotransmitter turnover in the medial prefrontal cortex of the rat following exposure to a novel environment.

    PubMed

    Handa, R J; Hejna, G M; Lorens, S A

    1997-03-14

    Previous studies have demonstrated that gonadal steroid hormones affect the neuroendocrine response to a novel environment and other stressors. Introduction to a novel environment also increases neurotransmitter turnover in the medial prefrontal cortex (MPFC). In this study, we examined the possibility that gonadal steroid hormones could similarly modulate the neurotransmitter response to a novel environment in the MPFC of the male rat. Male Fischer 344 rats at 3 months of age were gonadectomized (GDX'd) and implanted with Silastic capsules containing dihydrotestosterone propionate (DHTP, a non-aromatizable form of androgen), 17 beta-estradiol (E), or placebo. Control animals were left intact. Each of these groups was further divided into a group introduced to a novel environment or a home cage control group. Animals exposed to a novel environment were killed after spending 20 min in a novel open field, whereas control animals were killed immediately upon removal from their home cage. Using high performance liquid chromatography, the MPFC was assayed for tissue levels of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylalanine (DOPAC) and homovanillic acid (HVA); norepinephrine (NE) and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG); or serotonin (5-HT) and its metabolite 5-hydroxyindole acetic acid (5-HIAA). The introduction to a novel environment caused significant increases in turnover of all three neurochemicals examined as estimated by metabolite/precursor ratios. These increases were characterized by increases in DOPAC, HVA, MHPG and 5-HIAA coupled with decreases in DA, NE and 5-HT. There was no effect of GDX on neurotransmitter turnover, however, treatment of GDX animals with DHTP prevented the open field induced increase in DOPAC/DA, MHPG/NE, and 5-HIAA/5-HT ratio. Treatment of GDX animals with estrogen had the opposite effect of DHTP, DOPAC/DA and MHPG/NE ratios increased to a greater level following the introduction to a novel environment than

  5. Serotonin control of thermotaxis memory behavior in nematode Caenorhabditis elegans.

    PubMed

    Li, Yinxia; Zhao, Yunli; Huang, Xu; Lin, Xingfeng; Guo, Yuling; Wang, Daoyong; Li, Chaojun; Wang, Dayong

    2013-01-01

    Caenorhabditis elegans is as an ideal model system for the study of mechanisms underlying learning and memory. In the present study, we employed C. elegans assay system of thermotaxis memory to investigate the possible role of serotonin neurotransmitter in memory control. Our data showed that both mutations of tph-1, bas-1, and cat-4 genes, required for serotonin synthesis, and mutations of mod-5 gene, encoding a serotonin reuptake transporter, resulted in deficits in thermotaxis memory behavior. Exogenous treatment with serotonin effectively recovered the deficits in thermotaxis memory of tph-1 and bas-1 mutants to the level of wild-type N2. Neuron-specific activity assay of TPH-1 suggests that serotonin might regulate the thermotaxis memory behavior by release from the ADF sensory neurons. Ablation of ADF sensory neurons by expressing a cell-death activator gene egl-1 decreased the thermotaxis memory, whereas activation of ADF neurons by expression of a constitutively active protein kinase C homologue (pkc-1(gf)) increased the thermotaxis memory and rescued the deficits in thermotaxis memory in tph-1 mutants. Moreover, serotonin released from the ADF sensory neurons might act through the G-protein-coupled serotonin receptors of SER-4 and SER-7 to regulate the thermotaxis memory behavior. Genetic analysis implies that serotonin might further target the insulin signaling pathway to regulate the thermotaxis memory behavior. Thus, our results suggest the possible crucial role of serotonin and ADF sensory neurons in thermotaxis memory control in C. elegans.

  6. Metabolomics Approach Reveals Integrated Metabolic Network Associated with Serotonin Deficiency

    PubMed Central

    Weng, Rui; Shen, Sensen; Tian, Yonglu; Burton, Casey; Xu, Xinyuan; Liu, Yi; Chang, Cuilan; Bai, Yu; Liu, Huwei

    2015-01-01

    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. PMID:26154191

  7. 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.

  8. Initial evidence that polymorphisms in neurotransmitter-regulating genes contribute to being born small for gestational age.

    PubMed

    Morgan, Angharad R; Thompson, John M D; Waldie, Karen E; Cornforth, Christine M; Turic, Darko; Sonuga-Barke, Edmund J S; Lam, Wen-Jiun; Ferguson, Lynnette R; Mitchell, Edwin A

    2012-06-01

    Being born small for gestational age (SGA) is a putative risk factor for the development of later cognitive and psychiatric health problems. While the inter-uterine environment has been shown to play an important role in predicting birth weight, little is known about the genetic factors that might be important. Here we test the hypothesis that neurotransmitter-regulating genes implicated in psychiatric disorders previously shown to be associated with SGA (such as attention-deficit hyperactivity disorder) are themselves predictive of SGA. DNA was collected from 227 SGA and 319 appropriate for gestational age children taking part in the Auckland Birthweight Collaborative Study. Candidate single nucleotide polymorphisms in genes regulating activity within dopamine, serotonin, glutamate and gamma-aminobutyric acid pathways were genotyped. Multiple regression analysis, controlling for potentially confounding factors, supported nominally significant associations between SGA and single nucleotide polymorphisms in COMT, HTR2A, SLC1A1 and SLC6A1. This is the first evidence that genes implicated in psychiatric disorders previously linked to SGA status themselves predict SGA. This highlights the possibility that the link between SGA and psychiatric disorders such as attention-deficit hyperactivity disorder may in part be genetically determined - that SGA marks pre-existing genetic risk for later problems. PMID:27625810

  9. Initial evidence that polymorphisms in neurotransmitter-regulating genes contribute to being born small for gestational age.

    PubMed

    Morgan, Angharad R; Thompson, John M D; Waldie, Karen E; Cornforth, Christine M; Turic, Darko; Sonuga-Barke, Edmund J S; Lam, Wen-Jiun; Ferguson, Lynnette R; Mitchell, Edwin A

    2012-06-01

    Being born small for gestational age (SGA) is a putative risk factor for the development of later cognitive and psychiatric health problems. While the inter-uterine environment has been shown to play an important role in predicting birth weight, little is known about the genetic factors that might be important. Here we test the hypothesis that neurotransmitter-regulating genes implicated in psychiatric disorders previously shown to be associated with SGA (such as attention-deficit hyperactivity disorder) are themselves predictive of SGA. DNA was collected from 227 SGA and 319 appropriate for gestational age children taking part in the Auckland Birthweight Collaborative Study. Candidate single nucleotide polymorphisms in genes regulating activity within dopamine, serotonin, glutamate and gamma-aminobutyric acid pathways were genotyped. Multiple regression analysis, controlling for potentially confounding factors, supported nominally significant associations between SGA and single nucleotide polymorphisms in COMT, HTR2A, SLC1A1 and SLC6A1. This is the first evidence that genes implicated in psychiatric disorders previously linked to SGA status themselves predict SGA. This highlights the possibility that the link between SGA and psychiatric disorders such as attention-deficit hyperactivity disorder may in part be genetically determined - that SGA marks pre-existing genetic risk for later problems.

  10. Initial evidence that polymorphisms in neurotransmitter-regulating genes contribute to being born small for gestational age

    PubMed Central

    Morgan, Angharad R.; Thompson, John M.D.; Waldie, Karen E.; Cornforth, Christine M.; Turic, Darko; Sonuga-Barke, Edmund J.S.; Lam, Wen-Jiun; Ferguson, Lynnette R.; Mitchell, Edwin A.

    2012-01-01

    Being born small for gestational age (SGA) is a putative risk factor for the development of later cognitive and psychiatric health problems. While the inter-uterine environment has been shown to play an important role in predicting birth weight, little is known about the genetic factors that might be important. Here we test the hypothesis that neurotransmitter-regulating genes implicated in psychiatric disorders previously shown to be associated with SGA (such as attention-deficit hyperactivity disorder) are themselves predictive of SGA. DNA was collected from 227 SGA and 319 appropriate for gestational age children taking part in the Auckland Birthweight Collaborative Study. Candidate single nucleotide polymorphisms in genes regulating activity within dopamine, serotonin, glutamate and gamma-aminobutyric acid pathways were genotyped. Multiple regression analysis, controlling for potentially confounding factors, supported nominally significant associations between SGA and single nucleotide polymorphisms in COMT, HTR2A, SLC1A1 and SLC6A1. This is the first evidence that genes implicated in psychiatric disorders previously linked to SGA status themselves predict SGA. This highlights the possibility that the link between SGA and psychiatric disorders such as attention-deficit hyperactivity disorder may in part be genetically determined – that SGA marks pre-existing genetic risk for later problems.

  11. [Neurotransmitters, neurohormones and prolactin].

    PubMed

    Libertun, C; Arakelian, M C; Larrea, G A; Gorriño, L R; Becú, D

    1980-01-01

    After pointing out the reasons for undertaking the study of the regulation of prolactin secretion, the neuroendocrine mechanisms implicated in such secretion are discussed. Special attention is dedicated to the participation of chemical agents. Thus, the principal effects dealt with are: the net inhibition produced by dopamine and the less generalized inhibition effects of nicotine and somatostatin; the facilitatory action of serotoninergic pathways, TRH, histamine and endorphins. The dual effect described for GABA and noradrenaline, as well as some paradoxical actions, e.g., the antiserotoninergic and antihistaminergic H2 drugs which liberate prolactin in basal conditions but abolish the prolactin releasing effect of the respective agonist, or the immediate blocking effect of muscarinic agonists and antagonists are discussed. Finally, the possibility of a new mechanism of control at anterior pituitary receptors level is postulated.

  12. 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.

  13. 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

  14. 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

  15. Does the dopamine hypothesis explain schizophrenia?

    PubMed

    Lau, Chi-Ieong; Wang, Han-Cheng; Hsu, Jung-Lung; Liu, Mu-En

    2013-01-01

    The dopamine hypothesis has been the cornerstone in the research and clinical practice of schizophrenia. With the initial emphasis on the role of excessive dopamine, the hypothesis has evolved to a concept of combining prefrontal hypodopaminergia and striatal hyperdopaminergia, and subsequently to the present aberrant salience hypothesis. This article provides a brief overview of the development and evidence of the dopamine hypothesis. It will argue that the current model of aberrant salience explains psychosis in schizophrenia and provides a plausible linkage between the pharmacological and cognitive aspects of the disease. Despite the privileged role of dopamine hypothesis in psychosis, its pathophysiological rather than etiological basis, its limitations in defining symptoms other than psychosis, as well as the evidence of other neurotransmitters such as glutamate and adenosine, prompt us to a wider perspective of the disease. Finally, dopamine does explain the pathophysiology of schizophrenia, but not necessarily the cause per se. Rather, dopamine acts as the common final pathway of a wide variety of predisposing factors, either environmental, genetic, or both, that lead to the disease. Other neurotransmitters, such as glutamate and adenosine, may also collaborate with dopamine to give rise to the entire picture of schizophrenia. PMID:23843581

  16. Chitosan coated carbon fiber microelectrode for selective in vivo detection of neurotransmitters in live zebrafish embryos.

    PubMed

    Ozel, Rıfat Emrah; Wallace, Kenneth N; Andreescu, Silvana

    2011-06-10

    We report the development of a chitosan modified carbon fiber microelectrode for in vivo detection of serotonin. We find that chitosan has the ability to reject physiological levels of ascorbic acid interferences and facilitate selective and sensitive detection of in vivo levels of serotonin, a common catecholamine neurotransmitter. Presence of chitosan on the microelectrode surface was investigated using scanning electron microscopy (SEM) and cyclic voltammetry (CV). The electrode was characterized using differential pulse voltammetry (DPV). A detection limit of 1.6 nM serotonin with a sensitivity of 5.12 nA/μM, a linear range from 2 to 100 nM and a reproducibility of 6.5% for n=6 electrodes were obtained. Chitosan modified microelectrodes selectively measure serotonin in presence of physiological levels of ascorbic acid. In vivo measurements were performed to measure concentration of serotonin in the live embryonic zebrafish intestine. The sensor quantifies in vivo intestinal levels of serotonin while successfully rejecting ascorbic acid interferences. We demonstrate that chitosan can be used as an effective coating to reject ascorbic acid interferences at carbon fiber microelectrodes, as an alternative to Nafion, and that chitosan modified microelectrodes are reliable tools for in vivo monitoring of changes in neurotransmitter levels. PMID:21601035

  17. Chitosan coated carbon fiber microelectrode for selective in vivo detection of neurotransmitters in live zebrafish embryos

    PubMed Central

    Özel, Rıfat Emrah; Wallace, Kenneth N.; Andreescu, Silvana

    2011-01-01

    We report the development of a chitosan modified carbon fiber microelectrode for in vivo detection of serotonin. We find that chitosan has the ability to reject physiological levels of ascorbic acid interferences and facilitate selective and sensitive detection of in vivo levels of serotonin, a common catecholamine neurotransmitter. Presence of chitosan on the microelectrode surface was investigated using scanning electron microscopy (SEM) and cyclic voltammetry (CV). The electrode was characterized using differential pulse voltammetry (DPV). A detection limit of 1.6 nM serotonin with a sensitivity of 5.12 nA/µM, a linear range from 2 to 100 nM and a reproducibility of 6.5 % for n=6 electrodes were obtained. Chitosan modified microelectrodes selectively measure serotonin in presence of physiological levels of ascorbic acid. In vivo measurements were performed to measure concentration of serotonin in the live embryonic zebrafish intestine. The sensor quantifies in vivo intestinal levels of serotonin while successfully rejecting ascorbic acid interferences. We demonstrate that chitosan can be used as an effective coating to reject ascorbic acid interferences at carbon fiber microelectrodes, as an alternative to Nafion, and that chitosan modified microelectrodes are reliable tools for in vivo monitoring of changes in neurotransmitter levels. PMID:21601035

  18. 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

  19. Directed evolution reveals hidden properties of VMAT, a neurotransmitter transporter.

    PubMed

    Gros, Yael; Schuldiner, Shimon

    2010-02-12

    The vesicular neurotransmitter transporter VMAT2 is responsible for the transport of monoamines into synaptic and storage vesicles. VMAT2 is the target of many psychoactive drugs and is essential for proper neurotransmission and survival. Here we describe a new expression system in Saccharomyces cerevisiae that takes advantage of the polyspecificity of VMAT2. Expression of rVMAT2 confers resistance to acriflavine and to the parkinsonian toxin 1-methyl-4-phenylpyridinium (MPP(+)) by their removal into the yeast vacuole. This expression system allowed identification of a new substrate, acriflavine, and isolation of mutants with modified affinity to tetrabenazine (TBZ), a non-competitive inhibitor of VMAT2 that is used in the treatment of various movement disorders including Tourette syndrome and Huntington chorea. Whereas one type of mutant obtained displayed decreased affinity to TBZ, a second type showed only a slight decrease in the affinity to TBZ, displayed a higher K(m) to the neurotransmitter serotonin, but conferred increased resistance to acriflavine and MPP(+). A protein where both types of mutations were combined (with only three amino acid replacements) lost most of the properties of the neurotransmitter transporter (TBZ-insensitive, no transport of neurotransmitter) but displayed enhanced resistance to the above toxicants. The work described here shows that in the case of rVMAT2, loss of traits acquired in evolution of function (such as serotonin transport and TBZ binding) bring about an improvement in older functions such as resistance to toxic compounds. A process that has taken millions of years of evolution can be reversed by three mutations. PMID:20007701

  20. 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. PMID:16041566

  1. 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

  2. Common Drugs Inhibit Human Organic Cation Transporter 1 (OCT1)-Mediated Neurotransmitter Uptake

    PubMed Central

    Boxberger, Kelli H.; Hagenbuch, Bruno

    2014-01-01

    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. PMID:24688079

  3. RFamide neuropeptide actions on the molluscan ventricle: Interactions with primary neurotransmitters.

    PubMed

    Moulis, A; Huddart, H

    2006-01-01

    Different RFamide neuropeptides, some of non-molluscan origin, were examined for their effect on the ventricles of Buccinum undatum and Busycon canaliculatum. None of the peptides tested were inhibitory on these ventricles. All the peptides were extremely active, causing excitation of the preparations at low concentrations. The neuropeptides were then tested with the primary neurotransmitters. In the case of serotonin, the excitatory primary neurotransmitter, the RFamide neuropeptides induced a response, which was greatly enhanced by serotonin. Acetylcholine, the inhibitory neurotransmitter, induced relaxation whenever added, following a neuropeptide. The neuropeptides seemed to be independent of external Ca(2+), since in Ca(2+)-free media tension was induced. On the contrary, serotonin was dependent on external Ca(2+). These findings indicate that the neuropeptides generated tension via a different receptor to that of the primary neurotransmitters, using a different 2nd messenger and activating different Ca(2+) sources. Finally, the parent neuropeptide Phe-Leu-Arg-Phe-NH(2), when added following a different RFamide peptide, excited the preparation further, thus indicating the presence of a receptor that has higher affinity for some structures than others. When Phe-Met-Arg-Phe-NH(2) followed Phe-Leu-Arg-Phe-NH(2), no such response was recorded since the latter is of higher potency than the former.

  4. Multiple messengers in descending serotonin neurons: localization and functional implications.

    PubMed

    Hökfelt, T; Arvidsson, U; Cullheim, S; Millhorn, D; Nicholas, A P; Pieribone, V; Seroogy, K; Ulfhake, B

    2000-02-01

    In the present review article we summarize mainly histochemical work dealing with descending bulbospinal serotonin neurons which also express a number of neuropeptides, in particular substance P and thyrotropin releasing hormone. Such neurons have been observed both in rat, cat and monkey, and may preferentially innervate the ventral horns of the spinal cord, whereas the serotonin projections to the dorsal horn seem to lack these coexisting peptides. More recent studies indicate that a small population of medullary raphe serotonin neurons, especially at rostral levels, also synthesize the inhibitory neurotransmitter gamma-amino butyric acid (GABA). Many serotonin neurons contain the glutamate synthesizing enzyme glutaminase and can be labelled with antibodies raised against glutamate, suggesting that one and the same neuron may release several signalling substances, causing a wide spectrum of post- (and pre-) synaptic actions. PMID:10708921

  5. Mimicking subsecond neurotransmitter dynamics with femtosecond laser stimulated nanosystems.

    PubMed

    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

    2014-06-23

    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.

  6. 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…

  7. Trafficking of Vesicular Neurotransmitter Transporters

    PubMed Central

    Fei, Hao; Grygoruk, Anna; Brooks, Elizabeth S.; Chen, Audrey; Krantz, David E.

    2010-01-01

    Vesicular neurotransmitter transporters are required for the storage of all classical and amino acid neurotransmitters in secretory vesicles. Transporter expression can influence neurotransmitter storage and release, and trafficking targets the transporters to different types of secretory vesicles. Vesicular transporters traffic to synaptic vesicles as well as large dense core vesicles, and are recycled to synaptic vesicles at the nerve terminal. Some of the intrinsic signals for these trafficking events have been defined and include a dileucine motif present in multiple transporter subtypes, an acidic cluster in the neural isoform of the vesicular monoamine transporter (VMAT2) and a polyproline motif in the vesicular glutamate transporter VGLUT1. The sorting of VMAT2 and the vesicular acetylcholine transporter (VAChT) to secretory vesicles is regulated by phosphorylation. In addition, VGLUT1 uses alternative endocytic pathways for recycling back to synaptic vesicles following exocytosis. Regulation of these sorting events has the potential to influence synaptic transmission and behavior. PMID:18507811

  8. A voltammetric and mathematical analysis of histaminergic modulation of serotonin in the mouse hypothalamus.

    PubMed

    Samaranayake, Srimal; Abdalla, Aya; Robke, Rhiannon; Nijhout, H Frederik; Reed, Michael C; Best, Janet; Hashemi, Parastoo

    2016-08-01

    Histamine and serotonin are neuromodulators which facilitate numerous, diverse neurological functions. Being co-localized in many brain regions, these two neurotransmitters are thought to modulate one another's chemistry and are often implicated in the etiology of disease. Thus, it is desirable to interpret the in vivo chemistry underlying neurotransmission of these two molecules to better define their roles in health and disease. In this work, we describe a voltammetric approach to monitoring serotonin and histamine simultaneously in real time. Via electrical stimulation of the axonal bundles in the medial forebrain bundle, histamine release was evoked in the mouse premammillary nucleus. We found that histamine release was accompanied by a rapid, potent inhibition of serotonin in a concentration-dependent manner. We developed mathematical models to capture the experimental time courses of histamine and serotonin, which necessitated incorporation of an inhibitory receptor on serotonin neurons. We employed pharmacological experiments to verify that this serotonin inhibition was mediated by H3 receptors. Our novel approach provides fundamental mechanistic insights that can be used to examine the full extent of interconnectivity between histamine and serotonin in the brain. Histamine and serotonin are co-implicated in many of the brain's functions. In this paper, we develop a novel voltammetric method for simultaneous real-time monitoring of histamine and serotonin in the mouse premammillary nucleus. Electrical stimulation of the medial forebrain bundle evokes histamine and inhibits serotonin release. We show voltammetrically, mathematically, and pharmacologically that this serotonin inhibition is H3 receptor mediated. PMID:27167463

  9. A voltammetric and mathematical analysis of histaminergic modulation of serotonin in the mouse hypothalamus.

    PubMed

    Samaranayake, Srimal; Abdalla, Aya; Robke, Rhiannon; Nijhout, H Frederik; Reed, Michael C; Best, Janet; Hashemi, Parastoo

    2016-08-01

    Histamine and serotonin are neuromodulators which facilitate numerous, diverse neurological functions. Being co-localized in many brain regions, these two neurotransmitters are thought to modulate one another's chemistry and are often implicated in the etiology of disease. Thus, it is desirable to interpret the in vivo chemistry underlying neurotransmission of these two molecules to better define their roles in health and disease. In this work, we describe a voltammetric approach to monitoring serotonin and histamine simultaneously in real time. Via electrical stimulation of the axonal bundles in the medial forebrain bundle, histamine release was evoked in the mouse premammillary nucleus. We found that histamine release was accompanied by a rapid, potent inhibition of serotonin in a concentration-dependent manner. We developed mathematical models to capture the experimental time courses of histamine and serotonin, which necessitated incorporation of an inhibitory receptor on serotonin neurons. We employed pharmacological experiments to verify that this serotonin inhibition was mediated by H3 receptors. Our novel approach provides fundamental mechanistic insights that can be used to examine the full extent of interconnectivity between histamine and serotonin in the brain. Histamine and serotonin are co-implicated in many of the brain's functions. In this paper, we develop a novel voltammetric method for simultaneous real-time monitoring of histamine and serotonin in the mouse premammillary nucleus. Electrical stimulation of the medial forebrain bundle evokes histamine and inhibits serotonin release. We show voltammetrically, mathematically, and pharmacologically that this serotonin inhibition is H3 receptor mediated.

  10. Electrochemical quantification of serotonin in the live embryonic zebrafish intestine

    PubMed Central

    Njagi, John; Ball, Michael; Best, Marc; Wallace, Kenneth N.; Andreescu, Silvana

    2010-01-01

    We monitored real-time in vivo levels of serotonin release in the digestive system of intact zebrafish embryos during early development (5 dpf) using differential pulse voltammetry with implanted carbon fiber microelectrodes modified with carbon nanotubes dispersed in nafion. A detection limit of 1 nM, a linear range between 5 to 200 nM and a sensitivity of 83.65 nA·μM−1 were recorded. The microelectrodes were implanted at various locations in the intestine of zebrafish embryos. Serotonin levels of up to 29.9(±1.13) nM were measured in vivo in normal physiological conditions. Measurements were performed in intact live embryos without additional perturbation beyond electrode insertion. The sensor was able to quantify pharmacological alterations in serotonin release and provide the longitudinal distribution of this neurotransmitter along the intestine with high spatial resolution. In the presence of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), concentrations of 54.1(±1.05) nM were recorded while in the presence of p-chloro-phenylalanine (PCPA), a tryptophan hydroxylase inhibitor, the serotonin levels decreased to 7.2(±0.45) nM. The variation of serotonin levels was correlated with immunohistochemical analysis. We have demonstrated the first use of electrochemical microsensors for in vivo monitoring of intestinal serotonin levels in intact zebrafish embryos. PMID:20148518

  11. Electrochemical quantification of serotonin in the live embryonic zebrafish intestine.

    PubMed

    Njagi, John; Ball, Michael; Best, Marc; Wallace, Kenneth N; Andreescu, Silvana

    2010-03-01

    We monitored real-time in vivo levels of serotonin release in the digestive system of intact zebrafish embryos during early development (5 days postfertilization, dpf) using differential pulse voltammetry with implanted carbon fiber microelectrodes modified with carbon nanotubes dispersed in nafion. A detection limit of 1 nM, a linear range between 5 and 200 nM, and a sensitivity of 83.65 nA x microM(-1) were recorded. The microelectrodes were implanted at various locations in the intestine of zebrafish embryos. Serotonin levels of up to 29.9 (+/-1.13) nM were measured in vivo in normal physiological conditions. Measurements were performed in intact live embryos without additional perturbation beyond electrode insertion. The sensor was able to quantify pharmacological alterations in serotonin release and provide the longitudinal distribution of this neurotransmitter along the intestine with high spatial resolution. In the presence of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), concentrations of 54.1 (+/-1.05) nM were recorded while in the presence of p-chloro-phenylalanine (PCPA), a tryptophan hydroxylase inhibitor, the serotonin levels decreased to 7.2 (+/-0.45) nM. The variation of serotonin levels was correlated with immunohistochemical analysis. We have demonstrated the first use of electrochemical microsensors for in vivo monitoring of intestinal serotonin levels in intact zebrafish embryos. PMID:20148518

  12. 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…

  13. 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.

  14. A rapid and simple method for the simultaneous determination of four endogenous monoamine neurotransmitters in rat brain using hydrophilic interaction liquid chromatography coupled with atmospheric-pressure chemical ionization tandem mass spectrometry.

    PubMed

    Zhou, Wenbin; Zhu, Bangjie; Liu, Feng; Lyu, Chunming; Zhang, Shen; Yan, Chao; Cheng, Yu; Wei, Hai

    2015-10-01

    Endogenous monoamine neurotransmitters play an essential role in neural communication in mammalians. Many quantitative methods for endogenous monoamines have been developed during recent decades. Yet, matrix effect was usually a challenge in the quantification, in many cases asking for tedious sample preparation or sacrificing sensitivity. In this work, a simple, fast and sensitive method with no matrix effect was developed to simultaneously determine four endogenous monoamines including serotonin, dopamine, epinephrine and norepinephrine in rat brain tissues, using hydrophilic interaction liquid chromatography coupled with atmospheric-pressure chemical ionization tandem mass spectrometry. Various conditions, including columns, chromatographic conditions, ion source, MS/MS conditions, and brain tissue preparation methods, were optimized and validated. Pre-weighed 20mg brain sample could be effectively and reproducibly homogenized and protein-precipitated by 20 times value of 0.2% formic acid in cold organic solvents (methanol-acetonitrile, 10:90, v/v). This method exhibited excellent linearity for all analytes (regression coefficients>0.998 or 0.999). The precision, expressed as coefficients of variation, was less than 3.43% for intra-day analyses and ranged from 4.17% to 15.5% for inter-day analyses. Good performance was showed in limit of detection (between 0.3nM and 3.0nM for all analytes), recovery (90.8-120%), matrix effect (84.4-107%), accuracy (89.8-100%) and stability (88.3-104%). The validated method was well applied to simultaneously determine the endogenous serotonin, dopamine, epinephrine and norepinephrine in four brain sections of 18 Wistar rats. The quantification of four endogenous monoamines in rat brain performed excellently in the sensitivity, high throughput, simple sample preparation and matrix effect.

  15. MDMA (Ecstasy or Molly)

    MedlinePlus

    ... neurotransmitters (the chemical messengers of brain cells): serotonin , dopamine , and norepinephrine . Serotonin —plays a role in controlling ... a heightened sense of emotional closeness and empathy. Dopamine —helps to control movement, motivation, emotions, and sensations ...

  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. A current view of serotonin transporters.

    PubMed

    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

  18. Improved amino acid, bioenergetic metabolite and neurotransmitter profiles following human amnion epithelial cell transplant in intermediate maple syrup urine disease mice.

    PubMed

    Skvorak, Kristen J; Dorko, Kenneth; Marongiu, Fabio; Tahan, Veysel; Hansel, Marc C; Gramignoli, Roberto; Arning, Erland; Bottiglieri, Teodoro; Gibson, K Michael; Strom, Stephen C

    2013-06-01

    Orthotopic liver transplant (OLT) significantly improves patient outcomes in maple syrup urine disease (MSUD; OMIM: 248600), yet organ shortages point to the need for alternative therapies. Hepatocyte transplantation has shown both clinical and preclinical efficacy as an intervention for metabolic liver diseases, yet the availability of suitable livers for hepatocyte isolation is also limited. Conversely, human amnion epithelial cells (hAEC) may have utility as a hepatocyte substitute, and they share many of the characteristics of pluripotent embryonic stem cells while lacking their safety and ethical concerns. We reported that like hepatocytes, transplantation of hAEC significantly improved survival and lifespan, normalized body weight, and significantly improved branched-chain amino acid (BCAA) levels in sera and brain in a transgenic murine model of intermediate maple syrup urine disease (imsud). In the current report, we detail the neural and peripheral metabolic improvements associated with hAEC transplant in imsud mice, including amino acids associated with bioenergetics, the urea cycle, as well as the neurotransmitter systems for serotonin, dopamine, and gamma-aminobutyric acid (GABA). This stem cell therapy results in significant global correction of the metabolic profile that characterizes the disease, both in the periphery and the central nervous system, the target organ for toxicity in iMSUD. The significant correction of the disease phenotype, coupled with the theoretical benefits of hAEC, particularly their lack of immunogenicity and tumorigenicity, suggests that human amnion epithelial cells deserve serious consideration for clinical application to treat metabolic liver diseases.

  19. Different functions for homologous serotonergic interneurons and serotonin in species-specific rhythmic behaviours.

    PubMed

    Newcomb, James M; Katz, Paul S

    2009-01-01

    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. PMID:18782747

  20. 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

  1. 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.

  2. Vesicular neurotransmitter transporters: mechanistic aspects.

    PubMed

    Anne, Christine; Gasnier, Bruno

    2014-01-01

    Secondary transporters driven by a V-type H⁺-ATPase accumulate nonpeptide neurotransmitters into synaptic vesicles. Distinct transporter families are involved depending on the neurotransmitter. Monoamines and acetylcholine on the one hand, and glutamate and ATP on the other hand, are accumulated by SLC18 and SLC17 transporters, respectively, which belong to the major facilitator superfamily (MFS). GABA and glycine accumulate through a common SLC32 transporter from the amino acid/polyamine/organocation (APC) superfamily. Although crystallographic structures are not yet available for any vesicular transporter, homology modeling studies of MFS-type vesicular transporters based on distantly related bacterial structures recently provided significant advances, such as the characterization of substrate-binding pockets or the identification of spatial clusters acting as hinge points during the alternating-access cycle. However, several basic issues, such as the ion stoichiometry of vesicular amino acid transporters, remain unsettled.

  3. [Pediatric neurotransmitter disease in Japan].

    PubMed

    Shintaku, Haruo

    2012-09-01

    Pediatric neurotransmitter disease (PND) encompasses a range of rare genetic disorders that affect the metabolism of neurotransmitters in children. While these neurological disorders are often studied independently of each other, they all manifest central nervous system symptoms and require proper diagnosis and intervention at early stages. Since clinical symptoms of PND can be nonspecific, the conditions are often under-diagnosed, leaving patients without a chance to receive effective treatment. Envisioning PND as a whole, a comprehensive research effort is underway for a better understanding of pathophysiology and epidemiology in Japan, and toward the establishment of diagnostic criteria. The early diagnosis and development of new effective therapies are of urgent importance for these rare disorders that are not covered by newborn mass screening. For rarer forms of PND, at the same time, it is important to encourage recognition and understanding of the disease concept among healthcare professionals.

  4. 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. PMID:27638061

  5. 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.

  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 Central

    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 and

  7. Role of the serotonin transporter gene in temperament and character.

    PubMed

    Hamer, D H; Greenberg, B D; Sabol, S Z; Murphy, D L

    1999-01-01

    The biosocial model postulates that personality is comprised of two broad domains: temperament, which is largely due to inherited variations in specific monoamine neurotransmitter systems; and character, which arises from socioculturally learned differences in values, goals, and self-concepts and is the strongest predictor of personality disorders. The model also proposes that serotonin modulates the temperament trait of harm avoidance. We analyzed the association of temperament and character traits with the 5-HTTLPR, an inherited variation that modulates serotonin transporter gene expression, in 634 volunteer subjects. Contrary to theory, the 5-HTTLPR was most strongly associated with the character traits of cooperativeness and self-directedness. Associations with the temperament traits of reward dependence and harm avoidance were weaker and could be attributable largely to cross-correlations with the character traits and demographic variables. Psychometric analysis indicated that the serotonin transporter influences two broad areas of personality, negative affect and social disaffiliation, that are consistent across inventories but are more concisely described by the 5-factor model of personality than by the biosocial model. These results suggest that there is no fundamental mechanistic distinction between character and temperament in regard to the serotonin transporter gene, and that a single neurotransmitter can influence multiple personality traits.

  8. Further strategies for treating fibromyalgia: the role of serotonin and norepinephrine reuptake inhibitors.

    PubMed

    Mease, Philip J

    2009-12-01

    Fibromyalgia and associated conditions such as irritable bowel syndrome and temporomandibular disorder involve dysfunctions in central sensitization and pain modulation. Central nervous system dysfunction may also contribute to other symptoms characteristic of fibromyalgia, such as fatigue and sleep disturbance. Two key neurotransmitters in the pain modulation pathway are serotonin and norepinephrine. Preclinical studies using animal models of chronic pain have shown that pharmacologic agents that combine serotonergic and noradrenergic reuptake inhibition, thus augmenting the function of these neurotransmitters, have stronger analgesic effects than agents that inhibit reuptake of either neurotransmitter alone. Although tricyclic antidepressants (TCAs) inhibit reuptake of both serotonin and norepinephrine and have shown efficacy for the treatment of fibromyalgia, long-term use of these drugs is limited owing to poor tolerability. Unlike TCAs, the newer dual reuptake inhibitors of serotonin and norepinephrine, such as the drugs approved by the US Food and Drug Administration (FDA) for fibromyalgia, milnacipran and duloxetine, do not possess significant affinity for other neurotransmitter systems, resulting in diminished side effects and enhanced tolerability. Both duloxetine and milnacipran have shown efficacy in clinical trials by improving pain and other symptoms associated with fibromyalgia. Both compounds inhibit the serotonin and norepinephrine transporters; however, there is a difference in their affinities and selectivity for these transporters. Although duloxetine has affinity for both receptors, it is somewhat more selective for the serotonin transporter. In contrast, milnacipran is somewhat more selective for norepinephrine than serotonin reuptake inhibition. Pharmacologic agents that specifically target serotonin and norepinephrine reuptake may prove to be valuable tools in the treatment of fibromyalgia.

  9. 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.

  10. 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.

  11. 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

  12. 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...

  13. 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...

  14. (/sup 3/H)Spiroxatrine labels a serotonin/sub 1A/-like site in the rat hippocampus

    SciTech Connect

    Nelson, D.L.; Monroe, P.J.; Lambert, G.; Yamamura, H.I.

    1987-09-28

    (/sup 3/H)Spiroxatrine was examined as a potential ligand for the labeling of 5-HT/sub 1A/ sites in the rat hippocampus. Analysis o the binding of (/sup 3/H)spiroxatrine in the absence and presence of varying concentrations of three monoamine neurotransmitters revealed that serotonin (5-HT) had high affinity for the (/sup 3/H)spiroxatrine binding sites, consistent with the labeling of 5-HT/sub 1/ sites, while dopamine and norepinephrine had very low affinity. Saturation studies of the binding of (/sup 3/H)spiroxatrine revealed a single population of sites with a K/sub d/ = 2.21 nM. Further pharmacologic characterization with the 5-HT/sub 1A/ ligands 8-hydroxy-2-(di-ni-propylamino)tetralin, ipsapirone, and WB4101 and the butyrophenone compounds spiperone and haloperidol gave results that were consistent with (/sup 3/H)spiroxatrine labeling 5-HT/sub 1A/ sites. This ligand produced stable, reproducible binding with a good ratio of specific to nonspecific binding. The binding of (/sup 3/H)spiroxatrine was sensitive to GTP, suggesting that this ligand may act as an agonist. 21 references, 5 figures, 2 tables.

  15. Elevated hypothalamic/midbrain serotonin (monoamine) transporter availability in depressive drug-naive children and adolescents.

    PubMed

    Dahlström, M; Ahonen, A; Ebeling, H; Torniainen, P; Heikkilä, J; Moilanen, I

    2000-09-01

    Cumulative data suggest depression in adulthood being connected to reduced availability of brain serotonin while the role of dopamine remains less specific. Prospective studies have shown a continuity of depressive episodes from childhood to adulthood, combined with poor social function and excess mortality. The object of this study was to examine whether alterations in brain serotonin and/or dopamine transporter levels are already present in depressive children and adolescents. We examined 41 drug-naive patients (aged 7-17) by single photon emission tomography (SPET) using iodine-123-labelled 23-carbomethoxy-3P3(iodophenyl) tropane [123I]beta-CIT as a tracer for monoamine transporters. In addition to the ordinary clinical examination, the patients were given a structured interview and information was gathered from teachers and parents with questionnaires. The diagnoses were established by consensus evaluation between three child psychiatrists. To test the serotonin hypothesis and the dopamine hypothesis regarding depression in children and adolescents, the series was divided into groups with depression present (31) and no depression present (10). In this study, the depressive child and adolescent patients had significantly higher serotonin transporter availability (P < 0.02) in the hypothalamic/midbrain area. Age did not correlate to the hypothalamic/midbrain serotonin transporter binding ratio. No significant difference in dopamine transporter availability in striatum was found between the depressive and the nondepressive children and adolescents.

  16. 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

  17. 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.

  18. 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. PMID:26167657

  19. 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 PMID:27254754

  20. 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

  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. BASAL GANGLIA PATHOLOGY IN SCHIZOPHRENIA: DOPAMINE CONNECTIONS and ANOMALIES

    PubMed Central

    Perez-Costas, Emma; Melendez-Ferro, Miguel; Roberts, Rosalinda C.

    2010-01-01

    Schizophrenia is a severe mental illness that affects 1% of the world population. The disease usually manifests itself in early adulthood with hallucinations, delusions, cognitive and emotional disturbances and disorganized thought and behavior. Dopamine was the first neurotransmitter to be implicated in the disease, and though no longer the only suspect in schizophrenia pathophysiology, it obviously plays an important role. The basal ganglia are the site of most of the dopamine neurons in the brain and the target of antipsychotic drugs. In this review we will start with an overview of basal ganglia anatomy emphasizing dopamine circuitry. Then, we will review the major deficits in dopamine function in schizophrenia, emphasizing the role of excessive dopamine in the basal ganglia and the link to psychosis. PMID:20089137

  3. Developmental profiles of neurotransmitter receptors in respiratory motor nuclei

    PubMed Central

    Kubin, Leszek; Volgin, Denys V.

    2008-01-01

    We discuss the time course of postnatal development of selected neurotransmitter receptors in motoneurons that innervate respiratory pump and accessory respiratory muscles, with emphasis on other than classic respiratory signals as important regulatory factors. Functions of those brainstem motoneurons that innervate the pharynx and larynx change more dramatically during early postnatal development than those of spinal respiratory motoneurons. Possibly in relation to this difference, the time course of postnatal expression of distinct receptors for serotonin differ between the hypoglossal (XII) and phrenic motoneurons. In rats, distinct developmental patterns include a decline or increase that extends over the first 3−4 postnatal weeks, a rapid increase during the first two weeks, or a transient decline on postnatal days 11−14. The latter period coincides with major changes in many transmitters in brainstem respiratory regions that may be related to a brain-wide reconfiguration of sensorymotor processing resulting from eye and ear opening and beginning of a switch from suckling to mature forms of food seeking and processing. Such rapid neurochemical changes may impart increased vulnerability on the respiratory system. We also consider rapid eye movement sleep as a state during which some brain functions may revert to conditions typical of perinatal period. In addition to normal developmental processes, changes in the expression or function of neurotransmitter receptors may occur in respiratory motoneurons in response to injury, perinatal stress, or disease conditions that increase the load on respiratory muscles or alter the normal levels and patterns of oxygen delivery. PMID:18514591

  4. 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

  5. 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

  6. Combined serotonin (5-HT)1A agonism, 5-HT(2A) and dopamine D₂ receptor antagonism reproduces atypical antipsychotic drug effects on phencyclidine-impaired novel object recognition in rats.

    PubMed

    Oyamada, Yoshihiro; Horiguchi, Masakuni; Rajagopal, Lakshmi; Miyauchi, Masanori; Meltzer, Herbert Y

    2015-05-15

    Subchronic administration of an N-methyl-D-aspartate receptor (NMDAR) antagonist, e.g. phencyclidine (PCP), produces prolonged impairment of novel object recognition (NOR), suggesting they constitute a hypoglutamate-based model of cognitive impairment in schizophrenia (CIS). Acute administration of atypical, e.g. lurasidone, but not typical antipsychotic drugs (APDs), e.g. haloperidol, are able to restore NOR following PCP (acute reversal model). Furthermore, atypical APDs, when co-administered with PCP, have been shown to prevent development of NOR deficits (prevention model). Most atypical, but not typical APDs, are more potent 5-HT(2A) receptor inverse agonists than dopamine (DA) D2 antagonists, and have been shown to enhance cortical and hippocampal efflux and to be direct or indirect 5-HT(1A) agonists in vivo. To further clarify the importance of these actions to the restoration of NOR by atypical APDs, sub-effective or non-effective doses of combinations of the 5-HT(1A) partial agonist (tandospirone), the 5-HT(2A) inverse agonist (pimavanserin), or the D2 antagonist (haloperidol), as well as the combination of all three agents, were studied in the acute reversal and prevention PCP models of CIS. Only the combination of all three agents restored NOR and prevented the development of PCP-induced deficit. Thus, this triple combination of 5-HT(1A) agonism, 5-HT(2A) antagonism/inverse agonism, and D2 antagonism is able to mimic the ability of atypical APDs to prevent or ameliorate the PCP-induced NOR deficit, possibly by stimulating signaling cascades from D1 and 5-HT(1A) receptor stimulation, modulated by D2 and 5-HT(2A) receptor antagonism. PMID:25448429

  7. 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.

  8. Brain neurotransmitters and neuromodulators in pediatrics.

    PubMed

    Johnston, M V; Singer, H S

    1982-07-01

    Neurotransmitter and neuromodulatory systems provide the mechanism for communication between nerve cells in the central nervous system. Studies of synaptic neurotransmission within the brain during development and in pathologic conditions are furthering our knowledge of various pediatric disorders. Basic concepts of synaptic neurochemistry, evaluation strategies, and the development of neurotransmitter pathways are reviewed. Sections on movement and psychiatric disorders, hyperactivity, epilepsy, and hyperphenylalaninemia relate clinical pediatric situations to recently reported alterations of neurotransmitter substances. The emerging story of neuropeptides and their association with pain further illustrate the importance of neurotransmitter research.

  9. 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)

  10. Interactions between lysergic acid diethylamide and dopamine-sensitive adenylate cyclase systems in rat brain.

    PubMed

    Hungen, K V; Roberts, S; Hill, D F

    1975-08-22

    Investigations were carried out on the interactions of the hallucinogenic drug, D-lysergic acid diethylamide (D-LSD), and other serotonin antagonists with catecholamine-sensitive adenylate cyclase systems in cell-free preparations from different regions of rat brain. In equimolar concentration, D-LSD, 2-brono-D-lysergic acid diethylamide (BOL), or methysergide (UML) strongly blocked maximal stimulation of adenylate cyclase activity by either norepinephrine or dopamine in particulate preparations from cerebral cortices of young adult rats. D-LSD also eliminated the stimulation of adenylate cyclase activity of equimolar concentrations of norepinephrine or dopamine in particulate preparations from rat hippocampus. The effects of this hallucinogenic agent on adenylate cyclase activity were most striking in particulate preparations from corpus striatum. Thus, in 10 muM concentration, D-LSD not only completely eradicated the response to 10 muM dopamine in these preparations but also consistently stimulated adenylate cyclase activity. L-LSD (80 muM) was without effect. Significant activation of striatal adenylate cyclase was produced by 0.1 muM D-LSD. Activation of striatal adenylate cyclase of either D-LSD or dopamine was strongly blocked by the dopamine-blocking agents trifluoperazine, thioridazine, chlorpromazine, and haloperidol. The stimulatory effects of D-LSD and dopamine were also inhibited by the serotonin-blocking agents, BOL, 1-methyl-D-lysergic acid diethylamide (MLD), and cyproheptadine, but not by the beta-adrenergic-blocking agent, propranolol. However, these serotonin antagonists by themselves were incapable of stimulating adenylate cyclase activity in the striatal preparations. Several other hallucinogens, which were structurally related to serotonin, were also inactive in this regard, e.g., mescaline, N,N-dimethyltryptamine, psilocin and bufotenine. Serotonin itself produced a small stimulation of adenylate cyclase activity in striatal preparations and

  11. Neurochemical, behavioral and physiological effects of pharmacologically enhanced serotonin levels in serotonin transporter (SERT)-deficient mice

    PubMed Central

    Fox, Meredith A.; Jensen, Catherine L.; French, Helen T.; Stein, Alison R.; Huang, Su-Jan; Tolliver, Teresa J.; Murphy, Dennis L.

    2008-01-01

    Rationale Serotonin transporter (SERT) knockout (−/−) mice have an altered phenotype in adulthood, including high baseline anxiety and depressive-like behaviors, associated with increased baseline extracellular serotonin levels throughout life. Objectives To examine the effects of increases in serotonin following administration of the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) in SERT wildtype (+/+), heterozygous (+/−) and −/− mice. Results 5-HTP increased serotonin in all five brain areas examined, with ~2–5-fold increases in SERT +/+ and +/− mice, and greater 4.5–11.7-fold increases in SERT −/− mice. Behaviorally, 5-HTP induced exaggerated serotonin syndrome behaviors in SERT −/− mice, with similar effects in male and female mice. Studies suggest promiscuous serotonin uptake by the dopamine transporter (DAT) in SERT −/− mice, and here, the DAT blocker GBR 12909 enhanced 5-HTP-induced behaviors in SERT −/− mice. Physiologically, 5-HTP induced exaggerated temperature effects in SERT-deficient mice. The 5-HT1A antagonist WAY 100635 decreased 5-HTP-induced hypothermia in SERT +/+ and +/− mice, with no effect in SERT −/− mice, whereas the 5-HT7 antagonist SB 269970 decreased this exaggerated response in SERT −/− mice only. WAY 100635 and SB 269970 together completely blocked 5-HTP-induced hypothermia in SERT +/− and −/− mice. Conclusions These studies demonstrate that SERT −/− mice have exaggerated neurochemical, behavioral and physiological responses to further increases in serotonin, and provide the first evidence of intact 5-HT7 receptor function in SERT −/− mice, with interesting interactions between 5-HT1A and 5-HT7 receptors. As roles for 5-HT7 receptors in anxiety and depression were recently established, the current findings have implications for understanding the high anxiety and depressive-like phenotype of SERT-deficient mice. PMID:18712364

  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. Sustained N-methyl-D-aspartate receptor hypofunction remodels the dopamine system and impairs phasic signaling

    PubMed Central

    Ferris, Mark J.; Milenkovic, Marija; Liu, Shuai; Mielnik, Catharine A.; Beerepoot, Pieter; John, Carrie E.; España, Rodrigo A.; Sotnikova, Tatyana D.; Gainetdinov, Raul R.; Borgland, Stephanie L.; Jones, Sara R.; Ramsey, Amy J.

    2014-01-01

    Chronic N-methyl-D-aspartate receptor (NMDAR) hypofunction has been proposed as a contributing factor to symptoms of schizophrenia. However, it is unclear how sustained NMDAR hypofunction throughout development affects other neurotransmitter systems that have been implicated in the disease. Dopamine neuron biochemistry and activity were examined to determine whether sustained NMDAR hypofunction causes a state of hyperdopaminergia. We report that a global, genetic reduction in NMDARs led to a remodeling of dopamine neurons, substantially affecting two key regulators of dopamine homeostasis, i.e. tyrosine hydroxylase and the dopamine transporter. In NR1 knockdown mice, dopamine synthesis and release were attenuated, and dopamine clearance was increased. Although these changes would have the effect of reducing dopamine transmission, we demonstrated that a state of hyperdopaminergia existed in these mice because dopamine D2 autoreceptors were desensitized. In support of this conclusion, NR1 knockdown dopamine neurons have higher tonic firing rates. Although the tonic firing rates are higher, phasic signaling is impaired, and dopamine overflow cannot be achieved with exogenous high-frequency stimulation that models phasic firing. Through the examination of several parameters of dopamine neurotransmission, we provide evidence that chronic NMDAR hypofunction leads to a state of elevated synaptic dopamine. Compensatory mechanisms to attenuate hyperdopaminergia also impact the ability to generate dopamine surges through phasic firing. PMID:24754704

  14. 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,…

  15. The dopamine theory of addiction: 40 years of highs and lows.

    PubMed

    Nutt, David J; Lingford-Hughes, Anne; Erritzoe, David; Stokes, Paul R A

    2015-05-01

    For several decades, addiction has come to be viewed as a disorder of the dopamine neurotransmitter system; however, this view has not led to new treatments. In this Opinion article, we review the origins of the dopamine theory of addiction and discuss the ability of addictive drugs to elicit the release of dopamine in the human striatum. There is robust evidence that stimulants increase striatal dopamine levels and some evidence that alcohol may have such an effect, but little evidence, if any, that cannabis and opiates increase dopamine levels. Moreover, there is good evidence that striatal dopamine receptor availability and dopamine release are diminished in individuals with stimulant or alcohol dependence but not in individuals with opiate, nicotine or cannabis dependence. These observations have implications for understanding reward and treatment responses in various addictions. PMID:25873042

  16. The dopamine theory of addiction: 40 years of highs and lows.

    PubMed

    Nutt, David J; Lingford-Hughes, Anne; Erritzoe, David; Stokes, Paul R A

    2015-05-01

    For several decades, addiction has come to be viewed as a disorder of the dopamine neurotransmitter system; however, this view has not led to new treatments. In this Opinion article, we review the origins of the dopamine theory of addiction and discuss the ability of addictive drugs to elicit the release of dopamine in the human striatum. There is robust evidence that stimulants increase striatal dopamine levels and some evidence that alcohol may have such an effect, but little evidence, if any, that cannabis and opiates increase dopamine levels. Moreover, there is good evidence that striatal dopamine receptor availability and dopamine release are diminished in individuals with stimulant or alcohol dependence but not in individuals with opiate, nicotine or cannabis dependence. These observations have implications for understanding reward and treatment responses in various addictions.

  17. Activation of serotonin receptors promotes microglial injury-induced motility but attenuates phagocytic activity.

    PubMed

    Krabbe, Grietje; Matyash, Vitali; Pannasch, Ulrike; Mamer, Lauren; Boddeke, Hendrikus W G M; Kettenmann, Helmut

    2012-03-01

    Microglia, the brain immune cell, express several neurotransmitter receptors which modulate microglial functions. In this project we studied the impact of serotonin receptor activation on distinct microglial properties as serotonin deficiency not only has been linked to a number of psychiatric disease like depression and anxiety but may also permeate from the periphery through blood-brain barrier openings seen in neurodegenerative disease. First, we tested the impact of serotonin on the microglial response to an insult caused by a laser lesion in the cortex of acute slices from Cx3Cr1-GFP-/+ mice. In the presence of serotonin the microglial processes moved more rapidly towards the laser lesion which is considered to be a chemotactic response to ATP. Similarly, the chemotactic response of cultured microglia to ATP was also enhanced by serotonin. Quantification of phagocytic activity by determining the uptake of microspheres showed that the amoeboid microglia in slices from early postnatal animals or microglia in culture respond to serotonin application with a decreased phagocytic activity whereas we could not detect any significant change in ramified microglia in situ. The presence of microglial serotonin receptors was confirmed by patch-clamp experiments in culture and amoeboid microglia and by qPCR analysis of RNA isolated from primary cultured and acutely isolated adult microglia. These data suggest that microglia express functional serotonin receptors linked to distinct microglial properties. PMID:22198120

  18. Serotonin 2B receptor: upregulated with age and hearing loss in mouse auditory system.

    PubMed

    Tadros, Sherif F; D'Souza, Mary; Zettel, Martha L; Zhu, XiaoXia; Lynch-Erhardt, Martha; Frisina, Robert D

    2007-07-01

    Serotonin (5-HT) is a monoamine neurotransmitter. Serotonin may modulate afferent fiber discharges in the cochlea, inferior colliculus (IC) and auditory cortex. Specific functions of serotonin are exerted upon its interaction with specific receptors; one of those receptors is the serotonin 2B receptor. The aim of this study was to investigate the differences in gene expression of serotonin 2B receptors with age in cochlea and IC, and the possible correlation between gene expression and functional hearing measurements in CBA/CaJ mice. Immunohistochemical examinations of protein expression of IC in mice of different age groups were also performed. Gene expression results showed that serotonin 2B receptor gene was upregulated with age in both cochlea and IC. A significant correlation between gene expression and functional hearing results was established. Immunohistochemical protein expression studies of IC showed more serotonin 2B receptor cells in old mice relative to young adult mice, particularly in the external nucleus. We conclude that serotonin 2B receptors may play a role in the pathogenesis of age-related hearing loss.

  19. The Role of Dopamine and Its Dysfunction as a Consequence of Oxidative Stress.

    PubMed

    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.

  20. 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

  1. 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

  2. Signaling pathways take aim at neurotransmitter transporters.

    PubMed

    Robinson, Michael B

    2003-11-01

    Neurotransmitter transporters are the target of various pharmacological agents used to treat psychological or cognitive conditions, such as depression and attention-deficit disorder. In addition, some of the effects of stimulant-type drugs of abuse result from inhibition of neurotransmitter transporters. Robinson describes the intersection between neurotransmitter transporters and signaling pathways. Neurotransmitter transporters can be regulated by altering the rate of internalization and insertion into the plasma membrane to control cell surface expression or by altering the activity of the transporters within the membrane. As the mechanisms governing regulation of these transporters become elucidated, new potential therapeutic targets may be revealed, given the many processes affected by the activity of neurotransmitter transporters.

  3. X-ray structure of dopamine transporter elucidates antidepressant mechanism.

    PubMed

    Penmatsa, Aravind; Wang, Kevin H; Gouaux, Eric

    2013-11-01

    Antidepressants targeting Na(+)/Cl(-)-coupled neurotransmitter uptake define a key therapeutic strategy to treat clinical depression and neuropathic pain. However, identifying the molecular interactions that underlie the pharmacological activity of these transport inhibitors, and thus the mechanism by which the inhibitors lead to increased synaptic neurotransmitter levels, has proven elusive. Here we present the crystal structure of the Drosophila melanogaster dopamine transporter at 3.0 Å resolution bound to the tricyclic antidepressant nortriptyline. The transporter is locked in an outward-open conformation with nortriptyline wedged between transmembrane helices 1, 3, 6 and 8, blocking the transporter from binding substrate and from isomerizing to an inward-facing conformation. Although the overall structure of the dopamine transporter is similar to that of its prokaryotic relative LeuT, there are multiple distinctions, including a kink in transmembrane helix 12 halfway across the membrane bilayer, a latch-like carboxy-terminal helix that caps the cytoplasmic gate, and a cholesterol molecule wedged within a groove formed by transmembrane helices 1a, 5 and 7. Taken together, the dopamine transporter structure reveals the molecular basis for antidepressant action on sodium-coupled neurotransmitter symporters and elucidates critical elements of eukaryotic transporter structure and modulation by lipids, thus expanding our understanding of the mechanism and regulation of neurotransmitter uptake at chemical synapses.

  4. X-ray structure of dopamine transporter elucidates antidepressant mechanism.

    PubMed

    Penmatsa, Aravind; Wang, Kevin H; Gouaux, Eric

    2013-11-01

    Antidepressants targeting Na(+)/Cl(-)-coupled neurotransmitter uptake define a key therapeutic strategy to treat clinical depression and neuropathic pain. However, identifying the molecular interactions that underlie the pharmacological activity of these transport inhibitors, and thus the mechanism by which the inhibitors lead to increased synaptic neurotransmitter levels, has proven elusive. Here we present the crystal structure of the Drosophila melanogaster dopamine transporter at 3.0 Å resolution bound to the tricyclic antidepressant nortriptyline. The transporter is locked in an outward-open conformation with nortriptyline wedged between transmembrane helices 1, 3, 6 and 8, blocking the transporter from binding substrate and from isomerizing to an inward-facing conformation. Although the overall structure of the dopamine transporter is similar to that of its prokaryotic relative LeuT, there are multiple distinctions, including a kink in transmembrane helix 12 halfway across the membrane bilayer, a latch-like carboxy-terminal helix that caps the cytoplasmic gate, and a cholesterol molecule wedged within a groove formed by transmembrane helices 1a, 5 and 7. Taken together, the dopamine transporter structure reveals the molecular basis for antidepressant action on sodium-coupled neurotransmitter symporters and elucidates critical elements of eukaryotic transporter structure and modulation by lipids, thus expanding our understanding of the mechanism and regulation of neurotransmitter uptake at chemical synapses. PMID:24037379

  5. Expression Profiles of Neuropeptides, Neurotransmitters, and Their Receptors in Human Keratocytes In Vitro and In Situ.

    PubMed

    Słoniecka, Marta; Le Roux, Sandrine; Boman, Peter; Byström, Berit; Zhou, Qingjun; Danielson, Patrik

    2015-01-01

    Keratocytes, the quiescent cells of the corneal stroma, play a crucial role in corneal wound healing. Neuropeptides and neurotransmitters are usually associated with neuronal signaling, but have recently been shown to be produced also by non-neuronal cells and to be involved in many cellular processes. The aim of this study was to assess the endogenous intracellular and secreted levels of the neuropeptides substance P (SP) and neurokinin A (NKA), and of the neurotransmitters acetylcholine (ACh), catecholamines (adrenaline, noradrenaline and dopamine), and glutamate, as well as the expression profiles of their receptors, in human primary keratocytes in vitro and in keratocytes of human corneal tissue sections in situ. Cultured keratocytes expressed genes encoding for SP and NKA, and for catecholamine and glutamate synthesizing enzymes, as well as genes for neuropeptide, adrenergic and ACh (muscarinic) receptors. Keratocytes in culture produced SP, NKA, catecholamines, ACh, and glutamate, and expressed neurokinin-1 and -2 receptors (NK-1R and NK-2R), dopamine receptor D2, muscarinic ACh receptors, and NDMAR1 glutamate receptor. Human corneal sections expressed SP, NKA, NK-1R, NK-2R, receptor D2, choline acetyl transferase (ChAT), M3, M4 and M5 muscarinic ACh receptors, glutamate, and NMDAR1, but not catecholamine synthesizing enzyme or the α1 and β2 adrenoreceptors, nor M1 receptor. In addition, expression profiles assumed significant differences between keratocytes from the peripheral cornea as compared to those from the central cornea, as well as differences between keratocytes cultured under various serum concentrations. In conclusion, human keratocytes express an array of neuropeptides and neurotransmitters. The cells furthermore express receptors for neuropeptides/neurotransmitters, which suggests that they are susceptible to stimulation by these substances in the cornea, whether of neuronal or non-neuronal origin. As it has been shown that neuropeptides/neurotransmitters

  6. 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.

  7. Differential interactions of desipramine with amphetamine and methamphetamine: evidence that amphetamine releases dopamine from noradrenergic neurons in the medial prefrontal cortex.

    PubMed

    Shoblock, James R; Maisonneuve, Isabelle M; Glick, Stanley D

    2004-07-01

    Amphetamine is more effective than methamphetamine at raising dopamine levels in the prefrontal cortex. The current study tested the hypothesis that norepinephrine transporters are involved in this difference. Using microdialysis, dopamine, norepinephrine, and serotonin were measured in the rat prefrontal cortex after administration of methamphetamine or amphetamine, with and without perfusion of desipramine. Amphetamine raised norepinephrine levels more than methamphetamine did. Desipramine raised dopamine and serotonin levels but did not alter metabolite levels. Desipramine attenuated the increase in dopamine by amphetamine while increasing the dopamine released by methamphetamine. These data suggest that methamphetamine and amphetamine differ in altering prefrontal cortical dopamine levels and in interacting with norepinephrine transporters. It is proposed that amphetamine releases dopamine in the prefrontal cortex primarily through norepinephrine transporters, whereas methamphetamine interacts minimally with norepinephrine transporters.

  8. 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.

  9. 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

  10. Fast Phasic Release Properties of Dopamine Studied with a Channel Biosensor

    PubMed Central

    Kress, Geraldine J.; Shu, Hong-Jin; Yu, Andrew; Taylor, Amanda; Benz, Ann; Harmon, Steve

    2014-01-01

    Few other neurotransmitters are of as intense interest to neuropsychiatry and neurology as dopamine, yet existing techniques to monitor dopamine release leave an important spatiotemporal gap in our understanding. Electrochemistry and fluorescence imaging tools have been developed to fill the gap, but these methods have important limitations. We circumvent these limitations by introducing a dopamine-gated chloride channel into rat dorsal striatal medium spiny neurons, targets of strong dopamine innervation, thereby transforming dopamine from a slow transmitter into a fast transmitter and revealing new opportunities for studying moment-to-moment regulation of dopamine release. We demonstrate pharmacological and biophysical properties of the channel that make it suitable for fast, local dopamine measurements, and we demonstrate for the first time spontaneous and evoked responses to vesicular dopamine release in the dorsal striatum. Evoked dopamine currents were separated into a fast, monosynaptic component and a slower-rising and decaying disynaptic component mediated by nicotinic receptor activation. In summary, LGC-53 represents a dopamine biosensor with properties suitable for temporal separation of distinct dopamine signals in targets of dopamine innervation. PMID:25164674

  11. 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.

  12. Serotonin binds specifically and saturably to an actin-like protein isolated from rat brain synaptosomes.

    PubMed Central

    Small, D H; Wurtman, R J

    1984-01-01

    A soluble serotonin-binding protein was identified in a high-speed supernatant fraction of an osmotically shocked rat brain synaptosome (P2) preparation. The binding of serotonin was saturable (Bmax = 6.0 nmol per mg of protein) and was specific for serotonin and a few structurally related compounds including dopamine and norepinephrine. Binding of serotonin (1 microM) was inhibited approximately equal to 40% by chlorpromazine (10 microM). The affinity of serotonin for the binding protein was low in the crude extract (Kd = 1.7 X 10(-3)M). However, on purification by chromatography on a column of phenothiazine agarose, a higher affinity (Kd = 10(-5) M) binding component was also observed. The purified protein was greatly enriched in a polypeptide of Mr of 43,000 that comigrated on polyacrylamide gel with skeletal muscle actin. Muscle actin also bound serotonin, and the binding to actin was similar to that of the purified protein in both the specificity of the binding and the affinity for serotonin. It is likely that the serotonin-binding protein is identical to cytoplasmic G-actin or an actin-like protein of similar molecular weight. PMID:6583691

  13. Elevated spinal monoamine neurotransmitters after antenatal hypoxia-ischemia in rabbit cerebral palsy model

    PubMed Central

    Drobyshevsky, Alexander; Takada, Silvia Honda; Luo, Kehuan; Derrick, Matthew; Yu, Lei; Quinlan, Katharina A.; Vasquez-Vivar, Jeannette; Nogueira, Maria Inês; Tan, Sidhartha

    2014-01-01

    We hypothesized that a deficiency in the descending serotonergic input to spinal cord may underlie postnatal muscle hypertonia after global antenatal hypoxic-ischemic injury in a rabbit model of cerebral palsy. Neurotransmitter content was determined by HPLC in the spinal cord of newborns with and without muscle hypertonia after fetal global hypoxic-ischemic brain injury and naïve controls. Contrary to our hypothesis, serotonin levels in both cervical and lumbar expansions and norepinephrine in cervical expansion were increased in hypertonic kits relative to non-hypertonic kits and controls, with unchanged number of serotonergic cells in caudal raphe by stereological count. Serotonergic fiber length per unit of volume was also increased in hypertonic kits’ cervical and lumbar spinal cord, both in dorsal and ventral horns. Gene expression of serotonin transporter was increased and 5-HTR2 receptors were decreased in hypertonic kits relative to controls in cervical and lumbar cord. Intrathecal administration of nonselective serotonin receptor inhibitor methysergide decreased muscle tone in hypertonic kits only. Conversely, intrathecal administration of serotonin solution increased muscle tone only in non-hypertonic kits. We speculate that maturation of serotonergic system in spinal cord may be directly affected by decreased corticospinal connectivity after antenatal hypoxic-ischemic brain injury. PMID:25421613

  14. Action of selected serotonin antagonists on hyperthermia evoked by intracerebrally injected beta-endorphin.

    PubMed

    Martin, G E; Bacino, C B; Papp, N L

    1981-01-01

    Methergoline, an antagonist of cerebral serotonin receptors, has been shown to significantly reduce the rise in rectal temperature (Tre) produced by the intracerebral microinjection of beta-endorphin. In this study the role of serotonin in the increase in Tre elicited by beta-endorphin was further examined using three additional serotonin antagonists. beta-Endorphin was administered twice to rats using a crossover design in which half of the animals were first pretreated with the vehicle solution and half with the antagonist. Serotonin antagonists used were: methergoline, methysergide, cinanserin and cyproheptadine. Although methergoline did cause a marked reduction in the beta-endorphin-induced rise in Tre, neither methysergide, nor cinanserin, nor cyproheptadine produced a marked reduction in the hyperthermia. Since methergoline also interacts with the dopamine receptor, the effect of a dopamine antagonist, haloperidol, on the endorphin-evoked response was also examined. Haloperidol failed to attenuate the rise in Tre. The reason for the apparent discrepancy in the action of these serotonin antagonists is unclear. Further research may reveal distinct subpopulations of serotonin receptors at which these antagonists exert differential effects.

  15. 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.

  16. Rationality and emotionality: serotonin transporter genotype influences reasoning bias

    PubMed Central

    Bean, Stephanie E.; Anderson, Lindsay M.; Devaney, Joseph M.; Vaidya, Chandan J.

    2013-01-01

    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/SLG carriers of the serotonin transporter genotype (5-HTTLPR) were less accurate selectively for evaluating emotional relational reasoning problems with belief-logic conflict relative to LALA 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. PMID:22275169

  17. Molecular Mechanism of Dopamine Transport by Human Dopamine Transporter.

    PubMed

    Cheng, Mary Hongying; Bahar, Ivet

    2015-11-01

    Dopamine transporters (DATs) control neurotransmitter dopamine (DA) homeostasis by reuptake of excess DA, assisted by sodium and chloride ions. The recent resolution of DAT structure (dDAT) from Drosophila permits us for the first time to directly view the sequence of events involved in DA reuptake in human DAT (hDAT) using homology modeling and full-atomic microseconds accelerated simulations. Major observations are spontaneous closure of extracellular gates prompted by DA binding; stabilization of a holo-occluded intermediate; disruption of N82-N353 hydrogen bond and exposure to intracellular (IC) water triggered by Na2 dislocation; redistribution of a network of salt bridges at the IC surface in the inward-facing state; concerted tilting of IC-exposed helices to enable the release of Na(+) and Cl(-) ions; and DA release after protonation of D79. The observed time-resolved interactions confirm the conserved dynamics of LeuT-fold family, while providing insights into the mechanistic role of specific residues in hDAT.

  18. Central actions of a novel and selective dopamine antagonist

    SciTech Connect

    Schulz, D.W.

    1985-01-01

    Receptors for the neurotransmitter dopamine traditionally have been divided into two subgroups: the D/sub 1/ class, which is linked to the stimulation of adenylate cyclase-activity, and the D/sub 2/ class which is not. There is much evidence suggesting that it is the D/sub 2/ class which is not. There is much evidence suggesting that it is the D/sub 2/ dopamine receptor that mediates the physiological and behavioral actions of dopamine in the intact animal. However, the benzazepine SCH23390 is a dopamine antagonist which has potent behavioral actions while displaying apparent neurochemical selectivity for the D/sub 1/ class of dopamine receptors. The purpose of this dissertation was to (1) confirm and characterize this selectivity, and (2) test certain hypothesis related to possible modes of action of SCH233390. The inhibition of adenylate cyclase by SCH23390 occurred via an action at the dopamine receptor only. A radiolabeled analog of SCH23390 displayed the receptor binding properties of a specific high-affinity ligand, and regional receptor densities were highly correlated with dopamine levels. The subcellular distribution of (/sup 3/H)-SCH23390 binding did not correspond completely with that of dopamine-stimulated adenylate cyclase. The neurochemical potency of SCH23390 as a D/sub 1/ receptor antagonist was preserved following parental administration. A variety of dopamine agonists and antagonists displayed a high correlation between their abilities to compete for (/sup 3/H)-SCH23390 binding in vitro and to act at an adenylate cyclase-linked receptor. Finally, the relative affinities of dopamine and SCH23390 for both D/sub 1/ receptors and (/sup 3/H)-SCH23390 binding sites were comparable. It is concluded that the behavioral effects of SCH23390 are mediated by actions at D/sub 1/ dopamine receptors only, and that the physiological importance of this class of receptors should be reevaluated.

  19. Molecular cloning of genomic DNA and chromosomal assignment of the gene for human aromatic L-amino acid decarboxylase, the enzyme for catecholamine and serotonin biosynthesis

    SciTech Connect

    Sumi-Ichinose, Chiho ); Ichinose, Hiroshi; Nagatsu, Toshiharu ); Takahashi, Eiichi; Hori, Tadaaki )

    1992-03-03

    Aromatic L-amino acid decarboxylase (AADC) catalyzes the decarboxylation of both L-3,4-dihydroxyphenylalanine and L-5-hydroxytryptophan to dopamine and serotonin, respectively, which are major mammalian neurotransmitters and hormones belonging to catecholamines and indoleamines. This report describes the organization of the human AADC gene. The authors proved that the gene of human AADC consists of 15 exons spanning more than 85 kilobases and exists as a single copy in the haploid genome. The boundaries between exon and intron followed the AG/GT rule. The sizes of exons and introns ranged from 20 to 400 bp and from 1.0 to 17.7 kb, respectively, while the sizes of four introns were not determined. Untranslated regions located in the 5{prime} region of mRNA were encoded by two exons, exons 1 and 2. The transcriptional starting point was determined around G at position {minus}111 by primer extension and S1 mapping. There were no typical TATA box' and CAAT box' within 540 bp from the transcriptional starting point. The human AADC gene was mapped to chromosome band 7p12.1-p12.3 by fluorescence in situ hybridization. This is the first report on the genomic structure and chromosomal localization of the AADC gene in mammals.

  20. 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

  1. Validated methods for determination of neurotransmitters and metabolites in rodent brain tissue and extracellular fluid by reversed phase UHPLC-MS/MS.

    PubMed

    Bergh, Marianne Skov-Skov; Bogen, Inger Lise; Lundanes, Elsa; Øiestad, Åse Marit Leere

    2016-08-15

    Fast and sensitive methods for simultaneous determination of dopamine (DA), the two DA-metabolites homovanillic acid (HVA) and 3-methoxytyramine (3-MT), serotonin (5-HT) and the 5-HT-metabolite 5-hydroxyindoleacetic acid (5-HIAA), norepinephrine (NE), acetylcholine (ACh), glutamic acid (Glu) and γ-aminobutyric acid (GABA) in rodent brain tissue (1.0-4000nM) and extracellular fluid (ECF) (0.5-2000nM) based on ultra high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) have been developed. Of the three different sample preparation methods for brain tissue samples tested, a simple and rapid protein precipitation procedure with formic acid was found to give the best results. The neurotransmitters (NTs) and NT metabolites were separated using UHPLC with an Acquity UPLC HSS T3 C18 column (2.1×100mm, 1.8μm particle size) with acidic mobile phase. Gradient elution with methanol was used and quantification was performed using multiple reaction monitoring (MRM). The total run time was 5.2min including equilibration time. The methods were validated by determining calibration model, intra- and inter-day precision and accuracy, limit of detection (LOD), lower limit of quantification (LLOQ), matrix effects (ME), carry-over and stability. Surrogate analytes were used to enable determination of the recovery and ME of the endogenous analytes in brain tissue. The methods were applied for determination of NTs at basal levels in rodent brain ECF and brain tissue homogenate. The developed methods are valuable tools in the studies of mechanisms of drugs of abuse, and neurologic and psychiatric disease. PMID:27336704

  2. 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.

  3. 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. PMID:26604076

  4. Glucocorticoids Inhibit Basal and Hormone-Induced Serotonin Synthesis in Pancreatic Beta Cells.

    PubMed

    Hasni Ebou, Moina; Singh-Estivalet, Amrit; Launay, Jean-Marie; Callebert, Jacques; Tronche, François; Ferré, Pascal; Gautier, Jean-François; Guillemain, Ghislaine; Bréant, Bernadette; Blondeau, Bertrand; Riveline, Jean-Pierre

    2016-01-01

    Diabetes is a major complication of chronic Glucocorticoids (GCs) treatment. GCs induce insulin resistance and also inhibit insulin secretion from pancreatic beta cells. Yet, a full understanding of this negative regulation remains to be deciphered. In the present study, we investigated whether GCs could inhibit serotonin synthesis in beta cell since this neurotransmitter has been shown to be involved in the regulation of insulin secretion. To this aim, serotonin synthesis was evaluated in vitro after treatment with GCs of either islets from CD1 mice or MIN6 cells, a beta-cell line. We also explored the effect of GCs on the stimulation of serotonin synthesis by several hormones such as prolactin and GLP 1. We finally studied this regulation in islet in two in vivo models: mice treated with GCs and with liraglutide, a GLP1 analog, and mice deleted for the glucocorticoid receptor in the pancreas. We showed in isolated islets and MIN6 cells that GCs decreased expression and activity of the two key enzymes of serotonin synthesis, Tryptophan Hydroxylase 1 (Tph1) and 2 (Tph2), leading to reduced serotonin contents. GCs also blocked the induction of serotonin synthesis by prolactin or by a previously unknown serotonin activator, the GLP-1 analog exendin-4. In vivo, activation of the Glucagon-like-Peptide-1 receptor with liraglutide during 4 weeks increased islet serotonin contents and GCs treatment prevented this increase. Finally, islets from mice deleted for the GR in the pancreas displayed an increased expression of Tph1 and Tph2 and a strong increased serotonin content per islet. In conclusion, our results demonstrate an original inhibition of serotonin synthesis by GCs, both in basal condition and after stimulation by prolactin or activators of the GLP-1 receptor. This regulation may contribute to the deleterious effects of GCs on beta cells.

  5. Glucocorticoids Inhibit Basal and Hormone-Induced Serotonin Synthesis in Pancreatic Beta Cells

    PubMed Central

    Hasni Ebou, Moina; Singh-Estivalet, Amrit; Launay, Jean-Marie; Callebert, Jacques; Tronche, François; Ferré, Pascal; Gautier, Jean-François; Guillemain, Ghislaine; Bréant, Bernadette

    2016-01-01

    Diabetes is a major complication of chronic Glucocorticoids (GCs) treatment. GCs induce insulin resistance and also inhibit insulin secretion from pancreatic beta cells. Yet, a full understanding of this negative regulation remains to be deciphered. In the present study, we investigated whether GCs could inhibit serotonin synthesis in beta cell since this neurotransmitter has been shown to be involved in the regulation of insulin secretion. To this aim, serotonin synthesis was evaluated in vitro after treatment with GCs of either islets from CD1 mice or MIN6 cells, a beta-cell line. We also explored the effect of GCs on the stimulation of serotonin synthesis by several hormones such as prolactin and GLP 1. We finally studied this regulation in islet in two in vivo models: mice treated with GCs and with liraglutide, a GLP1 analog, and mice deleted for the glucocorticoid receptor in the pancreas. We showed in isolated islets and MIN6 cells that GCs decreased expression and activity of the two key enzymes of serotonin synthesis, Tryptophan Hydroxylase 1 (Tph1) and 2 (Tph2), leading to reduced serotonin contents. GCs also blocked the induction of serotonin synthesis by prolactin or by a previously unknown serotonin activator, the GLP-1 analog exendin-4. In vivo, activation of the Glucagon-like-Peptide-1 receptor with liraglutide during 4 weeks increased islet serotonin contents and GCs treatment prevented this increase. Finally, islets from mice deleted for the GR in the pancreas displayed an increased expression of Tph1 and Tph2 and a strong increased serotonin content per islet. In conclusion, our results demonstrate an original inhibition of serotonin synthesis by GCs, both in basal condition and after stimulation by prolactin or activators of the GLP-1 receptor. This regulation may contribute to the deleterious effects of GCs on beta cells. PMID:26901633

  6. Dopamine Signaling Regulates Fat Content through β-Oxidation in Caenorhabditis elegans

    PubMed Central

    Barros, Alexandre Guimarães de Almeida; Bridi, Jessika Cristina; de Souza, Bruno Rezende; de Castro Júnior, Célio; de Lima Torres, Karen Cecília; Malard, Leandro; Jorio, Ado; de Miranda, Débora Marques; Ashrafi, Kaveh; Romano-Silva, Marco Aurélio

    2014-01-01

    The regulation of energy balance involves an intricate interplay between neural mechanisms that respond to internal and external cues of energy demand and food availability. Compelling data have implicated the neurotransmitter dopamine as an important part of body weight regulation. However, the precise mechanisms through which dopamine regulates energy homeostasis remain poorly understood. Here, we investigate mechanisms through which dopamine modulates energy storage. We showed that dopamine signaling regulates fat reservoirs in Caenorhabditis elegans. We found that the fat reducing effects of dopamine were dependent on dopaminergic receptors and a set of fat oxidation enzymes. Our findings reveal an ancient role for dopaminergic regulation of fat and suggest that dopamine signaling elicits this outcome through cascades that ultimately mobilize peripheral fat depots. PMID:24465759

  7. 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.

  8. Neurotransmitters regulating feline aggressive behavior.

    PubMed

    Siegel, A; Schubert, K

    1995-01-01

    The experiments described in this review reveal that the expression and modulation of aggressive responses in the cat are organized by two distinct sets of pathways. One set of pathways is associated with the elicitation of a specific form of attack behavior. It includes the medial hypothalamus and its projections to the PAG for the expression of defensive rage behavior and the lateral hypothalamus and its descending projections for the expression of predatory attack behavior. The primary focus of the present review is upon the analysis of defensive rage behavior. It was demonstrated that the pathway from the medial hypothalamus to the PAG, which appears to be essential for elicitation of defensive rage, is powerfully excitatory and utilizes excitatory amino acids that act upon NMDA receptors within the PAG. The other pathways examined in this review arise from different nuclei of the amygdala and are modulatory in nature. Here, two facilitatory systems have been identified. The first involves a projection system from the basal complex of amygdala that projects directly to the PAG. Its excitatory effects are manifest through excitatory amino acids that act upon NMDA receptors within the PAG. The second facilitatory pathway arises from the medial nucleus of the amygdala. However, its projection system is directed to the medial hypothalamus rather than the PAG. Its neurotransmitter appears to be substance P that acts upon NK1 receptors within the medial hypothalamus (see Figure 10). It has yet to be determined whether substance P acts upon any of the other neurokinin receptor subtypes. It should also be pointed out that the substance P pathway from the medial amygdala to the medial hypothalamus functions to suppress predatory attack behavior elicited from the lateral hypothalamus. In this network, it is likely that the modulatory effects of the medial amygdala require the presence of a second, inhibitory pathway from the medial hypothalamus that innervates the

  9. Distinct effects of the serotonin-noradrenaline reuptake inhibitors milnacipran and venlafaxine on rat pineal monoamines.

    PubMed

    Muneoka, Katsumasa; Kuwagata, Makiko; Ogawa, Tetsuo; Shioda, Seiji

    2015-06-17

    Monoamine systems are involved in the pathology and therapeutic mechanism of depression. The pineal gland contains large amounts of serotonin as a precursor for melatonin, and its activity is controlled by noradrenergic sympathetic nerves. Pineal diurnal activity and its release of melatonin are relevant to aberrant states observed in depression. We investigated the effects on pineal monoamines of serotonin-noradrenaline reuptake inhibitors, which are widely used antidepressants. Four days of milnacipran treatment led to an increase in noradrenaline and serotonin levels, whereas 4 days of venlafaxine treatment reduced 5-hydroxyindoleacetic acid levels; both agents induced an increase in dopamine levels. Our data suggest that milnacipran increases levels of the precursor for melatonin synthesis by facilitating the noradrenergic regulation of pineal activity and that venlafaxine inhibits serotonin reuptake into noradrenergic terminals on the pineal gland. PMID:26016648

  10. A Neurobiological Hypothesis of Treatment-Resistant Depression – Mechanisms for Selective Serotonin Reuptake Inhibitor Non-Efficacy

    PubMed Central

    Coplan, Jeremy D.; Gopinath, Srinath; Abdallah, Chadi G.; Berry, Benjamin R.

    2014-01-01

    First-line treatment of major depression includes administration of a selective serotonin reuptake inhibitor (SSRI), yet studies suggest that remission rates following two trials of an SSRI are <50%. The authors examine the putative biological substrates underlying “treatment resistant depression (TRD)” with the goal of elucidating novel rationales to treat TRD. We look at relevant articles from the preclinical and clinical literature combined with clinical exposure to TRD patients. A major focus was to outline pathophysiological mechanisms whereby the serotonin system becomes impervious to the desired enhancement of serotonin neurotransmission by SSRIs. A complementary focus was to dissect neurotransmitter systems, which serve to inhibit the dorsal raphe. We propose, based on a body of translational studies, TRD may not represent a simple serotonin deficit state but rather an excess of midbrain peri-raphe serotonin and subsequent deficit at key fronto-limbic projection sites, with ultimate compromise in serotonin-mediated neuroplasticity. Glutamate, serotonin, noradrenaline, and histamine are activated by stress and exert an inhibitory effect on serotonin outflow, in part by “flooding” 5-HT1A autoreceptors by serotonin itself. Certain factors putatively exacerbate this scenario – presence of the short arm of the serotonin transporter gene, early-life adversity and comorbid bipolar disorder – each of which has been associated with SSRI-treatment resistance. By utilizing an incremental approach, we provide a system for treating the TRD patient based on a strategy of rescuing serotonin neurotransmission from a state of SSRI-induced dorsal raphe stasis. This calls for “stacked” interventions, with an SSRI base, targeting, if necessary, the glutamatergic, serotonergic, noradrenergic, and histaminergic systems, thereby successively eliminating the inhibitory effects each are capable of exerting on serotonin neurons. Future studies are recommended to test

  11. Acrylamide increases dopamine levels by affecting dopamine transport and metabolism related genes in the striatal dopaminergic system.

    PubMed

    Pan, Xiaoqi; Guo, Xiongxiong; Xiong, Fei; Cheng, Guihong; Lu, Qing; Yan, Hong

    2015-07-01

    Dopaminergic system dysfunction is proved to be a possible mechanism in acrylamide (ACR) -induced neurotoxicity. The neurotransmitter dopamine (DA) has an increasingly important role in the dopaminergic system. Thus, the goal of this study is to evaluate effects of ACR on dopamine and its metabolite levels, dopamine transport and metabolic gene expression in dopaminergic neurons. Male Sprague-Dawley (SD) rats were dosed orally with ACR at 0 (saline), 20, 30, and 40 mg/kg/day for 20 days. Splayed hind limbs, reduced tail flick time and abnormal gait which preceded other neurologic parameters were observed in the above rats. ACR significantly increased dopamine levels, decreased 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) contents in an area dependent manner in rat striatum. Immunohistochemical staining of the striatum revealed that the number of tyrosine hydroxylase (TH) positive cells significantly increased, while monoamine oxidase (MAO) positive cells were drastically reduced, which was consistent with changes in their mRNA and protein expressions. In addition, dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) expression levels were both down-regulated in the striatum. These results suggest that dopamine levels increase significantly in response to ACR, presumably due to changes in the dopamine transport and metabolism related genes expression in the striatal dopaminergic neurons.

  12. Exploration of inclusion complexes of neurotransmitters with β-cyclodextrin by physicochemical techniques

    NASA Astrophysics Data System (ADS)

    Roy, Mahendra Nath; Saha, Subhadeep; Kundu, Mitali; Saha, Binoy Chandra; Barman, Siti

    2016-07-01

    Molecular assemblies of β-cyclodextrin with few of the most important neurotransmitters, viz., dopamine hydrochloride, tyramine hydrochloride and (±)-epinephrine hydrochloride in aqueous medium have been explored by reliable spectroscopic and physicochemical techniques as potential drug delivery systems. Job plots confirm the 1:1 host-guest inclusion complexes, while surface tension and conductivity studies illustrate the inclusion process. The inclusion complexes were characterized by 1H NMR spectroscopy and association constants have been calculated by using Benesi-Hildebrand method. Thermodynamic parameters for the formation of inclusion complexes have been derived by van't Hoff equation, which demonstrate that the overall inclusion processes are thermodynamically favorable.

  13. Chlorophenylpiperazine analogues as high affinity dopamine transporter ligands.

    PubMed

    Motel, William C; Healy, Jason R; Viard, Eddy; Pouw, Buddy; Martin, Kelly E; Matsumoto, Rae R; Coop, Andrew

    2013-12-15

    Selective σ2 ligands continue to be an active target for medications to attenuate the effects of psychostimulants. In the course of our studies to determine the optimal substituents in the σ2-selective phenyl piperazines analogues with reduced activity at other neurotransmitter systems, we discovered that 1-(3-chlorophenyl)-4-phenethylpiperazine actually had preferentially increased affinity for dopamine transporters (DAT), yielding a highly selective DAT ligand. PMID:24211020

  14. Afferent Inputs to Neurotransmitter-Defined Cell Types in the Ventral Tegmental Area.

    PubMed

    Faget, Lauren; Osakada, Fumitaka; Duan, Jinyi; Ressler, Reed; Johnson, Alexander B; Proudfoot, James A; Yoo, Ji Hoon; Callaway, Edward M; Hnasko, Thomas S

    2016-06-21

    The ventral tegmental area (VTA) plays a central role in the neural circuit control of behavioral reinforcement. Though considered a dopaminergic nucleus, the VTA contains substantial heterogeneity in neurotransmitter type, containing also GABA and glutamate neurons. Here, we used a combinatorial viral approach to transsynaptically label afferents to defined VTA dopamine, GABA, or glutamate neurons. Surprisingly, we find that these populations received qualitatively similar inputs, with dominant and comparable projections from the lateral hypothalamus, raphe, and ventral pallidum. However, notable differences were observed, with striatal regions and globus pallidus providing a greater share of input to VTA dopamine neurons, cortical input preferentially on to glutamate neurons, and GABA neurons receiving proportionally more input from the lateral habenula and laterodorsal tegmental nucleus. By comparing inputs to each of the transmitter-defined VTA cell types, this study sheds important light on the systems-level organization of diverse inputs to VTA.

  15. Regulation of serotonin transporter gene expression in human glial cells by growth factors.

    PubMed

    Kubota, N; Kiuchi, Y; Nemoto, M; Oyamada, H; Ohno, M; Funahashi, H; Shioda, S; Oguchi, K

    2001-04-01

    The aims of this study were to identify monoamine transporters expressed in human glial cells, and to examine the regulation of their expression by stress-related growth factors. The expression of serotonin transporter mRNA was detected by reverse transcriptase-polymerase chain reaction in normal human astrocytes, whereas the dopamine transporter (DAT) and the norepinephrine transporter (NET) were not detected. The cDNA sequence of the "glial" serotonin transporter in astrocytes was consistent with that reported for the "neuronal" serotonin transporter (SERT). Moreover, we also demonstrated SERT expression in glial fibrillary acidic protein-positive cells by immunocytochemical staining in normal human astrocytes. Serotonin transporter gene expression was also detected in glioma-derived cell lines (A172, KG-1-C and KGK). Addition of basic fibroblast growth factor (bFGF) or epidermal growth factor (EGF) for 2 days increased serotonin transporter gene expression in astrocytes and JAR (human choriocarcinoma cell line). Basic fibroblast growth factor, but not epidermal growth factor, increased specific [3H]serotonin uptake in astrocytes in a time (1-4 days)- and concentration (20-100 ng/ml)-dependent manner. The expression of genes for basic fibroblast growth factor and epidermal growth factor receptors was detected in astrocytes. These findings suggest that the expression of the serotonin transporter in human glial cells is positively regulated by basic fibroblast growth factor. PMID:11301061

  16. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis.

    PubMed

    O'Mahony, S M; Clarke, G; Borre, Y E; Dinan, T G; Cryan, J F

    2015-01-15

    The brain-gut axis is a bidirectional communication system between the central nervous system and the gastrointestinal tract. Serotonin functions as a key neurotransmitter at both terminals of this network. Accumulating evidence points to a critical role for the gut microbiome in regulating normal functioning of this axis. In particular, it is becoming clear that the microbial influence on tryptophan metabolism and the serotonergic system may be an important node in such regulation. There is also substantial overlap between behaviours influenced by the gut microbiota and those which rely on intact serotonergic neurotransmission. The developing serotonergic system may be vulnerable to differential microbial colonisation patterns prior to the emergence of a stable adult-like gut microbiota. At the other extreme of life, the decreased diversity and stability of the gut microbiota may dictate serotonin-related health problems in the elderly. The mechanisms underpinning this crosstalk require further elaboration but may be related to the ability of the gut microbiota to control host tryptophan metabolism along the kynurenine pathway, thereby simultaneously reducing the fraction available for serotonin synthesis and increasing the production of neuroactive metabolites. The enzymes of this pathway are immune and stress-responsive, both systems which buttress the brain-gut axis. In addition, there are neural processes in the gastrointestinal tract which can be influenced by local alterations in serotonin concentrations with subsequent relay of signals along the scaffolding of the brain-gut axis to influence CNS neurotransmission. Therapeutic targeting of the gut microbiota might be a viable treatment strategy for serotonin-related brain-gut axis disorders.

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

    PubMed

    Levite, M

    2016-01-01

    Dopamine, a principal neurotransmitter, deserves upgrading to 'NeuroImmunotransmitter' thanks to its multiple, direct and powerful effects on most/all immune cells. Dopamine by itself is a potent activator of resting effector T cells (Teffs), via two independent ways: direct Teffs activation, and indirect Teffs activation by suppression of regulatory T cells (Tregs). The review covers the following findings: (i) T cells express functional dopamine receptors (DRs) D1R-D5R, but their level and function are dynamic and context-sensitive, (ii) DR membranal protein levels do not necessarily correlate with DR mRNA levels, (iii) different T cell types/subtypes have different DR levels and composition and different responses to dopamine, (iv) autoimmune and pro-inflammatory T cells and T cell leukaemia/lymphoma also express functional DRs, (v) dopamine (~10(-8) M) activates resting/naive Teffs (CD8(+) >CD4(+) ), (vi) dopamine affects Th1/Th2/Th17 differentiation, (vii) dopamine inhibits already activated Teffs (i.e. T cells that have been already activated by either antigen, mitogen, anti-CD3 antibodies cytokines or other molecules), (viii) dopamine inhibits activated Tregs in an autocrine/paracrine manner. Thus, dopamine 'suppresses the suppressors' and releases the inhibition they exert on Teffs, (ix) dopamine affects intracellular signalling molecules and cascades in T cells (e.g. ERK, Lck, Fyn, NF-κB, KLF2), (x) T cells produce dopamine (Tregs>Teffs), can release dopamine, mainly after activation (by antigen, mitogen, anti-CD3 antibodies, PKC activators or other), uptake extracellular dopamine, and most probably need dopamine, (xi) dopamine is important for antigen-specific interactions between T cells and dendritic cells, (xii) in few autoimmune diseases (e.g. multiple sclerosis/SLE/rheumatoid arthritis), and neurological/psychiatric diseases (e.g. Parkinson disease, Alzheimer's disease, Schizophrenia and Tourette), patient's T cells seem to have abnormal DRs

  18. Cognitive inflexibility after prefrontal serotonin depletion is behaviorally and neurochemically specific.

    PubMed

    Clarke, H F; Walker, S C; Dalley, J W; Robbins, T W; Roberts, A C

    2007-01-01

    We have previously demonstrated that prefrontal serotonin depletion impairs orbitofrontal cortex (OFC)-mediated serial discrimination reversal (SDR) learning but not lateral prefrontal cortex (PFC)-mediated attentional set shifting. To address the neurochemical specificity of this reversal deficit, Experiment 1 compared the effects of selective serotonin and selective dopamine depletions of the OFC on performance of the SDR task. Whereas serotonin depletions markedly impaired performance, OFC dopamine depletions were without effect. The behavioral specificity of this reversal impairment was investigated in Experiment 2 by examining the effect of OFC serotonin depletion on performance of a modified SDR task designed to distinguish between 3 possible causes of the impairment. The results showed that the reversal deficit induced by prefrontal serotonin depletion was not due to a failure to approach a previously unrewarded stimulus (enhanced learned avoidance) or reduced proactive interference. Instead, it was due specifically to a failure to inhibit responding to the previously rewarded stimulus. The neurochemical and behavioral specificity of this particular form of cognitive inflexibility is of particular relevance to our understanding of the aetiology and treatment of inflexible behavior apparent in many neuropsychiatric and neurodegenerative disorders involving the PFC.

  19. VEGF-induced antidepressant effects involve modulation of norepinephrine and serotonin systems.

    PubMed

    Udo, Hiroshi; Hamasu, Kousuke; Furuse, Mitsuhiro; Sugiyama, Hiroyuki

    2014-12-15

    Throughout life, we are exposed to a variety of stresses, which may be inevitable and noxious sometimes. During evolution, animals must have acquired some physiological means to counteract stress. Vascular endothelial growth factor (VEGF) is an angiogenic and neurogenic factor, which has been shown to elicit antidepressant-like effects in response to different external stimuli, potentially functioning as an anti-stress molecule. However, it remains largely unknown how VEGF modulates mood-related behaviors. To investigate molecular correlates, we analyzed monoaminergic systems of VEGF transgenic mice that display antidepressant-like behavior. Immunostaining showed that overall morphologies of monoaminergic nuclei and their processes were normal. However, we found imbalances in brain monoamine contents, in which the levels of norepinephrine and serotonin, but not dopamine, were decreased exclusively in the regions where VEGF was expressed. The turnover of norepinephrine showed a marked increase and serotonin turnover showed a modest reduction, whereas dopamine turnover was not affected. The protein levels of tyrosine hydroxylase and tryptophan hydroxylase, the rate-limiting enzymes of catecholamine and serotonin synthesis, remained constant. The mRNA levels of monoamine receptors were generally similar but adrenergic receptors of ADRα1A and ADRβ1 were down-regulated. Behavioral tests showed that serotonin- or norepinephrine-selective antidepressant drugs failed to additively enhance antidepressant-like behaviors, whereas monoamine depleting drugs attenuated VEGF-mediated antidepressant-like effect. These data suggest that VEGF-induced antidepressant-like effects involve modulation of norepinephrine and serotonin systems.

  20. Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward.

    PubMed

    Kishida, Kenneth T; Saez, Ignacio; Lohrenz, Terry; Witcher, Mark R; Laxton, Adrian W; Tatter, Stephen B; White, Jason P; Ellis, Thomas L; Phillips, Paul E M; Montague, P Read

    2016-01-01

    In the mammalian brain, dopamine is a critical neuromodulator whose actions underlie learning, decision-making, and behavioral control. Degeneration of dopamine neurons causes Parkinson's disease, whereas dysregulation of dopamine signaling is believed to contribute to psychiatric conditions such as schizophrenia, addiction, and depression. Experiments in animal models suggest the hypothesis that dopamine release in human striatum encodes reward prediction errors (RPEs) (the difference between actual and expected outcomes) during ongoing decision-making. Blood oxygen level-dependent (BOLD) imaging experiments in humans support the idea that RPEs are tracked in the striatum; however, BOLD measurements cannot be used to infer the action of any one specific neurotransmitter. We monitored dopamine levels with subsecond temporal resolution in humans (n = 17) with Parkinson's disease while they executed a sequential decision-making task. Participants placed bets and experienced monetary gains or losses. Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons. PMID:26598677

  1. Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward

    PubMed Central

    Kishida, Kenneth T.; Saez, Ignacio; Lohrenz, Terry; Witcher, Mark R.; Laxton, Adrian W.; Tatter, Stephen B.; White, Jason P.; Ellis, Thomas L.; Phillips, Paul E. M.; Montague, P. Read

    2016-01-01

    In the mammalian brain, dopamine is a critical neuromodulator whose actions underlie learning, decision-making, and behavioral control. Degeneration of dopamine neurons causes Parkinson’s disease, whereas dysregulation of dopamine signaling is believed to contribute to psychiatric conditions such as schizophrenia, addiction, and depression. Experiments in animal models suggest the hypothesis that dopamine release in human striatum encodes reward prediction errors (RPEs) (the difference between actual and expected outcomes) during ongoing decision-making. Blood oxygen level-dependent (BOLD) imaging experiments in humans support the idea that RPEs are tracked in the striatum; however, BOLD measurements cannot be used to infer the action of any one specific neurotransmitter. We monitored dopamine levels with subsecond temporal resolution in humans (n = 17) with Parkinson’s disease while they executed a sequential decision-making task. Participants placed bets and experienced monetary gains or losses. Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons. PMID:26598677

  2. [COMPARATIVE ANALYSIS OF SEROTONIN LEVELS IN RAT PLATELETS, SERUM AND BRAIN ON THE AGING].

    PubMed

    Taborskaya, K I; Frolova, M Yu; Kuleva, N V

    2016-01-01

    Serotonin functions as neurotransmitter in central nervous system and is involved in the regulation of vascular tone, gastro-intestinal motility and blood coagulation in the periphery. The appearance of new data on the significant correlation between serotonin levels in platelets and cerebrospinal fluid (Audhya et al., 2012) renewed interest in the hypothesis in which the platelet is seen as a model of cerotoninergic neuron. In our study, the levels of serotonin in platelets, serum and various brain regions of rats aged 6 and 24 months have been determined and comparatively analyzed. The method of high performance liquid chromatography was used. The decrease of serotonin level in platelets from 0.768 to 0.359 μg per 10(9) cells and its increase in the middle brain from 0.260 to 0.439 μg per 1 of wet weight have been clearly demonstrated in aging of animals. The differences in the content of serotonin in other parts of the brain and in the blood serum of young and old animals were statistically insignificant. Therefore, despite the attractiveness of the concept of platelet as a model of a neuron, the extrapolation of the data on platelet serotonin transport into neuronal ones requires caution, especially in the study of aging.

  3. Developmental Changes in Dopamine Neurotransmission in Adolescence: Behavioral Implications and Issues in Assessment

    ERIC Educational Resources Information Center

    Wahlstrom, Dustin; Collins, Paul; White, Tonya; Luciana, Monica

    2010-01-01

    Adolescence is characterized by increased risk-taking, novelty-seeking, and locomotor activity, all of which suggest a heightened appetitive drive. The neurotransmitter dopamine is typically associated with behavioral activation and heightened forms of appetitive behavior in mammalian species, and this pattern of activation has been described in…

  4. Blink Rate in Boys with Fragile X Syndrome: Preliminary Evidence for Altered Dopamine Function

    ERIC Educational Resources Information Center

    Roberts, J. E.; Symons, F. J.; Johnson, A.-M.; Hatton, D. D.; Boccia, M. L.

    2005-01-01

    Background: Dopamine, a neurotransmitter involved in motor and cognitive functioning, can be non-invasively measured via observation of spontaneous blink rates. Blink rates have been studied in a number of clinical conditions including schizophrenia, autism, Parkinsons, and attention deficit/hyperactivity disorder with results implicating either…

  5. Dopamine Regulation of Human Speech and Bird Song: A Critical Review

    ERIC Educational Resources Information Center

    Simonyan, Kristina; Horwitz, Barry; Jarvis, Erich D.

    2012-01-01

    To understand the neural basis of human speech control, extensive research has been done using a variety of methodologies in a range of experimental models. Nevertheless, several critical questions about learned vocal motor control still remain open. One of them is the mechanism(s) by which neurotransmitters, such as dopamine, modulate speech and…

  6. Pharmacological and signalling properties of a D2-like dopamine receptor (Dop3) in Tribolium castaneum.

    PubMed

    Verlinden, Heleen; Vleugels, Rut; Verdonck, Rik; Urlacher, Elodie; Vanden Broeck, Jozef; Mercer, Alison

    2015-01-01

    Dopamine is an important neurotransmitter in the central nervous system of vertebrates and invertebrates. Despite their evolutionary distance, striking parallels exist between deuterostomian and protostomian dopaminergic systems. In both, signalling is achieved via a complement of functionally distinct dopamine receptors. In this study, we investigated the sequence, pharmacology and tissue distribution of a D2-like dopamine receptor from the red flour beetle Tribolium castaneum (TricaDop3) and compared it with related G protein-coupled receptors in other invertebrate species. The TricaDop3 receptor-encoding cDNA shows considerable sequence similarity with members of the Dop3 receptor class. Real time qRT-PCR showed high expression in both the central brain and the optic lobes, consistent with the role of dopamine as neurotransmitter. Activation of TricaDop3 expressed in mammalian cells increased intracellular Ca(2+) signalling and decreased NKH-477 (a forskolin analogue)-stimulated cyclic AMP levels in a dose-dependent manner. We studied the pharmacological profile of the TricaDop3 receptor and demonstrated that the synthetic vertebrate dopamine receptor agonists, 2 - amino- 6,7 - dihydroxy - 1,2,3,4 - tetrahydronaphthalene hydrobromide (6,7-ADTN) and bromocriptine acted as agonists. Methysergide was the most potent of the antagonists tested and showed competitive inhibition in the presence of dopamine. This study offers important information on the Dop3 receptor from Tribolium castaneum that will facilitate functional analyses of dopamine receptors in insects and other invertebrates.

  7. Intrahippocampal Infusions of Anisomycin Produce Amnesia: Contribution of Increased Release of Norepinephrine, Dopamine, and Acetylcholine

    ERIC Educational Resources Information Center

    Qi, Zhenghan; Gold, Paul E.

    2009-01-01

    Intra-amygdala injections of anisomycin produce large increases in the release of norepinephrine (NE), dopamine (DA), and serotonin in the amygdala. Pretreatment with intra-amygdala injections of the beta-adrenergic receptor antagonist propranolol attenuates anisomycin-induced amnesia without reversing the inhibition of protein synthesis, and…

  8. Selective reduction by isolation rearing of 5-HT1A receptor-mediated dopamine release in vivo in the frontal cortex of mice.

    PubMed

    Ago, Y; Sakaue, M; Baba, A; Matsuda, T

    2002-10-01

    Serotonin (5-HT)1A receptors modulate in vivo release of brain monoaminergic neurotransmitters which may be involved in isolation-induced aggressive behavior. The present study examined the effect of isolation rearing on the 5-HT1A receptor-mediated modulation of dopamine (DA), 5-HT and noradrenaline (NA) release in the frontal cortex of mice. The selective 5-HT1A receptor agonist (S)-5-[-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242) increased the release of DA and NA and decreased the release of 5-HT in the frontal cortex of mice. The effect of MKC-242 on DA release was significantly less in isolation-reared mice than in group-reared mice, while effects of the drug on NA and 5-HT release did not differ between both groups. The effect of the other 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin on cortical DA release was also less in isolation-reared mice than in group-reared mice, and that of the drug on cortical 5-HT release did not differ between both groups. In contrast to MKC-242-induced DA release, amphetamine-induced increase in cortical DA release in vivo was greater in isolation-reared mice. The present findings suggest that isolation rearing enhances the activity of cortical dopaminergic neurons and reduces selectively the 5-HT1A receptor-mediated release of DA in the cortex.

  9. Dopamine induces an optimism bias in rats-Pharmacological proof for the translational validity of the ambiguous-cue interpretation test.

    PubMed

    Kregiel, J; Golebiowska, J; Popik, P; Rygula, R

    2016-01-15

    Recent findings have revealed that pharmacological enhancement of dopaminergic (DA) function by the administration of a dopaminergic precursor (dihydroxy-l-phenylalanine; l-DOPA) increases an optimism bias in humans. This effect is due to l-DOPA's impairment of the ability to update beliefs in response to undesirable information about the future. To test whether an 'optimistic' bias is also mediated by dopamine in animals, first, two groups of rats received either a dopaminergic precursor, l-DOPA, or a D2 receptor antagonist, haloperidol, and were subsequently tested using the ambiguous-cue interpretation (ACI) paradigm. To test whether similar effects might be observed when manipulating another neurotransmitter implicated in learning about reward and punishment, we administered the serotonin (5-HT) reuptake inhibitor escitalopram to a third group of animals and the selective and irreversible tryptophan hydroxylase inhibitor para-chlorophenylalanine (PCPA) to a fourth group. The results of our study demonstrated that prolonged (2 weeks), but not acute, l-DOPA administration induced optimistic bias in rats. Neither acute nor chronic treatment with the other tested compounds had significant effects on the cognitive judgment bias of rats. The convergence of these results with human studies suggests the translational validity of the ambiguous-cue interpretation paradigm in testing the effects of pharmacological manipulations on cognitive judgment bias (optimism/pessimism) in rats. PMID:26462571

  10. Developmental origins of brain disorders: roles for dopamine

    PubMed Central

    Money, Kelli M.; Stanwood, Gregg D.

    2013-01-01

    Neurotransmitters and neuromodulators, such as dopamine, participate in a wide range of behavioral and cognitive functions in the adult brain, including movement, cognition, and reward. Dopamine-mediated signaling plays a fundamental neurodevelopmental role in forebrain differentiation and circuit formation. These developmental effects, such as modulation of neuronal migration and dendritic growth, occur before synaptogenesis and demonstrate novel roles for dopaminergic signaling beyond neuromodulation at the synapse. Pharmacologic and genetic disruptions demonstrate that these effects are brain region- and receptor subtype-specific. For example, the striatum and frontal cortex exhibit abnormal neuronal structure and function following prenatal disruption of dopamine receptor signaling. Alterations in these processes are implicated in the pathophysiology of neuropsychiatric disorders, and emerging studies of neurodevelopmental disruptions may shed light on the pathophysiology of abnormal neuronal circuitry in neuropsychiatric disorders. PMID:24391541

  11. Detection and Quantification of Neurotransmitters in Dialysates

    PubMed Central

    Zapata, Agustin; Chefer, Vladimir I.; Shippenberg, Toni S.; Denoroy, Luc

    2010-01-01

    Sensitive analytical methods are needed for the separation and quantification of neurotransmitters obtained in microdialysate studies. This unit describes methods that permit quantification of nanomolar concentrations of monoamines and their metabolites (high-pressure liquid chromatography electrochemical detection), acetylcholine (HPLC-coupled to an enzyme reactor), and amino acids (HPLC-fluorescence detection; capillary electrophoresis with laser-induced fluorescence detection). PMID:19575473

  12. Trophic effects of neurotransmitters during brain maturation.

    PubMed

    Emerit, M B; Riad, M; Hamon, M

    1992-01-01

    Besides their neurotransmitter and/or neuromodulatory roles, many neuroactive substances synthesized and released during brain development can also directly influence neuronal differentiation. Transitory expression of neurotransmitters, their metabolic enzymes and their receptors is only one aspect of this trophic role. The most considerable progress in neurotrophic factor research has been made with the use of primary cultures of neuronal cells, and numerous studies have focused on the effects of neurotransmitters on the differentiation of cells at various stages of development. Thus, several neuropeptides like VIP, substance P, enkephalins, somatostatin, and monoamines, can modulate neuronal differentiation, but only during a limited period of fetal life. Among the monoamines, it was shown that, depending on the target, 5-HT stimulates the development of the neuropile, the myelinization of axons, the differentiation of the synaptic contacts, induces markers of monoaminergic neuron differentiation, inhibits the development of the growth cone, decreases the branching of neurites, and influences the survival, cell body size, and neurite outgrowth in several neuronal cultures. 5-HT can also indirectly influence the differentiation of serotonergic neurons by the intermediate of astrocytes, and it was shown in our laboratory that 5-HT1A agonists can stimulate the cholinergic parameters of primary cultures of rat fetal septal neurons. At the molecular level, the events triggered by neurotransmitters that underlie their neurotrophic action probably involve the transmembrane influx of calcium. To date, calcium regulation of cellular processes is one of the most rapidly expanding areas of research in developmental neurobiology. PMID:1358226

  13. Serotonin in the inferior colliculus.

    PubMed

    Hurley, Laura M; Thompson, Ann M; Pollak, George D

    2002-06-01

    It has been recognized for some time that serotonin fibers originating in raphe nuclei are present in the inferior colliculi of all mammalian species studied. More recently, serotonin has been found to modulate the responses of single inferior colliculus neurons to many types of auditory stimuli, ranging from simple tone bursts to complex species-specific vocalizations. The effects of serotonin are often quite strong, and for some neurons are also highly specific. A dramatic illustration of this is that serotonin can change the selectivity of some neurons for sounds, including species-specific vocalizations. These results are discussed in light of several theories on the function of serotonin in the IC, and of outstanding issues that remain to be addressed. PMID:12117504

  14. Dopamine metabolism in characterised neurones of Planorbis corneus.

    PubMed

    Osborne, N N; Priggemeier, E; Neuhoff, V

    1975-06-13

    A sensitive chromatographic procedure was used to study the metabolism of [14C]tyrosine, [3H]DOPA and [3H]dopamine in 3 defined cell-types situated in the nervous system of Planorbis corneus. One of the cell-types contains dopamine (GDC), the other serotonin (GSC) and the other neither amine (GC). The GDCs metabolise [14C]tyrosine to form DOPA and dopamine while the other two cells lack this ability. In contrast, the GDCs and the GSC, but not the GCs, metabolise [3H]DOPA to form dopamine. In addition the GDCs incorporate radioactivity from [3H]DOPA into DOPAC, homovanillic acid and methoxytyramine. After incubation of cells in [3H]dopamine, only the GDCs metabolise it to form DOPAC, homovanillic acid and methoxytyramine. In no instance did the GDCs form significant amounts of noradrenaline from the incorporated radioactive substances. These results, together with data on the amine histochemistry of the individual cell-types following pretretment of animals with drugs known to affect specific enzymes in the synthesis of amine transmitter substances, clearly demonstrate that the GDCs alone have the enzymes requisite for the biosynthesis and catabolism of dopamine, but not noradrenaline.

  15. Optogenetic activation of dorsal raphe serotonin neurons enhances patience for future rewards.

    PubMed

    Miyazaki, Kayoko W; Miyazaki, Katsuhiko; Tanaka, Kenji F; Yamanaka, Akihiro; Takahashi, Aki; Tabuchi, Sawako; Doya, Kenji

    2014-09-01

    Serotonin is a neuromodulator that is involved extensively in behavioral, affective, and cognitive functions in the brain. Previous recording studies of the midbrain dorsal raphe nucleus (DRN) revealed that the activation of putative serotonin neurons correlates with the levels of behavioral arousal [1], rhythmic motor outputs [2], salient sensory stimuli [3-6], reward, and conditioned cues [5-8]. The classic theory on serotonin states that it opposes dopamine and inhibits behaviors when aversive events are predicted [9-14]. However, the therapeutic effects of serotonin signal-enhancing medications have been difficult to reconcile with this theory [15, 16]. In contrast, a more recent theory states that serotonin facilitates long-term optimal behaviors and suppresses impulsive behaviors [17-21]. To test these theories, we developed optogenetic mice that selectively express channelrhodopsin in serotonin neurons and tested how the activation of serotonergic neurons in the DRN affects animal behavior during a delayed reward task. The activation of serotonin neurons reduced the premature cessation of waiting for conditioned cues and food rewards. In reward omission trials, serotonin neuron stimulation prolonged the time animals spent waiting. This effect was observed specifically when the animal was engaged in deciding whether to keep waiting and was not due to motor inhibition. Control experiments showed that the prolonged waiting times observed with optogenetic stimulation were not due to behavioral inhibition or the reinforcing effects of serotonergic activation. These results show, for the first time, that the timed activation of serotonin neurons during waiting promotes animals' patience to wait for a delayed reward.

  16. Neuroanatomical dichotomy of sexual behaviors in rodents: a special emphasis on brain serotonin.

    PubMed

    Angoa-Pérez, Mariana; Kuhn, Donald M

    2015-09-01

    Much of the social behavior in which rodents engage is related to reproduction, such as maintaining a breeding territory, seeking mates, mating, and caring for their young. Rodents belong to the internally fertilizing species that require sexual behavior for reproduction. The dyadic, heterosexual patterns of most mammalian species are sexually dimorphic, but they also share mutual components in both sexes: sexual attraction is reciprocal, sexual initiative is assumed, appetitive behavior is engaged in, and mating involves consummatory and postconsummatory phases in females as well as in males. Serotonin, a phylogenetically ancient molecule, is the most widely distributed neurotransmitter in the brain and its signaling pathways are essential for numerous functions including sexual behavior. Since the late 1960s, brain serotonergic neurotransmission has been considered to exert an inhibitory influence on the neural mechanisms mediating sexual behavior. This contention was based mainly on the observations that a decrease in central serotonergic activity facilitated the elicitation of sexual behavior, whereas an increase in central serotonergic activity attenuated it. However, the discovery of over 14 types of serotonin receptors has added numerous layers of complexity to the study of serotonin and sexual behavior. Evidence shows that, upon activation, certain receptor subtypes facilitate, whereas some others suppress, sexual behavior, as well as sexual arousal and motivation. Furthermore, the role of these receptors has been shown to be different in the male and female sexes. The use of serotonergic pharmacological interventions, mouse strains with genetic polymorphisms causing alterations in the levels of brain serotonin, and animal models with genetic manipulations of various serotonin effectors has helped delineate the fundamental role of this neurotransmitter in the regulation of sexual behavior. This review aims to examine the basics of the components of female

  17. Neuroanatomical dichotomy of sexual behaviors in rodents: a special emphasis on brain serotonin

    PubMed Central

    Angoa-Pérez, Mariana; Kuhn, Donald M.

    2016-01-01

    Much of the social behavior in which rodents engage is related to reproduction, such as maintaining a breeding territory, seeking mates, mating, and caring for young. Rodents belong to the internally fertilizing species that require sexual behavior for reproduction. The dyadic, heterosexual patterns of most mammalian species are sexually dimorphic, but they also share mutual components in both sexes: sexual attraction is reciprocal, sexual initiative is assumed, appetitive behavior is engaged in and mating involves consummatory and postconsummatory phases in females as well as in males. Serotonin, a phylogenetically ancient molecule, is the most widely distributed neurotransmitter in the brain and its signaling pathways are essential for numerous functions including sexual behavior. Since the late 1960’s, brain serotonergic neurotransmission has been considered to exert an inhibitory influence on the neural mechanisms mediating sexual behavior. This contention was based mainly on the observations that a decrease in central serotonergic activity facilitated the elicitation of sexual behavior while an increase in central serotonergic activity attenuated it. However, the discovery of over 14 types of serotonin receptors has added numerous layers of complexity to the study of serotonin and sexual behavior. Evidence shows that upon activation, certain receptor subtypes facilitate while some others suppress sexual behavior as well as sexual arousal and motivation. Furthermore, the role of these receptors has been shown to be differential in males versus females. The use of serotonergic pharmacological interventions, mouse strains with genetic polymorphisms causing alterations in the levels of brain serotonin as well as animal models with genetic manipulations of various serotonin effectors has helped delineate the fundamental role of this neurotransmitter in the regulation of sexual behavior. This review aims to examine the basics of the components of female and male

  18. Glutamate-dopamine-GABA interactions in the aging basal ganglia.

    PubMed

    Mora, Francisco; Segovia, Gregorio; Del Arco, Alberto

    2008-08-01

    The study of neurotransmitter interactions gives a better understanding of the physiology of specific circuits in the brain. In this review we focus mostly on our own results on the interaction of the neurotransmitters glutamate, dopamine and GABA in the basal ganglia during the normal process of aging. We review first the studies on the action of endogenous glutamate on the extracellular concentrations of dopamine and GABA in the neostriatum and nucleus accumbens during aging. It was found that there exists an age-related change in the interaction of glutamate, dopamine and GABA and that these effects of aging exhibit a dorsal-to-ventral pattern of effects with no changes in the dorsal parts (dorsal striatum) and changes in the most ventral parts (nucleus accumbens). Second we reviewed the data on the effects of different ionotropic and metabotropic glutamate receptor agonists on the extracellular concentrations of dopamine and GABA in the nucleus accumbens. The results obtained clearly show the different contribution of each glutamate receptor subtype in the age-related changes produced on the interaction of glutamate, dopamine and GABA in this area of the brain. Third the effects of an enriched environment on the action of AMPA and NMDA-receptor agonists in the nucleus accumbens of rats during aging are also evaluated. Finally, and since the nucleus accumbens has been suggested to play a role in emotion and motivation and also motor behaviour, we speculated on the possibility of a specific contribution for the different glutamatergic pathways terminating in the nucleus accumbens and their interaction with a decreased dopamine playing a relevant role in motor behaviour during aging.

  19. Imaging neurotransmitter uptake and depletion in astrocytes

    SciTech Connect

    Tan, W. |; Haydon, P.G.; Yeung, E.S.

    1997-08-01

    An ultraviolet (UV) laser-based optical microscope and charge-coupled device (CCD) detection system was used to obtain chemical images of biological cells. Subcellular structures can be easily seen in both optical and fluorescence images. Laser-induced native fluorescence detection provides high sensitivity and low limits of detection, and it does not require coupling to fluorescent dyes. We were able to quantitatively monitor serotonin that has been taken up into and released from individual astrocytes on the basis of its native fluorescence. Different regions of the cells took up different amounts of serotonin with a variety of uptake kinetics. Similarly, we observed different serotonin depletion dynamics in different astrocyte regions. There were also some astrocyte areas where no serotonin uptake or depletion was observed. Potential applications include the mapping of other biogenic species in cells as well as the ability to image their release from specific regions of cells in response to external stimuli. {copyright} {ital 1997} {ital Society for Applied Spectroscopy}

  20. Neurotransmitter Receptor Binding in Bovine Cerebral Microvessels

    NASA Astrophysics Data System (ADS)

    Peroutka, Stephen J.; Moskowitz, Michael A.; Reinhard, John F.; Synder, Solomon H.

    1980-05-01

    Purified preparations of microvessels from bovine cerebral cortex contain substantial levels of alpha-adrenergic, beta-adrenergic, and histamine 1 receptor binding sites but only negligible serotonin, muscarinic cholinergic, opiate, and benzodiazepine receptor binding. Norepinephrine and histamine may be endogenous regulators of the cerebral microcirculation at the observed receptors.

  1. Neurotransmitter Systems in a Mild Blast Traumatic Brain Injury Model: Catecholamines and Serotonin

    PubMed Central

    Arborelius, Ulf P.; Yoshitake, Takashi; Kehr, Jan; Hökfelt, Tomas; Risling, Mårten; Agoston, Denes

    2015-01-01

    Abstract Exposure to improvised explosive devices can result in a unique form of traumatic brain injury—blast-induced traumatic brain injury (bTBI). At the mild end of the spectrum (mild bTBI [mbTBI]), there are cognitive and mood disturbances. Similar symptoms have been observed in post-traumatic stress disorder caused b