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Sample records for monoamine neurotransmitter re-uptake

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

    Science.gov (United States)

    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.

  2. Specific responses of monoamine neurotransmitters to various acute stressors

    Institute of Scientific and Technical Information of China (English)

    Rongrong He; Guanyu Lin; Yifang Li; Keiich Abe; Xinsheng Yao; Hiroshi Kurihara

    2011-01-01

    This study determined the composition of histamine, serotonin and dopamine using high performance liquid chromatography and electrochemical detection, and compared the changes in monoamine levels in plasma, the cortex and midbrain of mice exposed to acute stressors, such as blood-drawing stimulation or restraint. Results demonstrated that plasma histamine levels were markedly increased when mice were exposed to blood-drawing stimulation and restraint stress. However, serotonin levels decreased in plasma of mice treated with restraint stress, and dopamine levels in plasma had no significant response to the two acute stressors. The three monoamines (histamine, serotonin and dopamine) increased at different degrees in restraint mice, but not in brain regions of blood-drawing stressed mice. Results indicated that histaminergic, serotonergic or dopaminergic systems have their own specific response to different acute stressors.

  3. Altered serous levels of monoamine neurotransmitter metabolites in patiens with refractory and non-refractory depression

    Institute of Scientific and Technical Information of China (English)

    Guiqing Zhang; Yanxia Zhang; Jianxia Yang; Min Hu; Yueqi Zhang; Xia Liang

    2012-01-01

    The study examined plasma metabolite changes of monoamine neurotransmitters in patients with treatment-resistant depression (TRD) and non-TRD before and after therapy. All 30 TRD and 30 non-TRD patients met the diagnostic criteria for a depressive episode in accordance with the International Classification of Diseases, Tenth Revision. Before treatment, and at 4, 6, and 8 weeks after treatment, the plasma metabolite products of monoamine neurotransmitters in TRD group, including 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenyl ethylene glycol and homovanillic acid, were significantly lower than those in the non-TRD group. After two types of anti-depressive therapy with 5-serotonin and norepinephrine reuptake inhibitor, combined with psychotherapy, the Hamilton Depression Rating Scale scores were significantly reduced in both groups of patients, and the serous levels of 5-hydroxyindoleacetic acid and 3-methoxy-4-hydroxyphenyl ethylene glycol were significantly increased. In contrast, the homovanillic acid level exhibited no significant change. The levels of plasma metabolite products of peripheral monoamine neurotransmitters in depressive patients may predict the degree of depression and the therapeutic effects of treatment.

  4. The molecular mechanism for overcoming the rate-limiting step in monoamine neurotransmitter transport

    DEFF Research Database (Denmark)

    Sinning, Steffen; Said, Saida; Malinauskaite, Lina

    structures of the bacterial homolog, LeuT, captured in a new conformation without substrate or sodium bound shows a dramatic rotation of an absolutely conserved leucine into the substrate site. Molecular dynamics simulations combined with functional studies on SERT support that this leucine must act...... membrane. The rate-limiting step in monoamine reuptake is the return of the empty transporter from an inward-facing to an outward-facing conformation without neurotransmitter and sodium bound. The molecular mechanism underlying this important conformational transition has not been described. Crystal...

  5. Liquid chromatography-electrochemical detection for studying the effects of tetrahydrobiopterin on monoamine neurotransmitters in rat striatum

    Institute of Scientific and Technical Information of China (English)

    ZHANG; Wen; ZHU; Wei; XU; Haihong; WAN; Fangli; GU; Jing; HA

    2005-01-01

    Tetrahydrobiopterin (BH4) is an essential co-factor in the biosynthesis of monoamine neurotransmitters.A nano-Pt/Pd modified electrode as the electrochemical detector (ED) for high-performance liquid chromatography (HPLC) coupled with microdialysis sampling, is used to explore the effect of administration of BH4 on the monoamine neurotransmitters in the rat striatum.The researches demonstrate that the contents of dopamine (DA), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) increase significantly with the administration of BH4.The pharmaceutical kinetics is carried out to research into the time course of BH4 effect on the concentration of monoamine neurotransmitters in rat striatum, which provides reliable data for pathology and pharmacology research on neuroscience.

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

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    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.

  7. 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

    DEFF Research Database (Denmark)

    Schou-Pedersen, Anne Marie Voigt; Hansen, Stine Normann; Tveden-Nyborg, Pernille

    2016-01-01

    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 d...... and is broadly applicable to monoamine measurements in cell cultures as well as brain biopsies from animal models used in preclinical neurochemistry....

  8. Effects of Moxa Smoke on Monoamine Neurotransmitters in SAMP8 Mice

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    Huanfang Xu

    2013-01-01

    Full Text Available Objectives. To investigate the anti-aging effects of moxa smoke on SAMP8 mice. Methods. Using 2×3 factorial design, exposure length (15 or 30 minutes daily, and concentration (low, 5–15 mg/m3; middle, 25–35 mg/m3; high, 85–95 mg/m3, 70 SAMP8 mice were randomly assigned, n=10/group, to a model group or one of six moxa smoke groups: L1, L2, M1, M2, H1, or H2. Ten SAMR1 mice were used as normal control. Mice in moxa smoke groups were exposed to moxa smoke at respective concentrations and exposure lengths; the model and normal control mice were not exposed. Cerebral 5-HT, DA, and NE levels were determined using ELISA. Results. Compared to normal control, the model group showed a significant decrease in 5-HT, DA, and NE. Compared to model group, 5-HT and NE were significantly higher in groups L2, M1, and M2 and DA was significantly so in L2 and M1. 5-HT, DA, and NE levels were the highest in group M1 among moxa smoke groups. A marked exposure length × concentration interaction was observed for 5-HT, DA, and NE. Conclusion. Moxa smoke increases monoamine neurotransmitter levels, which varies according to concentration and exposure length. Our finding suggests that the middle concentration of moxa smoke for 15 minutes seems the most beneficial.

  9. Online micro-solid-phase extraction based on boronate affinity monolithic column coupled with high-performance liquid chromatography for the determination of monoamine neurotransmitters in human urine.

    Science.gov (United States)

    Yang, Xiaoting; Hu, Yufei; Li, Gongke

    2014-05-16

    Quantification of monoamine neurotransmitters is very important in diagnosing and monitoring of patients with neurological disorders. We developed an online analytical method to selectively determine urinary monoamine neurotransmitters, which coupled the boronate affinity monolithic column micro-solid-phase extraction with high-performance liquid chromatography (HPLC). The boronate affinity monolithic column was prepared by in situ polymerization of vinylphenylboronic acid (VPBA) and N,N'-methylenebisacrylamide (MBAA) in a stainless capillary column. The prepared monolithic column showed good permeability, high extraction selectivity and capacity. The column-to-column reproducibility was satisfactory and the enrichment factors were 17-243 for four monoamine neurotransmitters. Parameters that influence the online extraction efficiency, including pH of sample solution, flow rate of extraction and desorption, extraction volume and desorption volume were investigated. Under the optimized conditions, the developed method exhibited low limit of detection (0.06-0.80μg/L), good linearity (with R(2) between 0.9979 and 0.9993). The recoveries in urine samples were 81.0-105.5% for four monoamine neurotransmitters with intra- and inter-day RSDs of 2.1-8.2% and 3.7-10.6%, respectively. The online analytical method was sensitive, accurate, selective, reliable and applicable to analysis of trace monoamine neurotransmitters in human urine sample.

  10. In vivo study on the monoamine neurotransmitters and their metabolites change in the striatum of Parkinsonian rats by liquid chromatography with an acetylene black nanoparticles modified electrode.

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    Lin, Li; Yang, Jie; Lin, Ruipo; Yu, Li; Gao, Hongchang; Yang, Shulin; Li, Xiaokun

    2013-01-01

    The variation in the concentration of monoamine neurotransmitters and their metabolites in an experimental Parkinsonian animal model established by unilateral 6-hydroxydopamine administration was studied. For the purpose of detecting monoamine neurotransmitters and their metabolites more sensitively, an acetylene black nanoparticles modified electrode was fabricated and used as the working electrode for an electrochemical detector in HPLC. The results indicated that the modified electrode exhibited efficiently electrocatalytic oxidation for monoamine neurotransmitters and their metabolites with relatively high sensitivity, long life, and stability. The linear ranges spanned four orders of magnitude (r>0.998) and the detectability was on the level of 0.1 nmolL(-1). The percent relative standard deviation (%RSD) for each compound at all concentration levels was lower than 2.57% and 1.94% for intra-day and inter-day precision, respectively. The mean recovery values were between 98.75% and 105.25%, and the %RSD was found to be less than 1.02%. Coupled with in vivo microdialysis sampling, the validated method was successfully applied to measure monoamine neurotransmitters and their metabolites in both sides of the striatum of conscious and freely moving Parkinsonian rats, and the extracellular monoamine neurotransmitters and their metabolites in the lesioned-side striatum of unilateral 6-hydroxydopamine-lesioned rats were lower than that in the intact side striatum or in the striatum of control rats.

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

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    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.

  12. Expression of brain derived neurotrophic factor, activity-regulated cytoskeleton protein mRNA, and enhancement of adult hippocampal neurogenesis in rats after sub-chronic and chronic treatment with the triple monoamine re-uptake inhibitor tesofensine.

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    Larsen, Marianne H; Rosenbrock, Holger; Sams-Dodd, Frank; Mikkelsen, Jens D

    2007-01-26

    The changes of gene expression resulting from long-term exposure to monoamine antidepressant drugs in experimental animals are key to understanding the mechanisms of action of this class of drugs in man. Many of these genes and their products are either relevant biomarkers or directly involved in structural changes that are perhaps necessary for the antidepressant effect. Tesofensine is a novel triple monoamine reuptake inhibitor that acts to increase noradrenaline, serotonin, and dopamine neurotransmission. This study was undertaken to examine the effect of sub-chronic (5 days) and chronic (14 days) administration of Tesofensine on the expression of brain derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton protein (Arc) in the rat hippocampus. Furthermore, hippocampi from the same animals were used to investigate the effect on cell proliferation by means of Ki-67- and NeuroD-immunoreactivity. We find that chronic, but not sub-chronic treatment with Tesofensine increases BDNF mRNA in the CA3 region of the hippocampus (35%), and Arc mRNA in the CA1 of the hippocampus (65%). Furthermore, the number of Ki-67- and neuroD-positive cells increased after chronic, but not sub-chronic treatment. This study shows that Tesofensine enhances hippocampal gene expression and new cell formation indicative for an antidepressant potential of this novel drug substance.

  13. Effect of aspartame on oxidative stress and monoamine neurotransmitter levels in lipopolysaccharide-treated mice.

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    Abdel-Salam, Omar M E; Salem, Neveen A; Hussein, Jihan Seid

    2012-04-01

    This study aimed at investigating the effect of the sweetener aspartame on oxidative stress and brain monoamines in normal circumstances and after intraperitoneal (i.p.) administration of lipopolysaccharide (LPS; 100 μg/kg) in mice. Aspartame (0.625-45 mg/kg) was given via subcutaneous route at the time of endotoxin administration. Mice were euthanized 4 h later. Reduced glutathione (GSH), lipid peroxidation (thiobarbituric acid-reactive substances; TBARS), and nitrite concentrations were measured in brain and liver. Tumor necrosis factor-alpha (TNF-α) and glucose were determined in brain. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were measured in liver. The administration of only aspartame (22.5 and 45 mg/kg) increased brain TBARS by 17.7-32.8%, decreased GSH by 25.6-31.6%, and increased TNF-α by 16.7-44%. Aspartame caused dose-dependent inhibition of brain serotonin, noradrenaline, and dopamine. Aspartame did not alter liver TBARS, nitrite, GSH, AST, ALT, or ALP. The administration of LPS increased nitrite in brain and liver by 26.8 and 37.1%, respectively; decreased GSH in brain and liver by 21.6 and 31.1%, respectively; increased brain TNF-α by 340.4%, and glucose by 39.9%, and caused marked increase in brain monoamines. LPS increased AST, ALT, and ALP in liver tissue by 84.4, 173.7, and 258.9%, respectively. Aspartame given to LPS-treated mice at 11.25 and 22.5 mg/kg increased brain TBARS by 15.5-16.9%, nitrite by 12.6-20.1%, and mitigated the increase in monoamines. Aspartame did not alter liver TBARS, nitrite, GSH, ALT, AST, or ALP. Thus, the administration of aspartame alone or in the presence of mild systemic inflammatory response increases oxidative stress and inflammation in the brain, but not in the liver.

  14. The molecular mechanism for overcoming the rate-limiting step in monoamine neurotransmitter transport

    DEFF Research Database (Denmark)

    Sinning, Steffen; Said, Saida; Malinauskaite, Lina

    as an endogenous substrate mimic in the empty transporter in order for it to overcome the transition from the inward-facing to the outward-facing conformation. We also show that the local conformational changes associated with the rotation of this conserved leucine explains how cation sites are perturbed...... and are targets for drugs of abuse such as cocaine, amphetamine and ecstasy as well as anxiolytics and antidepressants. The transporters undergo a series of concerted conformational changes in order to harness the driving force of co-transported cations to translocate the neurotransmitter across the neuronal...

  15. Effects of Acupuncture on Monoamine Neurotransmitters in Raphe Nuclei in Obese Rats

    Institute of Scientific and Technical Information of China (English)

    魏群利; 刘志诚

    2003-01-01

    Effects of acupuncture on the levels of neurotransmitters in the raphe nuclei were investigated in obese rats. It was found that the levels of tryptophan (Trp) and 5-hydroxyindoleacetic acid (5-HIAA) were increased, and 5-hydroxytryptamine (5-HT) level and 5-HT/5-HIAA ratio decreased in the raphe nuclei of the obese group as compared with the normal group; and that acupuncture could produce weight reduction, increase the 5-HT level and 5-HT/5-HIAA ratio, and decrease the contents of Trp and 5-HIAA, but did not change the levels of dopamine (DA) and noradrenaline (NA). It is indicated that benign regulative action of acupuncture on 5-HT and its metabolism in the raphe nuclei is possibly one of the factors for reducing weight by acupuncture.

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

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    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.

  17. Antidepressant like effects of hydrolysable tannins of Terminalia catappa leaf extract via modulation of hippocampal plasticity and regulation of monoamine neurotransmitters subjected to chronic mild stress (CMS).

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    Chandrasekhar, Y; Ramya, E M; Navya, K; Phani Kumar, G; Anilakumar, K R

    2017-02-01

    Terminalia catappa L. belonging to Combretaceae family is a folk medicine, known for its multiple pharmacological properties, but the neuro-modulatory effect of TC against chronic mild stress was seldom explored. The present study was designed to elucidate potential antidepressant-like effect of Terminalia cattapa (leaf) hydro-alcoholic extract (TC) by using CMS model for a period of 7 weeks. Identification of hydrolysable tannins was done by using LC-MS. After the CMS exposure, mice groups were administered with imipramine (IMP, 10mg/kg, i.p.) and TC (25, 50 and 100mg/kg of TC, p.o.). Behavioural paradigms used for the study included forced swimming test (FST), tail suspension test (TST) and sucrose preference test (SPT). After behavioural tests, monoamine neurotransmitter, cortisol, AchE, oxidative stress levels and mRNA expression studies relevant to depression were assessed. TC supplementation significantly reversed CMS induced immobility time in FST and other behavioural paradigms. Moreover, TC administration significantly restored CMS induced changes in concentrations of hippocampal neurotransmitters (5-HT, DA and NE) as well as levels of acetyl cholinesterase, cortisol, monoamine oxidases (MAO-A, MAO-B), BDNF, CREB, and p-CREB. It suggests that TC supplementation could supress stress induced depression by regulating monoamine neurotransmitters, CREB, BDNF, cortisol, AchE level as well as by amelioration of oxidative stress. Hence TC can be used as a complementary medicine against depression-like disorder.

  18. Associations between Purine Metabolites and Monoamine Neurotransmitters in First-Episode Psychosis

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    Jeffrey K Yao

    2013-06-01

    Full Text Available Schizophrenia (SZ is a biochemically complex disorder characterized by widespread defects in multiple metabolic pathways whose dynamic interactions, until recently, have been difficult to examine. Rather, evidence for these alterations has been collected piecemeal, limiting the potential to inform our understanding of the interactions amongst relevant biochemical pathways. We herein review perturbations in purine and neurotransmitter metabolism observed in early SZ using a metabolomic approach. Purine catabolism is an underappreciated, but important component of the homeostatic response of mitochondria to oxidant stress. We have observed a homeostatic imbalance of purine catabolism in first-episode neuroleptic-naive patients with SZ (FENNS. Precursor and product relationships within purine pathways are tightly correlated. Although some of these correlations persist across disease or medication status, others appear to be lost among FENNS suggesting that steady formation of the antioxidant uric acid via purine catabolism is altered early in the course of illness. As is the case for within-pathway correlations, there are also significant cross-pathway correlations between respective purine and tryptophan pathway metabolites. By contrast, purine metabolites show significant cross-pathway correlation only with tyrosine, and not with its metabolites. Furthermore, several purine metabolites (uric acid, guanosine, or xanthine are each significantly correlated with 5-hydroxyindoleacetic acid (5-HIAA in healthy controls, but not in FENNS at baseline or 4-week after antipsychotic treatment. Taken together, the above findings suggest that purine catabolism strongly associates with the tryptophan pathways leading to serotonin (5-HT and kynurenine metabolites. The Lack of a significant correlation between purine metabolites and 5-HIAA, suggests alterations in key 5-HT pathways that may both be modified by and contribute to oxidative stress via purine

  19. Mild closed head traumatic brain injury-induced changes in monoamine neurotransmitters in the trigeminal subnuclei of a rat model: mechanisms underlying orofacial allodynias and headache

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    Golam Mustafa

    2017-01-01

    Full Text Available Our recent findings have demonstrated that rodent models of closed head traumatic brain injury exhibit comprehensive evidence of progressive and enduring orofacial allodynias, a hypersensitive pain response induced by non-painful stimulation. These allodynias, tested using thermal hyperalgesia, correlated with changes in several known pain signaling receptors and molecules along the trigeminal pain pathway, especially in the trigeminal nucleus caudalis. This study focused to extend our previous work to investigate the changes in monoamine neurotransmitter immunoreactivity changes in spinal trigeminal nucleus oralis, pars interpolaris and nucleus tractus solitaries following mild to moderate closed head traumatic brain injury, which are related to tactile allodynia, touch-pressure sensitivity, and visceral pain. Our results exhibited significant alterations in the excitatory monoamine, serotonin, in spinal trigeminal nucleus oralis and pars interpolaris which usually modulate tactile and mechanical sensitivity in addition to the thermal sensitivity. Moreover, we also detected a robust alteration in the expression of serotonin, and inhibitory molecule norepinephrine in the nucleus tractus solitaries, which might indicate the possibility of an alteration in visceral pain, and existence of other morbidities related to solitary nucleus dysfunction in this rodent model of mild to moderate closed head traumatic brain injury. Collectively, widespread changes in monoamine neurotransmitter may be related to orofacial allodynhias and headache after traumatic brain injury.

  20. 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.

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    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.

  1. Determination of monoamine neurotransmitters and their metabolites in a mouse brain microdialysate by coupling high-performance liquid chromatography with gold nanoparticle-initiated chemiluminescence

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    Li Na; Guo Jizhao; Liu Bo; Yu Yuqi [Department of Chemistry, University of Science and Technology of China (USTC), JinZhai Road No: 96, 230026 Hefei, Anhui (China); Cui Hua, E-mail: hcui@ustc.edu.cn [Department of Chemistry, University of Science and Technology of China (USTC), JinZhai Road No: 96, 230026 Hefei, Anhui (China); Mao Lanqun; Lin Yuqing [Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences (CAS), 100080 Beijing (China)

    2009-07-10

    Our previous work showed that gold nanoparticles could trigger chemiluminescence (CL) between luminol and AgNO{sub 3}. In the present work, the effect of some biologically important reductive compounds, including monoamine neurotransmitters and their metabolites, reductive amino acids, ascorbic acid, uric acid, and glutathione, on the novel CL reaction were investigated for analytical purpose. It was found that all of them could inhibit the CL from the luminol-AgNO{sub 3}-Au colloid system. Among them, monoamine neurotransmitters and their metabolites exhibited strong inhibition effect. Taking dopamine as a model compound, the CL mechanism was studied by measuring absorption spectra during the CL reaction and the reaction kinetics via stopped-flow technique. The CL inhibition mechanism is proposed to be due to that these tested compounds competed with luminol for AgNO{sub 3} to inhibit the formation of luminol radicals and to accelerate deposition of Ag atoms on surface of gold nanoparticles, leading to a decrease in CL intensity. Based on the inhibited CL, a novel method for simultaneous determination of monoamine neurotransmitters and their metabolites was developed by coupling high-performance liquid chromatography with this CL reaction. The new method was successfully applied to determine the compounds in a mouse brain microdialysate. Compared with the reported HPLC-CL methods, the proposed method is simple, fast, and could determine more analytes. Moreover, the limits of linear ranges for NE, E, and DA using the proposed method were one order of magnitude lower than the luminol system without gold nanoparticles.

  2. Effects of Electric Acupuncture on Monoamine Neurotransmitters in Brains of Newborn Rats with Cerebral Palsy%电针对新生脑性麻痹大鼠单胺类神经递质的影响

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    林世坚; 刘振寰; 潘佩光; 赵勇; 祁岩超

    2009-01-01

    objective to detect the content of monoamine neurotransmitters in hippocampus, cortex, basal nucleus and the brainstem of newborn rats with cerebral palsy, to observe the effects of acupuncture on monoamine neurotransmitters, and to explore the mechanism of acupuncture treatment to newborn rats with cerebral palsy. Methods using the method of hypoxic ischemic to make the model of newborn rats with cerebral palsy,decapitating brain after giving acupuncture treatment, separating the required brain regions, and detecting the content of monoamine neurotransmitters with speetrophotometer.Results Compared with the sham operation group, the content of dopamine (DA), 5-Hydroxytryptamine (5-HT) in basal nucleus area of newborn rats with cerebral palsy, and norepinephrine (NE) in Brainstem area decreased significantly(P<0.05), which elevated ignificantly(P<0.05)afler acupuncture treatment. Conclusion it indicated that to improve the ontent of monoamine neurotransmitters in related brain areas may be one of the mechanisms in the acupuncture treatment of newborn rats with cerebral paraly.

  3. Involvement of the Cerebral Monoamine Neurotransmitters System in Antidepressant-Like Effects of a Chinese Herbal Decoction, Baihe Dihuang Tang, in Mice Model

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    Meng-Li Chen

    2012-01-01

    Full Text Available Baihe Dihuang Tang (BDT is a renowned Chinese herbal formula which is commonly used for treating patients with mental instability, absentmindedness, insomnia, deficient dysphoria, and other psychological diseases. These major symptoms closely associated with the depressive disorders. BDT was widely popular use for treating emotion-thought disorders for many years in China. In the present study, the antidepressant-like effect of BDT in mice was investigated by using the forced swim test (FST and the tail suspension test (TST. The underlying mechanism was explored by determining the effect of BDT on the level of cerebral monoamine neurotransmitters. BDT (9 and 18 g/kg, p.o. for 14 days administration significantly reduced the immobility time in both the FST and the TST without changing locomotion in the open field-test (OFT. Moreover, BDT treatment at the dose of 18 g/kg inhibited reserpine-induced ptosis. Meanwhile, BDT enhanced 5-HT and NA levels in mouse cerebrum as well as decreased the ratio of 5-HT compared to its metabolite, 5-HIAA, (turnover, 5-HIAA/5-HT after TST. The results demonstrated that the antidepressant-like effect of BDT is mediated, at least partially, via the central monoaminergic neurotransmitter system.

  4. Effect of Schisandra chinensis polysaccharide on intracerebral acetylcholinesterase and monoamine neurotransmitters in a D-galactose-induced aging brain mouse model

    Institute of Scientific and Technical Information of China (English)

    Mingsan Miao; Jianlian Gao; Guangwei Zhang; Xiao Ma; Ying Zhang

    2009-01-01

    BACKGROUND: The most prominent characteristic of brain aging is decreased learning and memory ability. The functions of learning and memory are closely related to intracerebral acetylcholinesterase (ACHE) and monoamine neurotransmitter activity. Previous studies have shown that Schisandra chinensis potysaccharide has an anti-aging effect. OBJECTIVE: To explore the effects of Schisandra chinensis polysaccharide on AChE activity and monoamine neurotransmitter content, as well as learning and memory ability in a D-galactose-induced aging mouse brain model compared with the positive control drug Kangnaoling. DESIGN, TIME AND SETTING: Completely randomized, controlled experiment based on neurobiochemistry was performed at the Pharmacological Laboratory, Henan University of Traditional Chinese Medicine from September to December 2003.MATERIALS: Schisandra chinensis was purchased from Henan Provincial Medicinal Company. Schisandra chinensis polysaccharide was obtained by water extraction and alcohol precipitation. Kangnaoling pellets were provided by Liaoning Tianlong Pharmaceutical (batch No. 20030804;state drug permit No. H21023095). A total of 50 six-week-old Kunming mice were randomly divided into five groups: blank control, model, Kangnaoling, high and low dosage Schisandra chinensis polysaccharide groups, with 10 mice per group. METHODS: Mice in the blank control group were subcutaneously injected with 0.5 mL/20 g normal saline into the nape of the neck each day, while the remaining mice were subcutaneously injected with 5% D-galactose saline solution (0.5 mL/20 g) in the nape for 40 days to induce a brain aging model. On day 11, mice in the high and low dosage Schisandra chinensis polysaccharide groups were intragastrically infused with 20 mg/mL and 10 mg/mL Schisandra chinensis polysaccharide solution (0.2 mL/10 g), respectively. Mice from the Kangnaoling group were intragastrically infused with 35 mg/mL Kangnaoling suspension (0.2 mL/10 g), and the mice in the

  5. Acupuncture Treatment Methods' Influence on the Monoamine Neurotransmitters and Correlative Diseases of Nervous System%针刺对单胺类神经递质及相关神经系统疾病的影响

    Institute of Scientific and Technical Information of China (English)

    陈乐乐; 岳增辉; 朱小姗

    2011-01-01

    The monoamine neurotransmitter regulates mammal's nervous system function, the visceral function, stress reaction and exciting or soothing to the central nerve system. The results from the present investigation suggest that many diseases of nervous system like Stroke, Parkinson Disease, Dementia, Depression and Morphine Dependence are both related to the abnormity of the monoamine neurotransmitters. Acupuncture has the good therapeutic action on many diseases of nervous system by adjusting the level of monoamine neurotransmitters.%单胺类(monoamines)神经递质对哺乳动物的神经系统功能、内脏功能、应激反应,以及对中枢神经系统的兴奋或抑制起着协调作用.目前的研究表明,许多神经系统疾病如脑卒中、帕金森病、老年性痴呆、抑郁症及吗啡戒断均与单胺类神经递质的异常有关.而针刺通过调节单胺类神经递质的水平,对许多神经系统疾病具有较好的治疗作用.

  6. Effects of Yulangsan polysaccharide on monoamine neurotransmitters, adenylate cyclase activity and brain-derived neurotrophic factor expression in a mouse model of depression induced by unpredictable chronic mild stress

    Institute of Scientific and Technical Information of China (English)

    Shuang Liang; Renbin Huang; Xing Lin; Jianchun Huang; Zhongshi Huang; Huagang Liu

    2012-01-01

    The present study established a mouse model of depression induced by unpredictable chronic mild stress. The model mice were treated with Yulangsan polysaccharide (YLSPS; 150, 300 and 600 mg/kg) for 21 days, and compared with fluoxetine-treated and normal control groups. Enzyme-linked immunosorbent assay, radioimmunity and immunohistochemical staining showed that following treatment with YLSPS (300 and 600 mg/kg), monoamine neurotransmitter levels, prefrontal cortex adenylate cyclase activity and hippocampal brain-derived neurotrophic factor expression were significantly elevated, and depression-like behaviors were improved. Open-field and novelty-suppressed feeding tests showed that mouse activity levels were increased and feeding latency was shortened following treatment. Our results indicate that YLSPS inhibits depression by upregulating monoamine neurotransmitters, prefrontal cortex adenylate cyclase activity and hippocampal brain-derived neurotrophic factor expression.

  7. Roles of monoamine neurotransmitters in the mechanism of drug addiction%单胺类神经递质在药物成瘾中的作用机制

    Institute of Scientific and Technical Information of China (English)

    杨黎华; 白洁

    2015-01-01

    药物成瘾是一种慢性复发性大脑疾病,各种成瘾性药物通过作用于奖赏系统,最终引起神经递质释放的改变,产生奖赏效应。其中,单胺类神经递质5-羟色胺(5-hydroxytryptamine,5-HT)、去甲肾上腺素( noradrenergic,NE)和多巴胺( dopamine,DA)在药物成瘾中起到重要作用,该文就单胺类神经递质在药物成瘾中的作用及机制进行综述。%Drug addiction is a chronic recrudescent brain dis-ease. Various addictive drugs acting on the reward system result in rewarding effects through changes in neurotransmitter patholog-ical release. Among these monoamine neurotransmitters, 5-hydroxytryptamine, norepinephrine and dopamine play key roles in drug addiction. This paper reviews, from a comprehensive perspective, the roles which monoamine neurotransmitters play in the drug addiction and the process of getting addictive.

  8. 基于单胺类神经递质调节发育算法的机器人视觉定位%Robot Vision Location Based on Developmental Algorithm of Monoamine Neurotransmitters Modulation

    Institute of Scientific and Technical Information of China (English)

    钱夔; 宋爱国; 章华涛; 张立云

    2014-01-01

    A robot vision location based on developmental algorithm of monoamine neurotransmitters modulation is pro-posed to solve the problem that a large number of neurons need to be allocated in vision location task based on general developmental algorithms. Firstly, the monoamine neurotransmitter theory of dopamine and serotonin controlling a vari-ety of physiological functions in the brain is introduced to realize neural modulation. Then, the developmental algorithm of monoamine neurotransmitters modulation is established based on general developmental algorithms. The robot uses au-tonomous trial and error strategies to complete the process of reinforcement learning, store “memory”, and dynamically change the learning rate, and ultimately it realizes vision location task. Experimental results show that the number of neu-rons to be allocated in advance in the proposed method is as few as the number of required knowledge concepts, which can significantly reduce the required number of neurons and increase algorithm efficiency.%针对基于普通发育算法实现机器人视觉定位任务时需分配大量神经元的问题,提出一种基于单胺类神经递质调节发育算法的机器人视觉定位方法。首先引入在脑内控制多种生理功能的多巴胺(dopamine)与5-羟色胺(serotonin)的单胺类神经递质理论,实现神经调节作用;然后结合普通发育算法,建立基于神经递质调节的发育算法。机器人采用自主试错策略完成强化学习过程,存储“记忆”,并可动态改变学习速率,最终实现视觉定位任务。实验结果证明该方法仅需提前配置与所需相关知识概念个数相同数量的神经元,显著减少了所需神经元数量,提高算法效率。

  9. Simultaneous extraction and determination of monoamine neurotransmitters in human urine for clinical routine testing based on a dual functional solid phase extraction assisted by phenylboronic acid coupled with liquid chromatography-tandem mass spectrometry.

    Science.gov (United States)

    Li, Xiaoguang Sunny; Li, Shu; Kellermann, Gottfried

    2017-02-10

    The major monoamine neurotransmitters, serotonin (5-HT) and catecholamines (i.e., norepinephrine (NE), epinephrine (E), and dopamine (DA)), are critical to the nervous system function, and imbalances of the neurotransmitters have been connected to a variety of diseases, making their measurement useful in a clinical setting. A simple, rapid, robust, sensitive, and specific LC-MS/MS method has been developed and validated for the simultaneous quantitation of urinary serotonin and catecholamines with low cost, which is ideal for routine clinical applications. A simple extraction from complex urine was accomplished using tailored solid phase extraction incorporating phenylboronic acid complexation on a 96-well HLB microplate for the sample extraction and resulted in significantly improved throughput, selectivity, and extraction recovery. Compared to 1-10 mL of urine typically used, this method required only 10 μL. A rapid chromatographic elution with a total cycle time of 6 min per sample compared to reported run times of 19-75 min was achieved on a PFP column. The sensitivity of l and 2 ng mL(-1) for the detection of low abundant E and NE combined with the high coverage of 1024 ng mL(-1) for DA enabled the multi-analyte detection of these biogenic amines in a single run. Good linearity (2.0-512, 1.0-512, 4.0-1024, and 4.0-1024 ng mL(-1) for NE, E, DA, and 5-HT, respectively), accuracy (87.6-104.0%), precision (≤8.0%), extraction recovery (69.6-103.7%), and matrix effect (87.1-113.1% for catecholamines and 63.6-71.4% for 5-HT) were obtained. No autosampler carryover was observed. The analytes were stable for 5 days at 20 °C, 14 days at 4 °C, and 30 days at -20 °C and five freeze-thaw cycles. The easy sample preparation, rapid LC, and multi-analyte MS detection allow two 96-well plates of samples to be extracted within 2 h and analyzed on an LC-MS/MS system within 24 h. The applicability and reliability of the assay were demonstrated by

  10. Kaempferia parviflora rhizome extract and Myristica fragrans volatile oil increase the levels of monoamine neurotransmitters and impact the proteomic profiles in the rat hippocampus: Mechanistic insights into their neuroprotective effects

    Directory of Open Access Journals (Sweden)

    Waluga Plaingam

    2017-10-01

    Full Text Available Potentially useful in the treatment of neurodegenerative disorders, Kaempferia parviflora and Myristica fragrans have been shown to possess a wide spectrum of neuropharmacological activities and neuroprotective effects in vivo and in vitro. In this study, we determined whether and how K. parviflora ethanolic extract and M. fragrans volatile oil could influence the levels of neurotransmitters and the whole proteomic profile in the hippocampus of Sprague Dawley (SD rats. The effects of K. parviflora and M. fragrans on protein changes were analyzed by two-dimensional gel electrophoresis (2D-gel, and proteins were identified by liquid chromatography tandem mass spectrometry (LC-MS/MS. The target proteins were then confirmed by Western blot. The levels of neurotransmitters were evaluated by reversed-phase high-performance liquid chromatography (RP-HPLC. The results showed that K. parviflora, M. fragrans and fluoxetine (the control drug for this study increased serotonin, norepinephrine and dopamine in the rat hippocampus compared to that of the vehicle-treated group. Our proteomic data showed that 37 proteins in the K. parviflora group were up-regulated, while 14 were down-regulated, and 27 proteins in the M. fragrans group were up-regulated, while 16 were down-regulated. In the fluoxetine treatment group, we found 29 proteins up-regulated, whereas 14 proteins were down-regulated. In line with the proteomic data, the levels of GFAP, PDIA3, DPYSL2 and p-DPYSL2 were modified in the SD rat groups treated with K. parviflora, M. fragrans and fluoxetine as confirmed by Western blot. K. parviflora and M. fragrans mediated not only the levels of monoamine neurotransmitters but also the proteomic profiles in the rat hippocampus, thus shedding light on the mechanisms targeting neurodegenerative diseases.

  11. Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects

    DEFF Research Database (Denmark)

    Appel, Lieuwe; Bergström, Mats; Buus Lassen, Jørgen;

    2014-01-01

    multiple doses of 0.125-1 mg TE at anticipated steady-state conditions. The mean striatal DAT occupancy varied dose-dependently between 18% and 77%. A sigmoid E(max) model well described the relationship between striatal DAT occupancy and TE plasma concentrations or doses. It was estimated that the maximum...

  12. A rapid and sensitive method for the analysis of brain monoamine neurotransmitters using ultra-fast liquid chromatography coupled to electrochemical detection.

    Science.gov (United States)

    Parrot, Sandrine; Neuzeret, Pierre-Charles; Denoroy, Luc

    2011-12-15

    Electrochemical detection is often used to detect catecholamines and indolamines in brain samples that have been separated by conventional reverse-phase high performance liquid chromatography (HPLC). This paper presents the transfer of an existing chromatographic method for the determination of monoamines in brain tissues using 5 μm granulometry HPLC columns to columns with a particle diameter less than 3 μm. Several parameters (repeatability, linearity, accuracy, limit of detection, and stability of samples) for this new ultrafast high performance liquid chromatography (UHPLC) method were examined after optimization of the analytical conditions. The separation of seven compounds, noradrenaline, dopamine and three of its metabolites, dihydroxyphenylacetic acid, homovanillic acid, and 3-methoxytyramine, and serotonin and its metabolite, 5-hydroxyindole-3-acetic acid was analyzed using this UHPLC-electrochemical detection method. The final method, which was applied to brain tissue extracts from mice, rats, and cats, decreased analysis time by a factor of 4 compared to HPLC, while guaranteeing good analytical performance.

  13. Fractal analysis of striatal dopamine re-uptake sites

    Energy Technology Data Exchange (ETDEWEB)

    Kuikka, J.T.; Bergstroem, K.A. [Department of Clinical Physiology, Kuopio University Hospital, Kuopio (Finland); Tiihonen, J.; Raesaenen, P. [Department of Forensic Psychiatry, University of Kuopio and Niuvanniemi Hospital, Kuopio (Finland); Karhu, J. [Department of Clinical Neurophysiology, Kuopio University Hospital, Kuopio (Finland)

    1997-09-01

    Spatial variation in regional blood flow, metabolism and receptor density within the brain and in other organs is measurable even with a low spatial resolution technique such as emission tomography. It has been previously shown that the observed variance increases with increasing number of subregions in the organ/tissue studied. This resolution-dependent variance can be described by fractal analysis. We studied striatal dopamine re-uptake sites in 39 healthy volunteers with high-resolution single-photon emission tomography using iodine-123 labelled 2{beta}-carbomethoxy-3{beta}-(4-iodophenyl)tropane ([{sup 123}I]{beta}-CIT). The mean fractal dimension was 1.15{+-}0.07. The results indicate that regional striatal dopamine re-uptake sites involve considerable spatial heterogeneity which is higher than the uniform density (dimension=1.00) but much lower than complete randomness (dimension=1.50). There was a gender difference, with females having a higher heterogeneity in both the left and the right striatum. In addition, we found striatal asymmetry (left-to-right heterogeneity ratio of 1.19{+-}0.15; P<0.001), suggesting functional hemispheric lateralization consistent with the control of motor behaviour and integrative functions. (orig.). With 5 figs., 1 tab.

  14. The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain.

    Science.gov (United States)

    Nagai, Fumiko; Nonaka, Ryouichi; Satoh Hisashi Kamimura, Kanako

    2007-03-22

    We developed a reproducible, simple, and small-scale method for determining the re-uptake and release of monoamines (dopamine, serotonin (5-HT) and norepinephrine) using rat brain synaptosomes. These assays were then applied to study the effects of different kinds of non-medically used psychoactive drugs on monoamine re-uptake and release. The phenethylamine derivatives, 4-fluoroamphetamine, 2-methylamino-3,4-methylene-dioxy-propiophenone (methylone), 1-(1,3-benzodioxol-5-yl)-2-butanamine (BDB), and N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB), had strong inhibitory effects on the re-uptake of dopamine, 5-HT and norepinephrine. 4-Fluoroamphetamine, methylone and BDB also strongly increased the release of the three monoamines, but MBDB increased 5-HT and norepinephrine release, but had little effect on dopamine release. However, 2,5-dimethoxy-4-iodophenethylamine (2C-I), 2,5-dimethoxy-4-ethylphenethylamine (2C-E), 2,5-dimethoxy-4-chlorophenethylamine (2C-C), 2,4,5-trimethoxyamphetamine (TMA-2) and 2,4,6-trimethoxyamphetamine (TMA-6), which are methoxylated phenethylamine derivatives, slightly influenced the re-uptake and release of monoamines. Alpha-metyltryptamine (AMT), a tryptamine derivative, was one of the strongest re-uptake inhibitors and releasers of the three monoamines. The tryptamine derivative, 5-methoxy-alpha-methyltryptamine (5-MeO-AMT), also strongly inhibited re-uptake and increased the release of the three monoamines. N,N-dipropyltryptamine (DPT), 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), 5-methoxy-N,N-methylisopropyltryptamine (5-MeO-MIPT), and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) inhibited monoamine re-uptake, but had a few effects on monoamine release. 1-(3-Chlorophenyl)piperazine (3CPP) and 1-(methoxyphenyl)piperazine (4MPP), which are piperazine derivatives, inhibited monoamine re-uptake and accelerated their release. The results suggest that some designer drugs strongly act on the central nerve system to the same

  15. Effect of Wendan Tablets on Behaviors and Monoamine Neurotransmitters in Rat Model of Anxiety%温胆片对焦虑模型大鼠行为学和单胺类神经递质的影响

    Institute of Scientific and Technical Information of China (English)

    刘小河; 杨忠奇; 冼绍祥; 杨明晔; 沈淑静; 黄灿; 袁天慧; 王琼

    2012-01-01

    Objective To observe the anti-anxiety effect of Wendan Tablets and its influences on the contents of monoamine neurotransmitters of 5-hydroxytryptamine (5-HT) , norepinephrine (NE) and dopamine (DA) in the hippocampus of rats with anxiety. Methods SD male rats were randomized into blank group, model group, western medicine group and low-, middle-, and high-dose Wendan Tablets groups. Except for the blank group, the rats of the rest groups were stimulated irregularly by empty bottles to induce anxiety. One week later, the rats in the blank group were given oral use of distilled water, western medicine group were given oral use of 10mg/kg diazepam suspension, and low-, middle-, and high-dose Wendan Tablets groups were given oral use of 0. 6, 1.2 and 2. 4 g/kg suspension of Wendan Tablets respectively for 2 weeks. One week after treatment, the times of abnormal behaviors of the rats were observed, and neurotransmitter contents in rat hippocampus were detected by high performance liquid chromatography after treatment for 2 weeks. Results The times of attacking behavior and exploratory behavior of the rats in Wendan Tablets groups were significantly decreased, while the times of grooming behavior were significantly increased. 5-HT, NE and DA contents in the hippocampus of rats were also decreased in Wendan Tablets groups. Conclusion The anti-anxiety mechanism of Wendan Tablets may be associated with decreasing the release of cerebral monoamine neurotransmitters in rats.%[目的]观察温胆片的抗焦虑作用及对大鼠海马组织单胺类神经递质5-羟色胺(5-HT)、去甲肾上腺素(NE)及多巴胺(DA)含量的影响.[方法]选用SD雄性大鼠60只,随机分为6组,即空白对照组,模型组,西药组,温胆片低、中、高剂量组.除空白对照组外,其他组均采取不确定性空瓶应激的方法复制大鼠焦虑模型.空白对照组和模型组以双蒸水灌胃,西药组灌服10 mg/kg地西泮混悬液,温胆片低、

  16. Effect of laser acupoint irradiation on monoamine neurotransmitter in the hypothalamus of insomnia rats%激光穴位照射对失眠大鼠下丘脑单胺类递质的影响

    Institute of Scientific and Technical Information of China (English)

    周鹏; 赵仓焕; 马晓明; 房显辉; 陈丽华; 占大权; 周蔚华

    2012-01-01

    Objective To observe the effect of laser acupoint irradiation on the content of monoamine neuro-transmitter such as N-Acetyl-5-Hydroxytryptamine ( 5-HT) , 5-Hydroxyindole-3-acetic acid ( 5-HIAA) , Dopamine (DA) and L-Noradrenaline (NA) in the hypothalamus of insomnia rats caused by DL-P-Chlorophenylalanine (PC-PA) ,and investigate the mechanism of laser acupoint irradiation treatment of insomnia. Methods 24 female SD rats were divided randomly into 4 groups with 6 rats in each group,I. E. The control group,the model group,the diazepam group and the laser acupoint irradiation group. The model of insomnia rats were established by PCPA abdominal injection and the acupoints of Shenmen (HT7) and Sanyinjiao (SP6) were chosed to be irradiated by He-Ne laser. The change of 5-HT,5-HIAA,DA,NE in the hypothalamus of rats were observed by Fluorescence spectrophotometry. Results After laser acupoint irradiation treatment, the content of 5-HT and 5-HIAA increased obviously in contrast with the model group ( P < 0.01) and the diazepam group ( P < 0. 05 ) , while that of NE and DA decreased obviously in contrast with the model group (P < 0.05) and the diazepam group (P < 0.05). Conclusion The mechanisms of laser acupoint irradiation in treating insomnia may related to its regulation on monoamine neurotransmitter.%目的 观察激光穴位照射对对氯苯丙氨酸(PCPA)所致失眠大鼠下丘脑单胺类神经递质5-羟色胺(5-HT)、5-羟吲哚乙酸(5-HIAA)、多巴胺(DA)、去甲肾上腺素(NE)含量的影响,探讨激光穴位照射治疗失眠的机制.方法 将SD大鼠24只随机分为4组:对照组、模型组、安定组、激光组,每组6只.腹腔注射PCPA建立失眠大鼠模型,氦氖激光照射神门和三阴交穴各10 min,用荧光分光光度分析法检测下丘脑5-HT、5-HIAA、DA、NE的变化.结果 激光组大鼠下丘脑5-HT、5-HIAA含量明显升高,与模型组比较差异有统计学意义(P<0.01),与安定组比

  17. Monoamine neurotransmitter changes in hippocampus at reserpine induced chronic animal model of depression%慢性利血平抑郁模型大鼠海马单胺类神经递质的变化

    Institute of Scientific and Technical Information of China (English)

    王永志; 赵静洁; 韩玉; 杜仪; 李宝金; 李杨帆; 刘路遥; 张一帆; 张银凤

    2013-01-01

    目的 探索利血平致慢性抑郁大鼠模型的合适剂量,观察不同剂量利血平对大鼠自发活动和体质量的影响,分析模型大鼠海马单胺类神经递质的变化特点.方法 60只大鼠随机分为5组,空白组,利血平0.3 mg/kg、0.4 mg/kg、0.5 mg/kg、0.6 mg/kg组,每组n=12;动物造模给予腹腔注射利血平注射液1次/d(按分组中的给药剂量给予),空白组给予同体积蒸馏水,连续用药14 d.分别对大鼠open-field得分和体质量进行测量,酶联免疫法检测大鼠海马单胺类神经递质的水平.结果 慢性腹腔注射利血平(0.5、0.6 mg/kg)可引起大鼠体质量减轻(P<0.01,P<0.05),0.4、0.5、0.6 mg/kg组出现抑郁样行为;0.3 mg/kg组体质量、open-field得分变化不明显.与空白组体质量[(278.75±4.65)]和抑郁open-field评分[(60.3±19.9)分]比较,0.5 mg/kg组14 d大鼠体质量[(256.17±4.89)g]与open-field行为评分[(43.4±8.4)分]差异有显著性(P<0.01).0.5 mg/kg利血平对7d组抑郁大鼠海马5-羟色胺(5-HT)含量有影响[(2.83±1.09) ng/ml,P<0.05],对14 d组5-HT含量无明显影响.与空白组比较,0.5 mg/kg组14d腹腔注射利血平对单胺类神经递5-羟色胺(5-HT)、多巴胺(DA)、去甲肾上腺素(NA)影响差异无统计学意义(P>0.05),但可见5-HT与NA含量呈显著负相关(r=-0.449,P<0.01).结论 慢性腹腔注射0.5 mg/kg利血平能引起大鼠抑郁样行为,利血平对海马单胺类神经递质的影响与用药时间相关.%Objective To observe the suitable dosage of reserpine for the establishment of rat model of depression and analyze the changes of monoamine neurotransmitter in hippocampus.Methods 60 rats were randomly divided into five groups:the normal group,the 0.3 mg/kg group,0.4 mg/kg group,0.5 mg/kg group and 0.6 mg/kg group,and 12 rats in each group.The model groups were intraperitoneally administrated by different dosage of reserpine (according to the dosage of the grouping) for 14 days and rats in

  18. 一次力竭运动小鼠中枢单胺类神经递质的代谢特点%Brain Monoamines Neurotransmitters Metabolism Induced by a Prolonged Exhaustive Exercise in Mice

    Institute of Scientific and Technical Information of China (English)

    赵丽; 吴建忠; 岳明; 吕媛媛; 王德刚

    2014-01-01

    Objective:To investigate the metabolic changes of central monoamine neurotransmitters in the prolonged exhaustive exercise,in order for the central mechanism of sports fatigue to provide a laboratory basis.Method:The C57/BL mice were 4 months of age,and randomly divided them into the sedentary control group(SC)and exhausted swimming group(SE).After exhaustive swimming the cortex,hypothalamus,striatum,hippocampus, brainstem and cerebellum were collected immediately.The brain monoamines levels(NE,DA,DOPAC,5-HT,5-HIAA)were measured with HPLC. Result:In exhaustive group,the concentrations of NE in the cerebral cortex,hippocampus and brainstem were significantly increased compared with the sedentary control group(P<0.05),but the concentrations of NE in the hypothalamus,striatum and cerebellum had a decreasing tendency.The levels of DA in the hippocampus and brainstem were significantly increased compared to those in the sedentary control group(P<0.01),in the cortex and striatum only had a increasing tendency,but the concentrations of DA in the hypothalamus was significantly increased compared to that in the sedentary control group.The levels of DOPAC only were increased in the brainstem.The levels of 5-HT in all six brain loci of SE group were significantly increased compared with those of SC group(P<0.05),and the metabolic product 5-HIAA were significantly increased in the cerebral cortex,hypothalamus and cerebellum (P<0.05).Conclusion:Exercise results in a different activation degree of brain monoamine neurons in brain loci.Exercise-induced increased 5-HT and NE levels can be indicators of central fatigue.%目的:探讨力竭运动中枢单胺类神经递质的代谢变化特点,以期为运动疲劳的中枢机制提供一定实验室依据。方法:4月龄C57/BL小鼠,随机分为安静对照组(SC组)和一次性游泳力竭组(SE组)。力竭游泳即刻取材(皮层、下丘脑、纹状体、海马、脑干和小脑)六个脑区,高功率

  19. Exercise Benefits Brain Function: The Monoamine Connection

    OpenAIRE

    Tzu-Wei Lin; Yu-Min Kuo

    2013-01-01

    The beneficial effects of exercise on brain function have been demonstrated in animal models and in a growing number of clinical studies on humans. There are multiple mechanisms that account for the brain-enhancing effects of exercise, including neuroinflammation, vascularization, antioxidation, energy adaptation, and regulations on neurotrophic factors and neurotransmitters. Dopamine (DA), noradrenaline (NE), and serotonin (5-HT) are the three major monoamine neurotransmitters that are known...

  20. Rapid determination of monoamine neurotransmitters and their metabolites by high performance liquid chromatography%高效液相色谱法快速检测单胺类神经递质及其代谢产物

    Institute of Scientific and Technical Information of China (English)

    伦立民; 车琳杰; 李世伟

    2006-01-01

    BACKGROUND: The determination of monoamine neurotransmitters and their metabolites is important in the experimental.research of Parkinson disease (PD) and experimental diagnosis of phaochromocytoma.OBJECTIVE: To develop a high performance liquid chromatography (HPLC) method for simultaneous and rapid determination of monoamine neurotransmitters and their metabolites which include epinephrine(E), norepinephrine(NE), dopamine(DA), 5'-hydroxytryptamine(5'-HT), 5-hydroxy3-indoleacetic acid(5-HIAA), homovanillic acid(HVA) and 3,4-dihydroxyphenylacetic acid(DOPAC).DESIGN: Case control observation and a randomized controlled animal experiment.SETTING: Department of Clinical Laboratory, Affiliated Hospital of Medical College, Qingdao University; Haiyang Branch, Affiliated Hospital of Medical College, Qingdao University.PARTICIPANTS: This experiment was carried out at Staff Room of Physiology, edical College, Qingdao University and Department of Clinical Laboratory, Affiliated Hospital of Medical College of Qingdao University from October to December 2003. ①Two patients with phaeochromocytoma were all confirmed by CT, MRI or pathologic section as well as physical sign. Twelve health volunteers were all university students and were excluded to suffer hypertension, endocrine system diseases and other diseases. ② Total 12 healthy female Wister rats weighed between 150 g to 180 g were chosen and randomly divided into control group and PD group with 6 rats in each.METHODS: The standard chromatograms of the standard solution of mixtures of seven substances (E, NE, DA, 5'-HT, 5-HIAA, HVA and DOPAC)were prepared and the precisions and recovery rates of the same samples were determined respectively. Urine samples of 24 hours obtained from 12 healthy volunteers and 2 patients with phaeochromocytoma were analyzed respectively by HPLC. The unilateral forebrain bundles in PD group were destroyed with 6-hydroxydopamine (6-OHDA) for monitoring release characteristics of monoamine

  1. Changes of Mental Health Status and Monoamine Neurotransmitter under the Military Stress of Soldiers in Surface Ships%舰艇部队军事应激下心理及血单胺类递质的改变

    Institute of Scientific and Technical Information of China (English)

    朱成全; 韦林山; 洪加津; 孙学刚

    2013-01-01

    before and after stress. Conclusion Military stress has significant impact on the mental health status and monoamine neurotransmitter in the peripheral blood of the military men in surface ships.

  2. 碳纳米管/聚吡咯修饰电极用于液相色谱测定帕金森大鼠脑中神经递质%Liquid Chromatography with Electrochemical Detection Using Multi-wall Carbon Nanotubes/Polypyrrole Composite Film Modified Electrode for in Vivo Analysis of Monoamine Neurotransmitters in Rat Striatal Microdialysate of Freely Moving Parkinsonian Rats

    Institute of Scientific and Technical Information of China (English)

    林丽; 余莉; 林瑞泼; 李雪燕; 杨树林; 李校堃

    2011-01-01

    A multi-wall carbon nanotubes/polypyrrole modified electrode that can be used as the working electrode in the high performance liquid chromatography with electrochemical detection to determine the monoamine neurotransmitters was developed. The voltammetric response of dopamine could be promoted by using the electrode. The peak currents of norepinephrine, epinephrine, dopa mine and 5-hydroxytryptamine were linear with their concentrations ranging from 5. 0 ×10-10 to 1. 0 ×10-6 mol/L, and the peak currents of 3 , 4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid and homovanillic acid were linear with their concentrations ranging from 1. 0 ×10-9 to 5. 0 × 10-4 mol/L.The correlation coefficients of the seven compounds were more than 0. 998. The detection limits were the level of 0. 1 nmol/L. Coupled with in vivo microdialysis sampling, the method had been success fully applied to measure monoamine neurotransmitters in rat striatum of freely moving Parkinsonian rats, and the monoamine neurotransmitters level of model group decreased compared with control group.%制备了碳纳米管/聚吡咯复合修饰电极,研究了多巴胺等单胺类神经递质在该修饰电极上的电化学行为.将此修饰电极作为电化学检测器,与高效液相色谱联用,测定了脑中7种神经递质及其代谢产物.结果表明:去甲肾上腺素、肾上腺素、多巴胺和5-羟色胺的线性范围为5.0×10(-10)~1.0×10(-5)mol/L;3,4-二羟基苯乙酸,5-羟吲哚乙酸和高香草酸的线性范围为1.0×10(9)~5.0×10(-4)mol/L;7种物质相关系数均大于0.998;检出限在0.1 nmol/L水平.结合微透析活体取样,测定了自由活动帕金森模型组大鼠脑纹状体中7种单胺类神经递质及其代谢产物的含量,较正常组有所降低.

  3. Effects of hexabromocyclododecane(HBCD) on monoamine neurotransmitters contents and monoamine oxidase activity of developmental rat brain%六溴环十二烷对发育期大鼠脑单胺类神经递质质量比及单胺氧化酶活性的影响

    Institute of Scientific and Technical Information of China (English)

    刘芳; 冀秀玲; 赵文娟; 殷明; 蒋惠男; 张江

    2012-01-01

    .01). As for the monoamine oxidase, an increase trend can be found with MAO activity in the range of 10 to 100 μg/kg doses and significantly changed at the dose of 100 μg/kg(p <0.05) . When the dose is kept at a level of 300 (μg/kg, the trend is likely to drop, though not enough significantly. DA, NE and 5 ~ HT were found to play a important role in the learning, memory and moods in the rats' brain. Changing the contents of DA, 5 - HT, disorders can be found with the central nervous system with the rats when the developmental HBCD was exposed to the NE and MAO activities. Compared with the dose of 300 μg/kg, severe effects were detected on the neurotransmitters and MAO at a level of 10-100 μg/kg. it indicates that HBCD has the feature of low-dosage and high toxicity to the developmental rat brain. Furthermore, the exposure dosages of 10 - 100 μg/kg can only produce a mirror effect in comparison with the content of HBCD in the real environment. However, HBCD of the environmental exposure levels proves to produce neurotoxicity and have effect on the learning and memory system of the developmental rats. Thus, it can be said that this paper has provided an important reference in the study of the HBCD exposure and its effect on the public health in the environment, especially on children ' s healthy growth.

  4. Detection and Quantification of Neurotransmitters in Dialysates

    OpenAIRE

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

    2009-01-01

    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).

  5. Monoamine transporters: Insights from molecular dynamics simulations

    Directory of Open Access Journals (Sweden)

    Julie eGrouleff

    2015-10-01

    Full Text Available The human monoamine transporters facilitate the reuptake of the neurotransmitters serotonin, dopamine, and norepinephrine from the synaptic cleft. Imbalance in monoaminergic neurotransmission is linked to various diseases including major depression, attention deficit hyperactivity disorder, schizophrenia and Parkinson’s disease. Inhibition of the monoamine transporters is thus an important strategy for treatment of such diseases. The monoamine transporters are sodium-coupled transport proteins belonging to the neurotransmitter/Na+ symporter (NSS family, and the publication of the first high-resolution structure of a NSS family member, the bacterial leucine transporter LeuT, in 2005, proved to be a major stepping stone for understanding this family of transporters. Structural data allows for the use of computational methods to study the monoamine transporters, which in turn has led to a number of important discoveries. The process of substrate translocation across the membrane is an intrinsically dynamic process. Molecular dynamics simulations, which can provide atomistic details of molecular motion on ns to ms timescales, are therefore well-suited for studying transport processes. In this review, we outline how molecular dynamics simulations have provided insight into the large scale motions associated with transport of the neurotransmitters, as well as the presence of external and internal gates, the coupling between ion and substrate transport, and differences in the conformational changes induced by substrates and inhibitors.

  6. Neurotransmitter transporters

    DEFF Research Database (Denmark)

    Gether, Ulrik; Andersen, Peter H; Larsson, Orla M

    2006-01-01

    The concentration of neurotransmitters in the extracellular space is tightly controlled by distinct classes of membrane transport proteins. This review focuses on the molecular function of two major classes of neurotransmitter transporter that are present in the cell membrane of neurons and....../or glial cells: the solute carrier (SLC)1 transporter family, which includes the transporters that mediate the Na(+)-dependent uptake of glutamate, and the SLC6 transporter family, which includes the transporters that mediate the Na(+)-dependent uptake of dopamine, 5-HT, norepinephrine, glycine and GABA....... Recent research has provided substantial insight into the structure and function of these transporters. In particular, the recent crystallizations of bacterial homologs are of the utmost importance, enabling the first reliable structural models of the mammalian neurotransmitter transporters...

  7. Influence of component formula of Suanzaoren Tang on hippocampus monoamine neurotransmitters and their metabolites in rats in elevated plus maze test%酸枣仁汤组分配方对高架十字迷宫大鼠海马单胺类递质及其代谢物的影响

    Institute of Scientific and Technical Information of China (English)

    王守勇; 谢鸣

    2012-01-01

    目的 观察酸枣仁汤组分配方对高架十字迷宫大鼠海马单胺类递质及其代谢物的影响,探讨其抗焦虑效用的有效组分及作用机理.方法 采用国际上通用的高架十字迷宫焦虑动物模型,观察酸枣仁汤组分配方对大鼠行为学的影响,高效液相色谱法测定大鼠海马单胺类递质去甲肾上腺素(NE)、5-羟色胺(5 -HT)、多巴胺(DA)及其代谢物的含量.结果 与空白对照组比较,全组分配方组和有效组分配方组及地西泮组大鼠进入开放臂次数比、在开放臂停留时间比均显著升高(P<0.01或P<0.05);有效组分配方组和地西泮组大鼠海马5-HT的含量均见显著降低(P<0.05),全组分配方组海马5-HT含量呈降低作用趋势;有效组分配方组大鼠海马高香草酸(HVA)含量显著升高(P<0.01).结论 酸枣仁汤全组分配方及其有效组分配方与地西泮具有某些相同的抗焦虑作用机制,可能涉及到降低海马5-HT含量;全组分配方及其有效组分配方对大鼠海马单胺类递质代谢的影响有所不同.%Objective To observe the influence of component formula of Suanzaoren Tang on hippocampus monoamine neurotransmitters and their metabolites in rats in elevated plus maze test (EPM) , and discuss its effective components and mechanism of anti-anxiety. Methods The influence of component formula of Suanzaoren Tang on rat ethology was observed by using international common-used anxiety animal model in EPM. The levels of monoamine neurotransmitters including noradrenaline (NE) , 5-hydroxytryptamine (5-HT) and dopamine (DA) and their metabolites were detected by applying HPLC. Results Compared with blank group, the ratio of entering times and retention time ratio in open arm increased significantly in whole component formula group (whole CF group) , effective component formula group (effective CF group) and diazepam group (P <0. 01 or P <0. 05). The level of 5-HT decreased significantly in

  8. 右美沙芬对小鼠大脑5-羟色胺含量的影响%Influences of Dextromethorphan on Monoamine Neurotransmitter 5-HT in Mouse Brain

    Institute of Scientific and Technical Information of China (English)

    李迎春; 张久亮; 周莉红

    2012-01-01

    Objective To study the antitussive mechanism of dextromethorphan. Methods By using reversed-phase high-performance liquid chromatography (RP-HPLC) with fluorescent light detector, we detected the effect of dextromethorphan on the contents of five kinds of monamine neurotransmitters in mouse brain with codeine phosphate serving as a positive drug. Results The results indicated that the antitussive mechanism of dextromethorphan was concerned with monanine neurotransmitter 5-HT. In the dextromethorphan group, 5-HT was 43. 50% higher than in the blank group (P<0.01) , and 5-HIAA was 35. 00% higher than in the blank group (P<0. 05). Dextromethorphan could increase the content of 5-HT in mouse brain to induce antitussive effects, while the antitussice effects of codeine phosphate had no relationship with serotonergic mechanisms. Conclusion The antitussive mechanism of dextromethorphan is related with the release of monanine neurotransmitter 5-HT in mouse brain.%目的 初步探讨右美沙芬通过增加小鼠脑部5-羟色胺(5-HT)的含量的镇咳机制.方法 采用反相高效液相-荧光检测(RP-HPLC-FLD)法,以磷酸可待因为对照药,测定右美沙芬对小鼠脑部5种单胺类神经递质含量的影响.结果 右美沙芬的镇咳机制与单胺类神经递质5-HT有关,右美沙芬组的5-HT含量比空白组增加了43.50%,差异有统计学意义(P <0.01),5-羟基吲哚乙酸(5-HIAA)含量比空白组增加35.00%,差异有统计学意义(P<0.05).结论 右美沙芬镇咳作用与小鼠脑部5-HT的释放有关.

  9. Selective serotonin re-uptake inhibitors (SSRIs) in the aquatic environment: an ecopharmacovigilance approach.

    Science.gov (United States)

    Silva, Liliana J G; Lino, Celeste M; Meisel, Leonor M; Pena, Angelina

    2012-10-15

    Selective serotonin re-uptake inhibitors (SSRIs) antidepressants are among the most prescribed pharmaceutical active substances throughout the world. The occurrence of these widely used compounds in different environmental compartments (wastewaters, surface, ground and drinking waters, and sediments), justify the growing concern about these emerging environmental pollutants. Viewing an ecopharmacovigilance approach, a comprehensive discussion of the state of the art regarding different contamination sources, fate, degradation and occurrence is presented. Information on the current distribution levels and fate in different environmental matrices continues to be sparse and measures are imperative to improve awareness and encourage precautionary actions to minimize SSRIs' environmental impact.

  10. Fluorescent Probes for Analysis and Imaging of Monoamine Oxidase Activity

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Dokyoung; Jun, Yong Woong; Ahn, Kyo Han [POSTECH, Pohang (Korea, Republic of)

    2014-05-15

    Monoamine oxidases catalyze the oxidative deamination of dietary amines and amine neurotransmitters, and assist in maintaining the homeostasis of the amine neurotransmitters in the brain. Dysfunctions of these enzymes can cause neurological and behavioral disorders including Parkinson's and Alzheimer's diseases. To understand their physiological roles, efficient assay methods for monoamine oxidases are essential. Reviewed in this Perspective are the recent progress in the development of fluorescent probes for monoamine oxidases and their applications to enzyme assays in cells and tissues. It is evident that still there is strong need for a fluorescent probe with desirable substrate selectivity and photophysical properties to challenge the much unsolved issues associated with the enzymes and the diseases.

  11. Analgesic effect of sinomenine on SSNI model rats and monoamine neurotransmitters in striatal extracellular fluid%青藤碱对SSNI模型大鼠镇痛效应和纹状体细胞外液单胺类递质的影响

    Institute of Scientific and Technical Information of China (English)

    张美玉; 李鹏; 王丹巧; 牛晓红; 王晔; 王志国; 张莹; 徐奭; 徐晓军

    2013-01-01

    Objective:To observe the analgesic effect of sinomenine on the neuropathic pain rat model induced by SSNI,and discuss its impact on monoamine neurotransmitters in striatal extracellular fluid.Method:Male SD rats were randomly divided into the sham operation group,the SSNI model group,the gabapentin group (100 mg·kg-1),the sinomenine high dose group (40mg·kg-1) and the sinomenine low dose group (20mg·kg-1).Mechanical hyperalgesia and cold pain sensitivity were evaluated by Von Frey hairs and cold spray.Striatum was sampled by microdialysis.High performance liquid chromatography-electrochemical detector (HPLC-ECD) were used to detect the content of such neurotransmitters as monoamine neurotransmitters noradrenaline (NE),dopamine (DA),5-hydroxy tryptamine (5-HT) and their metabolites dihydroxyphenylacetic phenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA).Result:SSNI model rats showed significant improvement in mechanical withdrawal threshold and cold pain sensitivity,significant decrease in intracerebral NE and notable increase in DA,5-HT and their metabolites.Compared with the model group,the sinomenine high dose group showed significant increase in mechanical withdrawal threshold at 60,90,180 and 240 min after abdominal administration (P<0.01),significant decrease in cold pain sensitivity score during 30-240 min (P<0.05).Sinomenine can significantly up-regulated NE content in striatal extracellular fluid during 45-135 min (P<0.05),remarkably reduce DA content and DOPAC at 45,75 and 135 min (P<0.05),5-HT content during 45-135 min,DOPAC during 75-165 min (P<0.05),and 5-HIAA during 45-135 min (P<0.05).Conclusion:Sinomenine has the intervention effect on neuropathic pain in SSNI model rats.Its mechanism may be related to disorder of monoamine neurotransmitters in striatal extracellular fluid.%目的:观察青藤碱对部分坐骨神经损伤(SSNI)诱导的神经病理性疼痛大鼠模型镇痛效应,并探讨其对纹状体细胞外液

  12. The Effects of Monoamine Neurotransmitters and Their Receptors in the Brain on Exercise-Induced Central Fatigue under Heat Stress%热应激下脑内单胺类神经递质及其受体对运动性中枢疲劳影响的研究进展

    Institute of Scientific and Technical Information of China (English)

    张念云; 张蕴琨

    2012-01-01

    Neurotransmitters such as Acetylcholine(Ach),norepinephrine(NE) and 5-hydroxytryptamine(5-HT) regulate body temperature in the hypothalamic,the regulation of receptor lies on the difference of its subtypes.In the high temperature environment,The Concentration of dopamine(DA),5-HT,NE Increased with the rise of brain and core body temperature.The active of 5-HTR2 increased body temperature,while The Active of 5-HTR1A reduced body temperature.In addition,DAR1 and DAR2 synergy to reduce body temperature.The changes of concetration and balance breakage in monoamine neurotransmitters is one of the important factors which caused central fatigue.The temperature of brain and core body increased in Heat stress conditions.The temperature of brain increased can cause central fatigue.The active of DA and NE Improved will inhibit central fatigue,and improve the exercise capacity under Heat stress conditions.However,5-HT can not do as DA and NE.%乙酰胆碱(Ach)、去甲肾上腺素(NE)和5-羟色胺(5-HT)等神经递质参与下丘脑的体温调节,其受体亚型的不同也有不同的调节作用。在高温环境中,多巴胺(DA)、5-HT、NE伴随大脑和核心体温的升高而增加。提高5-HTR2活性会引起体温升高,而提高5-HTR1A活性的则会引起体温降低,DAR1、DAR2两者协同作用于体温的降低。单胺类神经递质含量改变及平衡的破坏是导致运动性中枢疲劳发生的因素之一。热应激条件下机体大脑和核心温度升高,脑内热储备过多,导致中枢疲劳的发生,提高DA、NE的活性可抑制高温介导的中枢疲劳,改善热应激下运动能力,但未能证明在高温环境下长时间运动5-HT介导疲劳的特殊作用。

  13. 束缚应激所致小鼠脑区的神经递质和行为改变及运动干预效果%Restrained stress induced changes of brain monoamine neurotransmitters and behaviors of mice as well as exercise intervention effects

    Institute of Scientific and Technical Information of China (English)

    马磊; 黄文英; 杨念恩; 肖晓玲; 孙飙; 康学军

    2015-01-01

    In order to probe into the effects of restrained stress on monoamine neurotransmitters and behaviors of mice as well as aerobic exercise intervention effects, the authors selected 80 1-month old C57BL/6 mice, randomly divided them into 4 groups: a control group (Control, n=20), a restrained stress group (Stress, n=20), an exercise group (Ex, n=20) and an exercise + restrained stress group (Stress + Ex, n=20), fed the control group in a calm con-dition, let the restrained stress group suffer restrained stress for 2 weeks, let the exercise group exercise on a tread-mill 2 hours a day, let the exercise + restrained stress group suffer restrained stress and exercise on a treadmill si-multaneously, and revealed the following findings: in the behavior experiment, the mice in the restrained stress group had significantly decreased social behaviors and significantly increased levels of anxiety and depression be-haviors (P<0.05), while exercise intervention could alleviate the effects of restrained stress on these behaviors. Bio-chemical indexes indicated as well that aerobic exercise effectively alleviated retrained stress induced changes of behaviors and monoamine neurotransmitters. Conclusion: restrained stress will cause changes of social communica-tion and emotion related behaviors, while exercise intervention will play an effective role of alleviation.%为了探讨束缚应激对小鼠神经递质、行为的影响及有氧运动的干预效果。选用1月龄C57BL/6小鼠80只,随机分为4组:控制组(Control,n=20只)、束缚应激组(Stress,n=20只)、运动组(Ex,n=20只)、运动束缚应激组(Stress+Ex,n=20只)。控制组安静饲养,束缚应激组进行2周的束缚应激,运动组每天进行2 h跑台锻炼,运动束缚应激组同时进行束缚应激和跑台锻炼。结果发现:行为试验中,束缚应激组小鼠社交行为显著下降、焦虑及抑郁行为水平发生显著上升(P<0.05),而运动

  14. 参芪解郁方对产后抑郁大鼠单胺递质及其代谢产物变化的干预研究%Research of influence of Shenqijieyu prescription on changes of monoamine neurotransmitter and metabolite in rats with postpartum depression

    Institute of Scientific and Technical Information of China (English)

    侯秀娟; 唐启盛; 杨歆科; 李小黎; 赵瑞珍; 王旭

    2013-01-01

    Objective To explore interventional mechanism of Shenqijieyu prescription on postpartum depression (PPD) from the perspectives of changes of monoamine neurotransmitter and its related metabolite. Methods Female 2-3 month SD rats were selected and randomly divided into a blank group, a sham-operated group, a model group, a Chinese medicinal group and a western medicine group. The time points at 1st, 2nd, 4th, 6th week were set for observation in each group. The contents of prefrontal cortex, monoamine neurotransmitter in the hippocampus and its metabolite were detected with high performance liquid chromatography. Results The 5-hydroxytryptamine (5—HT), norepinephrine (NE) and dopamine (DA) in the prefrontal cortex and the hippocampus at each time point in the model group were reduced compared with those in the blank group and the sham-operated group (P< 0.01, P< 0.05). The 5-HT,NE in the prefrontal cortex at 2nd, 4th, 6th week in the Chinese medicinal group and at each time point in the western medicine group, as well as the 5-HT, NE in the hippocampus at each time point in the Chinese medicinal group and the western medicine group were increased compared with those in the model group (P < 0.01, P< 0.05). The DA in the prefrontal cortex at 4th, 6th week in the Chinese medicinal group and at 2nd, 4th, 6th week in the western medicine group, as well as DA in the hippocampus at 1st, 6th week in the Chinese medicinal group and at 1st week in the western medicine group were increased compared with those in the model group (P < 0.01, P < 0.05). The 5—hydroxyindole acetic acid (5—HIAA)in the prefrontal cortex and hippocampus at 1st week in the model group were higher than those in the blank group and the sham-operated group (P < 0.01, P < 0.05); the contents of two parts of 5-HIAA at the other time points and two parts of 3, 4-dihydroxy-phenyl acetic acid (DOPAC) at each time point were decreased compared with those in the blank group and the sham-operated group (P

  15. [Effect of occupational stress on neurotransmitters in petroleum workers].

    Science.gov (United States)

    Jiang, Yu; Lian, Yulong; Tao, Ning; Ge, Hua; Liu, Jiwen

    2015-09-01

    To explore the effects of occupational stress on neurotransmitters in petroleum workers. 178 petroleum workers with the length of service ≥ 1 year were recruited to the subjects by the questionnaire of OSI-R. The levels of 5-hydroxy tryptamine (5-HT), norepinephrine (NE), neuropeptide Y (NPY) and substance P (SP) in serum were measured. The subjects were classified into 3 groups according to the scores of occupational stress. The levels of 5-HT NE and SP for over 15 working years were higher than those of less than 15 years (P petroleum workers (P petroleum workers is correlated with serum monoamine and neuropeptides neurotransmitters, and it may affect serum levels of monoamine and neuropeptides neurotransmitters.

  16. The selective serotonin re-uptake inhibitors fluvoxamine and paroxetine differ in sexual inhibitory effects after chronic treatment.

    NARCIS (Netherlands)

    Waldinger, M.D.; Plas, A.; Pattij, T.; Oorschot, R. van; Coolen, L.M.; Veening, J.G.; Olivier, B.

    2002-01-01

    RATIONALE: The selective serotonin re-uptake inhibitors (SSRIs) delay orgasm and ejaculation in men. In men with rapid ejaculation it was shown that, of the SSRIs, paroxetine exerted the strongest delay in ejaculation and fluvoxamine the weakest. OBJECTIVES: In the present study, we compared the acu

  17. Alterations in Brain Monoamine Neurotransmitter Release at High Pressure

    Science.gov (United States)

    1989-01-01

    Services Division F 02-295-2188 ISD/ADMIN/hNXRI )D FORM 1473,84 MAR 83 APR edition may oe used until exnausted. SECURITY CLASIFICATION OF TWIS PAGE All...ml) of the synaptosomal preparation con- taining 3.0 3.5 mg ml protein were incubated for Is mm Of [3H]serotonin from synaptosome fractions iso- 370...Brauer R"’. Beaser RW. Sheehan ME (1978) Role of mono- S~napsin I ( protein I1). a nerse terminal-specific phospho- amnine neurotransmnitters in the

  18. Effects of Albizia Julibrissin Flower Total Flavonoids on Learning and Memory Abilities and Plasma Monoamine Neurotransmitters of Depression Model Rats%合欢花总黄酮对抑郁模型大鼠学习记忆能力及血浆单胺类神经递质的影响

    Institute of Scientific and Technical Information of China (English)

    郭超峰; 银胜高; 夏猛; 施学丽

    2013-01-01

    This study was aimed to observe effects of Albizia Julibrissin Flower Total Flavonoids (AJFTF) on the learning and memory abilities and plasma monoamine neurotransmitters 5-HT and NE content of depression model rats . A total of 90 SD rats were randomly divided into the normal group , model group , western medicine group ( Venlafaxine Hydrochloride 0 . 0125 g•kg-1 ) and high , middle and low dosage groups of AJFTF ( equivalent to the crude drug of 10 , 5 , 2 . 5 g•kg-1 ) . Depression model rats were induced by solitary cultiva-tion and chronic unpredictable stress . The learning and memory abilities of model rats were evaluated with the Morris water maze . And the plasma contents of 5-HT and NE were determined by enzyme-linked immunosor-bent assay ( ELISA ) . The results showed that AJFTF ( administered with high , middle and low dosage for 21 days ) significantly shortened the incubation period of the Morris water maze positioning and navigation ( P <0 . 05 or P < 0 . 01 ) , and increased the times of crossing the platform in space exploration ( P < 0 . 05 or P <0 . 01 ) . There was a certain dose-effect relationship . The AJFTF ( high , middle and low dosage ) increased the plasma contents of 5-HT and NE ( P < 0 . 05 ) . It was concluded that AJFTF can improve learning and memory abilities of depression model rats which indicates that AJFTF have potential antidepressant effects . Its action mechanism may be related to increase plasma monoamine neurotransmitter content of 5-HT and NE .%目的:观察合欢花总黄酮对抑郁模型大鼠学习记忆能力及血浆单胺类神经递质5-羟色胺(5-HT)、去甲肾上腺素(NE)含量的影响。方法:将90只SD大鼠随机分为正常组、模型组、西药组(盐酸文拉法辛0.0125 g·kg-1)、合欢花总黄酮高、中、低剂量组(相当于生药量10、5、2.5 g·kg-1)。以孤养加慢性不可预见性应激建立抑郁症大鼠模型。采用Morris水迷宫评价各组大鼠的

  19. 刺五加对睡眠剥夺大鼠学习记忆及海马单胺类神经递质的影响%Effects of Acanthopanax on Learning and Memory andMonoamine Neurotransmitters in Hippocampus of Sleep Deprived Rats

    Institute of Scientific and Technical Information of China (English)

    朱蕾; 张茹; 李廷利

    2012-01-01

    Objective: To study the protective mechanism of acanthopanax on learning and memory and monoamine neurotransmitters acetylcholinesterase ( AchE ) , serotonin ( 5-HT ) , norepinephrine ( NE ) , 5-hydroxindole acetic acid (5-HIAA) of hippocampus in sleep deprivation rats. Method: Total of 75 male wistar rats were randomized into 5 groups, large platform group, sleep deprivation group, three treatment groups (high, middle and low dose). Treatment groups were given Acanthopanax solution (11.2, 5.6, 2. 8 g·kg-1) for 7 days. The others were given distilled water. A small platform was used to establish rapid eye movement sleep ( REMS) deprivation model in rats. After 4 days, the ability of learning memory and space exploration was tested by Hexagonal maze in rats. The level of AchE, 5-HT, NE, 5-HIAA in hippocampus homogenate were measured. Result: Compared with a large platform, the number of errors of sleep deprivation group increased, the rate of cognitive reduced ( P < 0. 01 ) , but finding time was shorten ( P < 0. 05 ) . After administration of Acanthopanax solution, the number of errors reduced significantly, the rate of cognitive increased(P <0. 01 ) , finding time was shorten(P <0. 01 ) , the level of 5-HT, NE. 5-HIAA was higher in Acanthopanax solution than sleep deprivation group (P <0. 05 or P <0. 01). The AchE level in treatment groups was lower thanthat in sleep deprivation groupbut higher than large platform group (P <0. 05 or P <0. 01) . Conclusion: Acanthopanax can improve learning and memory ablity in sleep deprived rats, and the mechanism may involve regulating the sleep deprivation caused by disorders of monoamine neurotransmitter, accelerating the metabolic conversion of 5-HT, regulating NE, and AchE activity in the hippocampus.%目的:探讨刺五加对睡眠剥夺大鼠学习记忆能力及对海马单胺类神经递质AchE(乙酰胆碱酯酶),5-HT(5-羟色胺)、NE(去甲肾上腺素)、5-HIAA(5-羟吲哚乙酸)的影响.方法:将75

  20. Diagnosis and treatment of neurotransmitter disorders.

    Science.gov (United States)

    Pearl, Phillip L; Hartka, Thomas R; Taylor, Jacob

    2006-11-01

    The neurotransmitter disorders represent an enigmatic and enlarging group of neurometabolic conditions caused by abnormal neurotransmitter metabolism or transport. A high index of clinical suspicion is important, given the availability of therapeutic strategies. This article covers disorders of monoamine (catecholamine and serotonin) synthesis, glycine catabolism, pyridoxine dependency, and gamma-aminobutyric acid (GABA) metabolism. The technological aspects of appropriate cerebrospinal fluid (CSF) collection, shipment, study, and interpretation merit special consideration. Diagnosis of disorders of monoamines requires analysis of CSF homovanillic acid, 5-hydroxyindoleacetic acid, ortho-methyldopa, BH4, and neopterin. The delineation of new disorders with important therapeutic implications, such as cerebral folate deficiency and PNPO deficiency, serves to highlight the value of measuring CSF neurotransmitter precursors and metabolites. The impressive responsiveness of Segawa fluctuating dystonia to levodopa is a hallmark feature of previously unrecognized neurologic morbidity becoming treatable at any age. Aromatic amino acid decarboxylase and tyrosine hydroxylase deficiency have more severe phenotypes and show variable responsiveness to levodopa. Glycine encephalopathy usually has a poor outcome; benzoate therapy may be helpful in less affected cases. Pyridoxine-dependent seizures are a refractory but treatable group of neonatal and infantile seizures; rare cases require pyridoxal-5-phosphate. Succinic semialdehyde dehydrogenase deficiency is relatively common in comparison to the remainder of this group of disorders. Treatment directed at the metabolic defect with vigabatrin has been disappointing, and multiple therapies are targeted toward specific but protean symptoms. Other disorders of GABA metabolism, as is true of the wide spectrum of neurotransmitter disorders, will require increasing use of CSF analysis for diagnosis, and ultimately, treatment.

  1. Evidence that the methylation state of the monoamine oxidase A (MAOA) gene predicts brain activity of MAO A enzyme in healthy men

    National Research Council Canada - National Science Library

    Shumay, Elena; Logan, Jean; Volkow, Nora D; Fowler, Joanna S

    2012-01-01

    ...). PET brain imaging of monoamine oxidase A (MAO A)-an enzyme metabolizing neurotransmitters-revealed that MAO A levels vary widely between healthy men and this variability was not explained by the common MAOA genotype (VNTR genotype...

  2. The plasma membrane monoamine transporter (PMAT): Structure, function, and role in organic cation disposition.

    Science.gov (United States)

    Wang, J

    2016-11-01

    Plasma membrane monoamine transporter (PMAT) is a new polyspecific organic cation transporter that transports a variety of biogenic amines and xenobiotic cations. Highly expressed in the brain, PMAT represents a major uptake2 transporter for monoamine neurotransmitters. At the blood-cerebrospinal fluid (CSF) barrier, PMAT is the principal organic cation transporter for removing neurotoxins and drugs from the CSF. Here I summarize our latest understanding of PMAT and its roles in monoamine uptake and xenobiotic disposition. © 2016 American Society for Clinical Pharmacology and Therapeutics.

  3. Monoamine transporters: insights from molecular dynamics simulations

    Science.gov (United States)

    Grouleff, Julie; Ladefoged, Lucy Kate; Koldsø, Heidi; Schiøtt, Birgit

    2015-01-01

    The human monoamine transporters (MATs) facilitate the reuptake of the neurotransmitters serotonin, dopamine, and norepinephrine from the synaptic cleft. Imbalance in monoaminergic neurotransmission is linked to various diseases including major depression, attention deficit hyperactivity disorder, schizophrenia, and Parkinson’s disease. Inhibition of the MATs is thus an important strategy for treatment of such diseases. The MATs are sodium-coupled transport proteins belonging to the neurotransmitter/Na+ symporter (NSS) family, and the publication of the first high-resolution structure of a NSS family member, the bacterial leucine transporter LeuT, in 2005, proved to be a major stepping stone for understanding this family of transporters. Structural data allows for the use of computational methods to study the MATs, which in turn has led to a number of important discoveries. The process of substrate translocation across the membrane is an intrinsically dynamic process. Molecular dynamics simulations, which can provide atomistic details of molecular motion on ns to ms timescales, are therefore well-suited for studying transport processes. In this review, we outline how molecular dynamics simulations have provided insight into the large scale motions associated with transport of the neurotransmitters, as well as the presence of external and internal gates, the coupling between ion and substrate transport, and differences in the conformational changes induced by substrates and inhibitors. PMID:26528185

  4. 网络成瘾者血液中单胺类神经递质水平与治疗转归的相关性%Relationship of treatment outcome with monoamine neurotransmitter content in peripheral blood in patients with internet addiction disorder

    Institute of Scientific and Technical Information of China (English)

    宋来云; 黄淑燕; 郑小泳; 肖攀攀; 黄金焕; 梁雪玲; 李艳容; 徐伏莲

    2015-01-01

    目的 比较网络成瘾(IAD)者外周血中单胺类神经递质5-羟色胺(5-HT)、多巴胺(DA)、去甲肾上腺素(NE)浓度水平在治疗前后动态变化,分析其与治疗效果的相关性.方法 对治疗前后的35例网络成瘾者(研究组,IAD组)以及性别、年龄、受教育年限与之相匹配的35例健康志愿者(对照组)均采用高效液相色谱法(HPLC)检测外周血小板5-HT浓度,用酶联免疫吸附法(ELISA)检测血浆DA和NE浓度.用中文网络成瘾量表(CIAS)、家庭功能评定量表(FAD)、HAMD量表、HAMA量表评定两组网络成瘾严重程度和IAD组治疗效果.比较IAD组治疗前后5-HT、DA、NE浓度并与对照组比较,分析其与治疗效果(量表)的相关性.结果 (1)IAD组(治疗前)5-HT(427.82±136.28) ng/L,低于对照组的(522.63±123.25) ng/L(t=3.052,P<0.05),DA(65.29±32.52) ng/L,高于对照组的(35.76±22.34) ng/L(t=4.427,P<0.05),NE(493.24±137.65) ng/L,高于对照组的(415.28±118.34) ng/L(t=2.540,P<0.05).(2) IAD组(治疗后)5-HT(518.35±115.68) ng/L,高于IAD组的(治疗前)(427.82±136.28) ng/L(t=2.996,P<0.05),DA(36.45±29.47) ng/L,低于IAD组的(治疗前)(65.29±32.52) ng/L(t=3.887,P<0.05),NE (421.75±129.76) ng/L,低于IAD组的(治疗前)(493.24±137.65)(t=2.235,P<0.05).但IAD组(治疗后)与对照组比较,5-HT、DA和NE浓度差异均无统计学意义(均P>0.05).(3)5-HT浓度与量表评分(CIAS、FAD、HAMa+d)负相关(r=-0.653、-0.547、-0.409,均P<0.05),DA浓度与量表评分正相关(r=0.406、0.375、0.423,均P<0.05),NE浓度与量表评分正相关(r=0.505、0.338、0.545,均P<0.05).结论 网络成瘾者外周血中单胺类神经递质浓度可能与疗效相关;5-HT浓度与疗效正相关,DA、NE与疗效负相关.%Objective To investigate the changes of the concentrations of monoamine neurotransmitter serotonin (5-HT),dopamine (DA),norepinephrine (NE) in peripheral blood in patients with intemet addiction disorder (IAD) between before and

  5. 音乐电针和脉冲电针对慢性应激抑郁模型大鼠不同脑区单胺类神经递质表达的影响%Influence of Music Electro-acupuncture and Pulsed Electro-acupuncture on the Different Encephalic Regions of Monoamine Neurotransmitter Chronic Unpredictable Mild Stress Depression Model Rats

    Institute of Scientific and Technical Information of China (English)

    唐银杉; 纪倩; 曹瑾; 滕金艳; 邓晓丰; 李静; 李志刚

    2014-01-01

    electro-acupunc-ture group .All groups were treated with the chronic unpredictable mild stress stimulation combined with lonely rai-sing for 21 days except the normal control group .Behavior changes of rats were detected through open -field test , sugar consumption test and body weight examining .Detect the 5-HT,DA,NE of frontal lobe and hippocampal of each rat by radioimmunoassay .Results:After 21 days, Compared with normal control group ,the scores of behavior in model group decreased significantly (P<0.01).Compared with model group,the scores of horizontal activity and ver-tical activity,sugar consumption and weight in Fluoxetine group , music electro-acupuncture and pulsed electro -ac-upuncture increased significantly(P<0.05).Compared with normal control group ,the contents of frontal lobe and hippocampus’ 5-HT,DA,NE decreased significantly in model group (P<0.01).Compared with model group,the contents of frontal lobe and hippocampus ’ 5 -HT, DA, NE increased significantly in Fluoxetine group , music electro-acupuncture and pulsed electro-acupuncture group(P<0.05).Compared with pulsed electro-acupuncture group, the contents of 5-HT increased significantly in music electro -acupuncture group(P<0.05).Conclusion:Fluoxetine, pulsed electro-acupuncture and music electro-acupuncture could have a certain antidepressant effect on improving the behavior of depressive rats;music electro-acupuncture ’ s regulative effect on monoamine neuro-transmitter is much better than Fluoxetine and pulsed electro -acupuncture, which may be one of the mechanisms for treating depression .

  6. Experimental research on the effect of the Chaiyue decoction against MDD model of rat behavior and brain monoamine neurotransmitters%柴越汤对抑郁症模型大鼠行为学和脑内单胺类神经递质影响的实验研究

    Institute of Scientific and Technical Information of China (English)

    刘丽军; 张保伟

    2012-01-01

      目的:拟探讨柴越汤对慢性应激抑郁模型大鼠行为学和脑内单胺类神经递质影响,进而探讨其可能的作用及其机理.方法:采用孤养结合慢性轻度不可预见性应激复合造模法制备抑郁症模型,将60只雄性 Wistar 大鼠随机分成空白对照组、抑郁模型组、西药对照组、柴越汤组、小柴胡汤组和越鞠丸组.通过体重变化、糖水消耗和敞箱实验进行行为学评价,酶联免疫法测大鼠下丘脑神经递质5-HT和NE的变化,观察柴越汤对抑郁模型大鼠上述指标的影响.结果:21d造模和用药后发现模型组体重增长缓慢,治疗组体重较模型组体重明显增加(P<0.001);在敞箱实验中造模前各组大鼠行为学得分和糖水消耗百分比均无明显差异,造模和用药后发现模型组水平运动和垂直运动明显减少,治疗组能明显增加抑郁模型大鼠行为学得分和糖水消耗百分比与模型组比较均有统计学意义(P<0.001).酶联免疫法检测结果显示,与正常组比较模型组大鼠脑内5-HT、NE均明显下降有统计学意义(P<0.001),治疗组大鼠5-HT、NE均大于模型组,其中西药对照组、柴越汤组和越鞠丸组大鼠脑内5-HT、NE含量高于小柴胡汤组,有统计学意义(P<0.01).结论:柴越汤、小柴胡汤与越鞠丸对抑郁症具有良好的疗效,拆方后,小柴胡汤组、越鞠丸治疗抑郁症疗效较柴越汤略有下降.其作用机理可能与增加脑内5-HT、NE的含量,协调多种神经递质的失衡等有关.%  Objective:To investigate the effect of the Chaiyue decoction against MDD model of rat behavior and brain monoamine neurotransmitters, and provide the theory for clinical medication. Methods: All the groups except control group rats were induced and established the model of depression by isolated supporting and chronic unpredictable moderate intensity stimulation within the whole test. 60 healthy male

  7. Plasma norepinephrine in hypertensive rats reflects α2-adrenoceptor release control only when re-uptake is inhibited

    Directory of Open Access Journals (Sweden)

    Torill eBerg

    2012-11-01

    Full Text Available α2 adrenoceptors (AR lower central sympathetic output and peripheral catecholamine release, thereby protecting against sympathetic hyperactivity and hypertension. Norepinephrine re-uptake transporter effectively (NET removes norepinephrine from the synapse. Overflow to plasma will therefore not reflect release. Here we tested if inhibition of re-uptake allowed presynaptic α2AR release-control to be reflected as differences in norepinephrine overflow in anesthetized hypertensive (SHR and normotensive (WKY rats. We also tested if α2AR modulated the experiment-induced epinephrine secretion, and a phenylephrine-induced, α1-adrenergic vasoconstriction. Blood pressure was recorded through a femoral artery catheter, and cardiac output by ascending aorta flow. After pre-treatment with NET inhibitor (desipramine, and/or α2AR antagonist (yohimbine, L-659,066 or agonist (clonidine, ST-91, we injected phenylephrine. Arterial blood was sampled 15 min later. Plasma catecholamine concentrations were not influenced by phenylephrine, and therefore reflected effects of pre-treatment. Desipramine and α2AR antagonist separately had little effect on norepinephrine overflow. Combined, they increased norepinephrine overflow, particularly in SHR. Clonidine, but not ST-91, reduced, and pertussis toxin increased norepinephrine overflow in SHR and epinephrine secretion in both strains. L-659,066+clonidine (central α2AR-stimulation normalized the high blood pressure, heart rate and vascular tension in SHR. α2AR antagonists reduced phenylephrine induced vasoconstriction equally in WKY and SHR. Conclusions: α2AAR inhibition increased norepinephrine overflow only when re-uptake was blocked, and then with particular efficacy in SHR, possibly due to their high sympathetic tone. α2AAR inhibited epinephrine secretion, particularly in SHR. α2AAR supported α1AR-induced vasoconstriction equally in the two strains. α2AR malfunctions were therefore not detected in SHR

  8. A glial variant of the vesicular monoamine transporter is required to store histamine in the Drosophila visual system.

    Directory of Open Access Journals (Sweden)

    Rafael Romero-Calderón

    2008-11-01

    Full Text Available Unlike other monoamine neurotransmitters, the mechanism by which the brain's histamine content is regulated remains unclear. In mammals, vesicular monoamine transporters (VMATs are expressed exclusively in neurons and mediate the storage of histamine and other monoamines. We have studied the visual system of Drosophila melanogaster in which histamine is the primary neurotransmitter released from photoreceptor cells. We report here that a novel mRNA splice variant of Drosophila VMAT (DVMAT-B is expressed not in neurons but rather in a small subset of glia in the lamina of the fly's optic lobe. Histamine contents are reduced by mutation of dVMAT, but can be partially restored by specifically expressing DVMAT-B in glia. Our results suggest a novel role for a monoamine transporter in glia that may be relevant to histamine homeostasis in other systems.

  9. [Monoamines stimulations in experimental carcinogenesis].

    Science.gov (United States)

    Popov, I; Spuzić, I; Rakić, Lj

    1994-01-01

    Facts about the role of CNS monoamines in cancerogenesis have been accumulated for many years. The aim of the present study was to investigate the effect of interaction of psychoactive drug (Piracetam) and other treatments on survival time of tumour-bearing rats. 138 Wistar rats were used in the experiment. The animals were injected 1% 3--Methilcholantren suspension in 10% Tylose, s.c. under the dorsal skin of the neck in a dose of 3 mg/animal. Within 4-9 months after a single injection, the rats developed tumours at the site of injection. The surgical removal was performed when tumours reached the size of 1-3 cm. After surgical extirpation of tumours different groups of animals were treated by cyclophosphamide (s.c. one-time dose of 50 mg/kg for female and 100 mg/kg for male) or by psychoactive drug (Piracetam) administrated by GE tube 5 time/week, 100 mg/kg. Autopsy and histological examinations were carried out in all animals. Survival time (> 120 days) was the greatest in group B (Piracetam, after surgical removal of tumours) 81.2%, and group C (Cyclophosphamid, after surgical removal of tumours) 68.8% and in group A (only surgical removal of tumours) 50%. In group B the incidence of metastases was the smallest (87.1% of animals were without metastases), compared with group C (45.4% of animals were without metastases) and group A (27.3% of animals were without metastases). The diference is statistically significant. The mechanism of antineoplastic effect of Piracetam consisted of the interaction of influences both on metabolism of the Central nervous system and the tumour. Probably, it is the neurotransmitter modulation that had its effect on carcinogenesis not only by regulation/disregulation of brain homeostasis, but also via direct effect on intracellular processes during cell development and differentation.

  10. Selective serotonin re-uptake inhibitors potentiate gene blunting induced by repeated methylphenidate treatment: Zif268 versus Homer1a.

    Science.gov (United States)

    Van Waes, Vincent; Vandrevala, Malcolm; Beverley, Joel; Steiner, Heinz

    2014-11-01

    There is a growing use of psychostimulants, such as methylphenidate (Ritalin; dopamine re-uptake inhibitor), for medical treatments and as cognitive enhancers in the healthy. Methylphenidate is known to produce some addiction-related gene regulation. Recent findings in animal models show that selective serotonin re-uptake inhibitors (SSRIs), including fluoxetine, can potentiate acute induction of gene expression by methylphenidate, thus indicating an acute facilitatory role for serotonin in dopamine-induced gene regulation. We investigated whether repeated exposure to fluoxetine, in conjunction with methylphenidate, in adolescent rats facilitated a gene regulation effect well established for repeated exposure to illicit psychostimulants such as cocaine-blunting (repression) of gene inducibility. We measured, by in situ hybridization histochemistry, the effects of a 5-day repeated treatment with methylphenidate (5 mg/kg), fluoxetine (5 mg/kg) or a combination on the inducibility (by cocaine) of neuroplasticity-related genes (Zif268, Homer1a) in the striatum. Repeated methylphenidate treatment alone produced minimal gene blunting, while fluoxetine alone had no effect. In contrast, fluoxetine added to methylphenidate robustly potentiated methylphenidate-induced blunting for both genes. This potentiation was widespread throughout the striatum, but was most robust in the lateral, sensorimotor striatum, thus mimicking cocaine effects. For illicit psychostimulants, blunting of gene expression is considered part of the molecular basis of addiction. Our results thus suggest that SSRIs, such as fluoxetine, may increase the addiction liability of methylphenidate.

  11. Radiotracers for PET and SPECT studies of neurotransmitter systems

    Energy Technology Data Exchange (ETDEWEB)

    Fowler, J.S.

    1991-01-01

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

  12. Electrochemical Analysis of Neurotransmitters.

    Science.gov (United States)

    Bucher, Elizabeth S; Wightman, R Mark

    2015-01-01

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

  13. Electrochemical Analysis of Neurotransmitters

    Science.gov (United States)

    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.

  14. Focus On: Neurotransmitter Systems

    OpenAIRE

    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, a...

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

    Science.gov (United States)

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

    1991-01-01

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

  16. Neurotransmitters affecting time perception

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    BACKGROUND:It has been demonstrated that dopamine and acetylcholine are the main neurotransmitters that affect time perception,which is also affected by other neurotransmitters.OBJECTIVE:To summarize how the neurotransmitter affect the time perception,and put forward the perspectives for further study on time perception.RETRIEVE STRATEGY:An online search for related literatures published in English was conducted in Elsevier SDOL(ScienceDirect Online)database from May 1990 to March 2007 using key words of "timing neurotransmitter".Totally 69 literatures were collected,and they were primarily checked.Inclusive criteria:Reviews and experimental studies;correlative studies of timing neurotransmitter.Exclusive criteria:Repeated studies.LITERATURE EVALUATION:The literatures were mainly sourced from Cognitive Brain Research and Neuroscience,and they were analyzed according to the inclusive criteria.Nineteen of them were involved,and all were experimental studies and reviews.DATA SYNTHESIS:The studies on time perception are developed mainly concentrating on dopamine and acetylcholine.Dopamine D2 receptors mainly affect the speed of internal clock.Dopamine receptors play an important role in both timing excitation and inhibition,which suggests the bi-directional regulation of dopamine.Injection of dopamine agonist can affect the attention to timing information.Injection of BW813U(antagonist of acetylcholine) can induce memory disorder,which indicates the effect of acetylcholine on timing memory,and further study shows that it is the effect of acetylcholine in precentral medial area.In a word,the study on the neurotransmitters affecting time perception is still at the primary stage.CONCLUSION:Dopamine and acetylcholine are the neurotransmitters known to be related to time perception.Dopamine in the basal ganglia is related to internal-clock in the range of seconds and minutes;Acetylcholine in prefrontal cortex is related to the mechanisms of temporal memory and attention

  17. Monoamine fluctuations during the reproductive cycle of the Pacific lion's paw scallop Nodipecten subnodosus.

    Science.gov (United States)

    López-Sánchez, J Armando; Maeda-Martínez, Alfonso N; Croll, Roger P; Acosta-Salmón, Héctor

    2009-11-01

    The Pacific lion's paw scallop Nodipecten subnodosus has been one of the most important commercial species of mollusc in the Baja California peninsula in Mexico since 1990. This species is a functional hermaphrodite with tropical and sub-tropical distributions and experiences wide annual temperature oscillations influencing its physiological functions. We determined norepinephrine (NE), dopamine (DA), and serotonin (5-HT) concentrations in different organs (female and male gonads, digestive gland, adductor muscle, gill, mantle, and foot) of N. subnodosus, at 6 reproductive stages (resting, initial, maturing, mature, partially spent and fully spent). Monoamine concentrations were determined by HPLC fitted with an electrochemical detector. Results indicated that monoamine concentrations increased during maturing stage, peaked at mature stage and declined after spawning. NE concentrations were higher than the rest of monoamines followed by DA, and 5-HT. NE was present in all organs at all reproductive stages. DA concentrations were higher in the gill and digestive gland during all stages. 5-HT was only detectable in the male gonadic portion at all stages except at spent stage. NE was the most abundant neurotransmitter found in the female gonad of N. subnodosus, while 5-HT was the most abundant neurotransmitter found in the male gonad. Furthermore, these two neurotransmitters accumulated in the respective gonad tissues during the initial reproductive stages I to IV and then declined after spawning (stages V and VI). This suggests that this species utilized different neurotransmitters specific for each gender and that this utilization was related to the reproductive cycle.

  18. Effect of selective serotonin re-uptake inhibitors (SSRIs) on functional outcome in patients with acute ischemic stroke treated with tPA

    NARCIS (Netherlands)

    Miedema, I; Horvath, K M; Uyttenboogaart, M; Koopman, K; Lahr, Maarten; De Keyser, J; Luijckx, G J

    2010-01-01

    Background: Selective serotonin re-uptake inhibitors (SSRIs) may have therapeutic potential in the treatment of ischemic stroke by effects on neuronal cell survival and the plasticity of brain processes. In the present study, we investigated whether prior treatment with a SSRI is associated with mor

  19. Disturbed development of the enteric nervous system after in utero exposure of selective serotonin re-uptake inhibitors and tricyclic antidepressants. Part 1 : Literature review

    NARCIS (Netherlands)

    Nijenhuis, C.M.; Ter Horst, P.G.; de Jong-van den Berg, L.T.; Wilffert, B.

    2012-01-01

    The increase in selective serotonin re-uptake inhibitor (SSRI) use during pregnancy, questions concerning abnormal development of the enteric nervous system (ENS), increase in laxative use in children and the association of fluoxetine with infantile hypertrophic pyloric stenosis (IHPS) gave rise to

  20. Effect of selective serotonin re-uptake inhibitors (SSRIs) on functional outcome in patients with acute ischemic stroke treated with tPA

    NARCIS (Netherlands)

    Miedema, I; Horvath, K M; Uyttenboogaart, M; Koopman, K; Lahr, Maarten; De Keyser, J; Luijckx, G J

    2010-01-01

    Background: Selective serotonin re-uptake inhibitors (SSRIs) may have therapeutic potential in the treatment of ischemic stroke by effects on neuronal cell survival and the plasticity of brain processes. In the present study, we investigated whether prior treatment with a SSRI is associated with

  1. Ciproxifan, a histamine H3 receptor antagonist, reversibly inhibits monoamine oxidase A and B.

    Science.gov (United States)

    Hagenow, S; Stasiak, A; Ramsay, R R; Stark, H

    2017-01-13

    Ciproxifan is a well-investigated histamine H3 receptor (H3R) inverse agonist/antagonist, showing an exclusively high species-specific affinity at rodent compared to human H3R. It is well studied as reference compound for H3R in rodent models for neurological diseases connected with neurotransmitter dysregulation, e.g. attention deficit hyperactivity disorder or Alzheimer's disease. In a screening for potential monoamine oxidase A and B inhibition ciproxifan showed efficacy on both enzyme isoforms. Further characterization of ciproxifan revealed IC50 values in a micromolar concentration range for human and rat monoamine oxidases with slight preference for monoamine oxidase B in both species. The inhibition by ciproxifan was reversible for both human isoforms. Regarding inhibitory potency of ciproxifan on rat brain MAO, these findings should be considered, when using high doses in rat models for neurological diseases. As the H3R and monoamine oxidases are all capable of affecting neurotransmitter modulation in brain, we consider dual targeting ligands as interesting approach for treatment of neurological disorders. Since ciproxifan shows only moderate activity at human targets, further investigations in animals are not of primary interest. On the other hand, it may serve as starting point for the development of dual targeting ligands.

  2. Designing Modulators of Monoamine Transporters using Virtual Screening Techniques

    Directory of Open Access Journals (Sweden)

    Ole Valente Mortensen

    2015-09-01

    Full Text Available The plasma-membrane monoamine transporters (MATs, including the serotonin (SERT, norepinephrine (NET and dopamine (DAT transporters, serve a pivotal role in limiting monoamine-mediated neurotransmission through the reuptake of their respective monoamine neurotransmitters. The transporters are the main target of clinically used psychostimulants and antidepressants. Despite the availability of several potent and selective MAT substrates and inhibitors the continuing need for therapeutic drugs to treat brain disorders involving aberrant monoamine signaling provides a compelling reason to identify novel ways of targeting and modulating the MATs. Designing novel modulators of MAT function have been limited by the lack of three dimensional structure information of the individual MATs. However, crystal structures of LeuT, a bacterial homologue of MATs, in a substrate-bound occluded, substrate-free outward-open, and an apo inward-open state and also with competitive and noncompetitive inhibitors have been determined. In addition, several structures of the drosophila DAT have also been resolved. Together with computational modeling and experimental data gathered over the past decade, these structures have dramatically advanced our understanding of several aspects of SERT, NET, and DAT transporter function, including some of the molecular determinants of ligand interaction at orthosteric substrate and inhibitor binding pockets. In addition progress has been made in the understanding of how allosteric modulation of MAT function can be achieved. Here we will review all the efforts up to date that has been made through computational approaches employing structural models of MATs to design small molecule modulators to the orthosteric and allosteric sites using virtual screening techniques.

  3. Designing modulators of monoamine transporters using virtual screening techniques

    Science.gov (United States)

    Mortensen, Ole V.; Kortagere, Sandhya

    2015-01-01

    The plasma-membrane monoamine transporters (MATs), including the serotonin (SERT), norepinephrine (NET) and dopamine (DAT) transporters, serve a pivotal role in limiting monoamine-mediated neurotransmission through the reuptake of their respective monoamine neurotransmitters. The transporters are the main target of clinically used psychostimulants and antidepressants. Despite the availability of several potent and selective MAT substrates and inhibitors the continuing need for therapeutic drugs to treat brain disorders involving aberrant monoamine signaling provides a compelling reason to identify novel ways of targeting and modulating the MATs. Designing novel modulators of MAT function have been limited by the lack of three dimensional structure information of the individual MATs. However, crystal structures of LeuT, a bacterial homolog of MATs, in a substrate-bound occluded, substrate-free outward-open, and an apo inward-open state and also with competitive and non-competitive inhibitors have been determined. In addition, several structures of the Drosophila DAT have also been resolved. Together with computational modeling and experimental data gathered over the past decade, these structures have dramatically advanced our understanding of several aspects of SERT, NET, and DAT transporter function, including some of the molecular determinants of ligand interaction at orthosteric substrate and inhibitor binding pockets. In addition progress has been made in the understanding of how allosteric modulation of MAT function can be achieved. Here we will review all the efforts up to date that has been made through computational approaches employing structural models of MATs to design small molecule modulators to the orthosteric and allosteric sites using virtual screening techniques. PMID:26483692

  4. Neurotransmitter Switching? No Surprise.

    Science.gov (United States)

    Spitzer, Nicholas C

    2015-06-03

    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.

  5. Are vesicular neurotransmitter transporters potential treatment targets for temporal lobe epilepsy?

    Directory of Open Access Journals (Sweden)

    Joeri eVan Liefferinge

    2013-08-01

    Full Text Available The vesicular neurotransmitter transporters (VNTs are small proteins responsible for packing synaptic vesicles with neurotransmitters thereby determining the amount of neurotransmitter released per vesicle through fusion in both neurons and glial cells. Each transporter subtype was classically seen as a specific neuronal marker of the respective nerve cells containing that particular neurotransmitter or structurally related neurotransmitters. More recently, however, it has become apparent that common neurotransmitters can also act as co-transmitters, adding complexity to neurotransmitter release and suggesting intriguing roles for VNTs therein. We will first describe the current knowledge on vesicular glutamate transporters (VGLUT1/2/3, the vesicular excitatory amino acid transporter (VEAT, the vesicular nucleotide transporter (VNUT, vesicular monoamine transporters (VMAT1/2, the vesicular acetylcholine transporter (VAChT and the vesicular γ-aminobutyric acid (GABA transporter (VGAT in the brain. We will focus on evidence regarding transgenic mice with disruptions in VNTs in different models of seizures and epilepsy. We will also describe the known alterations and reorganizations in the expression levels of these VNTs in rodent models for temporal lobe epilepsy (TLE and in human tissue resected for epilepsy surgery. Finally, we will discuss perspectives on opportunities and challenges for VNTs as targets for possible future epilepsy therapies.

  6. Brain Monoamine Oxidase-A Activity Predicts Trait Aggression

    Science.gov (United States)

    Alia-Klein, Nelly; Goldstein, Rita Z.; Kriplani, Aarti; Logan, Jean; Tomasi, Dardo; Williams, Benjamin; Telang, Frank; Shumay, Elena; Biegon, Anat; Craig, Ian W.; Henn, Fritz; Wang, Gene-Jack; Volkow, Nora D.; Fowler, Joanna S.

    2008-01-01

    The genetic deletion of monoamine oxidase A (MAO A, an enzyme which breaks down the monoamine neurotransmitters norepinephrine, serotonin and dopamine) produces aggressive phenotypes across species. Therefore, a common polymorphism in the MAO A gene (MAOA, MIM 309850, referred to as high or low based on transcription in non-neuronal cells) has been investigated in a number of externalizing behavioral and clinical phenotypes. These studies provide evidence linking the low MAOA genotype and violent behavior but only through interaction with severe environmental stressors during childhood. Here, we hypothesized that in healthy adult males the gene product of MAO A in the brain, rather than the gene per se, would be associated with regulating the concentration of brain amines involved in trait aggression. Brain MAO A activity was measured in-vivo in healthy non-smoking men with positron emission tomography using a radioligand specific for MAO A (clorgyline labeled with carbon 11). Trait aggression was measured with the Multidimensional Personality Questionnaire (MPQ). Here we report for the first time that brain MAO A correlates inversely with the MPQ trait measure of aggression (but not with other personality traits) such that the lower the MAO A activity in cortical and subcortical brain regions the higher the self-reported aggression (in both MAOA genotype groups) contributing to more than a third of the variability. Since trait aggression is a measure used to predict antisocial behavior, these results underscore the relevance of MAO A as a neurochemical substrate of aberrant aggression. PMID:18463263

  7. Effects of nomifensine, an inhibitor of endogenous catecholamine re-uptake, in acromegaly, in hyperprolactinaemia, and against stimulated prolactin release in man.

    Science.gov (United States)

    Scanlon, M F; Gomez-Pan, A; Mora, B; Cook, D B; Dewar, J H; Hildyard, A; Weightman, D R; Evered, D C; Hall, R

    1977-01-01

    1. Nomifensine, an inhibitor of endogenous catecholamine re-uptake, did not affect the growth hormone (GH) or prolactin levels in patients with acromegaly or hyperprolactinaemia. It does not, therefore, have any therapeutic role in these conditions at the dosage used in this study. 2. It had no effect on thyrotrophin-releasing hormone (TRH)-induced thyrotrophin (TSH) or prolactin release in males, yet caused marked suppression of monoiodotyrosine (MIT)-induced prolactin release in males but not in females. 3. The significant suppression of MIT-induced prolactin release in males is likely to reflect the dopamine (DA) agonist activity of the drug and its lack of effect in the other situations tested could be dose related. 4. It is proposed that the difference in male and female patterns of prolactin response to MIT after nomifensine, could be due to a "damping" effect of oestrogen on the hypothalamic dopaminergic system.

  8. Effect of canagliflozin and metformin on cortical neurotransmitters in a diabetic rat model.

    Science.gov (United States)

    Arafa, Nadia M S; Marie, Mohamed-Assem S; AlAzimi, Sara Abdullah Mubarak

    2016-10-25

    The rapid economic development in the Arabian Gulf has resulted in lifestyle changes that have increased the prevalence of obesity and type 2 diabetes, with the greatest increases observed in Kuwait. Dyslipidemia and diabetes are risk factors for disruptions in cortical neurotransmitter homeostasis. This study investigated the effect of the antidiabetic medications canagliflozin (CAN) and metformin (MET) on the levels of cortical neurotransmitters in a diabetic rat model. The rats were assigned to the control (C) group, the diabetic group that did not receive treatment (D) or the diabetic group treated with either CAN (10 mg/kg) or MET (100 mg/kg) for 2 or 4 weeks. Blood and urine glucose levels and cortical acetylcholinesterase (AChE) activity were assayed, and amino acid and monoamine levels were measured using HPLC. The diabetic group exhibited a significant increase in AChE activity and a decrease in monoamine and amino acid neurotransmitter levels. In the CAN group, AChE was significantly lower than that in the D and D + MET groups after 2 weeks of treatment. In addition, a significant increase in some cortical monoamines and amino acids was observed in the D + MET and D + CAN groups compared with the D group. Histopathological analysis revealed the presence of severe focal hemorrhage, neuronal degeneration, and cerebral blood vessel congestion, with gliosis in the cerebrum of rats in the D group. The CAN-treated group exhibited severe cerebral blood vessel congestion after 2 weeks of treatment and focal gliosis in the cerebrum after 4 weeks of treatment. Focal gliosis in the cerebrum of rats in the MET-treated group was observed after 2 and 4 weeks of treatment. We conclude that the effect of CAN and MET on neurotransmitters is potentially mediated by their antihyperglycemic and antihyperlipidemic effects. In addition, the effects of CAN on neurotransmitters might be associated with its receptor activity, and the effect of MET on neurotransmitters

  9. Neurotransmitter: Sodium Symporters: Caught in the Act!

    DEFF Research Database (Denmark)

    Malinauskaite, Lina

    The neurotransmitter: sodium symporters in the neurons. Communication between neurons is mediated by the release of molecules called neurotransmitters (blue dots) from first neuron and sensed by receptors on the surface of the second (purple sphere). The signal is ended by active reuptake...... of these neurotransmitters by a family of proteins called neurotransmitter: sodium symporters (NSS), which are driven using the large concentration difference of sodium (orange dots) between the outside and the inside of the cell...

  10. Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice.

    Science.gov (United States)

    Singh, Chanpreet; Bortolato, Marco; Bali, Namrata; Godar, Sean C; Scott, Anna L; Chen, Kevin; Thompson, Richard F; Shih, Jean C

    2013-07-30

    The monoamine oxidase isoenzymes (MAOs) A and B play important roles in the homeostasis of monoaminergic neurotransmitters. The combined deficiency of MAO A and B results in significantly elevated levels of serotonin (5-hydroxytryptamine), norepinephrine, dopamine, and β-phenylethylamine; in humans and mice, these neurochemical changes are accompanied by neurodevelopmental perturbations as well as autistic-like responses. Ample evidence indicates that normal levels of monoamines in the hippocampus, amygdala, frontal cortex, and cerebellum are required for the integrity of learning and memory. Thus, in the present study, the cognitive status of MAO A/B knockout (KO) mice was examined with a wide array of behavioral tests. In comparison with male wild-type littermates, MAO A/B KO mice exhibited abnormally high and overgeneralized fear conditioning and enhanced eye-blink conditioning. These alterations were accompanied by significant increases in hippocampal long-term potentiation and alterations in the relative expression of NMDA glutamate receptor subunits. Our data suggest that chronic elevations of monoamines, because of the absence of MAO A and MAO B, cause functional alterations that are accompanied with changes in the cellular mechanisms underlying learning and memory. The characteristics exhibited by MAO A/B KO mice highlight the potential of these animals as a useful tool to provide further insight into the molecular bases of disorders associated with abnormal monoaminergic profiles.

  11. Calcium-sensing beyond neurotransmitters

    DEFF Research Database (Denmark)

    Gustavsson, Natalia; Han, Weiping

    2009-01-01

    synaptotagmins are located in brain and endocrine cells, and some of these synaptotagmins bind to phospholipids and calcium at levels that trigger regulated exocytosis of SVs and LDCVs. This led to the proposed synaptotagmin-calcium-sensor paradigm, that is, members of the synaptotagmin family function...... as calcium sensors for the regulated exocytosis of neurotransmitters, neuropeptides and hormones. Here, we provide an overview of the synaptotagmin family, and review the recent mouse genetic studies aimed at understanding the functions of synaptotagmins in neurotransmission and endocrine-hormone secretion......Neurotransmitters, neuropeptides and hormones are released through the regulated exocytosis of SVs (synaptic vesicles) and LDCVs (large dense-core vesicles), a process that is controlled by calcium. Synaptotagmins are a family of type 1 membrane proteins that share a common domain structure. Most...

  12. [Axolemmal transporters for neurotransmitter uptake].

    Science.gov (United States)

    García-López, M

    Neurotransmission is a fundamental process in interneuronal communication. It starts with the release of the neurotransmitter following a nerve impulse and ends either by uptake by specific specific transporters or by metabolization to an inactive compound. In this review we will consider the molecular, ion dependence and electrogenic properties of the axolemal transporters for neurotransmitters and also the pathological consequences of their impairment as well as the drugs that can interact with them. Most axolemmal transporters have been cloned and grouped into two large families according to their molecular characteristics and electrogenic properties: 1. Those dependent on Na+/Cl- include transporters of GABA, noradrenaline, dopamine, serotonin, choline, proline, betaine, glycine and taurine, and 2. Those dependent on Na+/K+, which include the transporters of glutamate, alanine, serine and cysteine. The clonation of transporters has permitted (and will continue to permit) the correlation of molecular alterations of transporters with different neuro-degenerative disorders (e.g. multiple sclerosis, Parkinson's disease, Alzheimer's disease), with brain lesions (e.g. cerebral ischemia, status epilepticus) and with psychiatric alterations (e.g. schizophrenia, depression). In this respect, chemical synthesis of new selective drugs which interact with the different systems for uptake of neurotransmitters will offer new approaches to the treatment of many disorders of the central nervous system which still have no satisfactory drug treatment.

  13. Regional brain monoamine concentrations and their alterations in bovine hypomagnesaemic tetany experimentally induced by a magnesium-deficient diet.

    Science.gov (United States)

    McCoy, M A; Young, P B; Hudson, A J; Davison, G; Kennedy, D G

    2000-12-01

    Monoamines are important brain neurotransmitters. An investigation was carried out to determine if hypomagnesaemic tetany was associated with alterations in regional brain monoamine concentrations in bovines. The results, established in cows with normal magnesium status, demonstrated that regional differences existed in the distribution and concentration of brain monoamines in the adult bovine, which were similar to those in other species. In magnesium-deficient cows, severe hypomagnesaemia and lowered cerebrospinal fluid (CSF) magnesium concentrations were associated with significant alterations in monoamine concentrations in some brain regions. Alterations in 3,4-dihydroxyphenylalanine (DOPA) and dihydroxyphenylacetic acid (DOPAC) concentrations in the corpus striatum, and dopamine (DA) in the cerebral cortex and cerebellum were recorded. These regions play an important role in both voluntary and involuntary motor function, and therefore these alterations may play a role in the aetiology of hypomagnesaemic tetany. However, there was no significant change in DA concentrations in the corpus striatum (the main dopaminergic region in the brain) associated with hypomagnesaemia. In addition, a significantly lower norepinephrine (NE) concentration in the corpus striatum of hypomagnesaemic animals was also recorded. Norephinephrine is generally excitatory and therefore lowered NE concentrations would be expected to result in depression rather than stimulation of motor function. Copyright 2000 Harcourt Publishers Ltd.

  14. A neurobiological perspective on attachment problems in sexual offenders and the role of selective serotonin re-uptake inhibitors in the treatment of such problems.

    Science.gov (United States)

    Beech, Anthony R; Mitchell, Ian J

    2005-02-01

    This paper describes what is currently known about attachment from the development, social-cognitive and biological literatures and outlines the impact on organisms given adverse development experiences that can have an effect upon attachment formation in childhood across these three literatures. We then describe the effects that 'insecure' attachment styles arising in childhood can affect brain chemistry and brain function and subsequently adult social/romantic relationships. In the paper, we note that a number of sexual offenders report adverse childhood experiences and that they possess attachment styles that, taken together, make it likely that they will either seek out intimate attachments in ways where they will have sex with children, perhaps confusing sex with intimacy or in aggressive ways as particularly happens with men who sexually assault adult women. The last section of the paper describes chemical treatment for sexual offenders, focusing on the use of selective serotonin re-uptake inhibitors (SSRIs). We note evidence for the role of SSRIs in promoting more social/affiliative behaviors and speculate on the effects that SSRIs have in the treatment of sexual offenders by targeting areas of the social brain. Here, we would argue that it would be useful to carry out treatment where there is a combination of SSRI treatment (to promote more prosocial feelings and behaviors) in conjunction with therapy that typically addresses thoughts and behaviors, i.e., cognitive-behavioral therapy/schema-focused therapy.

  15. A putative transport protein is involved in citrulline excretion and re-uptake during arginine deiminase pathway activity by Lactobacillus sakei.

    Science.gov (United States)

    Rimaux, Tom; Rivière, Audrey; Hebert, Elvira María; Mozzi, Fernanda; Weckx, Stefan; De Vuyst, Luc; Leroy, Frédéric

    2013-04-01

    Arginine conversion through the arginine deiminase (ADI) pathway is a common metabolic trait of Lactobacillus sakei which is ascribed to an arc operon and which inquisitively involves citrulline excretion and re-uptake. The aim of this study was to verify whether a putative transport protein (encoded by the PTP gene) plays a role in citrulline-into-ornithine conversion by L. sakei strains. This was achieved through a combination of fermentation experiments, gene expression analysis via quantitative real-time reverse transcription PCR (RT-qPCR) and construction of a PTP knock-out mutant. Expression of the PTP gene was modulated by environmental pH and was highest in the end-exponential or mid-exponential growth phase for L. sakei strains CTC 494 and 23K, respectively. In contrast to known genes of the arc operon, the PTP gene showed low expression at pH 7.0, in agreement with the finding that citrulline-into-ornithine conversion is inhibited at this pH. The presence of additional energy sources also influenced ADI pathway activity, in particular by decreasing citrulline-into-ornithine conversion. Further insight into the functionality of the PTP gene was obtained with a knock-out mutant of L. sakei CTC 494 impaired in the PTP gene, which displayed inhibition in its ability to convert extracellular citrulline into ornithine. In conclusion, results indicated that the PTP gene may putatively encode a citrulline/ornithine antiporter.

  16. Concentration-dependent effects of cocaine on monoamine-induced constriction of cannulated, pressurized cerebral arteries from fetal sheep.

    Science.gov (United States)

    Schreiber, M D; Madden, J A; Covert, R F; Hershenson, M B; Torgerson, L J

    1995-01-01

    Drugs, such as cocaine, which may alter monoamine neurotransmitter responsiveness, could adversely affect the regulation of cerebral vasculature. Cocaine exhibits at least two mechanisms that may alter vascular responsiveness: synaptic uptake inhibition, which may augment response to stimulation, and Na+ channel inhibition, which may attenuate response. To help elicit the concentration-dependent effects of cocaine, the effects of cocaine on monoamine neurotransmitter responsiveness were studied in vitro on fetal sheep cerebral arteries (120 days gestation). The changes in diameter of segments of cannulated, pressurized fetal sheep cerebral artery were measured with a videomicroscaler system. Cumulative concentration-response curves (10(-10) to 10(-4)M) were generated for two monoamines, norepinephrine and serotonin, alone and in the presence of cocaine (10(-5) or 10(-4)M). Cocaine caused concentration-dependent alteration of response. At 10(-4)M, cocaine attenuated mean maximal norepinephrine-induced vasoconstriction 46.2% (P < 0.05). At 10(-5)M, cocaine increased sensitivity to norepinephrine (log EC50 decreased -6.63 +/- 0.09 to -7.11 +/- 0.03) and to serotonin (log EC50 decreased -7.24 +/- 0.04 to -7.81 +/- 0.09) (P < 0.05). The higher concentration of cocaine (10(-4)M) did not significantly decrease log EC50 norepinephrine. Cocaine (10(-4)M) also attenuated the response to single doses of norepinephrine (10(-6)M) and serotonin (10(-6)M) by 26.5% and 40.0%, respectively (P < or = 0.05). It is concluded that cocaine has concentration-dependent effects on vasoconstriction of the fetal sheep cerebral artery in vitro. This cocaine-induced alteration of cerebral vascular responsiveness to monoamines may be important in the regulation of fetal cerebral blood flow.

  17. Monoamine theories of depression: historical impact on biomedical research.

    Science.gov (United States)

    Mulinari, Shai

    2012-01-01

    Monoamine theories associate depression with reduced brain monoamine levels. These theories achieved broad popularity in the mid-1960s. The present article reviews the historical development of monoamine theories and their subsequent impact on biomedical research. Alleged divisions between West European and US researchers over competing versions of the theories are investigated using bibliometrics. Subsequently, the application of monoamine theories in the NIMH Collaborative Program on the Psychobiology of Depression is covered. The article argues that the impact of monoamine theories is best explained by the ability of researchers, governmental agencies, and pharmaceutical companies to invoke theories that advance various projects and agendas.

  18. Neurotransmitters, Pharmacologic Synergy, and Clinical Strategies

    National Research Council Canada - National Science Library

    Stark, Martha

    2006-01-01

    ... of neurotransmitters and their receptor sites, more ingenious methods of drug administration, and more creative combinations of the various drugs, more than half our patients have psychiatric sympto...

  19. Comparison of monoamine reuptake inhibitors for the immobility time and serotonin levels in the hippocampus and plasma of sub-chronically forced swim stressed rats.

    Science.gov (United States)

    Abbas, Ghulam; Naqvi, Sabira; Dar, Ahsana

    2012-04-01

    The current study was aimed at comparing the behavioral and biochemical (5-hydroxytryptamine and 5-hydroxyindoleacetic acid levels) effects of monoamine reuptake inhibitors (fluoxetine, venlafaxine and imipramine) in sub-chronically forced swim stressed rats. At the given doses of 10, 20 and 30 mg/kg, among aforesaid antidepressants, the imipramine treatment alone caused significant decline in the immobility time of rats (IC(50) 20 mg/kg). In the hippocampus of rats, the imipramine treatment caused significant elevation of 5-hydroxytryptamine (5-HT) whereas, the fluoxetine and venlafaxine elicited significant increase in 5-hydroxyindoleacetic acid (5-HIAA) levels. Likewise, in the plasma of rats, the imipramine treatment significantly increased the 5-HIAA levels whereas, the fluoxetine and venlafaxine treatment significantly elevate the 5-HT levels. It can therefore be inferred that the imipramine did not act like other monoamine reuptake inhibitors in biochemical study, which could possibly underlie its ability to be detected in forced swim test (behavioral study). Moreover, the re-uptake inhibition of 5-HT is not accountable for the antidepressant action exhibited in forced swim test.

  20. Chloride binding site of neurotransmitter sodium symporters

    DEFF Research Database (Denmark)

    Kantcheva, Adriana Krassimirova; Quick, Matthias; Shi, Lei

    2013-01-01

    Neurotransmitter:sodium symporters (NSSs) play a critical role in signaling by reuptake of neurotransmitters. Eukaryotic NSSs are chloride-dependent, whereas prokaryotic NSS homologs like LeuT are chloride-independent but contain an acidic residue (Glu290 in LeuT) at a site where eukaryotic NSSs...

  1. Vesicular neurotransmitter transporter trafficking in vivo: moving from cells to flies.

    Science.gov (United States)

    Grygoruk, Anna; Fei, Hao; Daniels, Richard W; Miller, Bradley R; Chen, Audrey; DiAntonio, Aaron; Krantz, David E

    2010-01-01

    During exocytosis, classical and amino acid neurotransmitters are released from the lumen of synaptic vesicles to allow signaling at the synapse. The storage of neurotransmitters in synaptic vesicles and other types of secretory vesicles requires the activity of specific vesicular transporters. Glutamate and monoamines such as dopamine are packaged by VGLUTs and VMATs respectively. Changes in the localization of either protein have the potential to up- or down regulate neurotransmitter release, and some of the mechanisms for sorting these proteins to secretory vesicles have been investigated in cultured cells in vitro. We have used Drosophila molecular genetic techniques to study vesicular transporter trafficking in an intact organism and have identified a motif required for localizing Drosophila VMAT (DVMAT) to synaptic vesicles in vivo. In contrast to DVMAT, large deletions of Drosophila VGLUT (DVGLUT) show relatively modest deficits in localizing to synaptic vesicles, suggesting that DVMAT and DVGLUT may undergo different modes of trafficking at the synapse. Further in vivo studies of DVMAT trafficking mutants will allow us to determine how changes in the localization of vesicular transporters affect the nervous system as a whole and complex behaviors mediated by aminergic circuits.

  2. Monoamine oxidase A is highly expressed in classical Hodgkin lymphoma.

    Science.gov (United States)

    Li, Pei Chuan; Siddiqi, Imran N; Mottok, Anja; Loo, Eric Y; Wu, Chieh Hsi; Cozen, Wendy; Steidl, Christian; Shih, Jean Chen

    2017-10-01

    Monoamine oxidase A (MAOA) is a mitochondrial enzyme that catalyzes oxidative deamination of neurotransmitters and dietary amines and produces H2 O2 . It facilitates the progression of gliomas and prostate cancer, but its expression and functional relevance have not been studied in lymphoma. Here, we evaluated MAOA in 427 cases of Hodgkin and non-Hodgkin lymphoma and in a spectrum of reactive lymphoid tissues by immunohistochemistry on formalin-fixed, paraffin-embedded specimens. MAOA was expressed by Hodgkin Reed-Sternberg (HRS) cells in the majority of classical Hodgkin lymphomas (cHLs) (181/241; 75%), with 34.8% showing strong expression. Weak MAOA was also noted in a minority of primary mediastinal large B-cell lymphomas (8/47; 17%) and in a mediastinal gray-zone lymphoma. In contrast, no MAOA was found in non-neoplastic lymphoid tissues, nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL; 0/8) or any other non-Hodgkin lymphomas studied (0/123). MAOA was more common in Epstein-Barr virus (EBV)-negative compared to EBV-positive cHL (p Hodgkin-lymphoma-derived cell lines did not. The MAOA inhibitor clorgyline reduced the growth of L1236 cells and U-HO1 cells, and shRNA knockdown of MAOA reduced the growth of L1236 cells. Conversely, ectopic overexpression of MAOA increased the growth of MAOA-negative HDLM2 cells. Combined treatment with clorgyline and ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) was more effective in reducing cell growth than either regimen alone. In summary, MAOA is highly expressed in cHL and may reflect the distinct biology of this lymphoma. Further studies on the potential utility of MAOA as a diagnostic marker and therapeutic target are warranted. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  3. Process characterization of a monoamine oxidase

    DEFF Research Database (Denmark)

    Ramesh, Hemalata; Woodley, John

    2014-01-01

    .e, on biocatalyst development (e.g. improvement of expression levels), process development (e.g. improved oxygen supply, product removal strategies) or biocatalyst stabilization (e.g. through immobilization or directed evolution). This paper presents a systematic method to identify the bottleneck of a potential...... biocatalytic process using a monoamine oxidase to synthesise an intermediate in the manufacture of a drug for treating Hepatitis C (Telaprevir)....

  4. Imaging Monoamine Oxidase in the Human Brain

    Energy Technology Data Exchange (ETDEWEB)

    Fowler, J. S.; Volkow, N. D.; Wang, G-J.; Logan, Jean

    1999-11-10

    Positron emission tomography (PET) studies mapping monoamine oxidase in the human brain have been used to measure the turnover rate for MAO B; to determine the minimum effective dose of a new MAO inhibitor drug lazabemide and to document MAO inhibition by cigarette smoke. These studies illustrate the power of PET and radiotracer chemistry to measure normal biochemical processes and to provide information on the effect of drug exposure on specific molecular targets.

  5. The inhibition of monoamine oxidase by esomeprazole

    OpenAIRE

    2013-01-01

    Virtual screening of a library of drugs has suggested that esomeprazole, the S-enantiomer of omeprazole, may possess binding affinities for the active sites of the monoamine oxidase (MAO) A and B enzymes. Based on this finding, the current study examines the MAO inhibitory properties of esomeprazole. Using recombinant human MAO-A and MAO-B, IC50 values for the inhibition of these enzymes by esomeprazole were experimentally determined. To examine the reversibility of MAO inhibition by esomepra...

  6. Binding of Neurotransmitters to Lipid Membranes

    DEFF Research Database (Denmark)

    Peters, Günther H.J.; Werge, Mikkel; Elf-Lind, Maria Northved

    2014-01-01

    We have performed a series of thermodynamic measurements and molecular dynamics (MD) simulations to study the interactions between the neurotransmitters (NTs) 5-hydroxytryptamine (5-HT), g-aminobutyrate (GABA), glycine (GLY), acetylcholine (ACH) and glutamate (GLU) as well as the amidated...... as the most important interaction by which the NTs are anchored to the membrane. These distinctive interactions could be related to nonspecific effects of these neurotransmitters and could point to a bilayer-mediated modulation of nerve transmission. However, due to the strong variability in affinity observed...... for the different NTs, this attraction is not an inherent property of all neurotransmitters....

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

    Science.gov (United States)

    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.

  8. Prion-derived copper-binding peptide fragments catalyze the generation of superoxide anion in the presence of aromatic monoamines

    Directory of Open Access Journals (Sweden)

    Tomonori Kawano

    2007-01-01

    Full Text Available Objectives: Studies have proposed two opposing roles for copper-bound forms of prion protein (PrP as an anti-oxidant supporting the neuronal functions and as a pro-oxidant leading to neurodegenerative process involving the generation of reactive oxygen species. The aim of this study is to test the hypothesis in which putative copper-binding peptides derived from PrP function as possible catalysts for monoamine-dependent conversion of hydrogen peroxide to superoxide in vitro. Materials and methods: Four peptides corresponding to the copper (II-binding motifs in PrP were synthesized and used for analysis of peptide-catalyzed generation of superoxide in the presence of Cu (II and other factors naturally present in the neuronal tissues. Results: Among the Cu-binding peptides tested, the amino acid sequence corresponding to the Cu-binding site in the helical region was shown to be the most active for superoxide generation in the presence of Cu(II, hydrogen peroxide and aromatic monoamines, known precursors or intermediates of neurotransmitters. Among monoamines tested, three compounds namely phenylethylamine, tyramine and benzylamine were shown to be good substrates for superoxide-generating reactions by the Cu-bound helical peptide. Conclusions: Possible roles for these reactions in development of prion disease were suggested.

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

    Science.gov (United States)

    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.

  10. Vesicular monoamine transporter 2 and the acute and long-term response to 3,4-(±)-methylenedioxymethamphetamine.

    Science.gov (United States)

    Lizarraga, Lucina E; Cholanians, Aram B; Phan, Andy V; Herndon, Joseph M; Lau, Serrine S; Monks, Terrence J

    2015-01-01

    3,4-(±)-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a ring-substituted amphetamine derivative with potent psychostimulant properties. The neuropharmacological effects of MDMA are biphasic in nature, initially causing synaptic monoamine release, primarily of serotonin (5-HT). Conversely, the long-term effects of MDMA manifest as prolonged depletions in 5-HT, and reductions in 5-HT reuptake transporter (SERT), indicative of serotonergic neurotoxicity. MDMA-induced 5-HT efflux relies upon disruption of vesicular monoamine storage, which increases cytosolic 5-HT concentrations available for release via a carrier-mediated mechanism. The vesicular monoamine transporter 2 (VMAT2) is responsible for packaging monoamine neurotransmitters into cytosolic vesicles. Thus, VMAT2 is a molecular target for a number of psychostimulant drugs, including methamphetamine and MDMA. We investigated the effects of depressed VMAT2 activity on the adverse responses to MDMA, via reversible inhibition of the VMAT2 protein with Ro4-1284. A single dose of MDMA (20 mg/kg, subcutaneous) induced significant hyperthermia in rats. Ro4-1284 (10 mg/kg, intraperitoneal) pretreatment prevented the thermogenic effects of MDMA, instead causing a transient decrease in body temperature. MDMA-treated rats exhibited marked increases in horizontal velocity and rearing behavior. In the presence of Ro4-1284, MDMA-mediated horizontal hyperlocomotion was delayed and attenuated, whereas rearing activity was abolished. Finally, Ro4-1284 prevented deficits in 5-HT content in rat cortex and striatum, and reduced depletions in striatal SERT staining, 7 days after MDMA administration. In summary, acute inhibition of VMAT2 by Ro4-1284 protected against MDMA-mediated hyperthermia, hyperactivity, and serotonergic neurotoxicity. The data suggest the involvement of VMAT2 in the thermoregulatory, behavioral, and neurotoxic effects of MDMA.

  11. Research progress in monoamine transporters and monoamine transmitter reuptake inhibitors%单胺转运蛋白与单胺重摄取抑制剂研究进展

    Institute of Scientific and Technical Information of China (English)

    张亭亭; 薛瑞; 李云峰; 洪浩; 张有志

    2013-01-01

    Presynaptic membrane serotonin transporters ( SERT ) and norepinephrine transporter ( NET ), which are important neurotransmitter transporters, are responsible for reuptake of released serotonin ( 5-HT ) and norepinephrine ( NE ), respectively. The major function of these transporters is to terminate monoamine transmission by mediating uptake of neurotransmitters from extracellular space into neurons and glial cells. Drugs that inhibit the activity of monoamine transporters produce increased neurotransmitter levels in the synaptic cleft, leading to their therapeutic use in depression. As SERT and NET are pharmacological targets for most antidepressants, understanding about the molecular pharmacology of these transporters, including their localization and function, molecular structure and regulation, as well as drug binding sites and mechanism of action, is important to new antidepressant development.%5-羟色胺转运蛋白(serotonin transporter,SERT)和去甲肾上腺素转运蛋白(norepinephrine transporter,NET)是单胺类神经递质转运体,其功能是将释放到突触间隙的5-羟色胺(serotonin,5-HT)和去甲肾上腺素(norepinephrine,NE)分别转运入突触前神经细胞,以终止相应的突触信号传递.SERT、NET抑制剂可阻断5-HT和NE的重摄取,提高突触间隙单胺递质水平,从而发挥抗抑郁效应.SERT、NET作为主流抗抑郁药物的作用靶标,了解其分布与功能、分子结构和活性调节因素,以及单胺重摄取抑制剂的作用机制对抗抑郁药物研发及应用具有重要意义.

  12. NEUROTRANSMITTERS AND IMMUNITY: 1. DOPAMINE

    Directory of Open Access Journals (Sweden)

    Lucian Hritcu

    2007-08-01

    Full Text Available Dopamine is one of the principal neurotransmitters in the central nervous system (CNC, and its neuronal pathways are involved in several key functions such as behavior (Hefco et al., 2003a,b, control of movement, endocrine regulation, immune response (Fiserova et al., 2002; Levite et al., 2001, Hritcu et al., 2006a,b,c, and cardiovascular function. Dopamine has at least five G-protein, coupled receptor subtypes, D1-D5, each arising from a different gene (Sibley et al., 1993. Traditionally, these receptors have been classified into D1-like (the D1 and D5 and D2-like (D2, D3 and D4 receptors subtypes, primarily according to their ability to stimulate or inhibit adenylate cyclase, respectively, and to their pharmacological characteristics (Seeman et al., 1993. Receptors for dopamine (particularly of D2 subclass are the primary therapeutic target in a number of neuropathological disorders including schizophrenia, Parkinson’s disease and Huntington’s chorea (Seeman et al., 1987. Neither dopamine by itself, nor dopaminergic agonists by themselves, has been shown to activate T cell function. Nevertheless, lymphocytes are most probably exposed to dopamine since the primary and secondary lymphoid organs of various mammals are markedly innervated, and contain nerve fibers which stain for tyrosine hydroxylase (Weihe et al., 1991, the enzyme responsible for dopamine synthesis. Moreover, cathecolamines and their metabolites are present in single lymphocytes and in extracts of T and B cell clones, and pharmacological inhibition of tyrosine hydroxylase reduces catecholamine levels, suggesting catecholamine synthesis by lymphocytes (Bergquist et al., 1994. The existence of putative dopamine receptors of D2, D3, D4 and D5 subtypes on immune cells has been proposed of several authors, primarily on the basis of dopaminergic ligand binding assays and specific mRNA expression as monitored by reverse transcription-PCR. Several experiments evoked the idea of a

  13. Short- and long-term effects of MDMA ("ecstasy") on synaptosomal and vesicular uptake of neurotransmitters in vitro and ex vivo.

    Science.gov (United States)

    Bogen, Inger Lise; Haug, Kristin Huse; Myhre, Oddvar; Fonnum, Frode

    2003-01-01

    3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a commonly abused drug which has been shown to be neurotoxic to serotonergic neurons in many species. The exact mechanism responsible for the neurotoxicity of MDMA is, however, poorly understood. In this study, the effects of MDMA on the synaptosomal and vesicular uptake of neurotransmitters were investigated. Our results show that MDMA (0.5-20 microM) reduces both synaptosomal and vesicular uptake of serotonin and dopamine in a dose dependent manner in vitro, while the uptake of glutamate and gamma-aminobutyric acid (GABA) remains unaffected. Ex vivo experiments support the importance of the monoamines, with predominant dopaminergic inhibition at short-term exposure (3 x 15 mg/kg; 2-h intervals), and exclusively serotonergic inhibition at long-term exposure (2 x 10 mg/kg per day; 4 days). This study also compares MDMA and the structurally related antidepressant paroxetine, in an attempt to reveal possible cellular mechanisms for the serotonergic toxicity of MDMA. One important difference between paroxetine and MDMA is that only MDMA has the capability of inhibiting vesicular uptake of monoamines at doses used. We suggest that inhibition of the vesicular monoamine transporter-2, and a following increase in cytoplasmatic monoamine concentrations, might be crucial for the neurotoxic effect of MDMA.

  14. Zn2+ modulation of neurotransmitter transporters

    DEFF Research Database (Denmark)

    Nørgaard-Nielsen, K.; Gether, U.

    2006-01-01

    Neurotransmitter transporters located at the presynaptic or glial cell membrane are responsible for the stringent and rapid clearance of the transmitter from the synapse, and hence they terminate signaling and control the duration of synaptic inputs in the brain. Two distinct families of neurotra......Neurotransmitter transporters located at the presynaptic or glial cell membrane are responsible for the stringent and rapid clearance of the transmitter from the synapse, and hence they terminate signaling and control the duration of synaptic inputs in the brain. Two distinct families...... of neurotransmitter transporters have been identified based on sequence homology: (1) the neurotransmitter sodium symporter family (NSS), which includes the Na+/C1(-)-dependent transporters for dopamine, norepinephrine, and serotonin; and (2) the dicarboxylate/amino acid cation symporter family (DAACS), which...... indirectly suggested the possibility that several of the transporters are modulated by Zn2+ in vivo, and thus that Zn2+ can play a role as a neuromodulator by affecting the function of neurotransmitter transporters....

  15. Transcriptional coordination of synaptogenesis and neurotransmitter signaling.

    Science.gov (United States)

    Kratsios, Paschalis; Pinan-Lucarré, Bérangère; Kerk, Sze Yen; Weinreb, Alexis; Bessereau, Jean-Louis; Hobert, Oliver

    2015-05-18

    During nervous system development, postmitotic neurons face the challenge of generating and structurally organizing specific synapses with appropriate synaptic partners. An important unexplored question is whether the process of synaptogenesis is coordinated with the adoption of specific signaling properties of a neuron. Such signaling properties are defined by the neurotransmitter system that a neuron uses to communicate with postsynaptic partners, the neurotransmitter receptor type used to receive input from presynaptic neurons, and, potentially, other sensory receptors that activate a neuron. Elucidating the mechanisms that coordinate synaptogenesis, neuronal activation, and neurotransmitter signaling in a postmitotic neuron represents one key approach to understanding how neurons develop as functional units. Using the SAB class of Caenorhabditis elegans motor neurons as a model system, we show here that the phylogenetically conserved COE-type transcription factor UNC-3 is required for synaptogenesis. UNC-3 directly controls the expression of the ADAMTS-like protein MADD-4/Punctin, a presynaptically secreted synapse-organizing molecule that clusters postsynaptic receptors. UNC-3 also controls the assembly of presynaptic specializations and ensures the coordinated expression of enzymes and transporters that define the cholinergic neurotransmitter identity of the SAB neurons. Furthermore, synaptic output properties of the SAB neurons are coordinated with neuronal activation and synaptic input, as evidenced by UNC-3 also regulating the expression of ionotropic neurotransmitter receptors and putative stretch receptors. Our study shows how synaptogenesis and distinct, function-defining signaling features of a postmitotic neuron are hardwired together through coordinated transcriptional control.

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

    Science.gov (United States)

    Yang, Lichuan; Beal, M Flint

    2011-01-01

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

  17. A Yang-invigorating compound mixture alters neurotransmitters in rat telencephalon after exercise-induced fatigue

    Institute of Scientific and Technical Information of China (English)

    Hongzhen Liu; Li Zeng; Xiliang Kong; Lei Zhu; Benhua Hou

    2011-01-01

    The aim of this study was to observe the changes in monoamine and amino acid neurotransmitters in the telencephalon of rats at four functional states after exhaustive exercise and treatment with a Yang-invigorating compound recipe.The main components of this Chinese traditional medicine preparation included Radix Ginseng,Rhizoma Chuanxiong,Fructus Schisandrae,Cortex Cinnamomi,Cornu Cervi Pantotrichum,Radix Morindae Officinalis,and Gecko.This experiment showed that dopamine (DA),5-hydroxyindole acetic acid (5-HIAA),and γ-aminobutyric acid levels noticeably decreased,while DA/5-hydroxytryptamine (5-HT) increased.Furthermore,glutamate (Glu) and Glu/γ-aminobutyric acid significantly increased after 1 hour of exercise in rats in the exercise + medication group.The 5-HT and 5-HT/5-HIAA levels noticeably decreased,and DA/5-HT and Glu levels showed a robust and significant increase immediately after exhaustive exercise.The 5-HT,5-HT/5-HIAA levels sharply decreased,while DA/5-HT,Glu and γ-aminobutyric acid levels increased at 12 hours after exhaustion recovery.The results prove that Chinese herbal formula for strengthening Yang can induce changes in neurotransmitters in the telencephalon of rats after exhaustive exercise during the recovery process,and further improve central nervous system function.

  18. Subchronic exposure to arsenic disturbed the biogenic amine neurotransmitter level and the mRNA expression of synthetase in mice brains.

    Science.gov (United States)

    Zhang, J; Liu, X; Zhao, L; Hu, S; Li, S; Piao, F

    2013-06-25

    Little is known about the influence of arsenic (As) exposure on monoamine neurotransmitters and the underlying mechanisms, although arsenic toxicity on the central nervous system has been well documented. In the present study, the levels of norepinephrine (NE), dopamine (DA), and 5-HT were determined by high performance liquid chromatography in the cerebrum and cerebellum of mice exposed to 1, 2 and 4 ppm As2O3 through drinking water for 60 days. The ultra-structural change of vesicles in the synapses of mice brains was observed by transmission electron microscopy; the mRNA expressions of dopamine beta hydroxylase (DBH), tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) as NE, DA and 5-HT synthetases were quantitatively assessed by real time reverse transcription-polymerase chain reaction. It was shown that the concentrations of NE, DA and 5-HT in the cerebrum or cerebellum of mice exposed to As were significantly lower than those in the control group. The number of synaptic vesicles significantly decreased in the brain of mice exposed to As. Moreover, the expressions of TH, TPH and DBH genes were significantly lower in the brains of mice exposed to As than those in the controls. These results suggested that subchronic exposure to As might decrease the concentrations of the three monoamine neurotransmitters in the mouse brain and downregulate TH, TPH and DBH gene expressions. It was also indicated that the decreased concentrations of the three monoamine neurotransmitters in the brain might be related to the down-regulated gene expressions of these synthetases by As.

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

    Science.gov (United States)

    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. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Noradrenaline as a putative neurotransmitter mediating hypotension—induced FOs—like immunoreactivity in the supraoptic nucleus of the rat

    Institute of Scientific and Technical Information of China (English)

    SHENEH; XIASUN

    1995-01-01

    Hemorrhage or hypotension induces extensive Fos-like immunoreactivity in the magnocellular neurosecretory cells in the supraoptic nucleus of the hypothalamus in rat,especially in the vasopressin neurons.The present study was to explore the neurotransmitter mediating this effect,Microinfusion of the alpha-adrenergic blocker into the supraoptic nucleus reduced the hypotension-induced FOs.whereas beta-antagonist did not affect it significantly.Alaha1-and alpha2-antagonist,prazosin and yohimbine,both reduced the Fos-Positive cell counts.However,the effective dosage of yohimbine was much larger,Alpha1-agonist,methoxamine,induced abundant Fos-like immunoreactivity in the vasopressin cells in this nucleus,while beta-and alpha2-agonist did not elicit such effect.Administration of the noradrenergic re-uptake inhibitor desipramine,to this nucleus to locally accumulate the spontaneously released noradrenaline from the nerve terminals also induced Fos expression,mostly in the vasopressin cells.

  1. DRD4 dopamine receptor genotype and CSF monoamine metabolites in Finnish alcoholics and controls

    Energy Technology Data Exchange (ETDEWEB)

    Adamson, M.D.; Dean, M.; Goldman, D. [National Institute on Alcohol Abuse and Alcoholism, Rockville, MD (United States)] [and others

    1995-06-19

    The DRD4 dopamine receptor is thus far unique among neurotransmitter receptors in having a highly polymorphic gene structure that has been reported to produce altered receptor functioning. These allelic variations are caused by a 48-bp segment in exon III of the coding region which may be repeated from 2-10 times. Varying the numbers of repeated segments changes the length, structure, and, possibly, the functional efficiency of the receptor, which makes this gene an intriguing candidate for variations in dopamine-related behaviors, such as alcoholism and drug abuse. Thus far, these DRD4 alleles have been investigated for association with schizophrenia, bipolar disorder, Parkinson`s disease, and chronic alcoholism, and all have been largely negative for a direct association. We evaluated the DRD4 genotype in 226 Finish adult males, 113 of whom were alcoholics, many of the early onset type with features of impulsivity and antisocial traits. Genotype frequencies were compared to 113 Finnish controls who were free of alcohol abuse, substance abuse, and major mental illness. In 70 alcoholics and 20 controls, we measured CSF homovanillic acid (HVA), the major metabolite of dopamine, and 5-hydroxyindoleacetic acid (5-HIAA). No association was found between a particular DRD4 dopamine receptor allele and alcoholism. CSF concentrations of the monoamine metabolites showed no significant difference among the DRD4 genotypes. This study of the DRD4 dopamine receptor in alcoholics is the first to be conducted in a clinically and ethnically homogeneous population and to relate the DRD4 genotype to CSF monoamine concentrations. The results indicate that there is no association of the DRD4 receptor with alcoholism. 52 refs., 3 figs., 1 tab.

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

    DEFF Research Database (Denmark)

    Zhang, Mengliang

    2016-01-01

    that especially when the spinal cord is injured, they can also be produced in the spinal cord. In this review, I will present evidence for a possible pathway for two-step synthesis of dopamine and serotonin in the spinal cord. Published data from different sources and unpublished data from my own ongoing projects...

  3. Effects of Shuyusan on monoamine neurotransmitters expression in a rat model of chronic stress-induced depression

    Institute of Scientific and Technical Information of China (English)

    Yuanyuan Zhang; Jianjun Jia; Liping Chen; Zhitao Han; Yulan Zhao; Honghong Zhang; Yazhuo Hu

    2011-01-01

    Shuyusan, a traditional Chinese medicine, was shown to improve depression symptoms and behavioral scores, as well as increase 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid, and 5-hydroxytryptophan levels, in a rat model of chronic stress-induced depression. However, dopamine, noradrenalin, and 3-methoxy-4-hydroxyphenylglycol expressions remained unchanged following Shuyusan treatment. Compared with the model group, the number of 5-HT-positive neurons in layers 4-5 of the frontal cortex, as well as hippocampal CA1 and CA3 regions, significantly increased following Shuyusan treatment. These results suggested that Shuyusan improved symptoms in a rat model of chronic stress-induced depression with mechanisms that involved 5-HT, 5-HT metabolite, 5-HT precursor expressions.

  4. Thin film microelectrodes for electrochemical detection of neurotransmitters

    DEFF Research Database (Denmark)

    Larsen, Simon Tylsgaard

    An important signaling process in the nervous system is the release of chemical messengers called neurotransmitters from neurons. In this thesis alternative thin film electrode materials for applications targeting electrochemical detection of neurotransmitters in chip devices were evaluated...

  5. Altered neurotransmitter metabolism in adolescents with high-functioning autism

    NARCIS (Netherlands)

    Drenthen, G.S.; Barendse, E.M.; Aldenkamp, A.P.; Veenendaal, T. van; Puts, N.A.J.; Edden, R.A.E.; Zinger, S.; Thoonen, G.H.J.; Hendriks, M.P.H.; Kessels, R.P.C.; Jansen, J.F.A.

    2016-01-01

    Previous studies have suggested that alterations in excitatory/inhibitory neurotransmitters might play a crucial role in autism spectrum disorder (ASD). Proton magnetic resonance spectroscopy (1H-MRS) can provide valuable information about abnormal brain metabolism and neurotransmitter concentration

  6. Study of a possible role of the monoamine oxidase A (MAOA) gene in paranoid schizophrenia among a Chinese population.

    Science.gov (United States)

    Sun, Yuhui; Zhang, Jiexu; Yuan, Yanbo; Yu, Xin; Shen, Yan; Xu, Qi

    2012-01-01

    Monoamine oxidase A (MAOA) is the enzyme responsible for degradation of several monoamines, such as dopamine and serotonin that are considered as being two of the most important neurotransmitters involved in the pathophysiology of schizophrenia. To study a possible role of the MAOA gene in conferring susceptibility to schizophrenia, the present study genotyped the variable number of tandem repeat (VNTR) polymorphism and 41 SNPs across this gene among 555 unrelated patients with paranoid schizophrenia and 567 unrelated healthy controls. Quantitative real-time PCR analysis was employed to quantify expression of MAOA mRNA in 73 drug-free patients. While none of these genotyped DNA markers showed allelic association with paranoid schizophrenia, haplotypic association was found for the VNTR-rs6323, VNTR-rs1137070, and VNTR-rs6323-rs1137070 haplotypes in female subjects. Nevertheless, no significant change of the expression of MAOA mRNA was detected in either female or male patients with paranoid schizophrenia. Our study suggests that the interaction between genetic variants within the MAOA gene may contribute to an increased risk of paranoid schizophrenia, but the precise mechanism needs further investigation.

  7. Inhibition of Excessive Monoamine Oxidase A/B Activity Protects Against Stress-induced Neuronal Death in Huntington Disease.

    Science.gov (United States)

    Ooi, Jolene; Hayden, Michael R; Pouladi, Mahmoud A

    2015-12-01

    Monoamine oxidases (MAO) are important components of the homeostatic machinery that maintains the levels of monoamine neurotransmitters, including dopamine, in balance. Given the imbalance in dopamine levels observed in Huntington disease (HD), the aim of this study was to examine MAO activity in a mouse striatal cell model of HD and in human neural cells differentiated from control and HD patient-derived induced pluripotent stem cell (hiPSC) lines. We show that mouse striatal neural cells expressing mutant huntingtin (HTT) exhibit increased MAO expression and activity. We demonstrate using luciferase promoter assays that the increased MAO expression reflects enhanced epigenetic activation in striatal neural cells expressing mutant HTT. Using cellular stress paradigms, we further demonstrate that the increase in MAO activity in mutant striatal neural cells is accompanied by enhanced susceptibility to oxidative stress and impaired viability. Treatment of mutant striatal neural cells with MAO inhibitors ameliorated oxidative stress and improved cellular viability. Finally, we demonstrate that human HD neural cells exhibit increased MAO-A and MAO-B expression and activity. Altogether, this study demonstrates abnormal MAO expression and activity and suggests a potential use for MAO inhibitors in HD.

  8. The Role of Neurotrophins in Neurotransmitter Release

    OpenAIRE

    William J Tyler; Perrett, Stephen P.; Pozzo-Miller, Lucas D.

    2002-01-01

    The neurotrophins (NTs) have recently been shown to elicit pronounced effects on quantal neurotransmitter release at both central and peripheral nervous system synapses. Due to their activity-dependent release, as well as the subcellular localization of both protein and receptor, NTs are ideally suited to modify the strength of neuronal connections by “fine-tuning” synaptic activity through direct actions at presynaptic terminals. Here, using BDNF as a prototypical example, the authors provid...

  9. Dynamic neurotransmitter interactions measured with PET

    Energy Technology Data Exchange (ETDEWEB)

    Schiffer, W.K.; Dewey, S.L.

    2001-04-02

    Positron emission tomography (PET) has become a valuable interdisciplinary tool for understanding physiological, biochemical and pharmacological functions at a molecular level in living humans, whether in a healthy or diseased state. The utility of tracing chemical activity through the body transcends the fields of cardiology, oncology, neurology and psychiatry. In this, PET techniques span radiochemistry and radiopharmaceutical development to instrumentation, image analysis, anatomy and modeling. PET has made substantial contributions in each of these fields by providing a,venue for mapping dynamic functions of healthy and unhealthy human anatomy. As diverse as the disciplines it bridges, PET has provided insight into an equally significant variety of psychiatric disorders. Using the unique quantitative ability of PET, researchers are now better able to non-invasively characterize normally occurring neurotransmitter interactions in the brain. With the knowledge that these interactions provide the fundamental basis for brain response, many investigators have recently focused their efforts on an examination of the communication between these chemicals in both healthy volunteers and individuals suffering from diseases classically defined as neurotransmitter specific in nature. In addition, PET can measure the biochemical dynamics of acute and sustained drug abuse. Thus, PET studies of neurotransmitter interactions enable investigators to describe a multitude of specific functional interactions in the human brain. This information can then be applied to understanding side effects that occur in response to acute and chronic drug therapy, and to designing new drugs that target multiple systems as opposed to single receptor types. Knowledge derived from PET studies can be applied to drug discovery, research and development (for review, see (Fowler et al., 1999) and (Burns et al., 1999)). Here, we will cover the most substantial contributions of PET to understanding

  10. Ligand Binding in the Extracellular Vestibule of the Neurotransmitter Transporter Homologue LeuT.

    Science.gov (United States)

    Grouleff, Julie; Koldsø, Heidi; Miao, Yinglong; Schiøtt, Birgit

    2017-03-15

    The human monoamine transporters (MATs) facilitate the reuptake of monoamine neurotransmitters from the synaptic cleft. MATs are linked to a number of neurological diseases and are the targets of both therapeutic and illicit drugs. Until recently, no high-resolution structures of the human MATs existed, and therefore, studies of this transporter family have relied on investigations of the homologues bacterial transporters such as the leucine transporter LeuT, which has been crystallized in several conformational states. A two-substrate transport mechanism has been suggested for this transporter family, which entails that high-affinity binding of a second substrate in an extracellular site is necessary for the substrate in the central binding site to be transported. Compelling evidence for this mechanism has been presented, however, a number of equally compelling accounts suggest that the transporters function through a mechanism involving only a single substrate and a single high-affinity site. To shed light on this apparent contradiction, we have performed extensive molecular dynamics simulations of LeuT in the outward-occluded conformation with either one or two substrates bound to the transporter. We have also calculated the substrate binding affinity in each of the two proposed binding sites through rigorous free energy simulations. Results show that substrate binding is unstable in the extracellular vestibule and the substrate binding affinity within the suggested extracellular site is very low (0.2 and 3.3 M for the two dominant binding modes) compared to the central substrate binding site (14 nM). This suggests that for LeuT in the outward-occluded conformation only a single high-affinity substrate binding site exists.

  11. Leflunomide, a Reversible Monoamine Oxidase Inhibitor.

    Science.gov (United States)

    Petzer, Jacobus P; Petzer, Anél

    2016-01-01

    A screening study aimed at identifying inhibitors of the enzyme, monoamine oxidase (MAO), among clinically used drugs have indicated that the antirheumatic drug, leflunomide, is an inhibitor of both MAO isoforms. Leflunomide inhibits human MAO-A and MAO-B and exhibits IC50 values of 19.1 μM and 13.7 μM, respectively. The corresponding Ki values are 17.7 μM (MAO-A) and 10.1 μM (MAO-B). Dialyses of mixtures of the MAO enzymes and leflunomide show that inhibition of the MAOs by leflunomide is reversible. The principal metabolite of leflunomide, teriflunomide (A77 1726), in contrast is not an MAO inhibitor. This study concludes that, although leflunomide is only moderately potent as an MAO inhibitor, isoxazole derivatives may represent a general class of MAO inhibitors and this heterocycle may find application in MAO inhibitor design. In this respect, MAO inhibitors are used in the clinic for the treatment of depressive illness and Parkinson's disease, and are under investigation as therapy for certain types of cancer, Alzheimer's disease and age-related impairment of cardiac function.

  12. MONOAMINE OXIDASE: RADIOTRACER DEVELOPMENT AND HUMAN STUDIES.

    Energy Technology Data Exchange (ETDEWEB)

    FOWLER,J.S.; LOGAN,J.; VOLKOW,N.D.; WANG,G.J.; MACGREGOR,R.R.; DING,Y.S.

    2000-09-28

    PET is uniquely capable of providing information on biochemical transformations in the living human body. Although most of the studies of monoamine oxidase (MAO) have focused on measurements in the brain, the role of peripheral MAO as a phase 1 enzyme for the metabolism of drugs and xenobiotics is gaining attention (Strolin Benedetti and Tipton, 1998; Castagnoli et al., 1997.). MAO is well suited for this role because its concentration in organs such as kidneys, liver and digestive organs is high sometimes exceeding that in the brain. Knowledge of the distribution of the MAO subtypes within different organs and different cells is important in determining which substrates (and which drugs and xenobiotics) have access to which MAO subtypes. The highly variable subtype distribution with different species makes human studies even more important. In addition, the deleterious side effects of combining MAO inhibitors with other drugs and with foodstuffs makes it important to know the MAO inhibitory potency of different drugs both in the brain and in peripheral organs (Ulus et al., 2000). Clearly PET can play a role in answering these questions, in drug research and development and in discovering some of the factors which contribute to the highly variable MAO levels in different individuals.

  13. Monoamine oxidase inhibitory activities of heterocyclic chalcones.

    Science.gov (United States)

    Minders, Corné; Petzer, Jacobus P; Petzer, Anél; Lourens, Anna C U

    2015-11-15

    Studies have shown that natural and synthetic chalcones (1,3-diphenyl-2-propen-1-ones) possess monoamine oxidase (MAO) inhibition activities. Of particular importance to the present study is a report that a series of furanochalcones acts as MAO-B selective inhibitors. Since the effect of heterocyclic substitution, other than furan (and more recently thiophene, piperidine and quinoline) on the MAO inhibitory properties of the chalcone scaffold remains unexplored, the aim of this study was to synthesise and evaluate further heterocyclic chalcone analogues as inhibitors of the human MAOs. For this purpose, heterocyclic chalcone analogues that incorporate pyrrole, 5-methylthiophene, 5-chlorothiophene and 6-methoxypyridine substitution were examined. Seven of the nine synthesised compounds exhibited IC50 values chalcones are reversible and competitive MAO inhibitors. 4h, however, may exhibit tight-binding to MAO-B, a property linked to its thiophene moiety. We conclude that high potency chalcones such as 4h represent suitable leads for the development of MAO-B inhibitors for the treatment of Parkinson's disease and possibly other neurodegenerative disorders.

  14. Receptor desensitization by neurotransmitters in membranes: are neurotransmitters the endogenous anesthetics?

    Science.gov (United States)

    Cantor, Robert S

    2003-10-21

    A mechanism of anesthesia is proposed that addresses one of the most troubling peculiarities of general anesthesia: the remarkably small variability of sensitivity within the human population and across a broad range of animal phyla. It is hypothesized that in addition to the rapid, saturable binding of a neurotransmitter to its receptor that results in activation, the neurotransmitter also acts indirectly on the receptor by diffusing into the postsynaptic membrane and changing its physical properties, causing a shift in receptor conformational equilibrium (desensitization). Unlike binding, this slower indirect mechanism is nonspecific: each neurotransmitter will, in principle, affect all receptors in the membrane. For proteins modeled as having only resting and active conformational states, time-dependent ion currents are predicted that exhibit many characteristics of desensitization for both inhibitory and excitatory channels. If receptors have been engineered to regulate the time course of ion currents by this mechanism, then (a) mutations that significantly alter receptor sensitivity to this effect would be lethal and (b) by design, excitatory receptors would be inhibited, but inhibitory receptors activated, so that their effects are not counterproductive. The wide range of exogenous molecules that affect the physical properties of membranes as do neurotransmitters, but that do not bind to receptors, would thus inhibit excitatory channels and activate inhibitory channels, i.e., they would act as anesthesics. The endogenous anesthetics would thus be the neurotransmitters, the survival advantage conferred by their proper membrane-mediated desensitization of receptors explaining the selection pressure for anesthesic sensitivity.

  15. Characterizing Enzymatic Deposition for Microelectrode Neurotransmitter Detection

    Energy Technology Data Exchange (ETDEWEB)

    Hosein, W. K. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Yorita, A. M. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Tolosa, V. M. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2016-08-12

    The enzyme immobilization process, one step in creating an enzymatic biosensor, was characterized and analyzed as a function of its physical properties. The neural glutamic biosensor is a flexible device, effectively minimizing trauma to the area of implantation. The Multielectrode Array (MEA) is composed primarily of a proprietary polymer which has been successfully implanted into human subjects in recent years. This polymer allows the device the pliability that other devices normally lack, though this poses some challenges to implantation. The electrodes are made of Platinum (Pt), and can range in number from eight to thirty two electrodes per device. These electrodes are electroplated with a semipermeable polymer layer to improve selectivity of the electrode to the neurotransmitter of interest, in this case glutamate. A signal is created from the interaction of glutamate in the brain with the glutamate oxidase (GluOx) which is immobilized on the surface of the electrode by using crosslinking chemistry in conjunction with glutaraldehyde and Bovine Serum Albumin (BSA). The glutamate is oxidized by glutamate oxidase, producing α-ketoglutarate and hydrogen peroxide (H2O2) as a by-product. The production of H2O2 is crucial for detection of the presence of the glutamate within the enzymatic coating, as it diffuses through the enzyme layer and oxidizes at the surface of the electrode. This oxidation is detectable by measurable change in the current using amperometry. Hence, the MEA allows for in vivo monitoring of neurotransmitter activity in real time. The sensitivity of the sensor to these neurotransmitters is dependent on the thickness of the layer, which is investigated in these experiments in order to optimize the efficacy of the device to detecting the substrate, once implanted.

  16. Interaction of neurotransmitters with a phospholipid bilayer

    DEFF Research Database (Denmark)

    Peters, Günther H.J.; Werge, Mikkel; Elf-Lind, Maria Northved

    2014-01-01

    We have performed a series of molecular dynamics simulations to study the interactions between the neurotransmitters (NTs) γ-aminobutyrate (GABA), glycine (GLY), acetylcholine (ACH) and glutamate (GLU) as well as the amidated/acetylated γ-aminobutyrate (GABAneu) and the osmolyte molecule glycerol...... umbrella sampling simulations, which were conducted for the four naturally occurring NTs. Free energy profiles for ACH and GLU show a minimum of ∼2–3 kJ/mol close to the bilayer interface, while for GABA and GLY, a minimum of respectively ∼2 kJ/mol and ∼5 kJ/mol is observed when these NTs are located...

  17. The Role of Neurotrophins in Neurotransmitter Release

    Science.gov (United States)

    Tyler, William J.; Perrett, Stephen P.; Pozzo-Miller, Lucas D.

    2009-01-01

    The neurotrophins (NTs) have recently been shown to elicit pronounced effects on quantal neurotransmitter release at both central and peripheral nervous system synapses. Due to their activity-dependent release, as well as the subcellular localization of both protein and receptor, NTs are ideally suited to modify the strength of neuronal connections by “fine-tuning” synaptic activity through direct actions at presynaptic terminals. Here, using BDNF as a prototypical example, the authors provide an update of recent evidence demonstrating that NTs enhance quantal neurotransmitter release at synapses through presynaptic mechanisms. The authors further propose that a potential target for NT actions at presynaptic terminals is the mechanism by which terminals retrieve synaptic vesicles after exocytosis. Depending on the temporal demands placed on synapses during high-frequency synaptic transmission, synapses may use two alternative modes of synaptic vesicle retrieval, the conventional slow endosomal recycling or a faster rapid retrieval at the active zone, referred to as “kiss-and-run.” By modulating Ca2+ microdomains associated with voltage-gated Ca2+ channels at active zones, NTs may elicit a switch from the slow to the fast mode of endocytosis of vesicles at presynaptic terminals during high-frequency synaptic transmission, allowing more reliable information transfer and neuronal signaling in the central nervous system. PMID:12467374

  18. Chloride binding site of neurotransmitter sodium symporters.

    Science.gov (United States)

    Kantcheva, Adriana K; Quick, Matthias; Shi, Lei; Winther, Anne-Marie Lund; Stolzenberg, Sebastian; Weinstein, Harel; Javitch, Jonathan A; Nissen, Poul

    2013-05-21

    Neurotransmitter:sodium symporters (NSSs) play a critical role in signaling by reuptake of neurotransmitters. Eukaryotic NSSs are chloride-dependent, whereas prokaryotic NSS homologs like LeuT are chloride-independent but contain an acidic residue (Glu290 in LeuT) at a site where eukaryotic NSSs have a serine. The LeuT-E290S mutant displays chloride-dependent activity. We show that, in LeuT-E290S cocrystallized with bromide or chloride, the anion is coordinated by side chain hydroxyls from Tyr47, Ser290, and Thr254 and the side chain amide of Gln250. The bound anion and the nearby sodium ion in the Na1 site organize a connection between their coordinating residues and the extracellular gate of LeuT through a continuous H-bond network. The specific insights from the structures, combined with results from substrate binding studies and molecular dynamics simulations, reveal an anion-dependent occlusion mechanism for NSS and shed light on the functional role of chloride binding.

  19. Interaction of anesthetics with neurotransmitter release machinery proteins.

    Science.gov (United States)

    Xie, Zheng; McMillan, Kyle; Pike, Carolyn M; Cahill, Anne L; Herring, Bruce E; Wang, Qiang; Fox, Aaron P

    2013-02-01

    General anesthetics produce anesthesia by depressing central nervous system activity. Activation of inhibitory GABA(A) receptors plays a central role in the action of many clinically relevant general anesthetics. Even so, there is growing evidence that anesthetics can act at a presynaptic locus to inhibit neurotransmitter release. Our own data identified the neurotransmitter release machinery as a target for anesthetic action. In the present study, we sought to examine the site of anesthetic action more closely. Exocytosis was stimulated by directly elevating the intracellular Ca(2+) concentration at neurotransmitter release sites, thereby bypassing anesthetic effects on channels and receptors, allowing anesthetic effects on the neurotransmitter release machinery to be examined in isolation. Three different PC12 cell lines, which had the expression of different release machinery proteins stably suppressed by RNA interference, were used in these studies. Interestingly, there was still significant neurotransmitter release when these knockdown PC12 cells were stimulated. We have previously shown that etomidate, isoflurane, and propofol all inhibited the neurotransmitter release machinery in wild-type PC12 cells. In the present study, we show that knocking down synaptotagmin I completely prevented etomidate from inhibiting neurotransmitter release. Synaptotagmin I knockdown also diminished the inhibition produced by propofol and isoflurane, but the magnitude of the effect was not as large. Knockdown of SNAP-25 and SNAP-23 expression also changed the ability of these three anesthetics to inhibit neurotransmitter release. Our results suggest that general anesthetics inhibit the neurotransmitter release machinery by interacting with multiple SNARE and SNARE-associated proteins.

  20. Marine Toxins Potently Affecting Neurotransmitter Release

    Science.gov (United States)

    Meunier, Frédéric A.; Mattei, César; Molgó, Jordi

    Synapses are specialised structures where interneuronal communication takes place. Not only brain function is absolutely dependent on synaptic activity, but also most of our organs are intimately controlled by synaptic activity. Synapses re therefore an ideal target to act upon and poisonous species have evolved fascinating neurotoxins capable of shutting down neuronal communication by blocking or activating essential components of the synapse. By hijacking key proteins of the communication machinery, neurotoxins are therefore extremely valuable tools that have, in turn, greatly helped our understanding of synaptic biology. Moreover, analysis and understanding of the molecular strategy used by certain neurotoxins has allowed the design of entirely new classes of drugs acting on specific targets with high selectivity and efficacy. This chapter will discuss the different classes of marine neurotoxins, their effects on neurotransmitter release and how they act to incapacitate key steps in the process leading to synaptic vesicle fusion.

  1. Monoamine transporter availability in Parkinson's disease patients with or without depression

    Energy Technology Data Exchange (ETDEWEB)

    Hesse, Swen; Meyer, Philipp M.; Barthel, Henryk; Sabri, Osama [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Strecker, Karl; Wegner, Florian; Isaias, Ioannis Ugo; Schwarz, Johannes [University of Leipzig, Department of Neurology, Leipzig (Germany); Oehlwein, Christian [Specialized Parkinson' s Disease Outpatient Centre, Gera (Germany)

    2009-03-15

    Depression is a common symptom in patients suffering from Parkinson's disease (PD) and markedly reduces their quality of life. As post-mortem studies have shown, its presence may reflect extensive cell loss in the midbrain and brainstem with imbalances in monoaminergic neurotransmitters. However, in vivo evidence of specific monoaminergic deficits in depressed PD patients is still sparse. Therefore, we studied PD patients with depression (PD+D) and without depression (PD-D) using high-resolution single-photon emission computed tomography (SPECT) and the monoamine transporter marker [{sup 123}I]FP-CIT. A magnetic resonance imaging-based region-of-interest analysis was applied to quantify the specific-to-nondisplaceable [{sup 123}I]FP-CIT binding coefficient V{sub 3}'' in the striatum, thalamus and midbrain/brainstem regions. PD+D patients had significantly lower V{sub 3}'' compared with PD-D patients in the striatum (p<0.001), thalamus (p=0.002), and midbrain/brainstem (p=0.025). Only PD+D patients without selective serotonin reuptake inhibitor (SSRI) treatment showed lower thalamic and midbrain V{sub 3}'' than controls (p<0.001, p=0.029). In a small sub-group of SSRI-treated PD+D patients neither thalamic V{sub 3}'' nor midbrain/brainstem V{sub 3}'' differed from those in PD-D patients (p=0.168, p=0.201) or controls (p=0.384, p=0.318). Our data indicate that depression in PD is associated with a more pronounced loss of striatal dopamine transporter availability that is most likely secondary to increased dopaminergic degeneration. In addition, depressed PD patients have a lower availability of midbrain/brainstem monoamine transporters than nondepressed PD patients. These findings provide in vivo evidence in support of the known post-mortem data demonstrating more extensive nerve cell loss in PD with depression and indicate that SPECT imaging can help to identify pathophysiological changes underlying nonmotor

  2. Secondary Abnormalities of Neurotransmitters in Infants with Neurological Disorders

    Science.gov (United States)

    Garcia-Cazorla, A.; Serrano, M.; Perez-Duenas, B.; Gonzalez, V.; Ormazabal, A.; Pineda, M.; Fernandez-Alvarez, E.; Campistol, J. M. D.; Artuch, R. M. D.

    2007-01-01

    Neurotransmitters are essential in young children for differentiation and neuronal growth of the developing nervous system. We aimed to identify possible factors related to secondary neurotransmitter abnormalities in pediatric patients with neurological disorders. We analyzed cerebrospinal fluid (CSF) and biogenic amine metabolites in 56 infants…

  3. Antidepressant-Like Effects of Fractions Prepared from Danzhi-Xiaoyao-San Decoction in Rats with Chronic Unpredictable Mild Stress: Effects on Hypothalamic-Pituitary-Adrenal Axis, Arginine Vasopressin, and Neurotransmitters

    Directory of Open Access Journals (Sweden)

    Li-Li Wu

    2016-01-01

    Full Text Available The aim of the present study was to investigate the antidepressant-like effects of two fractions, including petroleum ether soluble fraction (Fraction A, FA and water-EtOH soluble fraction (Fraction B, FB prepared from the Danzhi-xiaoyao-san (DZXYS by using chronic unpredictable mild stress-induced depressive rat model. The results indicated that DZXYS could ameliorate the depression-like behavior in chronic stress model of rats. The inhibition of hyperactivity of HPA axis and the modulation of monoamine and amino acid neurotransmitters in the hippocampus may be the important mechanisms underlying the action of DZXYS antidepressant-like effect in chronically stressed rats.

  4. Quantitative distribution of monoamine oxidase A in brainstem monoamine nuclei is normal in major depression.

    Science.gov (United States)

    Ordway, G A; Farley, J T; Dilley, G E; Overholser, J C; Meltzer, H Y; Balraj, E K; Stockmeier, C A; Klimek, V

    1999-11-13

    An abnormal expression of noradrenergic proteins (e.g., tyrosine hydroxylase, norepinephrine transporters) in the locus coeruleus has recently been demonstrated in subjects with major depression and/or victims of suicide. Monoamine oxidase A (MAO-A) is a key enzyme in the catabolism of biogenic amines and is expressed in brain noradrenergic neurons. In this study, the binding of [3H]Ro41-1049 to MAO-A was measured by quantitative autoradiography at multiple levels along the rostral-caudal axis of the noradrenergic locus coeruleus from subjects with major depression and age- and postmortem interval-matched control subjects who were psychiatrically normal. [3H]Ro41-1049 binding to MAO-A was unevenly distributed along the axis of the locus coeruleus, paralleling an uneven number of neuromelanin-containing (noradrenergic) neurons throughout the nucleus. Accordingly, there was a significant correlation between the number of neuromelanin-containing neurons per section and the specific binding of [3H]Ro41-1049 at any particular level of the locus coeruleus in control subjects (r(2)=0.25; pdepression (r(2)=0.14; pdepression to psychiatrically normal control subjects. These findings demonstrate that the pathophysiology of major depression is not likely to involve abnormalities in MAO-A.

  5. Triple monoamine inhibitor tesofensine decreases food intake, body weight, and striatal dopamine D2/D3 receptor availability in diet-induced obese rats.

    Science.gov (United States)

    van de Giessen, Elsmarieke; de Bruin, Kora; la Fleur, Susanne E; van den Brink, Wim; Booij, Jan

    2012-04-01

    The novel triple monoamine inhibitor tesofensine blocks dopamine, serotonin and norepinephrine re-uptake and is a promising candidate for the treatment of obesity. Obesity is associated with lower striatal dopamine D2 receptor availability, which may be related to disturbed regulation of food intake. This study assesses the effects of chronic tesofensine treatment on food intake and body weight in association with changes in striatal dopamine D2/D3 receptor (D2/3R) availability of diet-induced obese (DIO) rats. Four groups of 15 DIO rats were randomized to one of the following treatments for 28 days: 1. tesofensine (2.0 mg/kg), 2. vehicle, 3. vehicle+restricted diet isocaloric to caloric intake of group 1, and 4. tesofensine (2.0 mg/kg)+ a treatment-free period of 28 days. Caloric intake and weight gain decreased significantly more in the tesofensine-treated rats compared to vehicle-treated rats, which confirms previous findings. After treatment discontinuation, caloric intake and body weight gain gradually increased again. Tesofensine-treated rats showed significantly lower D2/3R availability in nucleus accumbens and dorsal striatum than both vehicle-treated rats and vehicle-treated rats on restricted isocaloric diet. No correlations were observed between food intake or body weight and D2/3R availability. Thus, chronic tesofensine treatment leads to decreased food intake and weight gain. However, this appears not to be directly related to the decreased striatal D2/3R availability, which is mainly a pharmacological effect. Copyright © 2011 Elsevier B.V. and ECNP. All rights reserved.

  6. Cytoplasmic permeation pathway of neurotransmitter transporters.

    Science.gov (United States)

    Rudnick, Gary

    2011-09-06

    Ion-coupled solute transporters are responsible for transporting nutrients, ions, and signaling molecules across a variety of biological membranes. Recent high-resolution crystal structures of several transporters from protein families that were previously thought to be unrelated show common structural features indicating a large structural family representing transporters from all kingdoms of life. This review describes studies that led to an understanding of the conformational changes required for solute transport in this family. The first structure in this family showed the bacterial amino acid transporter LeuT, which is homologous to neurotransmitter transporters, in an extracellularly oriented conformation with a molecule of leucine occluded at the substrate site. Studies with the mammalian serotonin transporter identified positions, buried in the LeuT structure, that defined a potential pathway leading from the cytoplasm to the substrate binding site. Modeling studies utilized an inverted structural repeat within the LeuT crystal structure to predict the conformation of LeuT in which the cytoplasmic permeation pathway, consisting of positions identified in SERT, was open for diffusion of the substrate to the cytoplasm. From the difference between the model and the crystal structures, a simple "rocking bundle" mechanism was proposed, in which a four-helix bundle changed its orientation with respect to the rest of the protein to close the extracellular pathway and open the cytoplasmic one. Subsequent crystal structures from structurally related proteins provide evidence supporting this model for transport.

  7. Dirty electricity, chronic stress, neurotransmitters and disease.

    Science.gov (United States)

    Milham, Samuel; Stetzer, David

    2013-12-01

    Dirty electricity, also called electrical pollution, is high-frequency voltage transients riding along the 50 or 60 Hz electricity provided by the electric utilities. It is generated by arcing, by sparking and by any device that interrupts current flow, especially switching power supplies. It has been associated with cancer, diabetes and attention deficit hyperactivity disorder in humans. Epidemiological evidence also links dirty electricity to most of the diseases of civilization including cancer, cardiovascular disease, diabetes and suicide, beginning at the turn of the twentieth century. The dirty electricity level in a public library was reduced from over 10 000 Graham/Stetzer (G/S) units to below 50 G/S units by installing plug-in capacitive filters. Before cleanup, the urinary dopamine level of only one of seven volunteers was within normal levels, while four of seven phenylethylamine levels were normal. After an initial decline, over the next 18 weeks the dopamine levels gradually increased to an average of over 215 μg/g creatinine, which is well above 170 μg/g creatinine, the high normal level for the lab. Average phenylethylamine levels also rose gradually to slightly above 70 μg/g creatinine, the high normal level for the lab. Neurotransmitters may be biomarkers for dirty electricity and other electromagnetic field exposures. We believe that dirty electricity is a chronic stressor of electrified populations and is responsible for many of their disease patterns.

  8. Radiochemistry devoted to the production of monoamine oxidase (MAO-A and MAO-B) ligands for brain imaging with positron emission tomography.

    Science.gov (United States)

    Kersemans, Ken; Van Laeken, Nick; De Vos, Filip

    2013-01-01

    Monoamine oxidase (MAO) belongs to a family of flavin-containing integral enzymes that are present in the outer mitochondrial membrane in neurons and glial cells in the central nervous system. These enzymes catalyze the oxidative deamination of various neurotransmitters, biogenic amines, and xenobiotics, thereby influencing their availability and physiological activity in brain and body. Over the past decades, many potential positron emission tomography tracers have been put forward to visualize MAO in the brain with varying success, and recent publications on the topic illustrate the continuing interest in the field. The present review gives an overview of the compounds that have been put forward as possible MAO tracers in the brain and focuses on the radiochemical procedures that have been developed to produce them up till now. Relevant radioligands are grouped by the main radiochemical strategies that have been employed to synthesize them, and some interesting details and findings that are crucial to the radiosyntheses are provided.

  9. Synthetic and Natural Monoamine Oxidase Inhibitors as Potential Lead Compounds for Effective Therapeutics.

    Science.gov (United States)

    Pathak, Ashish; Srivastava, Amit K; Singour, Pradeep K; Gouda, Panchanan

    2016-01-01

    Monoamine oxidases A and B (MAO-A and B) play a critical role in the metabolism of intracellular neurotransmitters of the central nervous system. For decades, MAO inhibitors have proven their clinical efficacy as potential drug targets for several neurological and neurodegenerative diseases. Use of first generation non selective MAO inhibitors as neuropsychiatric drugs elicited several side effects like hypertensive crisis and cheese reaction. Therefore their use is now limited due to non-selectivity towards MAO isoforms and inhibition of metabolizing enzymes like cytochrome P450. Development of selective and specific MAO inhibitors like moclobemide, toloxatone improves their efficacy as disease-modifying effects in monotherapy as well as adjunctive therapy. Recently a lot of research has been done to elucidate the pharmacological potential of medicinal plants and their isolated bioactive constituents having MAO inhibitory activity. Herbs containing MAO inhibitors are extensively used for the development of potent synthetic drugs and as safe and effective alternatives to the available synthetic drugs in the treatment of neurodegenerative diseases such as depression, Parkinson and Alzheimer's. In several diseases like Parkinson natural MAO inhibitors prevented the neuron denaturalization by their dual action via enhancing neurotransmission of dopamine as well as lowering the generation of free radicals and toxins. Currently development of selective MAO inhibitors is still under study to achieve more effective therapies by using Computer Aided Drug Designing, Ligand-based models and structure-activity hypothesis. These approaches also facilitate understanding the interaction of newly designed molecule with MAO enzymes and the rationalization of probable mechanisms of action.

  10. Synthesis of symmetrical and non-symmetrical bivalent neurotransmitter ligands

    DEFF Research Database (Denmark)

    Stuhr-Hansen, Nicolai; Andersen, Jacob; Thygesen, Mikkel Boas

    2016-01-01

    A novel procedure for synthesis of bivalent neurotransmitter ligands was developed by reacting O-benzyl protected N-nosylated dopamine and serotonin with alkyl- or PEG-linked diols under Fukuyama-Mitsunobu conditions in the presence of DIAD/PPh3 generating three different bivalent neurotransmitter...... ligands in a one-pot reaction. The methodol. establishes a facile route towards bivalent neurotransmitter ligands, and libraries of in total 40 sym. and non-sym. bivalent and monovalent dopamine and serotonin compds. linked through alkyl or PEG spacers of varying length were prepd. Interestingly...

  11. Nitrogen heterocycles as potential monoamine oxidase inhibitors: Synthetic aspects

    Directory of Open Access Journals (Sweden)

    Pravin O. Patil

    2014-12-01

    Full Text Available The present review highlights the synthetic methods of monoamine oxidase inhibitors (MAO belonging to a group of nitrogen heterocycles such as pyrazoline, indole, xanthine, oxadiazole, benzimidazole, pyrrole, quinoxaline, thiazole and other related compounds (1990–2012. Moreover, it emphasizes salient findings related to chemical structures and the bioactivities of these heterocycles as MAO inhibitors. The aim of this review is to find out different methods for the synthesis of nitrogen containing heterocycles and their bioactivity related aspects as MAO inhibitors.

  12. A novel fluorogenic probe for monoamine oxidase assays

    Institute of Scientific and Technical Information of China (English)

    You You Lu; Yu Guang Wang; Bin Dai; Yi Qi Dai; Zhao Wang; Zheng Wei Fu; Qing Zhu

    2008-01-01

    Monoamine oxidase is flavoenzymes, widely distributed in mammals. It is well recognized that MAOs serve an important role in metabolism that they have close relationship with health .Along with the discoveries between MAOs and neurotic disease, more and more studies have been jumped in .In this paper, we design a new probe for assaying the activities of MAOs. The results showed that the probe [7-(3-aminopropoxy)coumarin] is simple, effective and sensitive for MAOB.

  13. Effect of acute swim stress on plasma corticosterone and brain monoamine levels in bidirectionally selected DxH recombinant inbred mouse strains differing in fear recall and extinction.

    Science.gov (United States)

    Browne, Caroline A; Hanke, Joachim; Rose, Claudia; Walsh, Irene; Foley, Tara; Clarke, Gerard; Schwegler, Herbert; Cryan, John F; Yilmazer-Hanke, Deniz

    2014-12-01

    Stress-induced changes in plasma corticosterone and central monoamine levels were examined in mouse strains that differ in fear-related behaviors. Two DxH recombinant inbred mouse strains with a DBA/2J background, which were originally bred for a high (H-FSS) and low fear-sensitized acoustic startle reflex (L-FSS), were used. Levels of noradrenaline, dopamine, and serotonin and their metabolites 3,4-dihydroxyphenyacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were studied in the amygdala, hippocampus, medial prefrontal cortex, striatum, hypothalamus and brainstem. H-FSS mice exhibited increased fear levels and a deficit in fear extinction (within-session) in the auditory fear-conditioning test, and depressive-like behavior in the acute forced swim stress test. They had higher tissue noradrenaline and serotonin levels and lower dopamine and serotonin turnover under basal conditions, although they were largely insensitive to stress-induced changes in neurotransmitter metabolism. In contrast, acute swim stress increased monoamine levels but decreased turnover in the less fearful L-FSS mice. L-FSS mice also showed a trend toward higher basal and stress-induced corticosterone levels and an increase in noradrenaline and serotonin in the hypothalamus and brainstem 30 min after stress compared to H-FSS mice. Moreover, the dopaminergic system was activated differentially in the medial prefrontal cortex and striatum of the two strains by acute stress. Thus, H-FSS mice showed increased basal noradrenaline tissue levels compatible with a fear phenotype or chronic stressed condition. Low corticosterone levels and the poor monoamine response to stress in H-FSS mice may point to mechanisms similar to those found in principal fear disorders or post-traumatic stress disorder.

  14. Mechanism for alternating access in neurotransmitter transporters.

    Science.gov (United States)

    Forrest, Lucy R; Zhang, Yuan-Wei; Jacobs, Miriam T; Gesmonde, Joan; Xie, Li; Honig, Barry H; Rudnick, Gary

    2008-07-29

    Crystal structures of LeuT, a bacterial homologue of mammalian neurotransmitter transporters, show a molecule of bound substrate that is essentially exposed to the extracellular space but occluded from the cytoplasm. Thus, there must exist an alternate conformation for LeuT in which the substrate is accessible to the cytoplasm and a corresponding mechanism that switches accessibility from one side of the membrane to the other. Here, we identify the cytoplasmic accessibility pathway of the alternate conformation in a mammalian serotonin transporter (SERT) (a member of the same transporter family as LeuT). We also propose a model for the cytoplasmic-facing state that exploits the internal pseudosymmetry observed in the crystal structure. LeuT contains two structurally similar repeats (TMs1-5 and TMs 6-10) that are inverted with respect to the plane of the membrane. The conformational differences between them result in the formation of the extracellular pathway. Our model for the cytoplasm-facing state exchanges the conformations of the two repeats and thus exposes the substrate and ion-binding sites to the cytoplasm. The conformational change that connects the two states primarily involves the tilting of a 4-helix bundle composed of transmembrane helices 1, 2, 6, and 7. Switching the tilt angle of this bundle is essentially equivalent to switching the conformation of the two repeats. Extensive mutagenesis of SERT and accessibility measurements, using cysteine reagents, are accommodated by our model. These observations may be of relevance to other transporter families, many of which contain internal inverted repeats.

  15. Extracellular Neurotransmitter Receptor Clustering: Think Outside the Box

    Institute of Scientific and Technical Information of China (English)

    Matthias Kneussel

    2010-01-01

    @@ Postsynaptic submembrane scaffolds cluster neurotransmitter receptors through intracellular protein-protein interactions. Growing evidence supports the view that extracellular factors can be almost as important to trigger synaptic receptor aggregation.

  16. SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

    DEFF Research Database (Denmark)

    Kristensen, Anders S; Andersen, Jacob; Jørgensen, Trine N

    2011-01-01

    The neurotransmitter transporters (NTTs) belonging to the solute carrier 6 (SLC6) gene family (also referred to as the neurotransmitter-sodium-symporter family or Na(+)/Cl(-)-dependent transporters) comprise a group of nine sodium- and chloride-dependent plasma membrane transporters for the monoa......The neurotransmitter transporters (NTTs) belonging to the solute carrier 6 (SLC6) gene family (also referred to as the neurotransmitter-sodium-symporter family or Na(+)/Cl(-)-dependent transporters) comprise a group of nine sodium- and chloride-dependent plasma membrane transporters....... Furthermore, psychostimulants such as cocaine and amphetamines have the SLC6 NTTs as primary targets. Beginning with the determination of a high-resolution structure of a prokaryotic homolog of the mammalian SLC6 transporters in 2005, the understanding of the molecular structure, function, and pharmacology...

  17. Analysis of neurotransmitters, neurosteroids and their metabolites in biological samples

    OpenAIRE

    2015-01-01

    Neurotransmitters and neurosteroids are compounds that regulate the functions of the brain. The neurotransmitters dopamine (DA) and serotonin (5-HT) play a role in several psychological conditions, including schizophrenia, depression and anxiety. DA also has an important role in Parkinson s disease. Neurosteroids are involved in neurodegenerative diseases. In Alzheimer s disease and multiple sclerosis, the levels of neurosteroids are decreased in certain areas of the brain. Neurosteroids diff...

  18. Selected hormonal and neurotransmitter mechanisms regulating feed intake in sheep.

    Science.gov (United States)

    Sartin, J L; Daniel, J A; Whitlock, B K; Wilborn, R R

    2010-11-01

    Appetite control is a major issue in normal growth and in suboptimal growth performance settings. A number of hormones, in particular leptin, activate or inhibit orexigenic or anorexigenic neurotransmitters within the arcuate nucleus of the hypothalamus, where feed intake regulation is integrated. Examples of appetite regulatory neurotransmitters are the stimulatory neurotransmitters neuropeptide Y (NPY), agouti-related protein (AgRP), orexin and melanin-concentrating hormone and the inhibitory neurotransmitter, melanocyte-stimulating hormone (MSH). Examination of messenger RNA (using in situ hybridization and real-time PCR) and proteins (using immunohistochemistry) for these neurotransmitters in ruminants has indicated that physiological regulation occurs in response to fasting for several of these critical genes and proteins, especially AgRP and NPY. Moreover, intracerebroventricular injection of each of the four stimulatory neurotransmitters can increase feed intake in sheep and may also regulate either growth hormone, luteinizing hormone, cortisol or other hormones. In contrast, both leptin and MSH are inhibitory to feed intake in ruminants. Interestingly, the natural melanocortin-4 receptor (MC4R) antagonist, AgRP, as well as NPY can prevent the inhibition of feed intake after injection of endotoxin (to model disease suppression of appetite). Thus, knowledge of the mechanisms regulating feed intake in the hypothalamus may lead to mechanisms to increase feed intake in normal growing animals and prevent the wasting effects of severe disease in animals.

  19. 经前期综合征相关神经递质及其受体研究进展%Research Progress of Neurotransmitters and the Receptors Involved in Premenstrual Syndrome

    Institute of Scientific and Technical Information of China (English)

    高兴笑

    2011-01-01

    经前期综合征(PMS)的发病机制十分复杂,目前尚未完全明确,与该病可能相关的神经递质主要包括单胺类、氨基酸类和肽类.国内外已有研究表明PMS与单胺类(以5-羟色胺为主)及氨基酸类(以谷氨酸、氨酪酸为主)神经递质有关,但有关肽类对PMS影响的研究较少较浅.现对可能涉及该病的神经递质及其受体进行归类综述,以期为进一步探讨PMS神经生化方面的微观机制提供参考.%Pathogenesis of premenstrual syndrome is so complicated that a clear understanding of it is still missing. Neurotransmitters,which may have close relation to PMS,including monoamines,aminoacids and neuropeptides. Domestic and abroad researches have found that PMS is closely related to monoamines( 5-HE、 DA and NE )and aminoacids( GABA and Glu are of greater importance ),but studies on neuropeptides are less and supeificial. Here is to introduce the development of neurotransmitters and their receptors related to PMS according to their categories, with expectation to provide references on neural and biochemical micro-mechanism for PMS.

  20. Alteration of behavior and monoamine levels attributable to Lactobacillus plantarum PS128 in germ-free mice.

    Science.gov (United States)

    Liu, Wei-Hsien; Chuang, Hsiao-Li; Huang, Yen-Te; Wu, Chien-Chen; Chou, Geng-Ting; Wang, Sabrina; Tsai, Ying-Chieh

    2016-02-01

    Probiotics, defined as live bacteria or bacterial products, confer a significant health benefit to the host, including amelioration of anxiety-like behavior and psychiatric illnesses. Here we administered Lactobacillus plantarum PS128 (PS128) to a germ-free (GF) mouse model to investigate the impact of the gut-brain axis on emotional behaviors. First, we demonstrated that chronic administration of live PS128 showed no adverse effects on physical health. Then, we found that administration of live PS128 significantly increased the total distance traveled in the open field test and decreased the time spent in the closed arm in the elevated plus maze test, whereas the administration of PS128 had no significant effects in the depression-like behaviors of GF mice. Also, chronic live PS128 ingestion significantly increased the levels of both serotonin and dopamine in the striatum, but not in the prefrontal cortex or hippocampus. These results suggest that the chronic administration of PS128 is safe and could induce changes in emotional behaviors. The behavioral changes are correlated with the increase in the monoamine neurotransmitters in the striatum. These findings suggest that daily intake of the L. plantarum strain PS128 could improve anxiety-like behaviors and may be helpful in ameliorating neuropsychiatric disorders.

  1. Neuronal monoamine reuptake inhibitors enhance in vitro susceptibility to chloroquine in resistant Plasmodium falciparum.

    OpenAIRE

    Coutaux, A F; Mooney, J. J.; Wirth, D. F.

    1994-01-01

    Chloroquine resistance in Plasmodium falciparum was reversed in vitro by the neuronal monoamine reuptake inhibitors and antidepressants desipramine, sertraline, fluoxetine, and norfluoxetine but not by carbamazepine, an antiseizure and mood-stabilizing tricyclic drug resembling desipramine which only weakly inhibits neuronal monoamine reuptake. These findings have important clinical implications for drug combination therapy.

  2. Liquid Chromatography-Tandem Mass Spectrometry in Studies of Neurotransmitters and Their Metabolites in the Brain

    OpenAIRE

    Uutela, PÀivi

    2009-01-01

    Neurotransmitters transfer chemically the electrical impulse from one neuron to another in the brain. The concentration of neurotransmitters in many neurological disorders is altered. The measurement of neurotransmitters in the brain is needed to understand how these diseases develop and how they can be treated. Neurotransmitters can be extracted from the brains of freely moving, alert animals by microdialysis technique. The concentration of neurotransmitters and their metabolites in brain mi...

  3. Cochlear Damage Affects Neurotransmitter Chemistry in the Central Auditory System

    Directory of Open Access Journals (Sweden)

    Donald Albert Godfrey

    2014-11-01

    Full Text Available Tinnitus, the perception of a monotonous sound not actually present in the environment, affects nearly 20% of the population of the United States. Although there has been great progress in tinnitus research over the past 25 years, the neurochemical basis of tinnitus is still poorly understood. We review current research about the effects of various types of cochlear damage on the neurotransmitter chemistry in the central auditory system and document evidence that different changes in this chemistry can underlie similar behaviorally measured tinnitus symptoms. Most available data have been obtained from rodents following cochlear damage produced by cochlear ablation, loud sound, or ototoxic drugs. Effects on neurotransmitter systems have been measured as changes in neurotransmitter level, synthesis, release, uptake, and receptors. In this review, magnitudes of changes are presented for neurotransmitter-related amino acids, acetylcholine, and serotonin. A variety of effects have been found in these studies that may be related to animal model, survival time, type of cochlear damage, or methodology. The overall impression from the evidence presented is that any imbalance of neurotransmitter-related chemistry could disrupt auditory processing in such a way as to produce tinnitus.

  4. Correlation between changes of central neurotransmitter expression and stress response in mice A restraint time-course analysis

    Institute of Scientific and Technical Information of China (English)

    Li Bao; Xinsheng Yao; Liang Zhao; Yanqing Lü; Hiroshi Kurihara

    2008-01-01

    BACKGROUND:Changes in central neurotransmitter expression play an important role in stress response and forms the basis for stress-induced psychological and behavior changes.OBJECTIVE:To observe the effects of different restraint stress intervals on brain monoamine neurotransmitter expression,and to investigate the correlation between stress response and neurotransmitter levels.DESIGN:Randomized controlled animal study.SETTING:Chinese Herb and Natural Medicine Institute,Pharmacological College of Jinan University.MATERIALS:Sixty 7-week-old male Kunming mice of clean grade,weighing 18-22 g,were provided by the Guangdong Medical Experimental Animal Center.The experiment was in accordance with animal ethics standards.METHODS:This study was performed at the Chinese Herb and Natural Medicine Institute,Pharmacological College of Jinan University from June 2006 to May 2007.A restraint device for mice was constructed according to published reports.Experimental mice were adaptively fed for 1 week and randomly divided into a control group(n=10)and an experimental group(n=50).The experimental group was sub-divided into five restraint intervals:4,8,12,18,and 24 hours(n=10 mice per time point).Animals in the experimental group were not allowed to eat or drink during the restraint period.Mice in the control group did not undergo restraint,but had identical food and water restrictions.Cerebral cortex and hypothalamus were separated based on observational times and protein was extracted using perchloric acid.Central monoamine neurotransmitter levels were measured using high performance liquid chromatography with electrochemical detection.MAIN OUTCOME MEASURES:Levels of norepinephrine(NE),dopamine hydrochloride(DA),3,4-dihydroxyphen-ylanetic acid (DOPAC),homovanillic acid(HVA),5-hydroxytryptamine(5-HT),and 5-hydroxyindoleac-etic acid(5-HIAA)in the cerebral cortex and hypothalamus of mice.RESULTS:Sixty mice were included in the final analysis.①NE levels in the cerebral

  5. Morphological alterations and acetylcholinesterase and monoamine oxidase inhibition in liver of zebrafish exposed to Aphanizomenon flos-aquae DC-1 aphantoxins.

    Science.gov (United States)

    Zhang, De Lu; Zhang, Jing; Hu, Chun Xiang; Wang, Gao Hong; Li, Dun Hai; Liu, Yong Ding

    2014-12-01

    Aphanizomenon flos-aquae is a cyanobacterium that produces neurotoxins or paralytic shellfish poisons (PSPs) called aphantoxins, which present threats to environmental safety and human health via eutrophication of water bodies worldwide. Although the molecular mechanisms of this neurotoxin have been studied, many questions remain unsolved, including those relating to in vivo hepatic neurotransmitter inactivation, physiological detoxification and histological and ultrastructural alterations. Aphantoxins extracted from the natural strain of A. flos-aquae DC-1 were analyzed by high-performance liquid chromatography. The main components were gonyautoxins 1 and 5 (GTX1, GTX5) and neosaxitoxin (neoSTX), which comprised 34.04%, 21.28%, and 12.77% respectively. Zebrafish (Danio rerio) were exposed intraperitoneally to 5.3 or 7.61 μg STX equivalents (eq)/kg (low and high doses, respectively) of A. flos-aquae DC-1 aphantoxins. Morphological alterations and changes in neurotransmitter conduction functions of acetylcholinesterase (AChE) and monoamine oxidase (MAO) in zebrafish liver were detected at different time points 1-24h post-exposure. Aphantoxin significantly enhanced hepatic alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and histological and ultrastructural damage in zebrafish liver at 3-12 h post-exposure. Toxin exposure increased the reactive oxygen species content and reduced total antioxidative capacity in zebrafish liver, suggesting oxidative stress. AChE and MAO activities were significantly inhibited, suggesting neurotransmitter inactivation/conduction function abnormalities in zebrafish liver. All alterations were dose- and time-dependent. Overall, the results indicate that aphantoxins/PSPs induce oxidative stress through inhibition of AChE and MAO activities, leading to neurotoxicity in zebrafish liver. The above parameters may be useful as bioindicators for investigating aphantoxins/PSPs and cyanobacterial blooms in nature

  6. Affinity of four polar neurotransmitters for lipid bilayer membranes

    DEFF Research Database (Denmark)

    Wang, Chunhua; Ye, Fengbin; Valardez, Gustavo F.

    2011-01-01

    Weak interactions of neurotransmitters and the lipid matrix in the synaptic membrane have been hypothesized to play a role in synaptic transmission of nerve signals, particularly with respect to receptor desensitization (Cantor, R. S. Biochemistry 2003, 42, 11891). The strength of such interactions......, however, was not measured, and this is an obvious impediment for further evaluation and understanding of a possible role for desensitization. We have used dialysis equilibrium to directly measure the net affinity of selected neurotransmitters for lipid membranes and analyzed this affinity data...... with respect to calorimetric measurements and molecular dynamics simulations. We studied an anionic (glutamate), a cationic (acetylcholine), and two zwitterionic (-aminobutyric acid and glycine) neurotransmitters, and membranes of pure dimyristoyl phosphatidylcholine (DMPC), DMPC doped with 10% anionic lipid...

  7. Leukemia Inhibitory Factor Induces Neurotransmitter Switching in Transgenic Mice

    Science.gov (United States)

    Bamber, Bruce A.; Masters, Brian A.; Hoyle, Gary W.; Brinster, Ralph L.; Palmiter, Richard D.

    1994-08-01

    Leukemia inhibitory factor (LIF) is a cytokine growth factor that induces rat sympathetic neurons to switch their neurotransmitter phenotype from noradrenergic to cholinergic in vitro. To test whether LIF can influence neuronal differentiation in vivo, we generated transgenic mice that expressed LIF in pancreatic islets under the control of the insulin promoter and evaluated the neurotransmitter phenotype of the pancreatic sympathetic innervation. We also used the insulin promoter to coexpress nerve growth factor in the islets, which greatly increased the density of sympathetic innervation and facilitated analysis of the effects of LIF. Our data demonstrate that tyrosine hydroxylase and catecholamines declined and choline acetyltransferase increased in response to LIF. We conclude that LIF can induce neurotransmitter switching of sympathetic neurons in vivo.

  8. 2-acetylphenol analogs as potent reversible monoamine oxidase inhibitors

    Directory of Open Access Journals (Sweden)

    Legoabe LJ

    2015-07-01

    Full Text Available Lesetja J Legoabe,1 Anél Petzer,1 Jacobus P Petzer1,21Centre of Excellence for Pharmaceutical Sciences, 2Department of Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South AfricaAbstract: Based on a previous report that substituted 2-acetylphenols may be promising leads for the design of novel monoamine oxidase (MAO inhibitors, a series of C5-substituted 2-acetylphenol analogs (15 and related compounds (two were synthesized and evaluated as inhibitors of human MAO-A and MAO-B. Generally, the study compounds exhibited inhibitory activities against both MAO-A and MAO-B, with selectivity for the B isoform. Among the compounds evaluated, seven compounds exhibited IC50 values <0.01 µM for MAO-B inhibition, with the most selective compound being 17,000-fold selective for MAO-B over the MAO-A isoform. Analyses of the structure–activity relationships for MAO inhibition show that substitution on the C5 position of the 2-acetylphenol moiety is a requirement for MAO-B inhibition, and the benzyloxy substituent is particularly favorable in this regard. This study concludes that C5-substituted 2-acetylphenol analogs are potent and selective MAO-B inhibitors, appropriate for the design of therapies for neurodegenerative disorders such as Parkinson’s disease.Keywords: monoamine oxidase, MAO, inhibition, 2-acetylphenol, structure–activity relationship

  9. Ricardo Miledi and the calcium hypothesis of neurotransmitter release.

    Science.gov (United States)

    Jeng, Jade-Ming

    2002-01-01

    Ricardo Miledi has made significant contributions to our basic understanding of how synapses work. Here I discuss aspects of Miledi's research that helped to establish the requirement of presynaptic calcium for neurotransmitter release, from his earliest scientific studies to his classic experiments in the squid giant synapse.

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

    Science.gov (United States)

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

    2007-12-01

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

  11. Inherited disorders of brain neurotransmitters: pathogenesis and diagnostic approach.

    Science.gov (United States)

    Szymańska, Krystyna; Kuśmierska, Katarzyna; Demkow, Urszula

    2015-01-01

    Neurotransmitters (NTs) play a central role in the efficient communication between neurons necessary for normal functioning of the nervous system. NTs can be divided into two groups: small molecule NTs and larger neuropeptide NTs. Inherited disorders of NTs result from a primary disturbance of NTs metabolism or transport. This group of disorders requires sophisticated diagnostic procedures. In this review we discuss disturbances in the metabolism of tetrahydrobiopterin, biogenic amines, γ-aminobutyric acid, foliate, pyridoxine-dependent enzymes, and also the glycine-dependent encephalopathy. We point to pathologic alterations of proteins involved in synaptic neurotransmission that may cause neurological and psychiatric symptoms. We postulate that synaptic receptors and transporter proteins for neurotransmitters should be investigated in unresolved cases. Patients with inherited neurotransmitters disorders present various clinical presentations such as mental retardation, refractory seizures, pyramidal and extrapyramidal syndromes, impaired locomotor patterns, and progressive encephalopathy. Every patient with suspected inherited neurotransmitter disorder should undergo a structured interview and a careful examination including neurological, biochemical, and imaging.

  12. The Top 5 Neurotransmitters from a Clinical Neurologist's Perspective

    DEFF Research Database (Denmark)

    Kondziella, Daniel

    2017-01-01

    Neurologists are proficient in neuroanatomy and -physiology but their understanding of neurochemistry tends to be mediocre. As a rule, we do not think in biochemical pathways and complex metabolic interactions but rather associate a few neurotransmitters with well-known brain diseases or drugs th...

  13. On-line radiochemical assay for monoamine oxidase utilizing high-performance liquid chromatography

    Energy Technology Data Exchange (ETDEWEB)

    Nissinen, E.; Linko-Loeppoenen SMae; Maennistoe P4

    1984-12-01

    A fast and sensitive assay for the determination of monoamine oxidase activity was developed. The method is based on the separation and quantitation of /sup 14/C-labeled assay products by high-performance liquid chromatography, which is interfaced directly into a flow-through radioactivity detector. This allows on-line quantitation of the radioactive compounds with picomole sensitivity. The method makes possible the complete separation and detection of the deaminated products of monoamine oxidase A and B substrates benzylamine and 5-hydroxytryptamine, respectively. This assay has been applied to the measurement of monoamine oxidase A and B activities in rat brain.

  14. Regulation of neurosteroid biosynthesis by neurotransmitters and neuropeptides

    Directory of Open Access Journals (Sweden)

    Jean-Luc eDo-Rego

    2012-01-01

    Full Text Available The enzymatic pathways leading to the synthesis of bioactive steroids in the brain are now almost completely elucidated in various groups of vertebrates and, during the last decade, the neuronal mechanisms involved in the regulation of neurosteroid production have received increasing attention. This report reviews the current knowledge concerning the effects of neurotransmitters, peptide hormones and neuropeptides on the biosynthesis of neurosteroids. Anatomical studies have been carried out to visualize the neurotransmitter- or neuropeptide-containing fibers contacting steroid-synthesizing neurons as well as the neurotransmitter, peptide hormones or neuropeptide receptors expressed in these neurons. Biochemical experiments have been conducted to investigate the effects of neurotransmitters, peptide hormones or neuropeptides on neurosteroid biosynthesis, and to characterize the type of receptors involved. Thus, it has been found that glutamate, acting through kainate and/or AMPA receptors, rapidly inactivates P450arom, and that melatonin produced by the pineal gland and eye inhibits the biosynthesis of 7-hydroxypregnenolone (7-OH-5P, while prolactin produced by the adenohypophysis enhances the formation of 7-OH-5P. It has also been demonstrated that the biosynthesis of neurosteroids is inhibited by GABA, acting through GABAA receptors, and neuropeptide Y, acting through Y1 receptors. In contrast, it has been shown that the octadecaneuropetide ODN, acting through central-type benzodiazepine receptors, the triakontatetraneuropeptide TTN, acting though peripheral-type benzodiazepine receptors, and vasotocine, acting through V1a-like receptors, stimulate the production of neurosteroids. Since neurosteroids are implicated in the control of various neurophysiological and behavioral processes, these data suggest that some of the neurophysiological effects exerted by neurotransmitters and neuropeptides may be mediated via the regulation

  15. Mechanism of chloride interaction with neurotransmitter:sodium symporters.

    Science.gov (United States)

    Zomot, Elia; Bendahan, Annie; Quick, Matthias; Zhao, Yongfang; Javitch, Jonathan A; Kanner, Baruch I

    2007-10-11

    Neurotransmitter:sodium symporters (NSS) have a critical role in regulating neurotransmission and are targets for psychostimulants, anti-depressants and other drugs. Whereas the non-homologous glutamate transporters mediate chloride conductance, in the eukaryotic NSS chloride is transported together with the neurotransmitter. In contrast, transport by the bacterial NSS family members LeuT, Tyt1 and TnaT is chloride independent. The crystal structure of LeuT reveals an occluded binding pocket containing leucine and two sodium ions, and is highly relevant for the neurotransmitter transporters. However, the precise role of chloride in neurotransmitter transport and the location of its binding site remain elusive. Here we show that introduction of a negatively charged amino acid at or near one of the two putative sodium-binding sites of the GABA (gamma-aminobutyric acid) transporter GAT-1 from rat brain (also called SLC6A1) renders both net flux and exchange of GABA largely chloride independent. In contrast to wild-type GAT-1, a marked stimulation of the rate of net flux, but not of exchange, was observed when the internal pH was lowered. Equivalent mutations introduced in the mouse GABA transporter GAT4 (SLC6A11) and the human dopamine transporter DAT (SLC6A3) also result in chloride-independent transport, whereas the reciprocal mutations in LeuT and Tyt1 render substrate binding and/or uptake by these bacterial NSS chloride dependent. Our data indicate that the negative charge, provided either by chloride or by the transporter itself, is required during binding and translocation of the neurotransmitter, probably to counterbalance the charge of the co-transported sodium ions.

  16. Amphetamines, new psychoactive drugs and the monoamine transporter cycle.

    Science.gov (United States)

    Sitte, Harald H; Freissmuth, Michael

    2015-01-01

    In monoaminergic neurons, the vesicular transporters and the plasma membrane transporters operate in a relay. Amphetamine and its congeners target this relay to elicit their actions: most amphetamines are substrates, which pervert the relay to elicit efflux of monoamines into the synaptic cleft. However, some amphetamines act as transporter inhibitors. Both compound classes elicit profound psychostimulant effects, which render them liable to recreational abuse. Currently, a surge of new psychoactive substances occurs on a global scale. Chemists bypass drug bans by ingenuous structural variations, resulting in a rich pharmacology. A credible transport model must account for their distinct mode of action and link this to subtle differences in activity and undesired, potentially deleterious effects.

  17. Amphetamines, new psychoactive drugs and the monoamine transporter cycle

    Science.gov (United States)

    Sitte, Harald H.; Freissmuth, Michael

    2015-01-01

    In monoaminergic neurons, the vesicular transporters and the plasma membrane transporters operate in a relay. Amphetamine and its congeners target this relay to elicit their actions: most amphetamines are substrates, which pervert the relay to elicit efflux of monoamines into the synaptic cleft. However, some amphetamines act as transporter inhibitors. Both compound classes elicit profound psychostimulant effects, which render them liable to recreational abuse. Currently, a surge of new psychoactive substances occurs on a global scale. Chemists bypass drug bans by ingenuous structural variations, resulting in a rich pharmacology. A credible transport model must account for their distinct mode of action and link this to subtle differences in activity and undesired, potentially deleterious effects. PMID:25542076

  18. Low platelet monoamine oxidase activity in pathological gambling

    Energy Technology Data Exchange (ETDEWEB)

    Carrasco, J.L. [Department of Psychiatry, Centro de Salud Mental, Parla Madrid (Spain); Saiz-Ruiz, J. [Department of Psychiatry and Haematology, Hospital Ramon y Cajal, Madrid (Spain); Hollander, E. [Department of Psychiatry, Mount Sinai School of Medicine, Queens Hospital Center, New York (United States); Cesar, J. [Department of Haematology, Hospital Ramon y Cajal, Madrid (Spain); Lopez-Ibor, J.J. Jr. [Department of Psychiatry, Hospital San Carlos, Complutense University, Madrid (Spain)

    1994-12-01

    Decreased platelet monoamine oxidase (MAO) activity has been reported in association with sensation-seeking personality type and in some mental disorders associated with a lack of impulse control. Pathological gambling itself has been related with both sensation-seeking and reduced impulse control. Platelet MAO activity was investigated in 15 DSM-III-R pathological gamblers from our outpatient clinic. Gamblers had a significantly lower platelet MAO activity than a group of 25 healthy controls. The range of MAO levels in gamblers was also significantly shorter than in controls. In controls, platelet MAO levels showed the previously described negative correlations with sensation-seeking scores but not in gamblers. The findings are consistent with previous studies showing an association of low platelet MAO activity with impulse control disorders and raise some interesting therapeutic alternatives for pathological gambling. (au) (40 refs.).

  19. Bepaling van enkele neurotransmitters, monoaminen, en metabolieten, met behulp van Continuous Flowapparatuur

    NARCIS (Netherlands)

    Eigeman L; Schonewille F; Borst M; van der Laan JW

    1986-01-01

    Bij het onderzoek in de psychofarmacologie kan kennis van de effecten van stoffen op de omzettingssnelheid van neurotransmitters een belangrijk aspect zijn. Met de huidige psychofarmaca lijken vooral de klassieke neurotransmitters zoals de monoaminen, noradrenaline, dopamine en serotonine van

  20. An Interface for Sensitive Analysis of Monoamine Neurotransmitters by Ion-Pair Chromatography–ESI-MS with Continuous On-Line Elimination of Ion-Pair Reagents

    OpenAIRE

    Shi,Shuyun; Zhao, Binqing; Yagnik, Gargey; Zhou, Feimeng

    2013-01-01

    A challenge in coupling ion-pair chromatography (IPC) on-line with electrospray ionization-mass spectrometry (ESI-MS) is that the nonvolatile ion-pair reagent (e.g., alkyl sulfate for amines or tetrabutylammonium for carboxylic acids) in the mobile phase suppresses the ESI-MS signals in the gas phase and their accumulation can clog the MS sampling interface. Consequently, IPC–ESI-MS is conducted either with a volatile ion-pair reagent, which could compromise the analyte separation efficiency,...

  1. Effect of Dimethoate on serum monoamines neurotransmitter in rats%乐果对大鼠血清单胺类递质的影响

    Institute of Scientific and Technical Information of China (English)

    阮国洪; 吴强恩; 顾平; 郑力行; 顾锡安; 周志俊

    2006-01-01

    目的 观察乐果染毒对大鼠血清单胺类递质去甲肾上腺素(NE)、肾上腺素(E)、5-羟色胺(5-HT)、多巴胺(DA)及其代谢物3,4-二羟苯乙酸(DOPAC)浓度变化的影响,探讨乐果中毒的非胆碱能机制.方法 雄性SD大鼠104只随机分为对照组(生理盐水)、乐果低(38.9mg/kg)、中(83.7mg/kg)、高(180.0mg/kg)3个剂量组,一次性腹腔注射染毒,给药后0.5、2、8、24 h断头处死并分离血清,用高效液相色谱电化学检测法检测血清中NE、E、5-HT、DA及其代谢物DOPAC的浓度.结果 不同时程的染毒组(低、中、高剂量组)血清中DA及其代谢物DOPAC和5-HT的浓度比对照组分别增加8.42%~248.42%、17.22%~68.21%.不同时程的染毒组血清NE和E的浓度比对照组分别减少9.65%~38.26%和11.00%~32.62%.5-HT浓度开始随染毒剂量增加而减少,但随染毒时程的增加,则随染毒剂量增加而增加.DA、DOPAC、NE、E和5-HT的浓度在不同时程的低、中、高剂量组间差异均有统计学意义(P<0.05).结论 DA、DOPAC和5-HT浓度有随染毒剂量和时程的增加而增加的趋势,NE和E浓度有随染毒剂量和时程的增加而减少的趋势,存在剂量时程效应关系.

  2. The use of multiscale molecular simulations in understanding a relationship between the structure and function of biological systems of the brain: the application to monoamine oxidase enzymes

    Directory of Open Access Journals (Sweden)

    Robert Vianello

    2016-07-01

    Full Text Available Aging society and therewith associated neurodegenerative and neuropsychiatric diseases, including depression, Alzheimer’s disease, obsessive disorders, and Parkinson’s disease, urgently require novel drug candidates. Targets include monoamine oxidases A and B (MAOs, acetylcholinesterase (AChE and butyrylcholinesterase (BChE, and various receptors and transporters. For rational drug design it is particularly important to combine experimental synthetic, kinetic, toxicological and pharmacological information with structural and computational work. This paper describes the application of various modern computational biochemistry methods in order to improve the understanding of a relationship between the structure and function of large biological systems including ion channels, transporters, receptors and metabolic enzymes. The methods covered stem from classical molecular dynamics simulations to understand the physical basis and the time evolution of the structures, to combined QM and QM/MM approaches to probe the chemical mechanisms of enzymatic activities and their inhibition. As an illustrative example, the later will focus on the monoamine oxidase family of enzymes, which catalyze the degradation of amine neurotransmitters in various parts of the brain, the imbalance of which is associated with the development and progression of a range of neurodegenerative disorders. Inhibitors that act mainly on MAO A are used in the treatment of depression, due to their ability to raise serotonin concentrations, while MAO B inhibitors decrease dopamine degradation and improve motor control in patients with Parkinson disease. Our results give strong support that both MAO isoforms, A and B, operate through the hydride transfer mechanism. Relevance of MAO catalyzed reactions and MAO inhibition in the context of neurodegeneration will be discussed.

  3. The use of LeuT as a model in elucidating binding sites for substrates and inhibitors in neurotransmitter transporters

    DEFF Research Database (Denmark)

    Løland, Claus Juul

    2015-01-01

    Background: The mammalian neurotransmitter transporters are complex proteins playing a central role in synaptic transmission between neurons by rapid reuptake of neurotransmitters. The proteins which transport dopamine, noradrenaline and serotonin belong to the Neurotransmitter:Sodium Symporters...

  4. Morphological alterations and acetylcholinesterase and monoamine oxidase inhibition in liver of zebrafish exposed to Aphanizomenon flos-aquae DC-1 aphantoxins

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, De Lu, E-mail: deluzh@163.com [Department of Lifescience and Biotechnology, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan 430070 (China); Zhang, Jing [College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072 (China); Hu, Chun Xiang, E-mail: cxhu@ihb.ac.cn [Key Laboratory of Algal Biology, Institute of Hydrobiology, The Chinese Academy of Sciences, Wuhan 430072 (China); Wang, Gao Hong; Li, Dun Hai; Liu, Yong Ding [Key Laboratory of Algal Biology, Institute of Hydrobiology, The Chinese Academy of Sciences, Wuhan 430072 (China)

    2014-12-15

    Highlights: • Aphantoxins induced zebrafish hepatic physiological and morphological changes. • AChE and MAO inhibition reflected abnormality of neurotransmitter inactivation. • ROS advance and T-AOC reduction suggested oxidative stress. • ALT, AST, histological and ultrastructural alterations indicated hepatic damage. - Abstract: Aphanizomenon flos-aquae is a cyanobacterium that produces neurotoxins or paralytic shellfish poisons (PSPs) called aphantoxins, which present threats to environmental safety and human health via eutrophication of water bodies worldwide. Although the molecular mechanisms of this neurotoxin have been studied, many questions remain unsolved, including those relating to in vivo hepatic neurotransmitter inactivation, physiological detoxification and histological and ultrastructural alterations. Aphantoxins extracted from the natural strain of A. flos-aquae DC-1 were analyzed by high-performance liquid chromatography. The main components were gonyautoxins 1 and 5 (GTX1, GTX5) and neosaxitoxin (neoSTX), which comprised 34.04%, 21.28%, and 12.77% respectively. Zebrafish (Danio rerio) were exposed intraperitoneally to 5.3 or 7.61 μg STX equivalents (eq)/kg (low and high doses, respectively) of A. flos-aquae DC-1 aphantoxins. Morphological alterations and changes in neurotransmitter conduction functions of acetylcholinesterase (AChE) and monoamine oxidase (MAO) in zebrafish liver were detected at different time points 1–24 h post-exposure. Aphantoxin significantly enhanced hepatic alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and histological and ultrastructural damage in zebrafish liver at 3–12 h post-exposure. Toxin exposure increased the reactive oxygen species content and reduced total antioxidative capacity in zebrafish liver, suggesting oxidative stress. AChE and MAO activities were significantly inhibited, suggesting neurotransmitter inactivation/conduction function abnormalities in zebrafish

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

    Science.gov (United States)

    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

  6. Determining the neurotransmitter concentration profile at active synapses.

    Science.gov (United States)

    Scimemi, Annalisa; Beato, Marco

    2009-12-01

    Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission.

  7. The Use of Multiscale Molecular Simulations in Understanding a Relationship between the Structure and Function of Biological Systems of the Brain: The Application to Monoamine Oxidase Enzymes.

    Science.gov (United States)

    Vianello, Robert; Domene, Carmen; Mavri, Janez

    2016-01-01

    activities and their inhibition. As an illustrative example, the later will focus on the monoamine oxidase family of enzymes, which catalyze the degradation of amine neurotransmitters in various parts of the brain, the imbalance of which is associated with the development and progression of a range of neurodegenerative disorders. Inhibitors that act mainly on MAO A are used in the treatment of depression, due to their ability to raise serotonin concentrations, while MAO B inhibitors decrease dopamine degradation and improve motor control in patients with Parkinson disease. Our results give strong support that both MAO isoforms, A and B, operate through the hydride transfer mechanism. Relevance of MAO catalyzed reactions and MAO inhibition in the context of neurodegeneration will be discussed.

  8. Appearance and distribution of peptidergic neurotransmitters in hippocampal primary culture

    OpenAIRE

    Thiele, Theodor

    2012-01-01

    The internal structure of the hippocampus, especially the development of neuronal circuits, is the subject of current research. The hippocampal primary culture represents a suitable model to study neuronal development and the impact of isolated stimuli and noxious. Focus of the following considerations are the neurons of the hippocampus, especially the peptidergic neurotransmitters somatostatin (SS), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP) and cholecystokinin (CCK). By us...

  9. Application of PEDOT-CNT Microelectrodes for Neurotransmitter Sensing

    OpenAIRE

    Samba, Ramona; Fuchsberber, Kai; Matiychyn, Ilona; Epple, Sebastian; Kiesel, Lydia; Stett, Alfred; Schuhmann, Wolfgang; Stelzle, Martin

    2016-01-01

    In this work, composite microelectrodes from poly(3,4-ethylenedioxythiophene) (PEDOT) and carbon nanotubes (CNT) are characterized as electrochemical sensing material for neurotransmitters. Dopamine can be detected using square wave voltammetry at these microelectrodes. The CNTs improve the sensitivity by a factor of two. In addition, the selectivity towards dopamine in the presence of ascorbic acid and uric acid was examined. While both electrodes, PEDOT and PEDOT-CNT are able to detect all ...

  10. Terahertz identification and quantification of neurotransmitter and neurotrophy mixture

    OpenAIRE

    Peng, Yan; Yuan, Xiaorong; Zou, Xiang; Chen, Wanqing; Huang, Hui; Zhao, Hongwei; Song, Bo; Chen, Liang; Zhu, Yiming

    2016-01-01

    Terahertz spectroscopy has been widely used for investigating the fingerprint spectrum of different substances. For cancerous tissues, the greatest difficulty is the absorption peaks of various substances contained in tissues overlap with each other, which are hard to identify and quantitative analyze. As a result, it is very hard to measure the presence of cancer cell and then to diagnose accurately. In this paper, we select three typical neurotransmitters (γ-aminobutyric acid, L-glutamic ac...

  11. Role of antioxidants in the protection of the nitrergic neurotransmitter.

    Science.gov (United States)

    Colpaert, Erwin E; Lefebvre, Romain A

    2002-06-01

    There is now compelling evidence that the L-arginine/nitric oxide (NO) pathway generates the non-adrenergic non-cholinergic (NANC) neurotransmitter which mediates smooth muscle relaxation in a variety of nitrergically-innervated tissues. However, one strange aspect of this nitrergic neurotransmission process is that certain drugs (i.e. superoxide generators and NO-scavengers) powerfully inhibit relaxations to exogenous NO, but have little or no effect on relaxations to electrical field stimulation. This thesis examined the possibility that in the nitrergically-innervated gastric fundus of the pig tissue antioxidants present in the neuroeffector junction might protect the endogenous nitrergic neurotransmitter (free radical NO) from attack by superoxide anions and scavenging activity, while exogenous NO would still be vulnerable before it reaches the nitrergic synapses within the tissue. We found that several antioxidants (in casu Cu/Zn superoxide dismutase, reduced glutathione, bilirubin) exerted a partial or complete protection of the relaxation induced by exogenous NO against the differentiating drugs under investigation. A close interrelationship between the endogenous nitrergic neurotransmitter and the antioxidants Cu/Zn superoxide dismutase and bilirubin (produced by the heme oxygenase/biliverdin reductase system) was corroborated by immunohistochemical data showing the presence of these latter defense systems in all nitrergic neurons. Pharmacological depletion further established a role for Cu/Zn superoxide dismutase in peripheral nitrergic neurotransmission. For glutathione, only a partial depletion could be obtained and this did not influence nitrergic neurotransmission.

  12. Profiling neurotransmitter receptor expression in the Ambystoma mexicanum brain.

    Science.gov (United States)

    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.

  13. Electrochemical techniques for subsecond neurotransmitter detection in live rodents.

    Science.gov (United States)

    Hascup, Kevin N; Hascup, Erin R

    2014-08-01

    Alterations in neurotransmission have been implicated in numerous neurodegenerative and neuropsychiatric disorders, including Alzheimer disease, Parkinson disease, epilepsy, and schizophrenia. Unfortunately, few techniques support the measurement of real-time changes in neurotransmitter levels over multiple days, as is essential for ethologic and pharmacodynamic testing. Microdialysis is commonly used for these research paradigms, but its poor temporal and spatial resolution make this technique inadequate for measuring the rapid dynamics (milliseconds to seconds) of fast signaling neurotransmitters, such as glutamate and acetylcholine. Enzymatic microelectrode arrays (biosensors) coupled with electrochemical recording techniques have demonstrated fast temporal resolution (less than 1 s), excellent spatial resolution (micron-scale), low detection limits (≤200 nM), and minimal damage (50 to 100 μm) to surrounding brain tissue. Here we discuss the benefits, methods, and animal welfare considerations of using platinum microelectrodes on a ceramic substrate for enzyme-based electrochemical recording techniques for real-time in vivo neurotransmitter recordings in both anesthetized and awake, freely moving rodents.

  14. Neurotransmitter receptor-mediated signaling pathways as modulators of carcinogenesis.

    Science.gov (United States)

    Schuller, Hildegard M

    2007-01-01

    The autonomic nervous system with its two antagonistic branches, the sympathicus and the parasympathicus, regulates the activities of all body functions that are not under voluntary control. While the autonomic regulation of organ functions has been extensively studied, little attention has been given to the potential role of neurohumoral transmission at the cellular level in the development of cancer. Studies conducted by our laboratory first showed that binding of the parasympathetic neurotransmitter, acetylcholine, as well as nicotine or its nitrosated cancer-causing derivative, NNK, to nicotinic acetylcholine receptors comprised of alpha7 subunits activated a mitogenic signal transduction pathway in normal and neoplastic pulmonary neuroendocrine cells. On the other hand, beta-adrenergic receptors (Beta-ARs), which transmit signals initiated by binding of the catecholamine neurotransmitters of the sympathicus, were identified by our laboratory as important regulators of cell proliferation in cell lines derived from human adenocarcinomas of the lungs, pancreas, and breast. The tobacco-specific carcinogen NNK bound with high affinity to Beta1- and Beta2-ARs, thus activating cAMP, protein kinase A, and the transcription factor CREB. Collectively, neurotransmitter receptors of the nicotinic and Beta-adrenergic families appear to regulate cellular functions essential for the development and survival of the most common human cancers.

  15. Neurotransmitters act as paracrine signals to regulate insulin secretion from the human pancreatic islet.

    Science.gov (United States)

    Rodriguez-Diaz, Rayner; Menegaz, Danusa; Caicedo, Alejandro

    2014-08-15

    In this symposium review we discuss the role of neurotransmitters as paracrine signals that regulate pancreatic islet function. A large number of neurotransmitters and their receptors has been identified in the islet, but relatively little is known about their involvement in islet biology. Interestingly, neurotransmitters initially thought to be present in autonomic axons innervating the islet are also present in endocrine cells of the human islet. These neurotransmitters can thus be released as paracrine signals to help control hormone release. Here we propose that the role of neurotransmitters may extend beyond controlling endocrine cell function to work as signals modulating vascular flow and immune responses within the islet.

  16. How LeuT shapes our understanding of the mechanisms of sodium-coupled neurotransmitter transporters.

    Science.gov (United States)

    Penmatsa, Aravind; Gouaux, Eric

    2014-03-01

    Neurotransmitter transporters are ion-coupled symporters that drive the uptake of neurotransmitters from neural synapses. In the past decade, the structure of a bacterial amino acid transporter, leucine transporter (LeuT), has given valuable insights into the understanding of architecture and mechanism of mammalian neurotransmitter transporters. Different conformations of LeuT, including a substrate-free state, inward-open state, and competitive and non-competitive inhibitor-bound states, have revealed a mechanistic framework for the transport and transport inhibition of neurotransmitters. The current review integrates our understanding of the mechanistic and pharmacological properties of eukaryotic neurotransmitter transporters obtained through structural snapshots of LeuT.

  17. Marine omega-3 polyunsaturated fatty acids induce sex-specific changes in reinforcer-controlled behaviour and neurotransmitter metabolism in a spontaneously hypertensive rat model of ADHD

    Directory of Open Access Journals (Sweden)

    Dervola Kine S

    2012-12-01

    Full Text Available Abstract Background Previous reports suggest that omega-3 (n-3 polyunsaturated fatty acids (PUFA supplements may reduce ADHD-like behaviour. Our aim was to investigate potential effects of n-3 PUFA supplementation in an animal model of ADHD. Methods We used spontaneously hypertensive rats (SHR. SHR dams were given n-3 PUFA (EPA and DHA-enriched feed (n-6/n-3 of 1:2.7 during pregnancy, with their offspring continuing on this diet until sacrificed. The SHR controls and Wistar Kyoto (WKY control rats were given control-feed (n-6/n-3 of 7:1. During postnatal days (PND 25–50, offspring were tested for reinforcement-dependent attention, impulsivity and hyperactivity as well as spontaneous locomotion. The animals were then sacrificed at PND 55–60 and their neostriata were analysed for monoamine and amino acid neurotransmitters with high performance liquid chromatography. Results n-3 PUFA supplementation significantly enhanced reinforcement-controlled attention and reduced lever-directed hyperactivity and impulsiveness in SHR males whereas the opposite or no effects were observed in females. Analysis of neostriata from the same animals showed significantly enhanced dopamine and serotonin turnover ratios in the male SHRs, whereas female SHRs showed no change, except for an intermediate increase in serotonin catabolism. In contrast, both male and female SHRs showed n-3 PUFA-induced reduction in non-reinforced spontaneous locomotion, and sex-independent changes in glycine levels and glutamate turnover. Conclusions Feeding n-3 PUFAs to the ADHD model rats induced sex-specific changes in reinforcement-motivated behaviour and a sex-independent change in non-reinforcement-associated behaviour, which correlated with changes in presynaptic striatal monoamine and amino acid signalling, respectively. Thus, dietary n-3 PUFAs may partly ameliorate ADHD-like behaviour by reinforcement-induced mechanisms in males and partly via reinforcement-insensitive mechanisms

  18. Selected chromone derivatives as inhibitors of monoamine oxidase.

    Science.gov (United States)

    Legoabe, Lesetja J; Petzer, Anél; Petzer, Jacobus P

    2012-09-01

    A previous study has shown that a series of C6-benzyloxy substituted chromones exhibit high binding affinities for human monoamine oxidase (MAO) B. In an attempt to discover additional chromones with potent and selective MAO-B inhibitory potencies and to further examine the structure-activity relationships of MAO-B inhibition by chromones, the series was expanded with homologues containing polar functional groups on C3 of the chromone ring. The results demonstrate that 6-[(3-bromobenzyl)oxy]chromones containing acidic and aldehydic functional groups on C3 act as potent reversible MAO-B inhibitors with IC(50) values of 2.8 and 3.7 nM, respectively. Interestingly, a 2-hydroxy-2,3-dihydro-1-benzopyran-4-one derivative as well as open-ring 2-acetylphenol analogues of the chromones also were potent MAO-B inhibitors with IC(50) values ranging from 4 to 11 nM. Chromone derivatives containing the benzyloxy substituent on C5 of the chromone ring, however, exhibit MAO-B inhibition potencies that are several orders of magnitude weaker. High potency inhibitors of MAO-B may find application in the therapy of neurodegenerative disorders such as Parkinson's disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Selected C7-substituted chromone derivatives as monoamine oxidase inhibitors.

    Science.gov (United States)

    Legoabe, Lesetja J; Petzer, Anél; Petzer, Jacobus P

    2012-12-01

    A series of C7-substituted chromone (1-benzopyran-4-one) derivatives were synthesized and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. The chromones are structurally related to a series of C7-functionalized coumarin (1-benzopyran-2-one) derivatives which has been reported to act as potent MAO inhibitors. The results of the current study document that the chromones are highly potent reversible inhibitors of MAO-B with IC(50) values ranging from 0.008 to 0.370 μM. While the chromone derivatives also exhibit affinities for MAO-A, with IC(50) values ranging from 0.495 to 8.03 μM, they are selective for the MAO-B isoform. Structure-activity relationships (SAR) show that 7-benzyloxy substitution of chromone is suitable for MAO-B inhibition with tolerance for a variety of substituents and substitution patterns on the benzyloxy ring. It may be concluded that 7-benzyloxychromones are appropriate lead compounds for the design of reversible and selective MAO-B inhibitors. With the aid of modeling studies, potential binding orientations and interactions of selected chromone derivatives in the MAO-A and -B active sites are examined. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. The effects of two chronic intermittent stressors on brain monoamines.

    Science.gov (United States)

    Campmany, L; Pol, O; Armario, A

    1996-03-01

    The effects of chronic exposure (27 days) to two different stressors on brain monoaminergic activity was studied in adult male rats. The stressors used were restraint in tubes (RES) and immobilization in wooden boards (IMO). Both chronically stressed and stress naive (control) rats were subjected to 0, 15, and 60 min of the same stressor to which they were chronically exposed. Previous chronic exposure to either RES or IMO significantly reduced ACTH response to the same stressor. Monoaminergic response to these stressors was studied by measuring the levels of noradrenaline (NA), serotonin (5-HT) and their metabolites: 3-methoxy,4-hydroxyphenyletileneglycol sulfate (MHPG-SO4) and 5-hydroxyindoleacetic acid (5-HIAA), respectively. The regions studied were: pons plus medulla, midbrain, hypothalamus, hippocampus, and frontal cortex. Previous chronic exposure to the stressors induced only few changes in the resting levels of the monoamines and their metabolites. In addition, monoaminergic response to the same stressor to which they were chronically exposed was always similar in control and chronically stressed rats. These data indicate that brain NA and 5-HT metabolism is less sensitive than ACTH to the process of habituation to a repeated stressor, at least in the gross areas of the brain analyzed in the present study.

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

    Science.gov (United States)

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

    2011-06-01

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

  2. Glucagon-related peptide 1 (GLP-1): hormone and neurotransmitter

    DEFF Research Database (Denmark)

    Larsen, Philip J; Holst, Jens Juul

    2005-01-01

    The interest in glucagon-like petide-1 (GLP-1) and other pre-proglucagon derived peptides has risen almost exponentially since seminal papers in the early 1990s proposed to use GLP-1 agonists as therapeutic agents for treatment of type 2 diabetes. A wealth of interesting studies covering both...... normal and pathophysiological role of GLP-1 have been published over the last two decades and our understanding of GLP-1 action has widened considerably. In the present review, we have tried to cover our current understanding of GLP-1 actions both as a peripheral hormone and as a central neurotransmitter...

  3. Name that neurotransmitter: using music to teach psychopharmacology concepts.

    Science.gov (United States)

    Hermanns, Melinda; Lilly, Mary LuAnne; Wilson, Kathy; Russell, Nathan Andrew

    2012-09-01

    The purpose of this article is to discuss the use of music (i.e., two original songs, "Neurotransmitter Twitter" and "Parkinson's Shuffle") to teach aspects of psychopharmacology to students in the course Psychiatric/Mental Health Nursing. Songs were incorporated in both the clinical and classroom settings. This innovative teaching method allowed students the opportunity to revisit the information through multiple exposures of the content for reinforcement and enhancement of student learning in a fun, creative approach. Brain-based research will be discussed, along with the process of development.

  4. Calcium-sensitive regulation of monoamine oxidase-A contributes to the production of peroxyradicals in hippocampal cultures: implications for Alzheimer disease-related pathology

    Directory of Open Access Journals (Sweden)

    Li XinMin

    2007-09-01

    Full Text Available Abstract Background Calcium (Ca2+ has recently been shown to selectively increase the activity of monoamine oxidase-A (MAO-A, a mitochondria-bound enzyme that generates peroxyradicals as a natural by-product of the deamination of neurotransmitters such as serotonin. It has also been suggested that increased intracellular free Ca2+ levels as well as MAO-A may be contributing to the oxidative stress associated with Alzheimer disease (AD. Results Incubation with Ca2+ selectively increases MAO-A enzymatic activity in protein extracts from mouse hippocampal HT-22 cell cultures. Treatment of HT-22 cultures with the Ca2+ ionophore A23187 also increases MAO-A activity, whereas overexpression of calbindin-D28K (CB-28K, a Ca2+-binding protein in brain that is greatly reduced in AD, decreases MAO-A activity. The effects of A23187 and CB-28K are both independent of any change in MAO-A protein or gene expression. The toxicity (via production of peroxyradicals and/or chromatin condensation associated with either A23187 or the AD-related β-amyloid peptide, which also increases free intracellular Ca2+, is attenuated by MAO-A inhibition in HT-22 cells as well as in primary hippocampal cultures. Conclusion These data suggest that increases in intracellular Ca2+ availability could contribute to a MAO-A-mediated mechanism with a role in AD-related oxidative stress.

  5. Effects of ferulic acid on oxidative stress, heat shock protein 70, connexin 43, and monoamines in the hippocampus of pentylenetetrazole-kindled rats.

    Science.gov (United States)

    Hussein, Abdelaziz M; Abbas, Khaled M; Abulseoud, Osama A; El-Hussainy, El-Hussainy M A

    2017-06-01

    The present study investigated the effects of ferulic acid (FA) on pentylenetetrazole (PTZ)-induced seizures, oxidative stress markers (malondialdehyde (MDA), catalase, and reduced glutathione (GSH)), connexin (Cx) 43, heat shock protein 70 (Hsp 70), and monoamines (serotonin (5-HT) and norepinephrine (NE)) levels in a rat model of PTZ-induced kindling. Sixty Sprague Dawley rats were divided into 5 equal groups: (a) normal group; (b) FA group: normal rats received FA at a dose of 40 mg/kg daily; (c) PTZ group: normal rats received PTZ at a dose of 50 mg/kg i.p. on alternate days for 15 days; (d) FA-before group: treatment was the same as for the PTZ group, except rats received FA; and (e) FA-after group: rats received FA from sixth dose of PTZ. PTZ caused a significant increase in MDA, Cx43, and Hsp70 along with a significant decrease in GSH, 5-HT, and NE levels and CAT activity in the hippocampus (p < 0.05). Pre- and post-treatment with FA caused significant improvement in behavioral parameters, MDA, CAT, GSH, 5-HT, NE, Cx43 expression, and Hsp70 expression in the hippocampal region (p < 0.05). We conclude that FA has neuroprotective effects in PTZ-induced epilepsy, which might be due to attenuation of oxidative stress and Cx43 expression and upregulation of neuroprotective Hsp70 and neurotransmitters (5-HT and NE).

  6. Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation

    Directory of Open Access Journals (Sweden)

    Kevin D Lominac

    2014-05-01

    Full Text Available Methamphetamine (MA is a highly addictive psychomotor stimulant, with life-time prevalence rates of abuse ranging from 5-10% world-wide. Yet, a paucity of research exists regarding MA addiction vulnerability/resiliency and neurobiological mediators of the transition to addiction that might occur upon repeated low-dose MA exposure, more characteristic of early drug use. As stimulant-elicited neuroplasticity within dopamine neurons innervating the nucleus accumbens (NAC and prefrontal cortex (PFC is theorized as central for addiction-related behavioral anomalies, we used a multi-disciplinary research approach in mice to examine the interactions between sub-toxic MA dosing, motivation for MA and mesocorticolimbic monoamines. Biochemical studies of C57BL/6J (B6 mice revealed short- (1 day, as well as longer-term (21 days, changes in extracellular dopamine, DAT and/or D2 receptors during withdrawal from 10, once daily, 2 mg/kg MA injections. Follow-up biochemical studies conducted in mice selectively bred for high versus low MA drinking (respectively, MAHDR vs. MALDR mice, provided novel support for anomalies in mesocorticolimbic dopamine as a correlate of genetic vulnerability to high MA intake. Finally, neuropharmacological targeting of NAC dopamine in MA-treated B6 mice demonstrated a bi-directional regulation of MA-induced place-conditioning. These results extend extant literature for MA neurotoxicity by demonstrating that even subchronic exposure to relatively low MA doses are sufficient to elicit relatively long-lasting changes in mesocorticolimbic dopamine and that drug-induced or idiopathic anomalies in mesocorticolimbic dopamine may underpin vulnerability/resiliency to MA addiction.

  7. 3-Coumaranone derivatives as inhibitors of monoamine oxidase

    Directory of Open Access Journals (Sweden)

    Van Dyk AS

    2015-10-01

    Full Text Available Adriaan S Van Dyk,1,2 Jacobus P Petzer,1,2 Anél Petzer,1 Lesetja J Legoabe1 1Centre of Excellence for Pharmaceutical Sciences, 2Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South Africa Abstract: The present study examines the monoamine oxidase (MAO inhibitory properties of a series of 20 3-coumaranone [benzofuran-3(2H-one] derivatives. The 3-coumaranone derivatives are structurally related to series of α-tetralone and 1-indanone derivatives, which have recently been shown to potently inhibit MAO, with selectivity for MAO-B (in preference to the MAO-A isoform. 3-Coumaranones are similarly found to selectively inhibit human MAO-B with half-maximal inhibitory concentration (IC50 values of 0.004–1.05 µM. Nine compounds exhibited IC50<0.05 µM for the inhibition of MAO-B. For the inhibition of human MAO-A, IC50 values ranged from 0.586 to >100 µM, with only one compound possessing an IC50<1 µM. For selected 3-coumaranone derivatives, it is established that MAO-A and MAO-B inhibition are reversible since dialysis of enzyme–inhibitor mixtures almost completely restores enzyme activity. On the basis of the selectivity profiles and potent action, it may be concluded that the 3-coumaranone derivatives are suitable leads for the development of selective MAO-B inhibitors as potential treatment for disorders such as Parkinson’s disease and Alzheimer’s disease. Keywords: benzofuran-3(2H-one, MAO, inhibition, reversible, competitive, Parkinson’s disease 

  8. The inhibition of monoamine oxidase by phenformin and pentamidine.

    Science.gov (United States)

    Barkhuizen, M; Petzer, A; Petzer, J P

    2014-09-01

    A computational study has suggested that phenformin, an oral hypoglycaemic drug, may bind to the active sites of the monoamine oxidase (MAO) A and B enzymes. The present study therefore investigates the MAO inhibitory properties of phenformin. Pentamidine, a structurally related diamidine compound, has previously been reported to be a MAO inhibitor and was included in this study as a reference compound. Using recombinant human MAO-A and MAO-B, this study finds that phenformin acts as a moderately potent MAO-A selective inhibitor with an IC50 value of 41 µM. Pentamidine, on the other hand, potently inhibits both MAO-A and MAO-B with IC50 values of 0.61 μM and 0.22 μM, respectively. An examination of the recoveries of the enzymatic activities after dilution and dialysis of the enzyme-inhibitor complexes shows that both compounds interact reversibly with the MAO enzymes. A kinetic analysis suggests that pentamidine acts as a competitive inhibitor with estimated Ki values of 0.41 μM and 0.22 μM for the inhibition of MAO-A and MAO-B, respectively. Phenformin also exhibited a competitive mode of MAO-A inhibition with an estimated Ki value of 65 µM. This study concludes that biguanide and amidine functional groups are most likely important structural features for the inhibition of the MAOs by phenformin and pentamidine, and compounds containing these and closely related functional groups should be considered as potential MAO inhibitors. Furthermore, the biguanide and amidine functional groups may act as useful moieties in the future design of MAO inhibitors.

  9. A survey of prescribing practices for monoamine oxidase inhibitors.

    Science.gov (United States)

    Balon, R; Mufti, R; Arfken, C L

    1999-07-01

    A survey examined prescribing practices for monoamine oxidase inhibitors (MAOIs) and explored reasons for the widely noted decline in their use. A one-page questionnaire was sent in 1997 to 1,129 members of the Michigan Psychiatric Association. A total of 717 responses were received, for a response rate of 64 percent. Only data from the 573 psychiatrists who were currently practicing were used. Twelve percent of the respondents never prescribed MAOIs, 27 percent had not prescribed them for at least three years, and 17 percent had prescribed them from one to three years ago. Thirty percent of the respondents had prescribed an MAOI within the past three months, and 14 percent between three and 12 months ago. The most frequent reasons for not prescribing the drugs were side effects and interactions with other medications (46 percent), preference for other medications (30 percent), and dietary restrictions necessary for patients taking MAOIs (19 percent). Ninety-two percent of respondents believed that MAOIs were useful for atypical depression, 64 percent for major depression, 54 percent for melancholic depression, 56 percent for panic disorder, 44 percent for social phobia, 27 percent for dysthymia, 12 percent for obsessive-compulsive disorder, and 19 percent for posttraumatic stress disorder. However, only 2 percent said they would use MAOIs as their first-line treatment in atypical depression, and only 3 percent would use them a first-line treatment in social phobia. The results document the commonly held view that practicing psychiatrists believe MAOIs are efficacious but use them infrequently, primarily due to concerns about side effects and drug interactions.

  10. Prenatal exposure to integerrimine N-oxide enriched butanolic residue from Senecio brasiliensis affects behavior and striatal neurotransmitter levels of rats in adulthood.

    Science.gov (United States)

    Sandini, Thaísa M; Udo, Mariana S B; Reis-Silva, Thiago M; Sanches, Daniel; Bernardi, Maria Martha; Flório, Jorge Camilo; Spinosa, Helenice de S

    2015-12-01

    Pyrrolizidine alkaloids (PAs) are toxins that are exclusively biosynthesized by plants and are commonly present in foods and herbs. PAs are usually associated with poisoning events in livestock and human beings. The aim of the present study was to evaluate the behavioral and neurochemical effects of prenatal exposure to PA integerrimine N-oxide of rats in adulthood. Pregnant Wistar rats received integerrimine N-oxide from the butanolic residue of Senecio brasiliensis by gavage on gestational days 6-20 at doses of 3, 6 and 9 mg/kg. During adulthood of the offspring, the following behavioral tests were performed: open-field, plus-maze, forced swimming, catalepsy and stereotypy. Histological analyses and monoamine levels were measured. Male offspring from dams that were exposed to 9 mg/kg showed an increase in locomotion in the open-field test, an increased frequency of entries and time spent in open arms in elevated plus-maze test, as well as decreased swimming time. In the female offspring from dams that were exposed to 9 mg/kg, there was an increased time of climbing in forced swimming and intensity of stereotyped behavior. The histological study indicates an increase in the number of multinucleated cells in the liver (6 and 9 mg/kg). In neurotransmitter analysis, specifically in the striatum, we observed change in dopamine and serotonin levels in the middle dose. Thus, our results indicate that prenatal exposure to integerrimine N-oxide changed behavior in adulthood and neurotransmitter levels in the striatum. Our results agree with previous studies, which showed that integerrimine N-oxide impaired physical and neurobehavioral development in childhood that can persist until adulthood. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. [Mechanisms of neurotransmitter release facilitation in strontium solutions].

    Science.gov (United States)

    Mukhamed'iarov, M A; Kochunova, Iu O; Telina, E N; Zefirov, A L

    2008-02-01

    Mechanisms of neurotransmitter release facilitation were studied using electrophysiological recording of end-plate currents (EPC) and nerve ending (NE) responses after substitution of extracellular Ca ions with Sr ions at the frog neuromuscular junction. The solutions with 0.5 mM concentration of Ca ions (calcium solution) or 1 mM concentration of Sr ions (strontium solution) were used where baseline neurotransmitter release (at low-frequency stimulation) is equal. Decay of paired-pulse facilitation of EPC at calcium solutions with increase of interpulse interval from 5 to 500 ms was well described by three-exponential function consisting of early, first and second components. Facilitation at strontium solutions was significantly diminished due mainly to decrease of early and first components. At the same time, EPC facilitation with rhythmic stimulation (10 or 50 imp/s) at strontium solutions was significantly increased. Also more pronounced decrease of NE response 3rd phase, reflecting potassium currents was detected under rhythmic stimulation of 50 imp/s at strontium solutions comparing to calcium solutions. It was concluded that facilitation sites underlying first and early components had lower affinity to Sr ions than to Ca ions. The enhancement of frequency facilitation at strontium solutions is mediated by two mechanisms: more pronounced broadening of NE action potential and increase of bivalent cation influx due to feebly marked activation of Ca(2+)-dependent potassium current by Sr ions, and slower dynamics of Sr(2+) removal from NE axoplasm comparing to Ca(2+).

  12. "Stiff neonate" with mitochondrial DNA depletion and secondary neurotransmitter defects.

    LENUS (Irish Health Repository)

    Moran, Margaret M

    2011-12-01

    Mitochondrial disorders comprise a heterogenous group. A neonate who presented with episodes of severe truncal hypertonia and apnea progressed to a hypokinetic rigid syndrome characterized by hypokinesia, tremulousness, profound head lag, absent suck and gag reflexes, brisk deep tendon reflexes, ankle and jaw clonus, and evidence of autonomic dysfunction. Analysis of cerebrospinal fluid neurotransmitters from age 7 weeks demonstrated low levels of amine metabolites (homovanillic acid and 5-hydroxyindoleacetic acid), tetrahydrobiopterin, and pyridoxal phosphate. Mitochondrial DNA quantitative studies on muscle homogenate demonstrated a mitochondrial DNA depletion disorder. Respiratory chain enzymology demonstrated decreased complex IV activity. Screening for mitochondrial DNA rearrangement disorders and sequencing relevant mitochondrial genes produced negative results. No clinical or biochemical response to treatment with pyridoxal phosphate, tetrahydrobiopterin, or l-dopa occurred. The clinical course was progressive, and the patient died at age 19 months. Mitochondrial disorders causing secondary neurotransmitter diseases are usually severe, but are rarely reported. This diagnosis should be considered in neonates or infants who present with hypertonia, hypokinesia rigidity, and progressive neurodegeneration.

  13. Identification of catecholamine neurotransmitters using fluorescence sensor array

    Energy Technology Data Exchange (ETDEWEB)

    Ghasemi, Forough [Department of Chemistry, Sharif University of Technology, Tehran 11155-9516 (Iran, Islamic Republic of); Hormozi-Nezhad, M. Reza, E-mail: hormozi@sharif.edu [Department of Chemistry, Sharif University of Technology, Tehran 11155-9516 (Iran, Islamic Republic of); Institute for Nanoscience and Nanotechnology, Sharif University of Technology, Tehran (Iran, Islamic Republic of); Mahmoudi, Morteza, E-mail: mahmoudi@stanford.edu [Department of Nanotechnology and Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 13169-43551 (Iran, Islamic Republic of); Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305-5101 (United States)

    2016-04-21

    A nano-based sensor array has been developed for identification and discrimination of catecholamine neurotransmitters based on optical properties of their oxidation products under alkaline conditions. To produce distinct fluorescence response patterns for individual catecholamine, quenching of thioglycolic acid functionalized cadmium telluride (CdTe) quantum dots, by oxidation products, were employed along with the variation of fluorescence spectra of oxidation products. The spectral changes were analyzed with hierarchical cluster analysis (HCA) and principal component analysis (PCA) to identify catecholamine patterns. The proposed sensor could efficiently discriminate the individual catecholamine (i.e., dopamine, norepinephrine, and L-DOPA) and their mixtures in the concentration range of 0.25–30 μmol L{sup −1}. Finally, we found that the sensor had capability to identify the various catecholamines in urine sample. - Highlights: • We have proposed a fluorescence sensor array to detect catecholamine neurotransmitters. • Visual differentiation of catecholamines is provided by fluorescence array fingerprints. • Discrimination of catecholamines from each other, and from their mixture is obtained on a PCA plot. • Proposed sensor array can be used for detection of catecholamines in urine samples.

  14. The amyloid pathology progresses in a neurotransmitter-specific manner.

    Science.gov (United States)

    Bell, Karen F S; Ducatenzeiler, Adriana; Ribeiro-da-Silva, Alfredo; Duff, Karen; Bennett, David A; Cuello, A Claudio

    2006-11-01

    Past studies using transgenic models of early-staged amyloid pathology, have suggested that the amyloid pathology progresses in a neurotransmitter-specific manner where cholinergic terminals appear most vulnerable, followed by glutamatergic terminals and finally by somewhat more resistant GABAergic terminals. To determine whether this neurotransmitter-specific progression persists at later pathological stages, presynaptic bouton densities, and the areas of occupation and localization of plaque adjacent dystrophic neurites were quantified in 18-month-old APP(K670N, M671L)+PS1(M146L) doubly transgenic mice. Quantification revealed that transgenic animals had significantly lower cholinergic, glutamatergic and GABAergic presynaptic bouton densities. Cholinergic and glutamatergic dystrophic neurites appear to be heavily influenced by fibrillar Abeta as both types displayed a decreasing area of occupation with respect to increasing plaque size. Furthermore, cholinergic dystrophic neurites reside in closer proximity to plaques than glutamatergic dystrophic neurites, while GABAergic dystrophic neurites were minimal regardless of plaque size. To investigate whether similarities exist in the human AD pathology, a monoclonal antibody (McKA1) against the human vesicular glutamate transporter 1 (VGluT1) was developed. Subsequent staining in AD brain tissue revealed the novel presence of glutamatergic dystrophic neurites, to our knowledge the first evidence of a structural glutamatergic deficit in the AD pathology.

  15. Brain monoamine metabolism is altered in rats following spontaneous, long-distance running.

    Science.gov (United States)

    Elam, M; Svensson, T H; Thorén, P

    1987-06-01

    Brain monoamine metabolism in rats was studied during spontaneous, long-term running in a microprocessor-controlled wheel cage. Immediately after heavy spontaneous exercise, DOPA accumulation was decreased in dopamine-rich brain regions such as the limbic forebrain and corpus striatum, indicating a decreased rate of synthesis of dopamine in brain. In contrast, DOPA accumulation was increased in the noradrenaline-predominated region of the brain stem, indicating an increased synthesis of noradrenaline in this region. Alterations in brain monoamine metabolism were normalized in exercising animals analysed 24 h after the last running period. Changes in brain monoamine metabolism may be involved in the mechanisms underlying the clinically observed psychological effects of physical exercise.

  16. A kinome wide screen identifies novel kinases involved in regulation of monoamine transporter function

    DEFF Research Database (Denmark)

    Vuorenpää, Anne Elina; Ammendrup-Johnsen, Ina; Jorgensen, Trine N.

    2016-01-01

    cells (CAD) and rat chromocytoma (PC12) cells. Whereas SIK3 likely transcriptionally regulated expression of the three transfected transporters, depletion of PKA C-α was shown to decrease SERT function. Depletion of PrKX caused decreased surface expression and function of DAT without changing protein...... levels, suggesting that PrKX stabilizes the transporter at the cell surface. Summarized, our data provide novel insight into kinome regulation of the monoamine transporters and identifies PrKX as a yet unappreciated possible regulator of monoamine transporter function....... in regulation of monoamine transporter function and surface expression. A primary screen in HEK 293 cells stably expressing DAT or SERT with siRNAs against 573 human kinases revealed 93 kinases putatively regulating transporter function. All 93 hits, which also included kinases previously implicated...

  17. [Glutamatergic neurotransmitter system in regulation of the gastrointestinal tract motor activity].

    Science.gov (United States)

    Alekseeva, E V; Popova, T S; Sal'nikov, P S

    2015-01-01

    The review include actual facts, demonstrating high probability of glutamatergic neurotransmitter system role in the regulation of the gastrointestinal tract motor activity. These facts suggest significant role of the glutamatergic neurotransmitter system dysfunction in forming motor activity disorders of the digestive tract, including in patients in critical condition. The analysis is based on results of multiple experimental and clinical researches of glutamic acid and other components of the glutamatergic neurotransmitter system in central nervous system and autonomic nervous system (with the accent on the enteral nervous system) in normal conditions and with functioning changes of the glutamatergic neurotransmitter system in case of inflammation, hupoxia, stress and in critical condition.

  18. Liquid chromatography-mass spectrometry platform for both small neurotransmitters and neuropeptides in blood, with automatic and robust solid phase extraction

    Science.gov (United States)

    Johnsen, Elin; Leknes, Siri; Wilson, Steven Ray; Lundanes, Elsa

    2015-03-01

    Neurons communicate via chemical signals called neurotransmitters (NTs). The numerous identified NTs can have very different physiochemical properties (solubility, charge, size etc.), so quantification of the various NT classes traditionally requires several analytical platforms/methodologies. We here report that a diverse range of NTs, e.g. peptides oxytocin and vasopressin, monoamines adrenaline and serotonin, and amino acid GABA, can be simultaneously identified/measured in small samples, using an analytical platform based on liquid chromatography and high-resolution mass spectrometry (LC-MS). The automated platform is cost-efficient as manual sample preparation steps and one-time-use equipment are kept to a minimum. Zwitter-ionic HILIC stationary phases were used for both on-line solid phase extraction (SPE) and liquid chromatography (capillary format, cLC). This approach enabled compounds from all NT classes to elute in small volumes producing sharp and symmetric signals, and allowing precise quantifications of small samples, demonstrated with whole blood (100 microliters per sample). An additional robustness-enhancing feature is automatic filtration/filter back-flushing (AFFL), allowing hundreds of samples to be analyzed without any parts needing replacement. The platform can be installed by simple modification of a conventional LC-MS system.

  19. Development of new radiopharmaceuticals for imaging monoamine oxidase B

    Energy Technology Data Exchange (ETDEWEB)

    Vasdev, Neil, E-mail: neil.vasdev@utoronto.ca; Sadovski, Oleg; Moran, Matthew D.; Parkes, Jun; Meyer, Jeffrey H.; Houle, Sylvain; Wilson, Alan A.

    2011-10-15

    Introduction: Imaging monoamine oxidase B (MAO-B) in the central nervous system with PET is an important goal for psychiatric studies. We here report an improved and automated radiosynthesis of N-(6-[{sup 18}F]-fluorohexyl)-N-methylpropargylamine ([{sup 18}F]FHMP; [{sup 18}F]-1), as well as the radiosynthesis of two new promising candidates for imaging cerebral MAO-B, namely, carbon-11-labeled 3-(4-[{sup 11}C]-methoxyphenyl)-6-methyl-2H-1-benzopyran-2-one ([{sup 11}C]-2) and N-((1H-pyrrol-2-yl)methyl)-N-[{sup 11}C]-methyl-1-phenylmethanamine ([{sup 11}C]-3). Methods: Fluorine-18-labeled 1 was prepared via a tosyloxy precursor in 29%{+-}5% uncorrected radiochemical yield, relative to [{sup 18}F]-fluoride. Both carbon-11-labeled compounds were prepared with [{sup 11}C]CH{sub 3}I using the 'LOOP' method in 11% and 18% uncorrected radiochemical yields, respectively, relative to starting [{sup 11}C]CO{sub 2}. All radiotracers had specific activities >37 GBq/{mu}mol and were >98% radiochemically pure at end of synthesis (<40 min). All radiotracers were evaluated by ex vivo biodistribution studies in conscious rodents. Results: A major radioactive metabolite in the rodent brain was observed following administration of [{sup 18}F]-1. While [{sup 11}C]-2 had moderate brain penetration and good clearance from normal brain tissue, distribution of radioactivity in brain was indicative of free and nonspecific binding. Good brain uptake was observed with [{sup 11}C]-3 (0.8%-1.4% injected dose per gram at 5 min postinjection), binding appeared to be reversible and distribution conformed with regional distribution of MAO-B in the rat brain. Preinjection of 3 or L-deprenyl showed a modest reduction (up to 25%) of brain activity. Conclusion: Carbon-11-labeled 3 was found to have the most favorable properties of the radiotracers evaluated; however, the signal-to-noise ratio was too low to warrant further in vivo imaging studies. Alternative radiotracers for imaging MAO

  20. Biophysics of risk aversion based on neurotransmitter receptor theory

    CERN Document Server

    Takahashi, Taiki

    2011-01-01

    Decision under risk and uncertainty has been attracting attention in neuroeconomics and neuroendocrinology of decision-making. This paper demonstrated that the neurotransmitter receptor theory-based value (utility) function can account for human and animal risk-taking behavior. The theory predicts that (i) when dopaminergic neuronal response is efficiently coupled to the formation of ligand-receptor complex, subjects are risk-aversive (irrespective of their satisfaction level) and (ii) when the coupling is inefficient, subjects are risk-seeking at low satisfaction levels, consistent with risk-sensitive foraging theory in ecology. It is further suggested that some anomalies in decision under risk are due to inefficiency of the coupling between dopamine receptor activation and neuronal response. Future directions in the application of the model to studies in neuroeconomics of addiction and neuroendocrine modulation of risk-taking behavior are discussed.

  1. Wireless Power Transfer for Autonomous Wearable Neurotransmitter Sensors.

    Science.gov (United States)

    Nguyen, Cuong M; Kota, Pavan Kumar; Nguyen, Minh Q; Dubey, Souvik; Rao, Smitha; Mays, Jeffrey; Chiao, J-C

    2015-09-23

    In this paper, we report a power management system for autonomous and real-time monitoring of the neurotransmitter L-glutamate (L-Glu). A low-power, low-noise, and high-gain recording module was designed to acquire signal from an implantable flexible L-Glu sensor fabricated by micro-electro-mechanical system (MEMS)-based processes. The wearable recording module was wirelessly powered through inductive coupling transmitter antennas. Lateral and angular misalignments of the receiver antennas were resolved by using a multi-transmitter antenna configuration. The effective coverage, over which the recording module functioned properly, was improved with the use of in-phase transmitter antennas. Experimental results showed that the recording system was capable of operating continuously at distances of 4 cm, 7 cm and 10 cm. The wireless power management system reduced the weight of the recording module, eliminated human intervention and enabled animal experimentation for extended durations.

  2. Wireless Power Transfer for Autonomous Wearable Neurotransmitter Sensors

    Directory of Open Access Journals (Sweden)

    Cuong M. Nguyen

    2015-09-01

    Full Text Available In this paper, we report a power management system for autonomous and real-time monitoring of the neurotransmitter L-glutamate (L-Glu. A low-power, low-noise, and high-gain recording module was designed to acquire signal from an implantable flexible L-Glu sensor fabricated by micro-electro-mechanical system (MEMS-based processes. The wearable recording module was wirelessly powered through inductive coupling transmitter antennas. Lateral and angular misalignments of the receiver antennas were resolved by using a multi-transmitter antenna configuration. The effective coverage, over which the recording module functioned properly, was improved with the use of in-phase transmitter antennas. Experimental results showed that the recording system was capable of operating continuously at distances of 4 cm, 7 cm and 10 cm. The wireless power management system reduced the weight of the recording module, eliminated human intervention and enabled animal experimentation for extended durations.

  3. Antidepressant Binding Site in a Bacterial Homologue of Neurotransmitter Transporters

    Energy Technology Data Exchange (ETDEWEB)

    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

  4. Neurotransmitter GABA activates muscle but not α7 nicotinic receptors.

    Science.gov (United States)

    Dionisio, Leonardo; Bergé, Ignacio; Bravo, Matías; Esandi, María Del Carmen; Bouzat, Cecilia

    2015-01-01

    Cys-loop receptors are neurotransmitter-activated ion channels involved in synaptic and extrasynaptic transmission in the brain and are also present in non-neuronal cells. As GABAA and nicotinic receptors (nAChR) belong to this family, we explored by macroscopic and single-channel recordings whether the inhibitory neurotransmitter GABA has the ability to activate excitatory nAChRs. GABA differentially activates nAChR subtypes. It activates muscle nAChRs, with maximal peak currents of about 10% of those elicited by acetylcholine (ACh) and 15-fold higher EC50 with respect to ACh. At the single-channel level, the weak agonism is revealed by the requirement of 20-fold higher concentration of GABA for detectable channel openings, a major population of brief openings, and absence of clusters of openings when compared with ACh. Mutations at key residues of the principal binding-site face of muscle nAChRs (αY190 and αG153) affect GABA activation similarly as ACh activation, whereas a mutation at the complementary face (εG57) shows a selective effect for GABA. Studies with subunit-lacking receptors show that GABA can activate muscle nAChRs through the α/δ interface. Interestingly, single-channel activity elicited by GABA is similar to that elicited by ACh in gain-of-function nAChR mutants associated to congenital myasthenic syndromes, which could be important in the progression of the disorders due to steady exposure to serum GABA. In contrast, GABA cannot elicit single-channel or macroscopic currents of α7 or the chimeric α7-serotonin-type 3 receptor, a feature important for preserving an adequate excitatory/inhibitory balance in the brain as well as for avoiding activation of non-neuronal receptors by serum GABA. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  5. Prepulse inhibition (PPI) disrupting effects of Glycyrrhiza glabra extract in mice: a possible role of monoamines.

    Science.gov (United States)

    Michel, Haidy E; Tadros, Mariane G; Abdel-Naim, Ashraf B; Khalifa, Amani E

    2013-06-07

    Liquorice extract was reported to have nootropic and/or antiamnestic effects. Prepulse inhibition (PPI) of startle response is a multimodal, cross-species phenomenon used as a measure of sensorimotor gating. Previous studies indicated that liquorice/its constituents augmented mouse brain monoamine levels. Increased brain monoamines' transmission was suggested to underlie PPI disruption. However, the effect of antiamnestic dose(s) of the extract on PPI has not been investigated despite the coexistence of impaired memory and PPI deficit in some neurological disorders. The effect of administration of the antiamnestic dose of the extract (150 mg/kg for 7 days) was tested on PPI of acoustic startle response in mice. It resulted in PPI disruption and therefore its effect on monoamines' levels was investigated in a number of mouse brain areas involved in PPI response mediation. Results demonstrated that the extract antiamnestic dose augmented cortical, hippocampal and striatal monoamine levels. It was therefore concluded that liquorice extract (150 mg/kg)-induced PPI deficit was mediated through augmenting monoaminergic transmission in the cortex, hippocampus and striatum. These findings can be further investigated in experimental models for autism, psychosis and Huntington's disease to decide the safety of using liquorice extract in ameliorating memory disturbance in disorders manifesting PPI deficit.

  6. Reducing the Burden of Difficult-to-Treat Major Depressive Disorder: Revisiting Monoamine Oxidase Inhibitor Therapy

    OpenAIRE

    Culpepper, Larry

    2013-01-01

    Objective: Difficult-to-treat depression (eg, depression with atypical or anxious symptoms, treatment-resistant depression, or depression with frequent recurrence) is a challenging real-world health issue. This critical review of the literature focuses on monoamine oxidase inhibitor (MAOI) therapy and difficult-to-treat forms of depression.

  7. Effects of rhynchophylline on monoamine transmitters of striatum and hippocampus in cerebral ischemic rats

    Institute of Scientific and Technical Information of China (English)

    LUYuan-Fu; XIEXiao-Long; WUQin; WENGuo-Rong; YANGSu-Fen; SHIJing-Shan

    2004-01-01

    AIM To investigate the effects of rhynchophylline ( Rhy on monoamine transmitters and its metabolites in striatum and hippocampus of cerebral ischemic rats. METItODS The cerebral ischemic injury of rat was induced by middle cerebral artery occlusion (MCAO). The extracellular fluid of striatum and hippocampus in cerebral ischemic rats was collected by using

  8. Monoamine Oxidase a Promoter Gene Associated with Problem Behavior in Adults with Intellectual/Developmental Disabilities

    Science.gov (United States)

    May, Michael E.; Srour, Ali; Hedges, Lora K.; Lightfoot, David A.; Phillips, John A., III; Blakely, Randy D.; Kennedy, Craig H.

    2009-01-01

    A functional polymorphism in the promoter of the gene encoding monoamine oxidase A has been associated with problem behavior in various populations. We examined the association of MAOA alleles in adult males with intellectual/developmental disabilities with and without established histories of problem behavior. These data were compared with a…

  9. Double-staining techniques allows electrophysiological identification of monoamine-containing neurons.

    Science.gov (United States)

    Audesirk, T E; Audesirk, G J

    1985-08-01

    Electrophysiological recording provides important evidence for positive identification of many neurons in gastropods. We describe a technique which combines intracellular recording and injection of a persistent, non-fluorescent dye (Fast Green) with subsequent histofluorescence treatment using a modification of the wholemount glyoxylic acid procedure developed by Barber (1983) to establish the presence or absence of monoamine transmitters in positively identified single gastropod neurons.

  10. Co-existence of functionally different vesicular neurotransmitter transporters

    Directory of Open Access Journals (Sweden)

    Agnieszka eMünster-Wandowski

    2016-02-01

    Full Text Available The vesicular transmitter transporters VGLUT, VGAT, VMAT2 and VAChT, define phenotype and physiological properties of neuronal subtypes. VGLUTs concentrate the excitatory amino acid glutamate, VGAT the inhibitory amino acid GABA, VMAT2 monoamines, and VAChT acetylcholine into synaptic vesicle (SV. Following membrane depolarization SV release their content into the synaptic cleft. A strict segregation of vesicular transporters is mandatory for the precise functioning of synaptic communication and of neuronal circuits. In the last years, evidence accumulates that subsets of neurons express more than one of these transporters leading to synaptic co-release of different and functionally opposing transmitters and modulation of synaptic plasticity. Synaptic co-existence of transporters may change during pathological scenarios in order to ameliorate misbalances in neuronal activity. In addition, evidence increases that transporters also co-exist on the same vesicle providing another layer of regulation. Generally, vesicular transmitter loading relies on an electrochemical gradient µH+ driven by the proton ATPase rendering the lumen of the vesicle with respect to the cytosol positive ( and acidic (pH. While the activity of VGLUT mainly depends on the component, VMAT, VGAT and VAChT work best at a high pH. Thus, a vesicular synergy of transporters depending on the combination may increase or decrease the filling of SV with the principal transmitter. We provide an overview on synaptic co-existence of vesicular transmitter transporters including changes in the excitatory/inhibitory balance under pathological conditions. Additionally, we discuss functional aspects of vesicular synergy of transmitter transporters.

  11. Co-existence of Functionally Different Vesicular Neurotransmitter Transporters.

    Science.gov (United States)

    Münster-Wandowski, Agnieszka; Zander, Johannes-Friedrich; Richter, Karin; Ahnert-Hilger, Gudrun

    2016-01-01

    The vesicular transmitter transporters VGLUT, VGAT, VMAT2 and VAChT, define phenotype and physiological properties of neuronal subtypes. VGLUTs concentrate the excitatory amino acid glutamate, VGAT the inhibitory amino acid GABA, VMAT2 monoamines, and VAChT acetylcholine (ACh) into synaptic vesicle (SV). Following membrane depolarization SV release their content into the synaptic cleft. A strict segregation of vesicular transporters is mandatory for the precise functioning of synaptic communication and of neuronal circuits. In the last years, evidence accumulates that subsets of neurons express more than one of these transporters leading to synaptic co-release of different and functionally opposing transmitters and modulation of synaptic plasticity. Synaptic co-existence of transporters may change during pathological scenarios in order to ameliorate misbalances in neuronal activity. In addition, evidence increases that transporters also co-exist on the same vesicle providing another layer of regulation. Generally, vesicular transmitter loading relies on an electrochemical gradient ΔμH(+) driven by the proton ATPase rendering the lumen of the vesicle with respect to the cytosol positive (Δψ) and acidic (ΔpH). While the activity of VGLUT mainly depends on the Δψ component, VMAT, VGAT and VAChT work best at a high ΔpH. Thus, a vesicular synergy of transporters depending on the combination may increase or decrease the filling of SV with the principal transmitter. We provide an overview on synaptic co-existence of vesicular transmitter transporters including changes in the excitatory/inhibitory balance under pathological conditions. Additionally, we discuss functional aspects of vesicular synergy of transmitter transporters.

  12. Maternal factors and monoamine changes in stress-resilient and susceptible mice: cross-fostering effects.

    Science.gov (United States)

    Prakash, Priya; Merali, Zul; Kolajova, Miroslava; Tannenbaum, Beth M; Anisman, Hymie

    2006-09-21

    Genetic factors influence stressor-provoked monoamine changes associated with anxiety and depression, but such effects might be moderated by early life experiences. To assess the contribution of maternal influences in determining adult brain monoamine responses to a stressor, strains of mice that were either stressor-reactive or -resilient (BALB/cByJ and C57BL/6ByJ, respectively) were assessed as a function of whether they were raising their biological offspring or those of the other strain. As adults, offspring were assessed with respect to stressor-provoked plasma corticosterone elevations and monoamine variations within discrete stressor-sensitive brain regions. BALB/cByJ mice demonstrated poorer maternal behaviors than C57BL/6ByJ dams, irrespective of the pups being raised. In response to a noise stressor, BALB/cByJ mice exhibited higher plasma corticosterone levels and elevated monoamine turnover in several limbic and hypothalamic sites. The stressor-provoked corticosterone increase in BALB/cByJ mice was diminished among males (but not females) raised by a C57BL/6ByJ dam. Moreover, increased prefrontal cortical dopamine utilization was attenuated among BALB/cByJ mice raised by a C57BL/6ByJ dam. These effects were asymmetrical as a C57BL/6ByJ mice raised by a BALB/cByJ dam did not exhibit increased stressor reactivity. It appears that stressors influence multiple neurochemical systems that have been implicated in anxiety and affective disorders. Although monoamine variations were largely determined by genetic factors, maternal influences contributed to stressor-elicited neurochemical changes in some regions, particularly dopamine activation within the prefrontal cortex.

  13. Insulin modulates cocaine-sensitive monoamine transporter function and impulsive behavior.

    Science.gov (United States)

    Schoffelmeer, Anton N M; Drukarch, Benjamin; De Vries, Taco J; Hogenboom, François; Schetters, Dustin; Pattij, Tommy

    2011-01-26

    Because insulin acutely enhances the function of dopamine transporters, the tyrosine kinase receptors activated by this hormone may modulate transporter-dependent neurochemical and behavioral effects of psychoactive drugs. In this respect, we examined the effects of insulin on exocytotic monoamine release and the efficacy of the monoamine transporter blocker cocaine in rat nucleus accumbens. Whereas insulin reduced electrically evoked exocytotic [(3)H]dopamine release in nucleus accumbens slices, the hormone potentiated the release-enhancing effect of cocaine thereon. The phosphatidylinositol 3-kinase inhibitor LY294002 abolished these effects, indicating the involvement of insulin receptors. Similar insulin effects were observed on the release of [(3)H]norepinephrine in nucleus accumbens slices, but not on that of [(3)H]serotonin, and were also apparent in medial prefrontal cortex slices. As might then be expected, insulin also potentiated the dopamine and norepinephrine release-enhancing effects of the selective monoamine uptake inhibitors GBR12909 and desmethylimipramine, respectively. In subsequent behavioral experiments, we investigated the role of insulin in motor impulsivity that depends on monoamine neurotransmission in the nucleus accumbens. Intracranial administration of insulin in the nucleus accumbens alone reduced premature responses in the five-choice serial reaction time task and enhanced the stimulatory effect of peripheral cocaine administration on impulsivity, resembling the observed neurochemical effects of the hormone. In contrast, cocaine-induced locomotor activity remained unchanged by intra-accumbal insulin application. These data reveal that insulin presynaptically regulates cocaine-sensitive monoamine transporter function in the nucleus accumbens and, as a consequence, impulsivity. Therefore, insulin signaling proteins may represent targets for the treatment of inhibitory control deficits such as addictive behaviors.

  14. REM sleep at its core—Circuits, neurotransmitters and pathophysiology

    Directory of Open Access Journals (Sweden)

    John ePeever

    2015-05-01

    Full Text Available REM sleep is generated and maintained by the interaction of a variety of neurotransmitter systems in the brainstem, forebrain and hypothalamus. Within these circuits lies a core region that is active during REM sleep, known as the subcoeruleus nucleus (SubC or sublaterodorsal nucleus. It is hypothesized that glutamatergic SubC neurons regulate REM sleep and its defining features such as muscle paralysis and cortical activation. REM sleep paralysis is initiated when glutamatergic SubC activate neurons in the ventral medial medulla (VMM, which causes release of GABA and glycine onto skeletal motoneurons. REM sleep timing is controlled by activity of GABAergic neurons in the ventrolateral periaqueductal gray (vlPAG and dorsal paragigantocellular reticular nucleus (DPGi as well as melanin-concentrating hormone (MCH neurons in the hypothalamus and cholinergic cells in the laterodorsal (LDT and pedunculo-pontine tegmentum (PPT in the brainstem. Determining how these circuits interact with the SubC is important because breakdown in their communication is hypothesized to underlie cataplexy/narcolepsy and REM sleep behaviour disorder (RBD. This review synthesizes our current understanding of mechanisms generating healthy REM sleep and how dysfunction of these circuits contributes to common REM sleep disorders such as cataplexy/narcolepsy and RBD.

  15. REM Sleep at its Core – Circuits, Neurotransmitters, and Pathophysiology

    Science.gov (United States)

    Fraigne, Jimmy J.; Torontali, Zoltan A.; Snow, Matthew B.; Peever, John H.

    2015-01-01

    Rapid eye movement (REM) sleep is generated and maintained by the interaction of a variety of neurotransmitter systems in the brainstem, forebrain, and hypothalamus. Within these circuits lies a core region that is active during REM sleep, known as the subcoeruleus nucleus (SubC) or sublaterodorsal nucleus. It is hypothesized that glutamatergic SubC neurons regulate REM sleep and its defining features such as muscle paralysis and cortical activation. REM sleep paralysis is initiated when glutamatergic SubC cells activate neurons in the ventral medial medulla, which causes release of GABA and glycine onto skeletal motoneurons. REM sleep timing is controlled by activity of GABAergic neurons in the ventrolateral periaqueductal gray and dorsal paragigantocellular reticular nucleus as well as melanin-concentrating hormone neurons in the hypothalamus and cholinergic cells in the laterodorsal and pedunculo-pontine tegmentum in the brainstem. Determining how these circuits interact with the SubC is important because breakdown in their communication is hypothesized to underlie narcolepsy/cataplexy and REM sleep behavior disorder (RBD). This review synthesizes our current understanding of mechanisms generating healthy REM sleep and how dysfunction of these circuits contributes to common REM sleep disorders such as cataplexy/narcolepsy and RBD. PMID:26074874

  16. Four-dimensional multi-site photolysis of caged neurotransmitters

    Directory of Open Access Journals (Sweden)

    Mary Ann eGo

    2013-12-01

    Full Text Available Neurons receive thousands of synaptic inputs that are distributed in space and time. The systematic study of how neurons process these inputs requires a technique to stimulate multiple yet highly targeted points of interest along the neuron's dendritic tree. Three-dimensional multi-focal patterns produced via holographic projection combined with two-photon photolysis of caged compounds can provide for highly localized release of neurotransmitters within each diffraction-limited focus, and in this way emulate simultaneous synaptic inputs to the neuron. However, this technique so far cannot achieve time-dependent stimulation patterns due to fundamental limitations of the hologram-encoding device and other factors that affect the consistency of controlled synaptic stimulation. Here, we report an advanced technique that enables the design and application of arbitrary spatio-temporal photostimulation patterns that resemble physiological synaptic inputs. By combining holographic projection with a programmable high-speed light-switching array, we have overcome temporal limitations with holographic projection, allowing us to mimic distributed activation of synaptic inputs leading to action potential generation. Our experiments uniquely demonstrate multi-site two-photon glutamate uncaging in three dimensions with submillisecond temporal resolution. Implementing this approach opens up new prospects for studying neuronal synaptic integration in four dimensions.

  17. Potential Antidepressant Role of Neurotransmitter CART: Implications for Mental Disorders

    Directory of Open Access Journals (Sweden)

    Peizhong Mao

    2011-01-01

    Full Text Available Depression is one of the most prevalent and debilitating public health concerns. Although no single cause of depression has been identified, it appears that interaction among genetic, epigenetic, biochemical, environmental, and psychosocial factors may explain its etiology. Further, only a fraction of depressed patients show full remission while using current antidepressants. Therefore, identifying common pathways of the disorder and using that knowledge to develop more effective pharmacological treatments are two primary targets of research in this field. Brain-enriched neurotransmitter CART (cocaine- and amphetamine-regulated transcript has multiple functions related to emotions. It is a potential neurotrophic factor and is involved in the regulation of hypothalamic-pituitary-adrenal axis and stress response as well as in energy homeostasis. CART is also highly expressed in limbic system, which is considered to have an important role in regulating mood. Notably, adolescents carrying a missense mutation in the CART gene exhibit increased depression and anxiety. Hence, CART peptide may be a novel promising antidepressant agent. In this paper, we summarize recent progress in depression and CART. In particular, we emphasize a new antidepressant function for CART.

  18. Contributions to the field of neurotransmitters by Japanese scientists, and reflections on my own research.

    Science.gov (United States)

    Otsuka, Masanori

    2007-03-01

    PART I DESCRIBES IMPORTANT CONTRIBUTIONS MADE BY SOME JAPANESE PIONEERS IN THE FIELD OF NEUROTRANSMITTERS: (their achievements in parentheses) J. Takamine (isolation and crystallization of adrenaline); K. Shimidzu (early hint for acetylcholine as a neurotransmitter); F. Kanematsu (donation of the Kanematsu Memorial Institute in Sydney); T. Hayashi (discovery of the excitatory action of glutamate and the inhibitory action of GABA); and I. Sano (discovery of a high concentration of dopamine in striatum, its reduction in a patient with Parkinson's disease and the treatment with DOPA). In Part II, I present some of my reflections on my research on neurotransmitters. The work of my colleagues and myself has made some significant contributions to the establishment of neurotransmitter roles played by GABA and substance P, the first amino acid and the first peptide neurotransmitters, respectively. By the early 1960s, 3 substances, i.e., acetylcholine, noradrenaline, and adrenaline, had been established as neurotransmitters. Now the number of neurotransmitters is believed to be as many as 50 or even more mainly due to the inclusion of several amino acids and a large number of peptide transmitters.

  19. Antidepressant Drugs Transactivate TrkB Neurotrophin Receptors in the Adult Rodent Brain Independently of BDNF and Monoamine Transporter Blockade

    OpenAIRE

    Tomi Rantamäki; Liisa Vesa; Hanna Antila; Antonio Di Lieto; Päivi Tammela; Angelika Schmitt; Klaus-Peter Lesch; Maribel Rios; Eero Castrén

    2011-01-01

    BACKGROUND: Antidepressant drugs (ADs) have been shown to activate BDNF (brain-derived neurotrophic factor) receptor TrkB in the rodent brain but the mechanism underlying this phenomenon remains unclear. ADs act as monoamine reuptake inhibitors and after prolonged treatments regulate brain bdnf mRNA levels indicating that monoamine-BDNF signaling regulate AD-induced TrkB activation in vivo. However, recent findings demonstrate that Trk receptors can be transactivated independently of their ne...

  20. Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter.

    OpenAIRE

    Erickson, J.D.; Schafer, M K; Bonner, T I; Eiden, L. E.; Weihe, E.

    1996-01-01

    A second isoform of the human vesicular monoamine transporter (hVMAT) has been cloned from a pheochromocytoma cDNA library. The contribution of the two transporter isoforms to monoamine storage in human neuroendocrine tissues was examined with isoform-specific polyclonal antibodies against hVMAT1 and hVMAT2. Central, peripheral, and enteric neurons express only VMAT2. VMAT1 is expressed exclusively in neuroendocrine, including chromaffin and enterochromaffin, cells. VMAT1 and VMAT2 are coexpr...

  1. A putative vesicular transporter expressed in Drosophila mushroom bodies that mediates sexual behavior may define a novel neurotransmitter system

    OpenAIRE

    Brooks, Elizabeth S.; Greer, Christina L.; Romero-Calderón, Rafael; Serway, Christine N.; Grygoruk, Anna; Haimovitz, Jasmine M.; Nguyen, Bac T.; Najibi, Rod; Tabone, Christopher J.; de Belle, J. Steven; Krantz, David E.

    2011-01-01

    Storage and release of classical and amino acid neurotransmitters requires vesicular transporters. Some neurons lack known vesicular transporters, suggesting additional neurotransmitter systems remain unidentified. Insect mushroom bodies (MBs) are critical for several behaviors, including learning, but the neurotransmitters released by the intrinsic Kenyon cells (KCs) remain unknown. Likewise, KCs do not express a known vesicular transporter. We report the identification of a novel Drosophila...

  2. A putative vesicular transporter expressed in Drosophila mushroom bodies that mediates sexual behavior may define a novel neurotransmitter system

    OpenAIRE

    Brooks, Elizabeth S.; Greer, Christina L.; Romero-Calderón, Rafael; Serway, Christine N.; Grygoruk, Anna; Haimovitz, Jasmine M.; Nguyen, Bac T.; Najibi, Rod; Tabone, Christopher J.; de Belle, J. Steven; Krantz, David E.

    2011-01-01

    Storage and release of classical and amino acid neurotransmitters requires vesicular transporters. Some neurons lack known vesicular transporters, suggesting additional neurotransmitter systems remain unidentified. Insect mushroom bodies (MBs) are critical for several behaviors, including learning, but the neurotransmitters released by the intrinsic Kenyon cells (KCs) remain unknown. Likewise, KCs do not express a known vesicular transporter. We report the identification of a novel Drosophila...

  3. Depolarization by K*O+ and glutamate activates different neurotransmitter release mechanisms in gabaergic neurons: vesicular versus non-vesicular release of gaba

    DEFF Research Database (Denmark)

    Belhage, Bo; Hansen, G.H.; Schousboe, Arne

    1993-01-01

    Neurotransmitter release, gaba release, membrane transporter, vesicles, intracellular CA*OH, neuron cultures......Neurotransmitter release, gaba release, membrane transporter, vesicles, intracellular CA*OH, neuron cultures...

  4. Efficacy, safety, and patient preference of monoamine oxidase B inhibitors in the treatment of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Bradley J Robottom

    2011-01-01

    Full Text Available Bradley J RobottomDepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD, USAAbstract: Parkinson's disease (PD is the second most common neurodegenerative disease and the most treatable. Treatment of PD is symptomatic and generally focuses on the replacement or augmentation of levodopa. A number of options are available for treatment, both in monotherapy of early PD and to treat complications of advanced PD. This review focuses on rasagiline and selegiline, two medications that belong to a class of antiparkinsonian drugs called monoamine oxidase B (MAO-B inhibitors. Topics covered in the review include mechanism of action, efficacy in early and advanced PD, effects on disability, the controversy regarding disease modification, safety, and patient preference for MAO-B inhibitors.Keywords: monoamine oxidase inhibitors, rasagiline, selegiline, Parkinson's disease, efficacy, safety

  5. Desmodeleganine, a new alkaloid from the leaves of Desmodium elegans as a potential monoamine oxidase inhibitor.

    Science.gov (United States)

    Zhi, Kang-Kang; Yang, Zhong-Duo; Shi, Dan-Feng; Yao, Xiao-Jun; Wang, Ming-Gang

    2014-10-01

    Desmodeleganine (1), a new potential monoamine oxidase inhibitor, along with three known alkaloids, bufotenin (2), hydroxy-N, N-dimethyltryptamine N(12)-oxide (3), 2-(5-methoxy-1H-indol-3-yl)-N, and N-dimethylethylamine (4) were isolated from the leaves of Desmodium elegans. Their structures were elucidated by IR, MS, 1D and 2D NMR spectra. 1 showed strong monoamine oxidase inhibitory activity with IC50 value of 13.92 ± 1.5 μM, when the IC50 value of iproniazid as a standard was 6.5 ± 0.5 μM. The molecular modeling was also performed to explore the binding mode of compounds 1, 2 at the active site of MAO-A and MAO-B.

  6. Frightening music triggers rapid changes in brain monoamine receptors: a pilot PET study.

    Science.gov (United States)

    Zhang, Ying; Chen, Qiaozhen; Du, Fenglei; Hu, Yanni; Chao, Fangfang; Tian, Mei; Zhang, Hong

    2012-10-01

    Frightening music can rapidly arouse emotions in listeners that mimic those from actual life-threatening experiences. However, studies of the underlying mechanism for perceiving danger created by music are limited. We investigated monoamine receptor changes induced by frightening music using (11)C-N-methyl-spiperone ((11)C-NMSP) PET. Ten healthy male volunteers were included, and their psychophysiologic changes were evaluated. Compared with the baseline condition, listening to frightening music caused a significant decrease in (11)C-NMSP in the right and left caudate nuclei, right limbic region, and right paralimbic region; a particularly significant decrease in the right anterior cingulate cortex; but an increase in the right frontal occipital and left temporal lobes of the cerebral cortex. Transient fright triggers rapid changes in monoamine receptors, which decrease in the limbic and paralimbic regions but increase in the cerebral cortex.

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

    Science.gov (United States)

    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.

  8. GABA not only a neurotransmitter: osmotic regulation by GABAAR signalling

    Directory of Open Access Journals (Sweden)

    Tiziana eCesetti

    2012-01-01

    Full Text Available In neurons the anionic channel γ-aminobutyric (GABA A receptor (GABAAR plays a central role in mediating both the neurotrophic and neurotransmitter role of GABA. Activation of this receptor by GABA also affects the function of non-neuronal cells in the central nervous system (CNS, as GABAARs are expressed in mature macroglia and in almost all progenitor types, including neural stem cells. The relevance of GABA signalling in non-neuronal cells has been comparatively less investigated than in neurons. However, it is becoming increasingly evident that these cells are direct targets of GABA regulation. In non-neuronal cells GABAAR activation leads to influx or efflux of chloride (Cl- depending on the electrochemical gradient. Ion transport is indissolubly associated to water fluxes across the plasma membrane and plays a key role in brain physiology. Therefore, GABAAR could affect osmotic tension in the brain by modulating ion gradients. In addition, since water movements also occur through specialized water channels and transporters, GABAAR signalling could affect the movement of water also by regulating the function of the channels and transporters involved, thereby affecting not only the direction of the water fluxes but also their dynamics. This regulation has consequences at the cellular level as it modulates cell volume and activates multiple intracellular signalling mechanisms important for cell proliferation, maturation and survival. It may also have consequences at the systemic level. For example, it may indirectly control neuronal excitability, by regulating the extracellular space and interstitial concentration of Cl-, and contribute to brain water homeostasis. Therefore, GABAergic osmotic regulation should be taken into account during the treatment of pathologies requiring the administration of GABAAR modulators and for the development of therapies for diseases causing water unbalance in the brain.

  9. Changes in free amino acid and monoamine concentrations in the chick brain associated with feeding behavior.

    Science.gov (United States)

    Tran, Phuong V; Chowdhury, Vishwajit S; Nagasawa, Mao; Furuse, Mitsuhiro

    2015-01-01

    Domesticated chicks are precocial and therefore have relatively well-developed feeding behavior. The role of hypothalamic neuropeptides in food-intake regulation in chicks has been reported for decades. However, we hypothesized that nutrients and their metabolites in the brain may be involved in food intake in chicks because these animals exhibit a very frequent feeding pattern. Therefore, the purpose of this study was to examine the feeding behavior of chicks as well as the associated changes in free amino acid and monoamine concentrations in the chick brain. The feeding behavior of chicks was recorded continuously for 6 h. The next day, brain and blood samples were collected when the chicks either attempted to have food (hungry group) or turned food down (satiated group), in order to analyze the concentrations of the free amino acids and monoamines. We confirmed that the feeding behavior of neonatal chicks was characterized by short resting periods between very brief times spent on food intake. Several free amino acids in the mesencephalon were significantly lower in the satiated group than in the hungry group, while l-histidine and l-glutamine were significantly higher. Notably, there was no change in the free amino acid concentrations in other brain regions or plasma. As for monoamines, serotonin and norepinephrine were significantly lower in the mesencephalon of the hungry group compared with the satiated group, but 5 hydroxyindolacetic acid (5-HIAA) was higher. In addition, serotonin and norepinephrine levels were significantly higher in the brain stem of the hungry chicks compared with the satiated group, but levels of 5-HIAA and homovanillic acid were lower. Levels of both dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid, were significantly higher in the diencephalon and telencephalon of the chicks in the hungry group. In conclusion, the changes in the free amino acids and monoamines in the brain may have some role in the feeding behavior of

  10. Altered monoamine and acylcarnitine metabolites in HIV-positive and HIV-negative subjects with depression

    Science.gov (United States)

    Cassol, Edana; Misra, Vikas; Morgello, Susan; Kirk, Gregory D.; Mehta, Shruti H.; Gabuzda, Dana

    2015-01-01

    Background Depression is a frequent comorbidity in HIV infection that has been associated with worse treatment outcomes and increased mortality. Recent studies suggest that increased innate immune activation and tryptophan catabolism are associated with higher risk of depression in HIV infection and other chronic inflammatory diseases, but the mechanisms leading to depression remain poorly understood. Methods The severity of depressive symptoms was assessed by Beck Depression Inventory or Center for Epidemiological Studies Depression Scale. Untargeted metabolomic profiling of plasma from 104 subjects (68 HIV-positive and 36 HIV-negative) across three independent cohorts was performed using liquid or gas chromatography followed by mass spectrometry. Cytokine profiling was by Bioplex array. Bioinformatic analysis was performed in Metaboanalyst and R. Results Decreased monoamine metabolites (phenylacetate, 4-hydroxyphenylacetate) and acylcarnitines (propionylcarnitine, isobutyrylcarnitine, isovalerylcarnitine, 2-methylbutyrylcarnitine) in plasma distinguished depressed subjects from controls in HIV-positive and HIV-negative cohorts, and these alterations correlated with the severity of depressive symptoms. In HIV-positive subjects, acylcarnitines and other markers of mitochondrial function correlated inversely with tryptophan catabolism, a marker of IFN responses, suggesting inter-relationships between inflammatory pathways, tryptophan catabolism, and metabolic alterations associated with depression. Altered metabolites mapped to pathways involved in monoamine metabolism, mitochondrial function, and inflammation, suggesting a model in which complex relationships between monoamine metabolism and mitochondrial bioenergetics contribute to biological mechanisms involved in depression that may be augmented by inflammation during HIV infection. Conclusions Integrated approaches targeting inflammation, monoamine metabolism, and mitochondrial pathways may be important for

  11. Genetic studies of two inherited human phenotypes : Hearing loss and monoamine oxidase activity

    OpenAIRE

    Balciuniene, Jorune

    2001-01-01

    This thesis focuses on the identification of genetic factors underlying two inherited human phenotypes: hearing loss and monoamine oxidase activity. Non-syndromic hearing loss segregating in a Swedish family was tested for linkage to 13 previously reported candidate loci for hearing disabilities. Linkage was found to two loci: DFNA12 (llq22-q24) and DFNA2 (lp32). A detailed analysis of the phenotypes and haplotypes shared by the affected individuals supported the hypothesis of digenic inheri...

  12. Synthesis, inhibition and binding of simple non-nitrogen inhibitors of monoamine transporters.

    Science.gov (United States)

    Petersen, Mikkel Due; Boye, Søren Valdgård; Nielsen, Erik Holm; Willumsen, Jeanette; Sinning, Steffen; Wiborg, Ove; Bols, Mikael

    2007-06-15

    A series of simple truncated analogues of phenyl tropanes, 2-arylcycloalk-1-enyl carboxylic acid methylesters, were prepared and investigated for their activity towards the dopamine, serotonin and norepinephrine transporters. The compounds were prepared from cyclic ketoesters, which were converted to enolic triflates and reacted with arylboronates using the Suzuki coupling. For comparison the corresponding piperidines were also made and investigated. The new compounds inhibit monoamine-transporters with Ki values ranging from 0.1 to 1000 microM.

  13. Mimicking Neurotransmitter Release in Chemical Synapses via Hysteresis Engineering in MoS2 Transistors.

    Science.gov (United States)

    Arnold, Andrew J; Razavieh, Ali; Nasr, Joseph R; Schulman, Daniel S; Eichfeld, Chad M; Das, Saptarshi

    2017-03-10

    Neurotransmitter release in chemical synapses is fundamental to diverse brain functions such as motor action, learning, cognition, emotion, perception, and consciousness. Moreover, improper functioning or abnormal release of neurotransmitter is associated with numerous neurological disorders such as epilepsy, sclerosis, schizophrenia, Alzheimer's disease, and Parkinson's disease. We have utilized hysteresis engineering in a back-gated MoS2 field effect transistor (FET) in order to mimic such neurotransmitter release dynamics in chemical synapses. All three essential features, i.e., quantal, stochastic, and excitatory or inhibitory nature of neurotransmitter release, were accurately captured in our experimental demonstration. We also mimicked an important phenomenon called long-term potentiation (LTP), which forms the basis of human memory. Finally, we demonstrated how to engineer the LTP time by operating the MoS2 FET in different regimes. Our findings could provide a critical component toward the design of next-generation smart and intelligent human-like machines and human-machine interfaces.

  14. FMRP Regulates Neurotransmitter Release and Synaptic Information Transmission by Modulating Action Potential Duration via BK channels

    OpenAIRE

    Deng, Pan-Yue; Rotman, Ziv; Blundon, Jay A.; Cho, Yongcheol; Cui, Jianmin; Cavalli, Valeria; Zakharenko, Stanislav S; Klyachko, Vitaly A.

    2013-01-01

    Loss of FMRP causes Fragile X syndrome (FXS), but the physiological functions of FMRP remain highly debatable. Here we show that FMRP regulates neurotransmitter release in CA3 pyramidal neurons by modulating action potential (AP) duration. Loss of FMRP leads to excessive AP broadening during repetitive activity, enhanced presynaptic calcium influx and elevated neurotransmitter release. The AP broadening defects caused by FMRP loss have a cell-autonomous presynaptic origin and can be acutely r...

  15. Complexins facilitate neurotransmitter release at excitatory and inhibitory synapses in mammalian central nervous system.

    Science.gov (United States)

    Xue, Mingshan; Stradomska, Alicja; Chen, Hongmei; Brose, Nils; Zhang, Weiqi; Rosenmund, Christian; Reim, Kerstin

    2008-06-03

    Complexins (Cplxs) are key regulators of synaptic exocytosis, but whether they act as facilitators or inhibitors is currently being disputed controversially. We show that genetic deletion of all Cplxs expressed in the mouse brain causes a reduction in Ca(2+)-triggered and spontaneous neurotransmitter release at both excitatory and inhibitory synapses. Our results demonstrate that at mammalian central nervous system synapses, Cplxs facilitate neurotransmitter release and do not simply act as inhibitory clamps of the synaptic vesicle fusion machinery.

  16. (/sup 11/C)clorgyline and (/sup 11/C)-L-deprenyl and their use in measuring functional monoamine oxidase activity in the brain using positron emission tomography

    Science.gov (United States)

    Fowler, J.S.; MacGregor, R.R.; Wolf, A.P.

    1986-04-17

    This invention involves a new strategy for imaging the activity of the enzyme monoamine oxidase in the living body by using /sup 11/C-labeled enzyme inhibitors which bind irreversibly to an enzyme as a result of catalysis. By using positron emission tomography to image the distribution of radioactivity produced by the body penetrating radiation emitted by carbon-11, a map of functionally active monoamine oxidase activity is obtained. Clorgyline and L-deprenyl are suicide enzyme inhibitors and irreversibly inhibit monoamine oxidase. When these inhibitors are labeled with carbon-11 they provide selective probes for monoamine oxidase localization and reactivity in vivo using positron emission tomography. 2 figs.

  17. The mitochondrial monoamine oxidase-aldehyde dehydrogenase pathway: a potential site of action of daidzin.

    Science.gov (United States)

    Rooke, N; Li, D J; Li, J; Keung, W M

    2000-11-02

    Recent studies showed that daidzin suppresses ethanol intake in ethanol-preferring laboratory animals. In vitro, it potently and selectively inhibits the mitochondrial aldehyde dehydrogenase (ALDH-2). Further, it inhibits the conversion of monoamines such as serotonin (5-HT) and dopamine (DA) into their respective acid metabolites, 5-hydroxyindole-3-acetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in isolated hamster or rat liver mitochondria. Studies on the suppression of ethanol intake and inhibition of 5-HIAA (or DOPAC) formation by six structural analogues of daidzin suggested a potential link between these two activities. This, together with the finding that daidzin does not affect the rates of mitochondria-catalyzed oxidative deamination of these monoamines, raised the possibility that the ethanol intake-suppressive (antidipsotropic) action of daidzin is not mediated by the monoamines but rather by their reactive biogenic aldehyde intermediates such as 5-hydroxyindole-3-acetaldehyde (5-HIAL) and/or 3,4-dihydroxyphenylacetaldehyde (DOPAL) which accumulate in the presence of daidzin. To further evaluate this possibility, we synthesized more structural analogues of daidzin and tested and compared their antidipsotropic activities in Syrian golden hamsters with their effects on monoamine metabolism in isolated hamster liver mitochondria using 5-HT as the substrate. Effects of daidzin and its structural analogues on the activities of monoamine oxidase (MAO) and ALDH-2, the key enzymes involved in 5-HT metabolism in the mitochondria, were also examined. Results from these studies reveal a positive correlation between the antidipsotropic activities of these analogues and their abilities to increase 5-HIAL accumulation during 5-HT metabolism in isolated hamster liver mitochondria. Daidzin analogues that potently inhibit ALDH-2 but have no or little effect on MAO are most antidipsotropic, whereas those that also potently inhibit MAO exhibit little, if

  18. 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.

    Science.gov (United States)

    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

  19. The Effect of Functional Mandibular Shift on the Muscle Spindle Systems in Head-Neck Muscles and the Related Neurotransmitter Histamine.

    Science.gov (United States)

    Du, Bing-Li; Li, Jiang-Ning; Guo, Hong-Ming; Li, Song; Liu, Biao

    2017-09-01

    The aim of this study is to explore the effects of abnormal occlusion and functional recovery caused by functional mandible deviation on the head and neck muscles and muscle spindle sensory-motor system by electrophysiological response and endogenous monoamine neurotransmitters' distribution in the nucleus of the spinal tract. Seven-week-old male Wistar rats were randomly divided into 7 groups: normal control group, 2W experimental control group, 2W functional mandible deviation group, 2W functional mandible deviation recovery group, 4W experimental control group, 4W functional mandible deviation group, 4W functional mandible deviation recovery group. Chewing muscles, digastric muscle, splenius, and trapezius muscle spindles electrophysiological response activities at the opening and closing state were recorded. And then the chewing muscles, digastric, splenius, trapezius, and neck trigeminal nucleus were taken for histidine decarboxylase (HDC) detection by high performance liquid chromatography (HPLC), immunofluorescence, and reverse-transcription polymerase chain reaction (RT-PCR). Histamine receptor proteins in the neck nucleus of the spinal tract were also examined by immunofluorescence and RT-PCR. Electromyography activity of chewing muscles, digastric, and splenius muscle was significantly asymmetric; the abnormal muscle electromyography activity was mainly detected at the ipsilateral side. After functional mandibular deviation, muscle sensitivity on the ipsilateral sides of the chewing muscle and splenius decreased, muscle excitement weakened, modulation depth decreased, and the muscle spindle afferent impulses of excitation transmission speed slowed down. Changes for digastric muscle electrical activity were contrary. The functions recovered at different extents after removing the deflector. However, trapezius in all the experimental groups and recovery groups exhibited bilateral symmetry electrophysiological responses, and no significant difference

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

    Science.gov (United States)

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

    2014-05-01

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

  1. Effects of 071031B, a novel serotonin and norepinephrine reuptake inhibitor, on monoamine system in mice and rats.

    Science.gov (United States)

    Xue, Rui; He, Xin-Hua; Yuan, Li; Chen, Hong-Xia; Zhang, Li-Ming; Yong, Zheng; Yu, Gang; Fan, Shi-Yong; Li, Yun-Feng; Zhong, Bo-Hua; Zhang, You-Zhi

    2016-01-01

    Our previous study indicated that 071031B, a novel potential serotonin and norepinephrine reuptake inhibitor, showed robust antidepressant activity in multiple depression models, and could simultaneously inhibit 5-HT and NE reuptake in vitro. The present study was to evaluate the effects of 071031B on monoamine system in vivo, by using pharmacological models, including 5-HTP induced head-twitch test, yohimbine toxicity potentiation test, and reserpine induced hypothermia test, and determining monoamine transmitter levels in reserpine induced monoamine depletion model or chronic unpredictable stress (CUS) model. Results in pharmacological models indicated that acute administration of 071031B at 5-20 mg/kg significantly enhanced 5-HTP induced head-twitch behavior, potentiated yohimbine induced lethal rate, and reversed reserpine induced hypothermia. Further monoamine assays demonstrated that acute or chronic administration of 071031B at 10 or 20 mg/kg increased 5-HT and/or NE levels in various brain regions in reserpine or CUS induced monoamine depletion models, respectively, without effect on DA and its metabolites. Our results revealed that 071031B produces potent inhibition of 5-HT and NE reuptake in vivo.

  2. Effects of 071031B, a novel serotonin and norepinephrine reuptake inhibitor, on monoamine system in mice and rats

    Directory of Open Access Journals (Sweden)

    Rui Xue

    2016-01-01

    Full Text Available Our previous study indicated that 071031B, a novel potential serotonin and norepinephrine reuptake inhibitor, showed robust antidepressant activity in multiple depression models, and could simultaneously inhibit 5-HT and NE reuptake in vitro. The present study was to evaluate the effects of 071031B on monoamine system in vivo, by using pharmacological models, including 5-HTP induced head-twitch test, yohimbine toxicity potentiation test, and reserpine induced hypothermia test, and determining monoamine transmitter levels in reserpine induced monoamine depletion model or chronic unpredictable stress (CUS model. Results in pharmacological models indicated that acute administration of 071031B at 5–20 mg/kg significantly enhanced 5-HTP induced head-twitch behavior, potentiated yohimbine induced lethal rate, and reversed reserpine induced hypothermia. Further monoamine assays demonstrated that acute or chronic administration of 071031B at 10 or 20 mg/kg increased 5-HT and/or NE levels in various brain regions in reserpine or CUS induced monoamine depletion models, respectively, without effect on DA and its metabolites. Our results revealed that 071031B produces potent inhibition of 5-HT and NE reuptake in vivo.

  3. Discovery of highly selective and potent monoamine oxidase B inhibitors: Contribution of additional phenyl rings introduced into 2-aryl-1,3,4-oxadiazin-5(6H)-one.

    Science.gov (United States)

    Lee, Jungeun; Lee, Yeongcheol; Park, So Jung; Lee, Joohee; Kim, Yeong Shik; Suh, Young-Ger; Lee, Jeeyeon

    2017-03-01

    Monoamine oxidase B (MAO-B) is a flavin adenine dinucleotide (FAD)-containing enzyme that plays a major role in the oxidative deamination of biogenic amines and neurotransmitters. Inhibiting MAO-B activity is a promising approach in the treatment of neurological disorders. Here, we report a series of 2-aryl-1,3,4-oxadiazin-5(6H)-one derivatives as highly selective and potent MAO-B inhibitors. Analysis of the binding sites of hMAO-A and hMAO-B led to design of linear analogs of 2-aryl-1,3,4-oxadiazin-5(6H)-one with an additional phenyl ring. Biological evaluation of the 26 new derivatives resulted in the identification of highly potent and selective inhibitors with optimal physicochemical properties to potentially cross the blood-brain barrier (BBB). Compounds 18a, 18b, 18e and 25b potently inhibited MAO-B, with IC50 values of 4-25 nM and excellent SI over MAO-A (18a > 25000, 18b > 8333 and 18e > 4000 and 25b > 4545). Docking results suggest that an optimal linker between two aromatic rings on the 2-aryl-1,3,4-oxadiazin-5(6H)-one scaffold is a key element in the binding and inhibition of MAO-B.

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

    Science.gov (United States)

    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.

  5. Neurotransmitter transporters expressed in glial cells as regulators of synapse function.

    Science.gov (United States)

    Eulenburg, Volker; Gomeza, Jesús

    2010-05-01

    Synaptic neurotransmission at high temporal and spatial resolutions requires efficient removal and/or inactivation of presynaptically released transmitter to prevent spatial spreading of transmitter by diffusion and allow for fast termination of the postsynaptic response. This action must be carefully regulated to result in the fine tuning of inhibitory and excitatory neurotransmission, necessary for the proper processing of information in the central nervous system. At many synapses, high-affinity neurotransmitter transporters are responsible for transmitter deactivation by removing it from the synaptic cleft. The most prevailing neurotransmitters, glutamate, which mediates excitatory neurotransmission, as well as GABA and glycine, which act as inhibitory neurotransmitters, use these uptake systems. Neurotransmitter transporters have been found in both neuronal and glial cells, thus suggesting high cooperativity between these cell types in the control of extracellular transmitter concentrations. The generation and analysis of animals carrying targeted disruptions of transporter genes together with the use of selective inhibitors have allowed examining the contribution of individual transporter subtypes to synaptic transmission. This revealed the predominant role of glial expressed transporters in maintaining low extrasynaptic neurotransmitter levels. Additionally, transport activity has been shown to be actively regulated on both transcriptional and post-translational levels, which has important implications for synapse function under physiological and pathophysiological conditions. The analysis of these mechanisms will enhance not only our understanding of synapse function but will reveal new therapeutic strategies for the treatment of human neurological diseases.

  6. Binding Mode Selection Determines the Action of Ecstasy Homologs at Monoamine Transporters.

    Science.gov (United States)

    Sandtner, Walter; Stockner, Thomas; Hasenhuetl, Peter S; Partilla, John S; Seddik, Amir; Zhang, Yuan-Wei; Cao, Jianjing; Holy, Marion; Steinkellner, Thomas; Rudnick, Gary; Baumann, Michael H; Ecker, Gerhard F; Newman, Amy Hauck; Sitte, Harald H

    2016-01-01

    Determining the structural elements that define substrates and inhibitors at the monoamine transporters is critical to elucidating the mechanisms underlying these disparate functions. In this study, we addressed this question directly by generating a series of N-substituted 3,4-methylenedioxyamphetamine analogs that differ only in the number of methyl substituents on the terminal amine group. Starting with 3,4-methylenedioxy-N-methylamphetamine, 3,4-methylenedioxy-N,N-dimethylamphetamine (MDDMA) and 3,4-methylenedioxy-N,N,N-trimethylamphetamine (MDTMA) were prepared. We evaluated the functional activities of the compounds at all three monoamine transporters in native brain tissue and cells expressing the transporters. In addition, we used ligand docking to generate models of the respective protein-ligand complexes, which allowed us to relate the experimental findings to available structural information. Our results suggest that the 3,4-methylenedioxyamphetamine analogs bind at the monoamine transporter orthosteric binding site by adopting one of two mutually exclusive binding modes. 3,4-methylenedioxyamphetamine and 3,4-methylenedioxy-N-methylamphetamine adopt a high-affinity binding mode consistent with a transportable substrate, whereas MDDMA and MDTMA adopt a low-affinity binding mode consistent with an inhibitor, in which the ligand orientation is inverted. Importantly, MDDMA can alternate between both binding modes, whereas MDTMA exclusively binds to the low-affinity mode. Our experimental results are consistent with the idea that the initial orientation of bound ligands is critical for subsequent interactions that lead to transporter conformational changes and substrate translocation.

  7. Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics.

    Science.gov (United States)

    Riba, Jordi; Valle, Marta; Urbano, Gloria; Yritia, Mercedes; Morte, Adelaida; Barbanoj, Manel J

    2003-07-01

    The effects of the South American psychotropic beverage ayahuasca on subjective and cardiovascular variables and urine monoamine metabolite excretion were evaluated, together with the drug's pharmacokinetic profile, in a double-blind placebo-controlled clinical trial. This pharmacologically complex tea, commonly obtained from Banisteriopsis caapi and Psychotria viridis, combines N,N-dimethyltryptamine (DMT), an orally labile psychedelic agent showing 5-hydroxytryptamine2A agonist activity, with monoamine oxidase (MAO)-inhibiting beta-carboline alkaloids (harmine, harmaline, and tetrahydroharmine). Eighteen volunteers with prior experience in the use of psychedelics received single oral doses of encapsulated freeze-dried ayahuasca (0.6 and 0.85 mg of DMT/kg of body weight) and placebo. Ayahuasca produced significant subjective effects, peaking between 1.5 and 2 h, involving perceptual modifications and increases in ratings of positive mood and activation. Diastolic blood pressure showed a significant increase at the high dose (9 mm Hg at 75 min), whereas systolic blood pressure and heart rate were moderately and nonsignificantly increased. Cmax values for DMT after the low and high ayahuasca doses were 12.14 ng/ml and 17.44 ng/ml, respectively. Tmax (median) was observed at 1.5 h after both doses. The Tmax for DMT coincided with the peak of subjective effects. Drug administration increased urinary normetanephrine excretion, but, contrary to the typical MAO-inhibitor effect profile, deaminated monoamine metabolite levels were not decreased. This and the negligible harmine plasma levels found suggest a predominantly peripheral (gastrointestinal and liver) site of action for harmine. MAO inhibition at this level would suffice to prevent first-pass metabolism of DMT and allow its access to systemic circulation and the central nervous system.

  8. DNA cloning of human liver monoamine oxidase A and B: Molecular basis of differences in enzymatic properties

    Energy Technology Data Exchange (ETDEWEB)

    Back, A.W.J.; Lan, N.C.; Johnson, D.L.; Abell, C.W.; Bembenek, M.E.; Kwan, S.W.; Seeburg, P.H.; Shih, J.C. (Univ. of Heidelberg (West Germany))

    1988-07-01

    The monoamine oxidases play a vital role in the metabolism of biogenic amines in the central nervous system and in peripheral tissues. Using oligonucleotide probes derived from three sequenced peptide fragments, the authors have isolated cDNA clones that encode the A and B forms of monoamine oxidase and have determined the nucleotide sequences of these cDNAs. Comparison of the deduced amino acid sequences shows that the A and B forms have subunit molecular weights of 59,700 and 58,800, respectively, and have 70% sequence identity. Both sequences contain the pentapeptide Ser-Gly-Gly-Cys-Tyr, in which the obligatory cofactor FAD is covalently bound to cysteine. Based on differences in primary amino acid sequences and RNA gel blot analysis of mRNAs, the A and B forms of monoamine oxidase appear to be derived from separate genes.

  9. Monoamines and sexual function in rats bred for increased catatonic reactivity.

    Science.gov (United States)

    Klochkov, D V; Alekhina, T A; Kuznetsova, E G; Barykina, N N

    2009-07-01

    Body weight, ovary and uterus weight, the nature of estral cycles, and hypothalamus dopamine and noradrenaline levels and plasma testosterone levels were studied in female GC rats, bred for increased catatonic reactivity, at different stages of the estral cycle (estrus, proestrus). The outbred Wistar strain served as controls. On the background of decreased body weight, GC females showed impairments to the morphological cyclical changes in the ovaries and uterus, with a reduction in ovary weight in diestrus (p rats showed higher levels of these monoamines in estrus and lower levels in diestrus. Plasma testosterone levels in female GC rats were higher in diestrus than in estrus and in Wistar rats.

  10. Relationship between pancreatic vesicular monoamine transporter 2 (VMAT2) and insulin expression in human pancreas

    OpenAIRE

    Saisho, Yoshifumi; Harris, Paul E.; Butler, Alexandra E.; Galasso, Ryan; GURLO, TATYANA; Rizza, Robert A.; Butler, Peter C.

    2008-01-01

    Vesicular monoamine transporter 2 (VMAT2) is expressed in pancreatic beta cells and has recently been proposed as a target for measurement of beta cell mass in vivo. We questioned, (1) What proportion of beta cells express VMAT2? (2) Is VMAT2 expressed by other pancreatic endocrine or non-endocrine cells? (3) Is the relationship between VMAT2 and insulin expression disturbed in type 1 (T1DM) or type 2 diabetes (T2DM)? Human pancreas (7 non-diabetics, 5 T2DM, 10 T1DM) was immunostained for ins...

  11. Chromone-2- and -3-carboxylic acids inhibit differently monoamine oxidases A and B.

    Science.gov (United States)

    Alcaro, Stefano; Gaspar, Alexandra; Ortuso, Francesco; Milhazes, Nuno; Orallo, Francisco; Uriarte, Eugenio; Yáñez, Matilde; Borges, Fernanda

    2010-05-01

    Chromone carboxylic acids were evaluated as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. The biological data indicated that only chromone-3-carboxylic acid is a potent hMAO-B inhibitor, with a high degree of selectivity for hMAO-B compared to hMAO-A. Conversely the chromone-2-carboxylic acid resulted almost inactive against both MAO isoforms. Docking experiments were performed to elucidate the reasons of the different MAO IC(50) data and to explain the absence of activity versus selectivity, respectively. 2010 Elsevier Ltd. All rights reserved.

  12. Monoamine oxidase B inhibitors from the fruits of Opuntia ficus-indica var. saboten.

    Science.gov (United States)

    Han, Y N; Choo, Y; Lee, Y C; Moon, Y I; Kim, S D; Choi, J W

    2001-02-01

    Three varieties of methyl citrate and 1-methyl malate were isolated from the fruits of Opuntia ficus-indica var. saboten Makino through in vitro bioassay-guided isolation for the inhibition on monoamine oxidase(MAO). The IC50 values for MAO-B of 1-monomethyl citrate, 1,3-dimethyl citrate, trimethyl citrate and 1-methyl malate were 0.19, 0.23, 0.61 and 0.25 mM, respectively. However, on MAO-A, their inhibitions showed only marginal activity.

  13. Convergent Pathways for Steroid Hormone-and Neurotransmitter-Induced Rat Sexual Behavior

    Science.gov (United States)

    Mani, S. K.; Allen, J. M. C.; Clark, J. H.; Blaustein, J. D.; O'Malley, B. W.

    1994-08-01

    Estrogen and progesterone modulate gene expression in rodents by activation of intracellular receptors in the hypothalamus, which regulate neuronal networks that control female sexual behavior. However, the neurotransmitter dopamine has been shown to activate certain steroid receptors in a ligand-independent manner. A dopamine receptor stimulant and a D_1 receptor agonist, but not a D_2 receptor agonist, mimicked the effects of progesterone in facilitating sexual behavior in female rats. The facilitatory effect of the neurotransmitter was blocked by progesterone receptor antagonists, a D_1 receptor antagonist, or antisense oligonucleotides to the progesterone receptor. The results suggest that in rodents neurotransmitters may regulate in vivo gene expression and behavior by means of cross-talk with steroid receptors in the brain.

  14. Growth cone neurotransmitter receptor activation modulates electric field-guided nerve growth.

    Science.gov (United States)

    Erskine, L; McCaig, C D

    1995-10-01

    We have studied the interactions between two nerve guidance cues, which alone induce substantial growth cone turning: endogenous neurotransmitters and small dc electric fields. d-tubocurarine, a nicotinic AChR (acetylcholine receptor) antagonist, inhibited field-induced cathodal orientation of cultured neurites, whereas atropine, a muscarinic AChR blocker, and suramin, a P2-purinoceptor antagonist, markedly enhanced the guidance properties of the applied field. These experiments implicate the activation of growth cone nicotinic AChRs by self-released acetylcholine in the mechanism underpinning electric field-induced neurite orientation and raise the possibility that growth cones release neurotransmitter prior to target interaction in order to assist their own pathfinding. Additionally, they provide the first evidence that coactivation of several neurotransmitter receptors may interact to regulate directed nerve growth. Such interaction in vivo, where guidance signals coexist, would add further levels of control to neurite guidance.

  15. Differential stimulation of the retina with subretinally injected exogenous neurotransmitter: A biomimetic alternative to electrical stimulation

    Science.gov (United States)

    Rountree, Corey M.; Inayat, Samsoon; Troy, John B.; Saggere, Laxman

    2016-12-01

    Subretinal stimulation of the retina with neurotransmitters, the normal means of conveying visual information, is a potentially better alternative to electrical stimulation widely used in current retinal prostheses for treating blindness from photoreceptor degenerative diseases. Yet, no subretinal electrical or chemical stimulation study has stimulated the OFF and ON pathways differentially through inner retinal activation. Here, we demonstrate the feasibility of differentially stimulating retinal ganglion cells (RGCs) through the inner nuclear layer of the retina with glutamate, a primary neurotransmitter chemical, in a biomimetic way. We show that controlled pulsatile delivery of glutamate into the subsurface of explanted wild-type rat retinas elicits highly localized simultaneous inhibitory and excitatory spike rate responses in OFF and ON RGCs. We also present the spatiotemporal characteristics of RGC responses to subretinally injected glutamate and the therapeutic stimulation parameters. Our findings could pave the way for future development of a neurotransmitter-based subretinal prosthesis offering more naturalistic vision and better visual acuity than electrical prostheses.

  16. Neurotransmitter Specific, Cellular-Resolution Functional Brain Mapping Using Receptor Coated Nanoparticles: Assessment of the Possibility.

    Directory of Open Access Journals (Sweden)

    Ebrahim Forati

    Full Text Available 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.

  17. Neurotransmitter Specific, Cellular-Resolution Functional Brain Mapping Using Receptor Coated Nanoparticles: Assessment of the Possibility

    Science.gov (United States)

    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

  18. Elevated levels of the vesicular monoamine transporter and a novel repetitive behavior in the Drosophila model of fragile X syndrome.

    Directory of Open Access Journals (Sweden)

    John M Tauber

    Full Text Available Fragile X Syndrome (FXS is characterized by mental impairment and autism in humans, and it often features hyperactivity and repetitive behaviors. The mechanisms for the disease, however, remain poorly understood. Here we report that the dfmr1 mutant in the Drosophila model of FXS grooms excessively, which may be regulated differentially by two signaling pathways. Blocking metabotropic glutamate receptor signaling enhances grooming in dfmr1 mutant flies, whereas blocking the vesicular monoamine transporter (VMAT suppresses excessive grooming. dfmr1 mutant flies also exhibit elevated levels of VMAT mRNA and protein. These results suggest that enhanced monoamine signaling correlates with repetitive behaviors and hyperactivity associated with FXS.

  19. Wide-range, picoampere-sensitivity multichannel VLSI potentiostat for neurotransmitter sensing.

    Science.gov (United States)

    Murari, Kartikeya; Thakor, Nitish; Stanacevic, Milutin; Cauwenberghs, Gert

    2004-01-01

    Neurotransmitter sensing is critical in studying nervous pathways and neurological disorders. A 16-channel current-measuring VLSI potentiostat with multiple ranges from picoamperes to microamperes is presented for electrochemical detection of electroactive neurotransmitters like dopamine, nitric oxide etc. The analog-to-digital converter design employs a current-mode, first-order single-bit delta-sigma modulator architecture with a two-stage, digitally reconfigurable oversampling ratio for ranging the conversion scale. An integrated prototype is fabricated in CMOS technology, and experimentally characterized. Real-time multi-channel acquisition of dopamine concentration in vitro is performed with a microfabricated sensor array.

  20. Astrocytic control of biosynthesis and turnover of the neurotransmitters glutamate and GABA

    DEFF Research Database (Denmark)

    Schousboe, Arne; Bak, Lasse Kristoffer; Waagepetersen, Helle S

    2013-01-01

    Glutamate and GABA are the quantitatively major neurotransmitters in the brain mediating excitatory and inhibitory signaling, respectively. These amino acids are metabolically interrelated and at the same time they are tightly coupled to the intermediary metabolism including energy homeostasis....... Astrocytes play a pivotal role in the maintenance of the neurotransmitter pools of glutamate and GABA since only these cells express pyruvate carboxylase, the enzyme required for de novo synthesis of the two amino acids. Such de novo synthesis is obligatory to compensate for catabolism of glutamate and GABA...

  1. Microfluidic platform for neurotransmitter sensing based on cyclic voltammetry and dielectrophoresis for in vitro experiments.

    Science.gov (United States)

    Mathault, Jessy; Zamprogno, Pauline; Greener, Jesse; Miled, Amine

    2015-08-01

    This paper presents a new microfluidic platform that can simultaneously measure and locally modulate neurotransmitter concentration in a neuron network. This work focuses on the development of a first prototype including a potentiostat and electrode functionalization to detect several neurotransmitter's simultaneously. We tested dopamine as proof of concept to validate functionality. The system is based on 320 bidirectional electrode array for dielectrophoretic manipulation and cyclic voltammetry. Each electrode is connected to a mechanical multiplexer in order to reduce noise interference and fully isolate the electrode. The multiplexing rate is 476 kHz and each electrode can drive a signal with an amplitude of 60 V pp for dielectrophoretic manipulation.

  2. Transition metal ion FRET uncovers K(+) regulation of a neurotransmitter/sodium symporter

    DEFF Research Database (Denmark)

    Billesbølle, Christian B; Mortensen, Jonas S; Sohail, Azmat

    2016-01-01

    Neurotransmitter/sodium symporters (NSSs) are responsible for Na(+)-dependent reuptake of neurotransmitters and represent key targets for antidepressants and psychostimulants. LeuT, a prokaryotic NSS protein, constitutes a primary structural model for these transporters. Here we show that K(+) in......(+)-effect. The K(+)-effect depended on an intact Na1 site and mutating the Na2 site potentiated K(+) binding by facilitating transition to the inward-facing state. The data reveal an unrecognized ability of K(+) to regulate the LeuT transport cycle....

  3. Long-lasting effects of feline amygdala kindling on monoamines, seizures and sleep.

    Science.gov (United States)

    Shouse, M N; Staba, R J; Saquib, S F; Farber, P R

    2001-02-16

    This report describes the relationship between monoamines, sleep and seizures before and 1-month after amygdala kindling in young cats (kindling (n=2); 5-min recording epochs were temporally adjusted to correspond to dialysate samples and differentiated according to dominant sleep or waking state (lasting > or =80% of 5-min epoch) and degree of spontaneous seizure activity (number and duration of focal versus generalized spikes and spike trains and behavioral seizure correlates). Post-kindling records in each cat were divided into two groups (n=1 record each) based on higher or lower spontaneous EEG and behavioral seizure activity and compared to pre-kindling records. We found: (1) before and after kindling, NE and 5-HT but not DA concentrations were significantly lower in sleep than waking at both sites; (2) after kindling, each cat showed cyclic patterns, as follows: (a) higher NE, 5-HT and DA concentrations accompanied increased seizure activity with delayed sleep onset latency and increased sleep fragmentation (reduced sleep state percentages, number of epochs and/or epoch duration) in one recording versus (b) lower monoaminergic concentrations accompanied reduced seizure activity, rapid sleep onset and reduced sleep disruption in the other recording. The alternating, post-kindling pattern suggested "rebound" effects which could explain some controversies in the literature about chronic effects of kindling on monoamines and sleep-waking state patterns.

  4. Monoamine oxidase B layer-by-layer film fabrication and characterization toward dopamine detection

    Energy Technology Data Exchange (ETDEWEB)

    Miyazaki, Celina Massumi; Pereira, Tamyris Paschoal [Universidade Federal de São Carlos, UFSCar, CCTS, Sorocaba, São Paulo (Brazil); Mascagni, Daniela Branco Tavares [Universidade Estadual de São Paulo — UNESP, Sorocaba, São Paulo (Brazil); Leite de Moraes, Marli [Universidade Federal de São Paulo, Unifesp, São José dos Campos, São Paulo (Brazil); Ferreira, Marystela, E-mail: marystela@ufscar.br [Universidade Federal de São Carlos, UFSCar, CCTS, Sorocaba, São Paulo (Brazil)

    2016-01-01

    In this work nanostructured film composites of the monoamine oxidase B (MAO-B) enzyme, free or encapsulated in liposomes, were fabricated by the layer-by-layer (LbL) self-assembly technique, employing polyethylene imine (PEI) as polycation. Initially, the MAO-B enzyme was incorporated into liposomes in order to preserve its enzymatic structure ensuring their activity and catalytic stability. The LbL film growth was monitored by surface plasmon resonance (SPR) by gold resonance angle shift analysis after each bilayer deposition. Subsequently, the films were applied as amperometric biosensors for dopamine detection using Prussian Blue (PB) as the electron mediator. The biosensor fabricated by MAO-B incorporated into liposomes composed of DPPG:POPG in the ratio (1:4) (w/w) showed the best performance with a sensitivity of 0.86 (μA cm{sup −2})/(mmol L{sup −1}) and a detection limit of 0.33 mmol L{sup −1}. - Highlights: • Monoamine oxidase B incorporation in liposomes was proposed to preserve the enzyme. • Layer-by-layer films composed of MAO-B (free and in liposomes) were fabricated. • Amperometric response using ITO/Prussian Blue covered with the MAO-B films was studied. • Sensitivity, limit of detection and apparent Michaelis–Menten constant were compared.

  5. Monoamines, BDNF, Dehydroepiandrosterone, DHEA-Sulfate, and Childhood Depression—An Animal Model Study

    Directory of Open Access Journals (Sweden)

    O. Malkesman

    2009-01-01

    Full Text Available Basal levels of monoamines and DHEA in four main limbic brain regions were measured in prepubertal Wistar Kyoto (WKY rats (a putative animal model of childhood depression. Basal levels of “Brain-Derived Neurotrophic Factor (BDNF” were also determined in two regions in the hippocampus, compared with Wistar strain controls. In the second phase, we examined the responsiveness of prepubertal WKY rats to different types of chronic antidepressant treatments: Fluoxetine, Desipramine, and dehydroepiandrosterone sulfate (DHEAS. WKY prepubertal rats exhibited different monoamine levels in the limbic system, reduced DHEA levels in the VTA and lower levels of BDNF in the hippocampus CA3 region compared to controls. In prepubertal WKY rats, only treatment with DHEAS produced a statistically significant decrease in immobility, compared to saline-administered controls in the forced swim test. Wistar controls were not affected by any antidepressant. The results imply that DHEA(S and BDNF may be involved in the pathophysiology and pharmacotherapy of childhood depression.

  6. Parasite manipulation of brain monoamines in California killifish (Fundulus parvipinnis) by the trematode Euhaplorchis californiensis

    Science.gov (United States)

    Shaw, J.C.; Korzan, W.J.; Carpenter, R.E.; Kuris, A.M.; Lafferty, K.D.; Summers, C.H.; Overli, O.

    2009-01-01

    California killifish (Fundulus parvipinnis) infected with the brain-encysting trematode Euhaplorchis californiensis display conspicuous swimming behaviours rendering them more susceptible to predation by avian final hosts. Heavily infected killifish grow and reproduce normally, despite having thousands of cysts inside their braincases. This suggests that E. californiensis affects only specific locomotory behaviours. We hypothesised that changes in the serotonin and dopamine metabolism, essential for controlling locomotion and arousal may underlie this behaviour modification. We employed micropunch dissection and HPLC to analyse monoamine and monoamine metabolite concentrations in the brain regions of uninfected and experimentally infected fish. The parasites exerted density-dependent changes in monoaminergic activity distinct from those exhibited by fish subjected to stress. Specifically, E. californiensis inhibited a normally occurring, stress-induced elevation of serotonergic metabolism in the raphae nuclei. This effect was particularly evident in the experimentally infected fish, whose low-density infections were concentrated on the brainstem. Furthermore, high E. californiensis density was associated with increased dopaminergic activity in the hypothalamus and decreased serotonergic activity in the hippocampus. In conclusion, the altered monoaminergic metabolism may explain behavioural differences leading to increased predation of the infected killifish by their final host predators. ?? 2008 The Royal Society.

  7. Potential of Natural Products of Herbal Origin as Monoamine Oxidase Inhibitors.

    Science.gov (United States)

    Orhan, Ilkay Erdogan

    2016-01-01

    Monoamine oxidase (MAO, E.C. 1.4.3.4) is a flavin-adenine type of enzyme with two isoforms referred to MAO-A and MAO-B that function for oxidation of monoamines. While MAO-A inhibitors are effective as antidepressant and anxiolytic drugs (e.g. chlorgyline, moclobemide, and lazabemide), inhibitors of MAO-B (e.g. Ldeprenyl, pargyline, and rasagiline) are used against neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Considering the need for novel MAO inhibitors due to side effects of the current ones, natural products have become attractive targets for researchers. Up till now, many studies revealed strong MAO inhibitory activity of flavonoid, xanthone, alkaloid, and coumarin derivatives from herbal sources, which also become good models for the synthetic MAO inhibitors. For this purpose, the present review focuses on examples of in vitro and in vivo MAO-inhibiting natural compounds of plant origin from a wide variety of chemical classes isolated mainly between 2000 - 2015.

  8. Effects of lamotrigine on PCP-evoked elevations in monoamine levels in the medial prefrontal cortex of freely moving rats.

    Science.gov (United States)

    Quarta, Davide; Large, Charles H

    2011-12-01

    Lamotrigine is suggested to have potential as an add-on treatment for patients with schizophrenia. Supporting evidence comes from the efficacy of the drug in models of psychotic-like behaviour induced by N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine (PCP). These drugs enhance levels of the monoamines in the cortex, which may contribute to their psychotomimetic effects. The ability of lamotrigine to prevent these neurochemical changes has not been examined. We studied PCP-evoked overflow of noradrenaline, dopamine and serotonin in the medial prefrontal cortex of awake rats using microdialysis. Rats were administered lamotrigine or vehicle, followed by PCP. Locomotor activity was also recorded before and after drug treatment. Lamotrigine did not have an influence on basal levels of the monoamines, but significantly reduced PCP-evoked overflow of dopamine and serotonin; PCP-evoked overflow of noradrenaline was also reduced by lamotrigine, but not to a significant degree. In contrast, PCP-induced hyperactivity was unaffected by lamotrigine. It is concluded that lamotrigine can modify PCP-evoked monoamine overflow in the cortex, consistent with an ability to prevent the psychotomimetic effects of NMDA receptor antagonists in rodents and humans. The dissociation between monoamine overflow and locomotor activity suggests the involvement of different brain circuits; relevance to the treatment of schizophrenia is also discussed.

  9. Monoamine content during the reproductive cycle of Perna perna depends on site of origin on the Atlantic Coast of Morocco.

    Science.gov (United States)

    Klouche, Mounia S; De Deurwaerdère, Philippe; Dellu-Hagedorn, Françoise; Lakhdar-Ghazal, Nouria; Benomar, Soumaya

    2015-09-09

    Bivalve molluscs such as Perna perna display temporal cycles of reproduction that result from the complex interplay between endogenous and exogenous signals. The monoamines serotonin, dopamine and noradrenaline represent possible endocrine and neuronal links between these signals allowing the molluscs to modulate reproductive functions in conjunction with environmental constraints. Here, we report a disruption of the reproductive cycle of mussels collected from two of three sites along the Moroccan atlantic coast soiled by industrial or domestic waste. Using high pressure liquid chromatography, we show that the temporal pattern of monoamine content in the gonads, pedal and cerebroid ganglia varied throughout the reproductive cycle (resting, developing, maturing, egg-laying) of mussels from the unpolluted site. Marked modification of monoamine tissue content was found between sites, notably in noradrenaline content of the gonads. Discriminant statistics revealed a specific impact of mussel location on the temporal variations of noradrenaline and serotonin levels in gonads and cerebroid ganglia. Correlation analyses showed profound and temporal changes in the monoamine content between organs and ganglia, at the two sites where the reproduction was disrupted. We suggest that environmental constraints lead to profound changes of monoaminergic systems, which thereby compromises the entry of mussels into their reproductive cycle.

  10. Neurotransmitters as food supplements: the effects of GABA on brain and behavior

    NARCIS (Netherlands)

    Boonstra, E.; Kleijn, R.; Colzato, L.S.; Alkemade, A.; Forstmann, B.U.; Nieuwenhuis, S.

    2015-01-01

    Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human cortex. The food supplement version of GABA is widely available online. Although many consumers claim that they experience benefits from the use of these products, it is unclear whether these supplements confer benef

  11. Effect of methylmercury on some neurotransmitters and oxidative damage of rats

    Institute of Scientific and Technical Information of China (English)

    CHENG Jin-ping; YANG Yi-chen; HU Wei-xuan; YANG Liu; WANG Wen-hua; JIA Jin-ping; LIN Xue-yu

    2005-01-01

    In order to study the molecular mechanism of injury in rat organs induced by methylmercury, and the relationship between neurotransmitter and oxidative damage in the toxicity process of rat injury by methylmercury was studied. The control group was AChE, ACh, NOS, NO, MDA, SOD, GSH-Px and GSH in different organs of rats were determined with conventional methods. The results showed that after exposure to methylmercury for 7 d, the mercury content in brain of exposure groups increased clearly and had significant difference compared with the control group( P< 0.01). In rat's brain, serum, liver and kidney, the content of ACh and AChE were all decreased; the content of NOS and NO were all increased; the content of MDA was increased compared with the control group,the exposure groups had significant difference ( P < 0.01 ); the content of SOD, GSH and GSH-Px was decreased compared with the control group, the exposure groups had significant difference( P < 0.01). It could be concluded that methylmercury did effect the change of neurotransmitter and free radical. They participated in the toxicity process of injury by methylmercury. The damage of neurotransmitter maybe cause the chaos of free radical and the chaos of free radical may also do more damage to neurotransmitter vice versa.

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

    Science.gov (United States)

    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.

  13. Treatment with Tyrosine a Neurotransmitter Precursor Reduces Environmental Stress in Humans

    Science.gov (United States)

    1989-01-01

    brain norepinephrine and dopamine. catecholaminergic neurotransmitters. In animals, administration of tyrosine, a food constituent and precursor of the...Profile of Mood States. Stanford Sleepiness Scale) ENVIRONMENTAL STRESSORS that have been employed to evaluate a variety of psychoactive drugs foods ... tyramine . However. Plasma tyrosine levels were significantly elevated during behav- this amine is not detectable in the plasma of animals after they

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

    Science.gov (United States)

    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.

  15. Tetanus Toxin Action : Inhibition of Neurotransmitter Release Linked to Synaptobrevin Proteolysis

    NARCIS (Netherlands)

    Link, Egenhard; Edelmann, Lambert; Chou, Judy H.; Binz, Thomas; Yamasaki, Shinji; Eisel, Uli; Baumert, Marion; Südhof, Thomas C.; Niemann, Heiner; Jahn, Reinhard

    1992-01-01

    Tetanus toxin is a potent neurotoxin that inhibits the release of neurotransmitters from presynaptic nerve endings. The mature toxin is composed of a heavy and a light chain that are linked via a disulfide bridge. After entry of tetanus toxin into the cytoplasm, the released light chain causes block

  16. Glucose is necessary to maintain neurotransmitter homeostasis during synaptic activity in cultured glutamatergic neurons

    DEFF Research Database (Denmark)

    Bak, Lasse K; Schousboe, Arne; Sonnewald, Ursula

    2006-01-01

    Glucose is the primary energy substrate for the adult mammalian brain. However, lactate produced within the brain might be able to serve this purpose in neurons. In the present study, the relative significance of glucose and lactate as substrates to maintain neurotransmitter homeostasis was inves...

  17. Tetanus Toxin Action : Inhibition of Neurotransmitter Release Linked to Synaptobrevin Proteolysis

    NARCIS (Netherlands)

    Link, Egenhard; Edelmann, Lambert; Chou, Judy H.; Binz, Thomas; Yamasaki, Shinji; Eisel, Uli; Baumert, Marion; Südhof, Thomas C.; Niemann, Heiner; Jahn, Reinhard

    1992-01-01

    Tetanus toxin is a potent neurotoxin that inhibits the release of neurotransmitters from presynaptic nerve endings. The mature toxin is composed of a heavy and a light chain that are linked via a disulfide bridge. After entry of tetanus toxin into the cytoplasm, the released light chain causes block

  18. 神经递质在睡眠中的作用%Effect of neurotransmitter in sleep

    Institute of Scientific and Technical Information of China (English)

    初建平; 孟昭义

    2003-01-01

    @@ INTRODUCTION Sleep- wake rhythm is isolated from day- night rhythm of natural world;Sleep depends on the regulation of special structure of central nerve system and correlated neurotransmitters.This paper mainly introduces the research progress of neurotransmitter correlated to sleep.It benefits the comprehension of physiology,pathology and pharmacology of sleep and recognition of sleep.

  19. Direct assessment of substrate binding to the Neurotransmitter:Sodium Symporter LeuT by solid state NMR

    DEFF Research Database (Denmark)

    Erlendsson, Simon; Gotfryd, Kamil; Larsen, Flemming Hofmann

    2017-01-01

    The Neurotransmitter:Sodium Symporters (NSSs) represent an important class of proteins mediating sodium-dependent uptake of neurotransmitters from the extracellular space. The substrate binding stoichiometry of the bacterial NSS protein, LeuT, and thus the principal transport mechanism, has been ...

  20. Aminorex, a metabolite of the cocaine adulterant levamisole, exerts amphetamine like actions at monoamine transporters.

    Science.gov (United States)

    Hofmaier, Tina; Luf, Anton; Seddik, Amir; Stockner, Thomas; Holy, Marion; Freissmuth, Michael; Ecker, Gerhard F; Schmid, Rainer; Sitte, Harald H; Kudlacek, Oliver

    2014-07-01

    Psychostimulants such as amphetamine and cocaine are illicitly used drugs that act on neurotransmitter transporters for dopamine, serotonin or norepinephrine. These drugs can by themselves already cause severe neurotoxicity. However, an additional health threat arises from adulterant substances which are added to the illicit compound without declaration. One of the most frequently added adulterants in street drugs sold as cocaine is the anthelmintic drug levamisole. We tested the effects of levamisole on neurotransmitter transporters heterologously expressed in HEK293 cells. Levamisole was 100 and 300-fold less potent than cocaine in blocking norepinephrine and dopamine uptake, and had only very low affinity for the serotonin transporter. In addition, levamisole did not trigger any appreciable substrate efflux. Because levamisole and cocaine are frequently co-administered, we searched for possible allosteric effects; at 30μM, a concentration at which levamisole displayed already mild effects on norepinephrine transport it did not enhance the inhibitory action of cocaine. Levamisole is metabolized to aminorex, a formerly marketed anorectic drug, which is classified as an amphetamine-like substance. We examined the uptake-inhibitory and efflux-eliciting properties of aminorex and found it to exert strong effects on all three neurotransmitter transporters in a manner similar to amphetamine. We therefore conclude that while the adulterant levamisole itself has only moderate effects on neurotransmitter transporters, its metabolite aminorex may exert distinct psychostimulant effects by itself. Given that the half-time of levamisole and aminorex exceeds that of cocaine, it may be safe to conclude that after the cocaine effect "fades out" the levamisole/aminorex effect "kicks in".

  1. Aminorex, a metabolite of the cocaine adulterant levamisole, exerts amphetamine like actions at monoamine transporters☆

    Science.gov (United States)

    Hofmaier, Tina; Luf, Anton; Seddik, Amir; Stockner, Thomas; Holy, Marion; Freissmuth, Michael; Ecker, Gerhard F.; Schmid, Rainer; Sitte, Harald H.; Kudlacek, Oliver

    2014-01-01

    Psychostimulants such as amphetamine and cocaine are illicitly used drugs that act on neurotransmitter transporters for dopamine, serotonin or norepinephrine. These drugs can by themselves already cause severe neurotoxicity. However, an additional health threat arises from adulterant substances which are added to the illicit compound without declaration. One of the most frequently added adulterants in street drugs sold as cocaine is the anthelmintic drug levamisole. We tested the effects of levamisole on neurotransmitter transporters heterologously expressed in HEK293 cells. Levamisole was 100 and 300-fold less potent than cocaine in blocking norepinephrine and dopamine uptake, and had only very low affinity for the serotonin transporter. In addition, levamisole did not trigger any appreciable substrate efflux. Because levamisole and cocaine are frequently co-administered, we searched for possible allosteric effects; at 30 μM, a concentration at which levamisole displayed already mild effects on norepinephrine transport it did not enhance the inhibitory action of cocaine. Levamisole is metabolized to aminorex, a formerly marketed anorectic drug, which is classified as an amphetamine-like substance. We examined the uptake-inhibitory and efflux-eliciting properties of aminorex and found it to exert strong effects on all three neurotransmitter transporters in a manner similar to amphetamine. We therefore conclude that while the adulterant levamisole itself has only moderate effects on neurotransmitter transporters, its metabolite aminorex may exert distinct psychostimulant effects by itself. Given that the half-time of levamisole and aminorex exceeds that of cocaine, it may be safe to conclude that after the cocaine effect “fades out” the levamisole/aminorex effect “kicks in”. PMID:24296074

  2. Therapeutic applications of selective and non-selective inhibitors of monoamine oxidase A and B that do not cause significant tyramine potentiation.

    Science.gov (United States)

    Youdim, Moussa B H; Weinstock, Marta

    2004-01-01

    The major side effect with the use of first generation of non selective monoamine oxidase (MAO) inhibitors as neuropsychiatric drugs was what became known as the "cheese reaction". Namely, potentiation of sympathomimetic activity of ingested tyramine present in cheese and other food stuff, resulting from its ability to release noradrenaline, when prevented from metabolism by MAO. The identification of two forms of MAO, termed types A and B and their selective irreversible inhibitors resolved some of this problems. However irreversible MAO-A inhibitors continue to induce a cheese reaction, whereas MAO-B inhibitors at their selective dosage did not and led to introduction of L-deprenyl (selegiline) as an anti-Parkinson drug, since dopamine is equally well metabolized by both enzyme forms. The cheese reaction is a consequence of inhibition of MAO-A, the enzyme responsible for metabolism of noradrenaline and serotonin, located in peripheral adrenergic neurons. The consequence of these findings were the development of reversible MAO-A inhibitors (RIMA), moclobemide and brofaromin, as antidepressants and possible anti-Parkinson activity, with limited tyramine potentiation, since the amine can displace the inhibitor from its binding site on the enzyme. It has always been deemed a greater pharmacological advantage to inhibit both forms of the enzymes to get the full functional activities of the amine neurotransmitters, and without inducing a "cheese reaction". This was not possible until recently, with the development of the novel cholinesterase-brain selective MAO-AB inhibitor, TV3326 (N-propargyl-(3R)-aminoidnan-5-yl-ethyl methylcarbamate hemitartiate), a carbamate derivative of the irreversible MAO-B inhibitor anti-Parkinson drug, rasagiline. This drug is a brain selective MAO-A and B inhibitor, with little inhibition of liver and small intestine enzymes. Pharmacologically it has limited tyramine potentiation, very similar to moclobemide and being a MAO-AB inhibitor it

  3. A putative vesicular transporter expressed in Drosophila mushroom bodies that mediates sexual behavior may define a novel neurotransmitter system

    Science.gov (United States)

    Brooks, Elizabeth S.; Greer, Christina L.; Romero-Calderón, Rafael; Serway, Christine N.; Grygoruk, Anna; Haimovitz, Jasmine M.; Nguyen, Bac T.; Najibi, Rod; Tabone, Christopher J.; de Belle, J. Steven; Krantz, David E.

    2011-01-01

    Summary Storage and release of classical and amino acid neurotransmitters requires vesicular transporters. Some neurons lack known vesicular transporters, suggesting additional neurotransmitter systems remain unidentified. Insect mushroom bodies (MBs) are critical for several behaviors, including learning, but the neurotransmitters released by the intrinsic Kenyon cells (KCs) remain unknown. Likewise, KCs do not express a known vesicular transporter. We report the identification of a novel Drosophila gene portabella (prt) that is structurally similar to known vesicular transporters. Both larval and adult brains express PRT in the KCs of the MBs. Additional PRT cells project to the central complex and optic ganglia. prt mutation causes an olfactory learning deficit and an unusual defect in the male’s position during copulation that is rescued by expression in KCs. Since prt is expressed in neurons that lack other known vesicular transporters or neurotransmitters, it may define a previously unknown neurotransmitter system responsible for sexual behavior and a component of olfactory learning. PMID:22017990

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

    Science.gov (United States)

    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

  5. The dependence of neuronal encoding efficiency on Hebbian plasticity and homeostatic regulation of neurotransmitter release

    Science.gov (United States)

    Faghihi, Faramarz; Moustafa, Ahmed A.

    2015-01-01

    Synapses act as information filters by different molecular mechanisms including retrograde messenger that affect neuronal spiking activity. One of the well-known effects of retrograde messenger in presynaptic neurons is a change of the probability of neurotransmitter release. Hebbian learning describe a strengthening of a synapse between a presynaptic input onto a postsynaptic neuron when both pre- and postsynaptic neurons are coactive. In this work, a theory of homeostatic regulation of neurotransmitter release by retrograde messenger and Hebbian plasticity in neuronal encoding is presented. Encoding efficiency was measured for different synaptic conditions. In order to gain high encoding efficiency, the spiking pattern of a neuron should be dependent on the intensity of the input and show low levels of noise. In this work, we represent spiking trains as zeros and ones (corresponding to non-spike or spike in a time bin, respectively) as words with length equal to three. Then the frequency of each word (here eight words) is measured using spiking trains. These frequencies are used to measure neuronal efficiency in different conditions and for different parameter values. Results show that neurons that have synapses acting as band-pass filters show the highest efficiency to encode their input when both Hebbian mechanism and homeostatic regulation of neurotransmitter release exist in synapses. Specifically, the integration of homeostatic regulation of feedback inhibition with Hebbian mechanism and homeostatic regulation of neurotransmitter release in the synapses leads to even higher efficiency when high stimulus intensity is presented to the neurons. However, neurons with synapses acting as high-pass filters show no remarkable increase in encoding efficiency for all simulated synaptic plasticity mechanisms. This study demonstrates the importance of cooperation of Hebbian mechanism with regulation of neurotransmitter release induced by rapid diffused retrograde

  6. Monoamines tissue content analysis reveals restricted and site-specific correlations in brain regions involved in cognition.

    Science.gov (United States)

    Fitoussi, A; Dellu-Hagedorn, F; De Deurwaerdère, P

    2013-01-01

    The dopamine (DA), noradrenalin (NA) and serotonin (5-HT) monoaminergic systems are deeply involved in cognitive processes via their influence on cortical and subcortical regions. The widespread distribution of these monoaminergic networks is one of the main difficulties in analyzing their functions and interactions. To address this complexity, we assessed whether inter-individual differences in monoamine tissue contents of various brain areas could provide information about their functional relationships. We used a sensitive biochemical approach to map endogenous monoamine tissue content in 20 rat brain areas involved in cognition, including 10 cortical areas and examined correlations within and between the monoaminergic systems. Whereas DA content and its respective metabolite largely varied across brain regions, the NA and 5-HT contents were relatively homogenous. As expected, the tissue content varied among individuals. Our analyses revealed a few specific relationships (10%) between the tissue content of each monoamine in paired brain regions and even between monoamines in paired brain regions. The tissue contents of NA, 5-HT and DA were inter-correlated with a high incidence when looking at a specific brain region. Most correlations found between cortical areas were positive while some cortico-subcortical relationships regarding the DA, NA and 5-HT tissue contents were negative, in particular for DA content. In conclusion, this work provides a useful database of the monoamine tissue content in numerous brain regions. It suggests that the regulation of these neuromodulatory systems is achieved mainly at the terminals, and that each of these systems contributes to the regulation of the other two.

  7. Lack of platelet monoamine oxidase activity in Cebus monkeys (Cebus albifrons).

    Science.gov (United States)

    Heintz, R; Richardson, M A; Perumal, A S; Casey, D E

    1989-01-01

    1. Recent evidence suggests that monoamine oxidase (MAO) plays an important role modulating the extrapyramidal syndromes produced by neuroleptic drugs in both human and nonhuman primates. 2. To evaluate the possibility of using peripheral blood platelet MAO-B levels as indices of central nervous system MAO-B effects, we measured platelet MAO-B levels in Cebus monkeys that were previously tested with neuroleptics (N = 36) or drug naive (N = 6). 3. No platelet MAO-B was consistently detectable in these blood samples. 4. Thus platelet measures of MAO-B do not reliably reflect brain MAO-B function in nonhuman primates and do not offer a useful model for studying blood-brain MAO-B relationships.

  8. Monoamine oxidase B layer-by-layer film fabrication and characterization toward dopamine detection.

    Science.gov (United States)

    Miyazaki, Celina Massumi; Pereira, Tamyris Paschoal; Mascagni, Daniela Branco Tavares; de Moraes, Marli Leite; Ferreira, Marystela

    2016-01-01

    In this work nanostructured film composites of the monoamine oxidase B (MAO-B) enzyme, free or encapsulated in liposomes, were fabricated by the layer-by-layer (LbL) self-assembly technique, employing polyethylene imine (PEI) as polycation. Initially, the MAO-B enzyme was incorporated into liposomes in order to preserve its enzymatic structure ensuring their activity and catalytic stability. The LbL film growth was monitored by surface plasmon resonance (SPR) by gold resonance angle shift analysis after each bilayer deposition. Subsequently, the films were applied as amperometric biosensors for dopamine detection using Prussian Blue (PB) as the electron mediator. The biosensor fabricated by MAO-B incorporated into liposomes composed of DPPG:POPG in the ratio (1:4) (w/w) showed the best performance with a sensitivity of 0.86 (μA cm(-2))/(mmol L(-1)) and a detection limit of 0.33 mmol L(-1).

  9. Monoamine oxidase and transaminase screening: biotransformation of 2-methyl-6-alkylpiperidines by Neopestalotiopsis sp. CBMAI 2030.

    Science.gov (United States)

    Costa, Jonas Henrique; da Costa, Bruna Zucoloto; de Angelis, Derlene Attili; Marsaioli, Anita Jocelyne

    2017-08-01

    High-throughput screening detected transaminases (TAs) and monoamine oxidases (MAOs) in fungi by applying a fluorogenic probe. Strains F026, F037, F041, F053, and F057 showed the highest enzymatic conversions (31, 60, 30, 40, and 32%, respectively) and where evaluated for their ability to transform piperidines. Strain F053 (Neopestalotiopsis sp. CBMAI 2030) revealed unusual enzymatic activity to deracemize 2-methyl-6-alkylpiperidines. Neopestalotiopsis sp. CBMAI 2030 was capable to convert 2-methyl-6-propylpiperidine, 2-methyl-6-butylpiperidine, and 2-methyl-6-pentylpiperidine in piperideine with 11, 14, and 24% conversion, respectively. The activity was enhanced by cultivating the fungus with 2-methyl-6-pentylpiperidine (38% conversion and 73% ee).

  10. [Substrate-inhibitory analysis of monoamine oxidase from hepatopancreas of the octopus Bathypolypus arcticus].

    Science.gov (United States)

    Basova, I N; Iagodina, O V

    2012-01-01

    Study of the substrate-inhibitory specificity of mitochondrial monoamine oxidase (MAO) of hepatopancreas of the octopus Bathypolypus arcticus revealed distinctive peculiarities of catalytic properties of this enzyme. The studied enzyme, on one hand, like the classic MAO of homoiothermal animals, is able to deaminate tyramine, serotonin, benzylamine, tryptamine, beta-phenylethylamine, while, on the other hand, deaminates histamine and does not deaminate putrescine--classic substrates of diamine oxidase (DAO). Results of the substrate-inhibitory analysis with use of chlorgiline and deprenyl are indirect proofs of the existence in the octopus hepatopancreas of one molecular MAO form. Semicarbazide and pyronine G turned out to be weak irreversible inhibitors, four derivatives of acridine--irreversible inhibitors of the intermediate effectiveness with respect to the octopus hepatopancreas MAO; specificity of action of inhibitors at deamination of different substrates was equal.

  11. ”Ping-pong gaze” secondary to monoamine oxidase inhibitor overdose

    Directory of Open Access Journals (Sweden)

    Amy Attaway

    2016-01-01

    Full Text Available An infrequent manifestation of monoamine oxidase inhibitor (MAOI toxicity is “ping-pong gaze” (PPG. We describe the case of a 26-year-old female who was found unresponsive after taking 40 tablets of phenelzine. On presentation to the hospital, her eyes were moving in characteristic “ping pong” fashion. After 6 hours her gaze terminated. The following day her neurologic exam was benign and she had no long-term sequelae. While the etiology of PPG is unknown, it is most often seen with irreversible structural brain damage. However, a detailed literature review revealed that previous cases of MAOI toxicity where the patient survived have all had complete neurologic recovery.

  12. Improved method for HPLC analysis of polyamines, agmatine and aromatic monoamines in plant tissue

    Science.gov (United States)

    Slocum, R. D.; Flores, H. E.; Galston, A. W.; Weinstein, L. H.

    1989-01-01

    The high performance liquid chromatographic (HPLC) method of Flores and Galston (1982 Plant Physiol 69: 701) for the separation and quantitation of benzoylated polyamines in plant tissues has been widely adopted by other workers. However, due to previously unrecognized problems associated with the derivatization of agmatine, this important intermediate in plant polyamine metabolism cannot be quantitated using this method. Also, two polyamines, putrescine and diaminopropane, also are not well resolved using this method. A simple modification of the original HPLC procedure greatly improves the separation and quantitation of these amines, and further allows the simulation analysis of phenethylamine and tyramine, which are major monoamine constituents of tobacco and other plant tissues. We have used this modified HPLC method to characterize amine titers in suspension cultured carrot (Daucas carota L.) cells and tobacco (Nicotiana tabacum L.) leaf tissues.

  13. Improved method for HPLC analysis of polyamines, agmatine and aromatic monoamines in plant tissue

    Science.gov (United States)

    Slocum, R. D.; Flores, H. E.; Galston, A. W.; Weinstein, L. H.

    1989-01-01

    The high performance liquid chromatographic (HPLC) method of Flores and Galston (1982 Plant Physiol 69: 701) for the separation and quantitation of benzoylated polyamines in plant tissues has been widely adopted by other workers. However, due to previously unrecognized problems associated with the derivatization of agmatine, this important intermediate in plant polyamine metabolism cannot be quantitated using this method. Also, two polyamines, putrescine and diaminopropane, also are not well resolved using this method. A simple modification of the original HPLC procedure greatly improves the separation and quantitation of these amines, and further allows the simulation analysis of phenethylamine and tyramine, which are major monoamine constituents of tobacco and other plant tissues. We have used this modified HPLC method to characterize amine titers in suspension cultured carrot (Daucas carota L.) cells and tobacco (Nicotiana tabacum L.) leaf tissues.

  14. A Study on Antitoxic Role of Vesicular Monoamine Transporter 2 in Transgenic Chinese Hamster Overy Cells

    Institute of Scientific and Technical Information of China (English)

    叶民; 丁新生; 董海蓉; 仇镇宁; 管晓虹

    2003-01-01

    Objective:To study the antitoxic role of vesicular monoamine transporter 2 (VMAT2) in transpgenic Chinese Hamster ovary(CHO) cell.Methods:With the technology of transgene from PC12 to CHO,MTT reduction assay was used to detect MPP+ toxic effect on wild type CHO(wtCHO) and transgenic CHO.Meanwhile,the role of reserpine was also observed in MPP+ toxic effects.Results:The sensitivity of transgenic CHO to MPP+ was much less than that of wtCHO with 0.5 mmol/L MPP+.Transgenic CHO had the same sensitivity as wtCHO if rotenone was given.WtCHO,by given reserpine alone,didn''''''''t change its sensitivity to MPP+.Conclusions:VMAT2 has protective effect on transgenic CHO by transporting MPP+ to vesicles.

  15. The resurgence of neurotransmitter modulation in Parkinson’s disease with safinamide

    Directory of Open Access Journals (Sweden)

    Müller T

    2015-03-01

    Full Text Available Thomas Müller Department of Neurology, St Joseph Hospital Berlin-Weißensee, Berlin, Germany Abstract: The main feature of Parkinson’s disease is slowly ongoing neuronal death. Changes of neurotransmission of biogenic amines, such as dopamine, cause the heterogeneity of motor and non-motor symptoms. Therefore, compounds with a broad spectrum of mechanisms of action are ideal candidates for the treatment of the disease. Safinamide reduces dopamine turnover by reversible monoamine oxidase B inhibition, blockage of voltage-dependent sodium channels, and modulation of calcium channels and of glutamate release. Safinamide requires one-time daily intake within a dose range of 50 and 100 mg. Clinical trials demonstrated that safinamide is well tolerated and safe and ameliorates motor behavior when combined with dopamine agonist only or dopamine agonist and levodopa. Safinamide is a putative, important drug for the therapy of Parkinson’s disease with an efficacy superior to available irreversible monoamine oxidase B inhibitors or N-methyl-D-aspartate receptor antagonists. Keywords: MAO-B inhibition, glutamate release inhibition, dopamine substitution, glutamate

  16. Interference of the noradrenergic neurotoxin DSP4 with neuronal and nonneuronal monoamine transporters.

    Science.gov (United States)

    Wenge, Birger; Bönisch, Heinz

    2009-12-01

    The haloalkylamine DSP4 (N[-2-chloroethyl]-N-ethyl-2-bromobenzylamine) is a noradrenergic neurotoxin, which is used for the chemical denervation of noradrenergic neurons, and it has been proposed to be a selective substrate for the neuronal, Na(+)- and Cl(-)-dependent noradrenaline transporter (NAT). In the present study, we investigated whether DSP4 not only interacts with the human NAT (hNAT) but also with other neuronal monoamine transporters such as the transporters for dopamine (hDAT) and serotonin (hSERT) or with nonneuronal (Na(+)-independent) monoamine transporters also known as organic cation transporters (OCTs), such as hOCT(1), hOCT(2), and hOCT(3). Using human embryonic kidney HEK293 cells heterologously expressing the corresponding transporter, we show that DSP4 irreversibly inhibits the hNAT, hDAT, hSERT, and hOCT(3). However, this inhibition includes a reversible component at the hDAT, hSERT, and hOCT(3) but not at the hNAT. The inhibitory potency of DSP4 at the neuronal transporters was highest at the hNAT (IC(50) about 5 microM), and it was about five and 40 times lower at the hSERT and hDAT, respectively. DSP4 inhibited all three hOCTs with high potency (IC(50) about 1 microM) but in a completely reversible manner at hOCT(1) and hOCT(2). Cytotoxicity by 24-h exposure of hNAT- or hOCT-expressing cells to low DSP4 concentrations (DSP4's high-affinity uptake through the NAT together with its completely irreversible mode of interaction with the NAT may contribute to its selectivity as noradrenergic neurotoxin.

  17. Involvement of monoamines and proinflammatory cytokines in mediating the anti-stress effects of Panax quinquefolium.

    Science.gov (United States)

    Rasheed, Naila; Tyagi, Ethika; Ahmad, Ausaf; Siripurapu, Kiran Babu; Lahiri, Shawon; Shukla, Rakesh; Palit, Gautam

    2008-05-08

    Panax quinquefolium (PQ) is well acclaimed in literature for its effects on central and peripheral nervous system. The present study explores the effects of PQ on stress induced changes of corticosterone level in plasma, monoamines (NA, DA and 5-HT) and interleukin (IL-2 and IL-6) levels in cortex and hippocampus regions of brain and also indicate their possible roles in modulating stress. Mice subjected to chronic unpredictable stress (CUS, for 7 days) showed significant increase in plasma corticosterone level and depletion of noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT) levels in cortex and hippocampal regions along with an increased level of IL-2 and IL-6 in the same areas. Aqueous suspension of PQ was administered daily at a dose of 100 and 200mg/kg p.o. prior to the stress regimen and its effects on selected stress markers in plasma and brain was evaluated. PQ at a dose of 200mg/kg p.o. was found to be effective in normalizing the CUS induced elevation of plasma corticosterone and IL-2, IL-6 levels in brain. Moreover, it was significantly effective in reinstating the CUS induced depletion of NA, DA and 5-HT in hippocampus, while NA and 5-HT in cortex of brain. However, PQ at a dose of 100mg/kg p.o. was found ineffective in regulating any of these CUS induced changes. Present study provides an insight into the possible role of PQ on hyperactive HPA axis in the regulation of immediate stress effectors like corticosterone, cytokines and brain monoamines. In this study, PQ has emerged as a potential therapeutic in the cure of stress related disorders and needs to be evaluated in clinical studies to ascertain its efficacy.

  18. Spontaneous recurrent seizures in rats: amino acid and monoamine determination in the hippocampus.

    Science.gov (United States)

    Cavalheiro, E A; Fernandes, M J; Turski, L; Naffah-Mazzacoratti, M G

    1994-01-01

    Rats subjected to structural brain damage induced by sustained convulsions triggered by systemic administration of pilocarpine (PILO) are a useful model for investigation of the mechanisms essential for seizure generation and spread in rodents. After PILO administration, three distinct phases are observed: (a) an acute period of 1-2 days' duration corresponding to a pattern of repetitive limbic seizures and status epilepticus; (b) a seizure-free (silent) period characterized by a progressive return to normal EEG and behavior of 4-44 days' duration; and (c) a period of spontaneous recurrent seizures (SRS) starting 5-45 days after PILO administration and lasting throughout the animal's life. PILO (320-350 mg/kg intraperitoneally, i.p.) was administered to rats, and the content of hippocampal monoamines and amino acids was measured in the acute, silent, and SRS periods by liquid chromatography. Norepinephrine (NE) level was decreased during all periods whereas dopamine (DA) content was increased. Serotonin (5-hydroxytryptamine, 5-HT) was increased only in the acute period. Utilization rate measurement of monoamines showed increased NE consumption and decreased DA consumption during all phases. 5-HT utilization rate was increased only in the acute period. Amino acid content showed a decrease in aspartate (ASP) and glutamate (GLU) concentrations associated with increased gamma-aminobutyric acid (GABA) level during the acute period. The silent phase was characterized by a decrease in glycine (GLY) and GABA levels and an increase in GLU concentration. The SRS period showed an increase in all amino acid concentrations. These findings show important neurochemical changes in the course of establishment of an epileptic focus after brain damage induced by status epilepticus triggered by pilocarpine.

  19. The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue.

    Science.gov (United States)

    Baumann, Michael H; Ayestas, Mario A; Partilla, John S; Sink, Jacqueline R; Shulgin, Alexander T; Daley, Paul F; Brandt, Simon D; Rothman, Richard B; Ruoho, Arnold E; Cozzi, Nicholas V

    2012-04-01

    The nonmedical use of 'designer' cathinone analogs, such as 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxymethcathinone (methylone), is increasing worldwide, yet little information is available regarding the mechanism of action for these drugs. Here, we employed in vitro and in vivo methods to compare neurobiological effects of mephedrone and methylone with those produced by the structurally related compounds, 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine. In vitro release assays using rat brain synaptosomes revealed that mephedrone and methylone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity. In vivo microdialysis in rat nucleus accumbens showed that i.v. administration of 0.3 and 1.0 mg/kg of mephedrone or methylone produces dose-related increases in extracellular dopamine and serotonin (5-HT), with the magnitude of effect on 5-HT being greater. Both methcathinone analogs were weak motor stimulants when compared with methamphetamine. Repeated administrations of mephedrone or methylone (3.0 and 10.0 mg/kg, s.c., 3 doses) caused hyperthermia but no long-term change in cortical or striatal amines, whereas similar treatment with MDMA (2.5 and 7.5 mg/kg, s.c., 3 doses) evoked robust hyperthermia and persistent depletion of cortical and striatal 5-HT. Our data demonstrate that designer methcathinone analogs are substrates for monoamine transporters, with a profile of transmitter-releasing activity comparable to MDMA. Dopaminergic effects of mephedrone and methylone may contribute to their addictive potential, but this hypothesis awaits confirmation. Given the widespread use of mephedrone and methylone, determining the consequences of repeated drug exposure warrants further study.

  20. Monoamine oxidase inhibitors: nature of their interaction with rabbit pancreatic islets to alter insluin secretion.

    Science.gov (United States)

    Feldman, J M; Chapman, B

    1975-12-01

    Using an in vitro rabbit pancreas system, we studied the effect of monoamine oxidase (MAO) inhibitors on flucose-stimulated insulin secretion. We evaluated the effect of both brief (15 min) and prolonged (60 min) exposure of pancreas segments to non-hydrazine (harmine, alpha-methyltryptamine, tranylcypromine and pargyline) and hydrazine (phenelzine, nialamide, iproniazid) type MAO inhibitors. All of the hydrazine type MAO inhibitors potentiated glucose-stimulated insulin secretion. Of the non-hydrazine inhibitors, only harmine and alpha-methyltryptamine potentiated glucose-stimulated insulin secretion. Hydrazine, although not itself an MAO inhibitor, also potentiated insulin secretion. Sixty minutes of exposure to tranylcypromine or alpha-methyltryptamine caused a decrease in insulin secretion. These MAO inhibitors are primary amines and primary amines can inhibit insulin secretion. The dopamine (DA) or serotonin (5-HT) content of the B-cells was increased by incubating rabbit pancreas with L-3, 4-dihydroxyphenylalanine (L-Dopa) or 5-hydroxytryptophan (5-HTP) for forty-five minutes prior to stimulation with glucose. Non-hydrazine MAO inhibitors increased dopamine inhibition of insulin secretion and either did not alter, or decreased serotonin inhibition of insulin secretion. Rabbit pancreatic islets were isolated using the collagenase digestion technique. The MAO activity of islet homogenates was determined using 5-HT and DA as substrates. Rabbit islet MAO has only one-tenth the specific activity against 5-HT (35 +/- 8.7 mumumoles/mg/min, M +/- SEM) that it has against DA (357 +/- 62.3 mumumoles/mg/min). This suggests that one reason that MAT inhibitors do not increase serotonin inhibition of insulin secretion is because MAO is not the major pathway for 5-HT inactivation in rabbit pancreatic islets. These studies suggest that MAO inhibitors alter insulin secretion, by both decreasing B-cell monoamine degradation and by mechanisms that do not involve MAO inhibition.

  1. Iododerivative of pargyline: A potential tracer for the exploration of monoamine oxidase sites by SPECT

    Energy Technology Data Exchange (ETDEWEB)

    Lena, Isabelle; Ombetta, Jean-Edouard; Chalon, Sylvie; Dognon, Anne-Marie; Baulieu, Jean-Louis; Frangin, Yves; Garreau, Lucette; Besnard, Jean-Claude; Guilloteau, Denis

    1995-08-01

    Monoamine oxidases are important in the regulation of monoaminergic neurotransmission. An increase in monoamine oxidase B (MAO B) has been observed in some neurodegenerative diseases, and therefore quantification of cerebral MAO B activity by SPECT would be useful for the diagnosis and therapeutic follow-up of these disorders. We have developed an iodinated derivative of pargyline, a selective inhibitor of MAO B, in order to explore this enzyme by SPECT. Stable bromo and iodo derivatives of pargyline were synthesized and chemically characterized. The radioiodinated ligand [{sup 125}I]-2-iodopargyline was obtained with high specific activity from the bromo precursor by nucleophilic exchange. Affinity and selectivity of 2-iodopargyline were tested in vitro. Biodistribution study of [{sup 125}I]-2-iodopargyline was performed in rats. Radioiodinated ligand were obtained in a no-carrier-added form. 2-iodopargyline has a higher in vitro affinity for MAO B than pargyline. However, the in vitro selectivity for MAO B was better for pargyline than for 2-iodopargyline. Ex vivo autoradiographic studies and in vivo saturation studies with selective inhibitors of MAO showed that the cerebral biodistribution of [{sup 125}I]-2-iodopargyline in the rat is consistent with high level binding to MAO B sites in the pineal gland and in the thalamus. In conclusion, 2-iodopargyline preferentially binds in vivo to MAO B sites with high affinity. However, its selectivity for MAO B in rats is not very high, whereas this ligand binds to a lesser extent to MAO A. It will be then of great value to evaluate the specificity of 2-iodopargyline in humans. This new ligand labeled with {sup 123}I should therefore be a suitable tool for SPECT exploration of MAO B in the human brain.

  2. The Designer Methcathinone Analogs, Mephedrone and Methylone, are Substrates for Monoamine Transporters in Brain Tissue

    Science.gov (United States)

    Baumann, Michael H; Ayestas, Mario A; Partilla, John S; Sink, Jacqueline R; Shulgin, Alexander T; Daley, Paul F; Brandt, Simon D; Rothman, Richard B; Ruoho, Arnold E; Cozzi, Nicholas V

    2012-01-01

    The nonmedical use of ‘designer' cathinone analogs, such as 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxymethcathinone (methylone), is increasing worldwide, yet little information is available regarding the mechanism of action for these drugs. Here, we employed in vitro and in vivo methods to compare neurobiological effects of mephedrone and methylone with those produced by the structurally related compounds, 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine. In vitro release assays using rat brain synaptosomes revealed that mephedrone and methylone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity. In vivo microdialysis in rat nucleus accumbens showed that i.v. administration of 0.3 and 1.0 mg/kg of mephedrone or methylone produces dose-related increases in extracellular dopamine and serotonin (5-HT), with the magnitude of effect on 5-HT being greater. Both methcathinone analogs were weak motor stimulants when compared with methamphetamine. Repeated administrations of mephedrone or methylone (3.0 and 10.0 mg/kg, s.c., 3 doses) caused hyperthermia but no long-term change in cortical or striatal amines, whereas similar treatment with MDMA (2.5 and 7.5 mg/kg, s.c., 3 doses) evoked robust hyperthermia and persistent depletion of cortical and striatal 5-HT. Our data demonstrate that designer methcathinone analogs are substrates for monoamine transporters, with a profile of transmitter-releasing activity comparable to MDMA. Dopaminergic effects of mephedrone and methylone may contribute to their addictive potential, but this hypothesis awaits confirmation. Given the widespread use of mephedrone and methylone, determining the consequences of repeated drug exposure warrants further study. PMID:22169943

  3. Relationship of monoamine oxidase A binding to adaptive and maladaptive personality traits.

    Science.gov (United States)

    Soliman, A; Bagby, R M; Wilson, A A; Miler, L; Clark, M; Rusjan, P; Sacher, J; Houle, S; Meyer, J H

    2011-05-01

    Monoamine oxidase A (MAOA) is an important enzyme that metabolizes monoamines such as serotonin, norepinephrine and dopamine in the brain. In prefrontal cortex, low MAOA binding is associated with aggression and high binding is associated with major depressive disorder (MDD) and also risk for recurrence of depressive episodes. In rodent models, low MAOA levels are associated with increased aggression and fear conditioning, and decreased social and exploratory investigative behaviors. Our objective was to measure MAOA binding in prefrontal cortex and concurrently evaluate a broad range of validated personality traits. We hypothesized that prefrontal MAOA binding would correlate negatively with angry-hostility, a trait related to aggression/anger, and positively with traits intuitively related to adaptive investigative behavior. Participants were aged 19-49 years, healthy and non-smoking. MAOA binding was measured with [11C]harmine positron emission tomography (PET) in prefrontal brain regions and personality traits were measured with the NEO Personality Inventory Revised (NEO PI-R). Prefrontal MAOA binding correlated negatively with angry-hostility (r=-0.515, p=0.001) and positively with deliberation (r=0.514, p=0.001). In a two-factor regression model, these facets explained 38% of variance in prefrontal MAOA binding. A similar relationship was found in prefrontal cortex subregions. We propose a new continuum describing the relationship between personality and MAOA: deliberate/thoughtful contrasting aggressive/impulsive. Additionally, the association between high MAOA binding and greater deliberation may explain why some people have moderately high levels of MAOA, although very high levels occur during MDD. In health, higher MAOA binding is associated with an adaptive personality facet.

  4. The Met receptor tyrosine kinase prevents zebrafish primary motoneurons from expressing an incorrect neurotransmitter

    Directory of Open Access Journals (Sweden)

    Eisen Judith S

    2008-07-01

    Full Text Available Abstract Background Expression of correct neurotransmitters is crucial for normal nervous system function. How neurotransmitter expression is regulated is not well-understood; however, previous studies provide evidence that both environmental signals and intrinsic differentiation programs are involved. One environmental signal known to regulate neurotransmitter expression in vertebrate motoneurons is Hepatocyte growth factor, which acts through the Met receptor tyrosine kinase and also affects other aspects of motoneuron differentiation, including axonal extension. Here we test the role of Met in development of motoneurons in embryonic zebrafish. Results We found that met is expressed in all early developing, individually identified primary motoneurons and in at least some later developing secondary motoneurons. We used morpholino antisense oligonucleotides to knock down Met function and found that Met has distinct roles in primary and secondary motoneurons. Most secondary motoneurons were absent from met morpholino-injected embryos, suggesting that Met is required for their formation. We used chemical inhibitors to test several downstream pathways activated by Met and found that secondary motoneuron development may depend on the p38 and/or Akt pathways. In contrast, primary motoneurons were present in met morpholino-injected embryos. However, a significant fraction of them had truncated axons. Surprisingly, some CaPs in met morpholino antisense oligonucleotide (MO-injected embryos developed a hybrid morphology in which they had both a peripheral axon innervating muscle and an interneuron-like axon within the spinal cord. In addition, in met MO-injected embryos primary motoneurons co-expressed mRNA encoding Choline acetyltransferase, the synthetic enzyme for their normal neurotransmitter, acetylcholine, and mRNA encoding Glutamate decarboxylase 1, the synthetic enzyme for GABA, a neurotransmitter never normally found in these motoneurons, but

  5. Laurate Biosensors Image Brain Neurotransmitters In Vivo: Can an Antihypertensive Medication Alter Psychostimulant Behavior?

    Directory of Open Access Journals (Sweden)

    Vivek Murthy

    2008-07-01

    Full Text Available Neuromolecular Imaging (NMI with novel biosensors enables the selective detection of neurotransmitters in vivo within seconds, on line and in real time. Biosensors remain in place for continuing studies over a period of months. This biotechnological advance is based on conventional electrochemistry; the biosensors detect neurotransmitters by electron transfer. Simply stated, biosensors adsorb electrons from each neurotransmitter at specific oxidation potentials; the current derived from electron transfer is proportional to neurotransmitter concentration. Selective electron transfer properties of these biosensors permit the imaging of neurotransmitters, metabolites and precursors. The novel BRODERICK PROBE® biosensors we have developed, differ in formulation and detection capabilities from biosensors/electrodes used in conventional electrochemistry/ voltammetry. In these studies, NMI, specifically, the BRODERICK PROBE® laurate biosensor images neurotransmitter signals within mesolimbic neuronal terminals, nucleus accumbens (NAc; dopamine (DA, serotonin (5-HT, homovanillic acid (HVA and Ltryptophan (L-TP are selectively imaged. Simultaneously, we use infrared photobeams to monitor open-field movement behaviors on line with NMI in the same animal subjects. The goals are to investigate integrated neurochemical and behavioral effects of cocaine and caffeine alone and co-administered and further, to use ketanserin to decipher receptor profiles for these psychostimulants, alone and co-administered. The rationale for selecting this medication is: ketanserin (a is an antihypertensive and cocaine and caffeine produce hypertension and (b acts at 5-HT2A/2C receptors, prevalent in NAc and implicated in hypertension and cocaine addiction. Key findings are: (a the moderate dose of caffeine simultaneously potentiates cocaine's neurochemical and behavioral responses. (b ketanserin simultaneously inhibits cocaine-increased DA and 5-HT release in

  6. 奥卡西平联合选择性5-羟色胺再摄取抑制剂治疗激越性抑郁的开放性研究%An open study of oxcarbazepine combined with selective serotonin re-uptake inhibitor in treating outpatients with agitated depression

    Institute of Scientific and Technical Information of China (English)

    马永春; 陈正昕; 金卫东

    2010-01-01

    目的 观察和评价门诊32例激越性抑郁患者在应用选择性5-羟色胺再摄取抑制剂(SSRI)的基础上联合应用奥卡西平的效果与不良反应.方法 对符合抑郁症诊断标准同时伴有激越症状的32例患者在应用SSRI的基础上联合应用奥卡西平(0.3 g/片,第1、2天1片,第3天起2片,7 d内根据情况用至4~5片)治疗,观察8周,应用汉密尔顿抑郁评定量表(HAMD)、汉密尔顿焦虑评定量表(HAMA)、杨氏躁狂评定量表(YMRS)评价疗效和不良反应.结果 32例患者奥卡西平平均用量为(1020±65)mg/d.临床有效率为87.5%(28/32),痊愈率为65.6%(21/32).治疗后1周、2周、4周、8周的有效率和痊愈率分别是28.1%(9/32)与6.3%(2/32)、37.5%(12/321与12.5%(4/32)、46.9%05/32)与31.3%(10/32)、90.6%(29/32)与65.6%(21/32).患者治疗后1周、2周、4周、8周的各量表评分与治疗前比较差异均有统计学意义(P<0.05).32例患者中没有1例出现转躁狂现象.结论 奥卡西平联合SSRI治疗激越性抑郁可获得较好的疗效.%Objective To observe the efficacy and safety of oxcarbazepine combined with selective serotonin re-uptake inhibitor (SSRI) in the treatment of outpatients with agitated depression. Methods Thirty-two outpatients with agitated symptoms meeting CCMD-3 depression criteria were treated with oxcarbazepine combined with SSRI for 8 w: the dosage of oxcarbazepine changed dairy (1st and 2nd d, 0.3 g; 3rd d, 0.6 g; 7th and 8th, 1.2-1.5 g). The efficacy and side effects were assessed by Hamilton depression scale, Hamilton anxiety rating scale and Young manic-state rating scale. Results The mean dosage of oxcarbazepine in 32 patients was (1020±65) mg/d. Their mean effective rate and full remission rate 87.5% and 65.6%,respectively. The mean effective rate and full remission rate 1, 2, 4 and 8 w after the treatment were 28.1% (9/32) and 6.3% (2/32), 37.5% (12/32) and 12.5% (4/32), 46.9% (15/32) and 31.3% (10/32), and 90.6% (29/32) and 65

  7. Study on Psychoprophylaxis and Monoamines Neurotransmitter of Patients with Burning Month Syndrome%灼口综合征患者的心理健康状况及其单胺类神经递质研究

    Institute of Scientific and Technical Information of China (English)

    林梅; 李秉琦; 顾芳; 岳玉敏; 黄玉云; 陈谦明; 曾光明; 夏娟

    2001-01-01

    目的从与痛觉联系紧密的心理因素和单胺类神经递质方面对灼口综合征患者进行测定和分析.方法灼口综合征(BMS)组选择初诊患者30例,其中男性4例,女性26例.对照组为30例年龄、性别相似的健康人.采用艾森克个性问卷量表(EPQ)对受试者进行个性测定,并将L值(谎言值)>50分者排除.采用修订的临床症状自评量表(SCL-90)检测受试者的情绪状况.在晨9时平和状态下抽空腹静脉血2ml,用高效液相色谱-电化学检测法测定血浆中肾上腺素和去甲肾上腺素浓度.结果BMS组P值(精神质)、N值(神经质)分高于对照组(P<0.05),E值(内外相)低于对照组(P<0.05),两组间个性类型分布具有显著性差异(P<0.05).BMS组以内向不稳定型为主,对照组以外向稳定型为主.BMS组有强迫、忧郁、人际关系敏感度、焦虑等9个因子分值高于对照组(P<0.05),存在明显的情绪障碍.BMS女性患者血浆去甲肾上腺素水平高于对照组(P<0.01).结论BMS患者的个性特征提高了机体对各种不良刺激的反应性,明显的情绪障碍可导致中枢神经系统和交感神经功能的失调,这可能与BMS的发生有内在的联系.

  8. 抽动-秽语综合征患儿尿香草扁桃酸的变化及意义%Changes and significances of monoamine neurotransmitter vanillyl mandelic acids in urine of Tourette's syndrome patients

    Institute of Scientific and Technical Information of China (English)

    常会波; 王珺; 李尔珍; 王立文; 吴建新

    2013-01-01

    目的 了解抽动-秽语综合征(tourette's syndrome,TS)患儿尿单氨类神经递质代谢产物香草扁桃酸(vanillylmandelic acid,VMA)水平,探讨其与疾病发生的意义.方法 以40例TS患儿为病例组,33例健康儿童作为正常对照组.采集研究对象的尿液,经高效液相色谱法分离后利用库仑阵列电化学检测香草扁桃酸(VMA)水平,紫外检测器检测作为校正因素的肌酐含量.利用VMA/Cr代表尿样中VMA的水平.结果 病例组尿液VMA/Cr值为:(1.597±0.095)μg/mg,对照组VMA/Cr值为(2.198±0.112)μg/mg,病例组尿液VMA/Cr均值显著低于对照组(P<0.001),病例组和对照组VMA/Cr均值男女之间差异均无统计学意义.结论 TS患儿中存在VMA水平异常.

  9. High-throughput screening for monoamine oxidase-A and monoamine oxidase-B inhibitors using one-step fluorescence assay

    Institute of Scientific and Technical Information of China (English)

    Hong-mei GUANG; Guan-hua DU

    2006-01-01

    Aim: To develop high-throughput screening (HTS) assays for monoamine oxidase (MAO)-A and MAO-B inhibitors. Methods: A fluorescence probe based method measuring MAO-A and MAO-B activity was established and optimized, with its sensitivity, stability and specificity evaluated. Reaction conditions including enzyme sources, substrate concentrations, incubation volume and reaction time in 384-well format were optimized to achieve sensitive and low consumptive goal. Results: In optimized conditions, dynamic parameters of MAO-A and MAO-B were obtained. The Km value of serotonin to MAO-A was 1.66 μmol/L, while that of benzylamine to MAO-B was 0.80 umol/L. The IC50 value of clorgyline to MAO-A was 2.99 nmol/L, and that of deprenyl to MAO-B was 7.04 nmol/L, matching those obtained from traditional spectrometric assays. Among tested samples, one compound exerted an inhibitory effect on MAO-A activity with IC50 as 0.36 μmol/L, and three compounds had an inhibitory effect on MAO-B activity with IC50 as 0.13,0.19, and 0.13 μmol/L. The Z' factor was 0.71±0.03 and 0.75±0.03 in MAO-A-inhibitor and MAO-B-inhibitor HTS system, respectively. Conclusion: The established assays can be well applied to MAO-A and MAO-B inhibitor screening with high quality, precision and reproducibility.

  10. Antidepressant drugs transactivate TrkB neurotrophin receptors in the adult rodent brain independently of BDNF and monoamine transporter blockade.

    Directory of Open Access Journals (Sweden)

    Tomi Rantamäki

    Full Text Available BACKGROUND: Antidepressant drugs (ADs have been shown to activate BDNF (brain-derived neurotrophic factor receptor TrkB in the rodent brain but the mechanism underlying this phenomenon remains unclear. ADs act as monoamine reuptake inhibitors and after prolonged treatments regulate brain bdnf mRNA levels indicating that monoamine-BDNF signaling regulate AD-induced TrkB activation in vivo. However, recent findings demonstrate that Trk receptors can be transactivated independently of their neurotrophin ligands. METHODOLOGY: In this study we examined the role of BDNF, TrkB kinase activity and monoamine reuptake in the AD-induced TrkB activation in vivo and in vitro by employing several transgenic mouse models, cultured neurons and TrkB-expressing cell lines. PRINCIPAL FINDINGS: Using a chemical-genetic TrkB(F616A mutant and TrkB overexpressing mice, we demonstrate that ADs specifically activate both the maturely and immaturely glycosylated forms of TrkB receptors in the brain in a TrkB kinase dependent manner. However, the tricyclic AD imipramine readily induced the phosphorylation of TrkB receptors in conditional bdnf⁻/⁻ knock-out mice (132.4±8.5% of control; P = 0.01, indicating that BDNF is not required for the TrkB activation. Moreover, using serotonin transporter (SERT deficient mice and chemical lesions of monoaminergic neurons we show that neither a functional SERT nor monoamines are required for the TrkB phosphorylation response induced by the serotonin selective reuptake inhibitors fluoxetine or citalopram, or norepinephrine selective reuptake inhibitor reboxetine. However, neither ADs nor monoamine transmitters activated TrkB in cultured neurons or cell lines expressing TrkB receptors, arguing that ADs do not directly bind to TrkB. CONCLUSIONS: The present findings suggest that ADs transactivate brain TrkB receptors independently of BDNF and monoamine reuptake blockade and emphasize the need of an intact tissue context for the

  11. FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels.

    Science.gov (United States)

    Deng, Pan-Yue; Rotman, Ziv; Blundon, Jay A; Cho, Yongcheol; Cui, Jianmin; Cavalli, Valeria; Zakharenko, Stanislav S; Klyachko, Vitaly A

    2013-02-20

    Loss of FMRP causes fragile X syndrome (FXS), but the physiological functions of FMRP remain highly debatable. Here we show that FMRP regulates neurotransmitter release in CA3 pyramidal neurons by modulating action potential (AP) duration. Loss of FMRP leads to excessive AP broadening during repetitive activity, enhanced presynaptic calcium influx, and elevated neurotransmitter release. The AP broadening defects caused by FMRP loss have a cell-autonomous presynaptic origin and can be acutely rescued in postnatal neurons. These presynaptic actions of FMRP are translation independent and are mediated selectively by BK channels via interaction of FMRP with BK channel's regulatory β4 subunits. Information-theoretical analysis demonstrates that loss of these FMRP functions causes marked dysregulation of synaptic information transmission. FMRP-dependent AP broadening is not limited to the hippocampus, but also occurs in cortical pyramidal neurons. Our results thus suggest major translation-independent presynaptic functions of FMRP that may have important implications for understanding FXS neuropathology.

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

    Directory of Open Access Journals (Sweden)

    Min H. Kim

    2016-11-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  14. Neurotransmitter evaluation in the hippocampus of rats after intracerebral injection of TsTX scorpion toxin

    Directory of Open Access Journals (Sweden)

    ALA Nencioni

    2009-01-01

    Full Text Available TsTX is an α-type sodium channel toxin that stimulates the discharge of neurotransmitters from neurons. In the present study we investigated which neurotransmitters are released in the hippocampus after TsTX injection and if they are responsible for electrographic or histopathological effects. Microdialysis revealed that the toxin increased glutamate extracellular levels in the hippocampus; however, levels of gamma-aminobutyric acid (GABA, glycine, 5-hydroxyindoleacetic acid (5-HIAA, homovanillic acid (HVA and 3,4-dihydroxyphenylacetic acid (DOPAC were not significantly altered. Neurodegeneration in pyramidal cells of hippocampus and electroencephalographic alterations caused by the toxin were blocked by pretreatment with riluzole, a glutamate release inhibitor. The present results suggest a specific activity of TsTX in the hippocampus which affects only glutamate release.

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

    Science.gov (United States)

    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.

  16. Parallel expression of synaptophysin and evoked neurotransmitter release during development of cultured neurons

    DEFF Research Database (Denmark)

    Ehrhart-Bornstein, M; Treiman, M; Hansen, Gert Helge;

    1991-01-01

    and neurotransmitter release were measured in each of the culture types as a function of development for up to 8 days in vitro, using the same batch of cells for both sets of measurements to obtain optimal comparisons. The content and the distribution of synaptophysin in the developing cells were assessed...... by quantitative immunoblotting and light microscope immunocytochemistry, respectively. In both cell types, a close parallelism was found between the temporal pattern of development in synaptophysin expression and neurotransmitter release. This temporal pattern differed between the two types of neurons....... The cerebral cortex neurons showed a biphasic time course of increase in synaptophysin content, paralleled by a biphasic pattern of development in their ability to release [3H]GABA in response to depolarization by glutamate or elevated K+ concentrations. In contrast, a monophasic, approximately linear increase...

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

    Science.gov (United States)

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

    2007-09-07

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

  18. [Detection of neurotransmitter interactions with PET and SPECT by pharmacological challenge paradigms].

    Science.gov (United States)

    Schlösser, R

    2000-01-01

    Functional brain imaging with positron emission tomography (PET) and single photon emission computerized tomography (SPECT) enables the in vivo study of specific neurochemical processes in the context of normal regulatory mechanisms and pathophysiological alterations of the brain. By combining these methods with pharmacological challenge-paradigms, the study of functional interactions of different neurotransmitter systems is possible. This review will present data from animal and healthy volunteer studies as well as first data from investigations in different patient populations with regard to this research direction. Especially, interactions of different neurotransmitter systems with the dopaminergic and the cholinergic system will be discussed. The database acquired so far confirms existing models of neuronal feedback-circuits, and the first clinical results are consistent with the hypothesis of an increased dopaminergic responsivity in schizophrenic patients. These results open up new perspectives for a further evaluation of treatment response predictors from drug-challenge studies and for the development of new drug treatments for neuropsychiatric disorders.

  19. Control of neurotransmitter release by an internal gel matrix in synaptic vesicles.

    Science.gov (United States)

    Reigada, David; Díez-Pérez, Ismael; Gorostiza, Pau; Verdaguer, Albert; Gómez de Aranda, Inmaculada; Pineda, Oriol; Vilarrasa, Jaume; Marsal, Jordi; Blasi, Joan; Aleu, Jordi; Solsona, Carles

    2003-03-18

    Neurotransmitters are stored in synaptic vesicles, where they have been assumed to be in free solution. Here we report that in Torpedo synaptic vesicles, only 5% of the total acetylcholine (ACh) or ATP content is free, and that the rest is adsorbed to an intravesicular proteoglycan matrix. This matrix, which controls ACh and ATP release by an ion-exchange mechanism, behaves like a smart gel. That is, it releases neurotransmitter and changes its volume when challenged with small ionic concentration change. Immunodetection analysis revealed that the synaptic vesicle proteoglycan SV2 is the core of the intravesicular matrix and is responsible for immobilization and release of ACh and ATP. We suggest that in the early steps of vesicle fusion, this internal matrix regulates the availability of free diffusible ACh and ATP, and thus serves to modulate the quantity of transmitter released.

  20. The magnitude and significance of Ca2+ domains for release of neurotransmitter.

    Science.gov (United States)

    Aharon, S; Parnas, H; Parnas, I

    1994-11-01

    It is now widely accepted that localized high concentrations of Ca2+ (Ca2+ domains) play a major role in controlling the time course of neurotransmitter release. In the present work we calculate the magnitude and the time course of Ca2+ domains that evolve in the vicinity of a Ca2+ channel and an adjacent release site. In the calculations we consider a accurately dimensioned Ca2+ channel. Moreover, the Ca2+ current is continuously adjusted with regard to the accumulated intracellular Ca2+ and, in addition, endogenous buffers are considered. The calculations, carried out by the software FIDAP, based on finite element method, show that the Ca2+ concentrations achieved near the release sites are significantly lower than claimed by other investigators. Furthermore, we present arguments indicating that the Ca2+ domains, regardless of their magnitude, do not play a role in controlling the time course of release of neurotransmitter.

  1. Effects of the Bee Venom Herbal Acupuncture on the Neurotransmitters of the Rat Brain Cortex

    Directory of Open Access Journals (Sweden)

    Hyoung-Seok Yun

    2001-02-01

    Full Text Available In order to study the effects of bee venom Herbal Acupuncture on neurotransmitters in the rat brain cortex, herbal acupuncture with bee venom group and normal saline group was performed at LI4 bilaterally of the rat. the average optical density of neurotransmitters from the cerebral cortex was analysed 30 minutes after the herbal aqupuncture, by the immunohistochemistry. The results were as follows: 1. The density of NADPH-diaphorase in bee venom group was increased significantly at the motor cortex, visual cortex, auditory cortex, cingulate cortex, retrosplenial cortex and perirhinal cortex compared to the normal saline group. 2. The average optical density of vasoactive intestinal peptide in bee venom group had significant changes at the insular cortex, retrosplenial cortex and perirhinal cortex, compared to the normal saline group. 3. The average optical density of neuropeptide-Y in bee venom group increased significantly at the visual cortex and cingulate cortex, compared to the normal saline group.

  2. Influence of ketamine on amino acid neurotransmitters secretion by nerve cells in vitro

    Directory of Open Access Journals (Sweden)

    Mingxian Shi

    2016-04-01

    Full Text Available In order to study the influence of amino acid neurotransmitters secreted by the nerve cells after ketamine treatment, the nerve cells were cultured in vitro to exclude the interference of other factors in vivo and treated with three different doses of ketamine (1, 3 and 5 µg/mL. Then, the concentration of neuronal amino acid neurotransmitters was examined at 0, 15, 30, 45, 60, 90, 120 min after treatment. The trends of each amino acid concentration after ketamine treatment were nearly the same among the different treatment doses. After 15 min of adapting time, ketamine decreased the excitatory amino acid glutamic acid and aspartic acid concentration, and increased the concentration of the inhibitory amino acid glycine. Their concentrations showed a tendency to return approximately to the original level after 120 min.

  3. Corticosterone modulation of neurotransmitter receptors in rat hippocampus: a quantitative autoradiographic study

    Energy Technology Data Exchange (ETDEWEB)

    Biegon, A. (Hoffmann-La Roche, Inc., Nutley, NJ (USA). Dept. of Pharmacology); Rainbow, T.C. (Pennsylvania Univ., Philadelphia (USA). School of Medicine); McEwen, B.S. (Rockefeller Univ., New York (USA))

    1985-04-22

    The effect of adrenalectomy (ADX) and corticosterone (CORT) replacement on neurotransmitter receptors was studied in dorsal hippocampus of rat using quantitative autoradiography. ADX for one week causes an increase in (/sup 3/H)5-HT binding to 5-HT/sub 1/ receptors which is significant in the CA1 cell field. CORT treatment of ADX rats for 3-5 days results in localized reductions of (/sup 3/H)5-HT binding including a partial reversal of the increase observed after ADX in CA1. CORT treatment of ADX animals also decreases binding of (/sup 3/H)QNB to muscarinic receptors in the dorsal hippocampus, with a significant effect in an area designated as subiculum. No influence of CORT was detected on (/sup 3/H)prazosin binding to alpha/sub 1/ adrenergic receptors in dorsal hippocampus. Possible mechanisms for hormone effects on neurotransmitter receptor levels are discussed.

  4. Swim pacemaker response to bath applied neurotransmitters in the cubozoan Tripedalia cystophora.

    Science.gov (United States)

    Bielecki, Jan; Nachman, Gösta; Garm, Anders

    2013-09-01

    The four rhopalia of cubomedusae are integrated parts of the central nervous system carrying their many eyes and thought to be the centres of visual information processing. Rhopalial pacemakers control locomotion through a complex neural signal transmitted to the ring nerve and the signal frequency is modulated by the visual input. Since electrical synapses have never been found in the cubozoan nervous system all signals are thought to be transmitted across chemical synapses, and so far information about the neurotransmitters involved are based on immunocytochemical or behavioural data. Here we present the first direct physiological evidence for the types of neurotransmitters involved in sensory information processing in the rhopalial nervous system. FMRFamide, serotonin and dopamine are shown to have inhibitory effect on the pacemaker frequency. There are some indications that the fast acting acetylcholine and glycine have an initial effect and then rapidly desensitise. Other tested neuroactive compounds (GABA, glutamate, and taurine) could not be shown to have a significant effect.

  5. Synapsin II desynchronizes neurotransmitter release at inhibitory synapses by interacting with presynaptic calcium channels.

    Science.gov (United States)

    Medrihan, Lucian; Cesca, Fabrizia; Raimondi, Andrea; Lignani, Gabriele; Baldelli, Pietro; Benfenati, Fabio

    2013-01-01

    In the central nervous system, most synapses show a fast mode of neurotransmitter release known as synchronous release followed by a phase of asynchronous release, which extends over tens of milliseconds to seconds. Synapsin II (SYN2) is a member of the multigene synapsin family (SYN1/2/3) of synaptic vesicle phosphoproteins that modulate synaptic transmission and plasticity, and are mutated in epileptic patients. Here we report that inhibitory synapses of the dentate gyrus of Syn II knockout mice display an upregulation of synchronous neurotransmitter release and a concomitant loss of delayed asynchronous release. Syn II promotes γ-aminobutyric acid asynchronous release in a Ca(2+)-dependent manner by a functional interaction with presynaptic Ca(2+) channels, revealing a new role in synaptic transmission for synapsins.

  6. CDK5 serves as a major control point in neurotransmitter release.

    Science.gov (United States)

    Kim, Sung Hyun; Ryan, Timothy A

    2010-09-09

    CDK5 is an important kinase in nervous system function, controlling neural development and postsynaptic signal integration. Here we show that CDK5 plays a major role in controlling neurotransmitter release. Inhibition of CDK5 activity, by either acute or genetic means, leads to profound potentiation of presynaptic function, including unmasking of previously "silent" synapses. Removal of CDK5 activity additionally unlocks access to the resting synaptic vesicle pool, which normally remains recalcitrant to exocytosis and recycling even following prolonged action potential stimuli. Presynaptic CDK5 levels are additionally severely depleted by chronic neuronal silencing, a treatment that is functionally similar to CDK5 knockdown with regard to presynaptic potentiation. Thus CDK5 appears to be an integral element in presynaptic homeostatic scaling, and the resting vesicle pool appears to provide a potent functional presynaptic homeostatic control parameter. These studies thus pinpoint CDK5 as a major control point for modulation of neurotransmitter release in mammalian neurons.

  7. Activity-dependent neurotransmitter-receptor matching at the neuromuscular junction.

    Science.gov (United States)

    Borodinsky, Laura N; Spitzer, Nicholas C

    2007-01-02

    Signaling in the nervous system requires matching of neurotransmitter receptors with cognate neurotransmitters at synapses. The vertebrate neuromuscular junction is the best studied cholinergic synapse, but the mechanisms by which acetylcholine is matched with acetylcholine receptors are not fully understood. Because alterations in neuronal calcium spike activity alter transmitter specification in embryonic spinal neurons, we hypothesized that receptor expression in postsynaptic cells follows changes in transmitter expression to achieve this specific match. We find that embryonic vertebrate striated muscle cells normally express receptors for glutamate, GABA, and glycine as well as for acetylcholine. As maturation progresses, acetylcholine receptor expression prevails. Receptor selection is altered when early neuronal calcium-dependent activity is perturbed, and remaining receptor populations parallel changes in transmitter phenotype. In these cases, glutamatergic, GABAergic, and glycinergic synaptic currents are recorded from muscle cells, demonstrating that activity regulates matching of transmitters and their receptors in the assembly of functional synapses.

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

    Science.gov (United States)

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

    2008-10-01

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

  9. New Trends and Perspectives in the Evolution of Neurotransmitters in Microbial, Plant, and Animal Cells.

    Science.gov (United States)

    Roshchina, Victoria V

    2016-01-01

    The evolutionary perspective on the universal roles of compounds known as neurotransmitters may help in the analysis of relations between all organisms in biocenosis-from microorganisms to plant and animals. This phenomenon, significant for chemosignaling and cellular endocrinology, has been important in human health and the ability to cause disease or immunity, because the "living environment" influences every organism in a biocenosis relationship (microorganism-microorganism, microorganism-plant, microorganism-animal, plant-animal, plant-plant and animal-animal). Non-nervous functions of neurotransmitters (rather "biomediators" on a cellular level) are considered in this review and ample consideration is given to similarities and differences that unite, as well as distinguish, taxonomical kingdoms.

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

    Science.gov (United States)

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

    2015-01-21

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

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

    OpenAIRE

    John, Carrie E.; Jones, Sara R

    2007-01-01

    Fast scan cyclic voltammetry is an electrochemical technique used to measure dynamics of transporter-mediated monoamine uptake in real time and provides a tool to evaluate the detailed effects of monoamine uptake inhibitors and releasers on dopamine and serotonin transporter function. We measured the effects of cocaine, methylphenidate, 2β-propanoyl–3β-(4tolyl) tropane (PTT), fluoxetine, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), phentermine and fenfluramine on do...

  12. Piperidine-Based Nocaine/Modafinil Hybrid Ligands as Highly Potent Monoamine Transporter Inhibitors: Efficient Drug Discovery by Rational Lead Hybridization

    Science.gov (United States)

    Zhou, Jia; He, Rong; Johnson, Kenneth M.; Ye, Yanping; Kozikowski, Alan P.

    2005-01-01

    Some piperidine-based nocaine/modafinil hybrid ligands have been designed, synthesized, and found to display an improved potency at all three monoamine transporters and particularly for DAT and/or NET. Some highly active and selective monoamine transporter inhibitors with low nanomolar to subnanomolar potency were identified. Ligands of this type may find important applications as positron emission tomography imaging tools and in the treatment of central nervous system disorders such as depression and sleep apnea. PMID:15537337

  13. Aspects of astrocyte energy metabolism, amino acid neurotransmitter homoeostasis and metabolic compartmentation

    DEFF Research Database (Denmark)

    Kreft, Marko; Bak, Lasse Kristoffer; Waagepetersen, Helle S

    2012-01-01

    Astrocytes are key players in brain function; they are intimately involved in neuronal signalling processes and their metabolism is tightly coupled to that of neurons. In the present review, we will be concerned with a discussion of aspects of astrocyte metabolism, including energy-generating pat......-generating pathways and amino acid homoeostasis. A discussion of the impact that uptake of neurotransmitter glutamate may have on these pathways is included along with a section on metabolic compartmentation....

  14. Mechanical tension contributes to clustering of neurotransmitter vesicles at presynaptic terminals

    OpenAIRE

    2009-01-01

    Memory and learning in animals are mediated by neurotransmitters that are released from vesicles clustered at the synapse. As a synapse is used more frequently, its neurotransmission efficiency increases, partly because of increased vesicle clustering in the presynaptic neuron. Vesicle clustering has been believed to result primarily from biochemical signaling processes that require the connectivity of the presynaptic terminal with the cell body, the central nervous system, and the postsynapt...

  15. The dependence of neuronal encoding efficiency on Hebbian plasticity and homeostatic regulation of neurotransmitter release

    Directory of Open Access Journals (Sweden)

    Faramarz eFaghihi

    2015-04-01

    Full Text Available Synapses act as information filters by different molecular mechanisms including retrograde messenger that affect neuronal spiking activity. One of the well-known effects of retrograde messenger in presynaptic neurons is a change of the probability of neurotransmitter release. Hebbian learning describe a strengthening of a synapse between a presynaptic input onto a postsynaptic neuron when both pre- and postsynaptic neurons are coactive. In this work, a theory of homeostatic regulation of neurotransmitter release by retrograde messenger and Hebbian plasticity in neuronal encoding is presented. Encoding efficiency was measured for different synaptic conditions. In order to gain high encoding efficiency, the spiking pattern of a neuron should be dependent on the intensity of the input and show low levels of noise. In this work, we represent spiking trains as zeros and ones (corresponding to non-spike or spike in a time bin, respectively as words with length equal to three. Then the frequency of each word (here eight words is measured using spiking trains. These frequencies are used to measure neuronal efficiency in different conditions and for different parameter values. Results show that neurons that have synapses acting as band-pass filters show the highest efficiency to encode their input when both Hebbian mechanism and homeostatic regulation of neurotransmitter release exist in synapses. Specifically, the integration of homeostatic regulation of feedback inhibition with Hebbian mechanism and homeostatic regulation of neurotransmitter release in the synapses leads to even higher efficiency when high stimulus intensity is presented to the neurons. However, neurons with synapses acting as high-pass filters show no remarkable increase in encoding efficiency for all simulated synaptic plasticity mechanisms.

  16. Effect of paroxetine combined with climen on hormone levels and neurotransmitters in patients with perimenopausal depression

    Institute of Scientific and Technical Information of China (English)

    Wei-Ling Huang

    2016-01-01

    Objective:To analyze the effect of paroxetine combined with climen on hormone levels and neurotransmitters in patients with perimenopausal depression. Methods:A total of 96 cases of perimenopausal women who met the diagnosis of depression and were treated in our hospital from July 2012 to March 2015 were selected as research subjects and randomly divided into observation group and control group, each group with 48 cases. Control group received paroxetine therapy alone, observation group received paroxetine combined with climen therapy, serum hormone and neurotransmitter levels of two groups were compared, and severity of menopause and depression was detected after treatment. Results:E2 level of observation group after treatment was higher than that of control group, and levels of FSH and LH were lower than those of control group;serum NE, 5-HT, DA, Glu and Asp values of observation group after treatment were higher than those of control group, and values of GABA and Gly were lower than those of control group;KI, MRS and HAMD scores of observation group after treatment were lower than those of control group. Conclusion:Paroxetine combined with climen therapy for patients with perimenopausal depression can effectively optimize the levels of hormones and neurotransmitters in patients and reduce the symptom severity of menopause and depression.

  17. [Single and combining effects of Calculus Bovis and zolpidem on inhibitive neurotransmitter of rat striatum corpora].

    Science.gov (United States)

    Liu, Ping; He, Xinrong; Guo, Mei

    2010-04-01

    To investigate the correlation effects between single or combined administration of Calculus Bovis or zolpidem and changes of inhibitive neurotransmitter in rat striatum corpora. Sampling from rat striatum corpora was carried out through microdialysis. The content of two inhibitive neurotransmitters in rat corpus striatum- glycine (Gly) and gama aminobutyric acid (GABA), was determined by HPLC, which involved pre-column derivation with orthophthaladehyde, reversed-phase gradient elution and fluorescence detection. GABA content of rat striatum corpora in Calculus Bovis group was significantly increased compared with saline group (P Calculus Boris plus zolpidem group were increased largely compared with saline group as well (P Calculus Bovis group was higher than combination group (P Calculus Bovis or zolpidem group was markedly increased compared with saline group or combination group (P Calculus Bovis group, zolpidem group and combination group. The magnitude of increase was lower in combination group than in Calculus Bovis group and Zolpidem group, suggesting that Calculus Bovis promoted encephalon inhibition is more powerful than zolpidem. The increase in two inhibitive neurotransmitters did not show reinforcing effect in combination group, suggesting that Calculus Bovis and zolpidem may compete the same receptors. Therefore, combination of Calculus Bovis containing drugs and zolpidem has no clinical significance. Calculus Bovis shouldn't as an aperture-opening drugs be used for resuscitation therapy.

  18. Excitatory and inhibitory neurotransmitters in the generation and degeneration of hippocampal neuroarchitecture.

    Science.gov (United States)

    Mattson, M P; Kater, S B

    1989-01-30

    The possibility that excitatory and inhibitory inputs to neurons can affect the generation and degeneration of neuroarchitecture was examined in hippocampal pyramidal neurons in isolated cell culture. Dendritic outgrowth and cell survival were directly monitored in neurons exposed to: the excitatory neurotransmitter glutamate, the inhibitory transmitter GABA, anticonvulsants or combinations of these agents. Glutamate caused a graded series of changes in pyramidal neuron cytoarchitecture: a selective inhibition in dendritic outgrowth and dendritic pruning was observed with subtoxic levels of glutamate while cell death was induced by higher levels. Low levels of GABA alone or in combination with diazepam, carbamazepine, phenobarbital or phenytoin were without effect on dendrite outgrowth while higher levels caused moderate reductions in outgrowth. Neither GABA nor the anticonvulsants affected cell survival. GABA plus diazepam, phenobarbital, carbamazepine and phenytoin each significantly reduced the dendritic regression and cell death normally caused by glutamate. Elevation of extracellular K+ to 50 mM caused dendritic regression and 100 mM K+ caused cell death; these effects were greatly reduced by GABA and anticonvulsants. The calcium channel blocker Co2+ prevented the dendritic regression and cell death caused by both glutamate and K+ indicating that calcium influx was required for the neuroarchitectural responses. Taken together, these results demonstrate that neurotransmitters and neuromodulatory drugs can have direct and interactive effects on both neurite outgrowth and cell survival. Such neurotransmitter actions may play roles in both the formation and degeneration of the neuronal circuits in which they participate in information coding.

  19. Sympathetic Neurotransmitters Modulate Osteoclastogenesis and Osteoclast Activity in the Context of Collagen-Induced Arthritis.

    Directory of Open Access Journals (Sweden)

    Dominique Muschter

    Full Text Available Excessive synovial osteoclastogenesis is a hallmark of rheumatoid arthritis (RA. Concomitantly, local synovial changes comprise neuronal components of the peripheral sympathetic nervous system. Here, we wanted to analyze if collagen-induced arthritis (CIA alters bone marrow-derived macrophage (BMM osteoclastogenesis and osteoclast activity, and how sympathetic neurotransmitters participate in this process. Therefore, BMMs from Dark Agouti rats at different CIA stages were differentiated into osteoclasts in vitro and osteoclast number, cathepsin K activity, matrix resorption and apoptosis were analyzed in the presence of acetylcholine (ACh, noradrenaline (NA vasoactive intestinal peptide (VIP and assay-dependent, adenylyl cyclase activator NKH477. We observed modulation of neurotransmitter receptor mRNA expression in CIA osteoclasts without affecting protein level. CIA stage-dependently altered marker gene expression associated with osteoclast differentiation and activity without affecting osteoclast number or activity. Neurotransmitter stimulation modulated osteoclast differentiation, apoptosis and activity. VIP, NA and adenylyl cyclase activator NKH477 inhibited cathepsin K activity and osteoclastogenesis (NKH477, 10(-6 M NA whereas ACh mostly acted pro-osteoclastogenic. We conclude that CIA alone does not affect metabolism of in vitro generated osteoclasts whereas stimulation with NA, VIP plus specific activation of adenylyl cyclase induced anti-resorptive effects probably mediated via cAMP signaling. Contrary, we suggest pro-osteoclastogenic and pro-resorptive properties of ACh mediated via muscarinic receptors.

  20. Neuromodulating mice and men: Are there functional species differences in neurotransmitter concentration?

    Science.gov (United States)

    Fitzgerald, Paul J

    2009-07-01

    I examine evidence that the concentration of certain modulatory neurotransmitters varies across species, including differences between rodents and primates. Microdialysis studies indicate that the baseline concentration of serotonin, norepinephrine, dopamine, and acetylcholine, as measured in the prefrontal cortex of awake animals, may differ between rats and macaque monkeys. These differences may extend to mice and humans, as well. If there are differences in the tonic concentration of these neurotransmitters, this may affect the functioning of these transmitter systems in multiple ways, including potential effects on neuropsychiatric conditions such as the various mental illnesses and modeling of them in animals. Species differences in transmitter concentration may also have neuropharmacological implications, and may be relevant to the phenomenon of differences in speed of drug response between humans and rodents. This paper is divided into three sections that address related questions about the potential concentration differences: (1) Are there species differences in baseline neurotransmitter concentration? (2) Are the putative differences functional? (3) What might the functional differences be? Consideration of the existing evidence indicates that there may indeed be functional species differences in the modulatory transmitter systems.

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

    Science.gov (United States)

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

    2015-05-22

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

  2. The Molecular Basis of Memory. Part 3: Tagging with emotive neurotransmitters.

    Directory of Open Access Journals (Sweden)

    Gerard eMarx

    2014-04-01

    Full Text Available Many neurons of all animals that exhibit memory (snails, worms, flies, vertebrae present arborized shapes with many varicosities and boutons. These neurons, release neurotransmitters and contain ionotropic receptors that produce and sense electrical signals (ephaptic transmission. The extended shapes maximize neural contact with the surrounding neutrix (neural extracellular matrix (nECM+ diffusible (neurometals and neurotransmitters as well as with other neurons. We propose a tripartite mechanism of animal memory based on the dynamic interactions of splayed neurons with the neutrix. Their interactions form cognitive units of information (cuinfo, metal-centered complexes within the nECM around the neuron. Emotive content is provided by NTs, which embody molecular links between physiologic (body responses and psychic feelings. We propose that neurotransmitters form mixed complexes with cuinfo used for tagging emotive memory.Thus, NTs provide encoding option not available to a Turing, binary-based, device.The neurons employ combinatorially diverse options, with > 10 NMs and > 90 NTs for encoding (flavoring cuinfo with emotive tags. The neural network efficiently encodes, decodes and consolidates related (entangled sets of cuinfo into a coherent pattern, the basis for emotionally imbued memory, critical for determining a behavioral choice aimed at survival. The tripartite mechanism with tagging of NTs permits of a causal connection between physiology and psychology.

  3. Detection of amino acid neurotransmitters by surface enhanced Raman scattering and hollow core photonic crystal fiber

    Science.gov (United States)

    Tiwari, Vidhu S.; Khetani, Altaf; Monfared, Ali Momenpour T.; Smith, Brett; Anis, Hanan; Trudeau, Vance L.

    2012-03-01

    The present work explores the feasibility of using surface enhanced Raman scattering (SERS) for detecting the neurotransmitters such as glutamate (GLU) and gamma-amino butyric acid (GABA). These amino acid neurotransmitters that respectively mediate fast excitatory and inhibitory neurotransmission in the brain, are important for neuroendocrine control, and upsets in their synthesis are also linked to epilepsy. Our SERS-based detection scheme enabled the detection of low amounts of GLU (10-7 M) and GABA (10-4 M). It may complement existing techniques for characterizing such kinds of neurotransmitters that include high-performance liquid chromatography (HPLC) or mass spectrography (MS). This is mainly because SERS has other advantages such as ease of sample preparation, molecular specificity and sensitivity, thus making it potentially applicable to characterization of experimental brain extracts or clinical diagnostic samples of cerebrospinal fluid and saliva. Using hollow core photonic crystal fiber (HC-PCF) further enhanced the Raman signal relative to that in a standard cuvette providing sensitive detection of GLU and GABA in micro-litre volume of aqueous solutions.

  4. [Changes in the monoamine content in different parts of hypothalamus depending on the stages of the estrous cycle].

    Science.gov (United States)

    Babichev, V N; Adamskaia, E I

    1976-01-01

    Fluorimetric determination of monoamines in various regions of the hypothalamus and at different stages of the estral cycle in rats showed that the serotonin, noradrenaline, and particularly dophamine content changed both in the course of the cycle and at different time (10, 15 and 18 hours) of the same stage of the cycle. Dophamine concentration in the arcuate area--the centre of the tonic activity--reached its maximum at 18 hours of the diestrus-2 (D2) and fell to the minimum at 10 hours of the proestrus (P). Noradrenaline level in the preoptic area increased at 18 hours of the D2 and fell at 10 hours of the P. It is supposed that in the hypothalamic regulation of the estral cycle at least two monoamines (dopamine and noradrenaline) took part; the trigger role belongs to noradrenaline of the preoptic area (the cyclic centre).

  5. The role of the monoamine oxidase A gene in moderating the response to adversity and associated antisocial behavior: a review

    Directory of Open Access Journals (Sweden)

    Buades-Rotger M

    2014-07-01

    Full Text Available Macià Buades-Rotger,1,2 David Gallardo-Pujol1,3 1Department of Personality, Faculty of Psychology, University of Barcelona, Barcelona, Spain; 2Department of Neurology, University of Lübeck, Lübeck, Germany; 3Institute for Brain, Cognition and Behavior (IR3C, University of Barcelona, Barcelona, Spain Abstract: Hereditary factors are increasingly attracting the interest of behavioral scientists and practitioners. Our aim in the present article is to introduce some state-of-the-art topics in behavioral genetics, as well as selected findings in the field, in order to illustrate how genetic makeup can modulate the impact of environmental factors. We focus on the most-studied polymorphism to date for antisocial responses to adversity: the monoamine oxidase A gene. Advances, caveats, and promises of current research are reviewed. We also discuss implications for the use of genetic information in applied settings. Keywords: behavioral genetics, antisocial behaviors, monoamine oxidase A

  6. Vascular dysfunction in Chronic Mild Stress (CMS) induced depression model in rats: monoamine homeostasis and endothelial dysfunction

    DEFF Research Database (Denmark)

    Bouzinova, Elena; Wiborg, Ove; Aalkjær, Christian

    -dependent relaxation and endothelial NO synthase (eNOS) were increased in arteries from anhedonic rats. Inhibition of cyclooxygenase (COX) activity revealed increased COX-2-dependent relaxation in anhedonic group. In contrast, eNOS- and COXindependent relaxation to acetylcholine (EDH-like response) was significantly...... decreased cardiac output and unchanged blood pressure, suggesting increased total peripheral resistance. Small mesenteric and femoral arteries from CMS and non-stressed rats responded similarly to noradrenaline (NA) under control conditions but inhibition of neuronal reuptake with cocaine increased NA...... sensitivity stronger in anhedonic than in resilient and non-stressed groups. In contrast, corticosterone-sensitive extra-neuronal monoamine uptake was diminished in rats exposed to CMS. These changes in monoamine homeostasis were associated with upregulation neuronal NA transporter and reduced expression...

  7. Vascular dysfunction in Chronic Mild Stress (CMS) induced depression model in rats: monoamine homeostasis and endothelial dysfunction

    DEFF Research Database (Denmark)

    Bouzinova, Elena; Wiborg, Ove; Aalkjær, Christian;

    Major depression and cardiovascular diseases have strong co-morbidity but the reason for this is unknown. In CMS model of depression only some rats develop depression-like symptoms (i.e. anhedonia, measured by sucrose intake) while others are resilient to 8 weeks of CMS. Anhedonic rats have...... decreased cardiac output and unchanged blood pressure, suggesting increased total peripheral resistance. Small mesenteric and femoral arteries from CMS and non-stressed rats responded similarly to noradrenaline (NA) under control conditions but inhibition of neuronal reuptake with cocaine increased NA...... sensitivity stronger in anhedonic than in resilient and non-stressed groups. In contrast, corticosterone-sensitive extra-neuronal monoamine uptake was diminished in rats exposed to CMS. These changes in monoamine homeostasis were associated with upregulation neuronal NA transporter and reduced expression...

  8. Lower Monoamine Oxidase-A Total Distribution Volume in Impulsive and Violent Male Offenders with Antisocial Personality Disorder and High Psychopathic Traits: An [(11)C] Harmine Positron Emission Tomography Study.

    Science.gov (United States)

    Kolla, Nathan J; Matthews, Brittany; Wilson, Alan A; Houle, Sylvain; Bagby, R Michael; Links, Paul; Simpson, Alexander I; Hussain, Amina; Meyer, Jeffrey H

    2015-10-01

    Antisocial personality disorder (ASPD) often presents with highly impulsive, violent behavior, and pathological changes in the orbitofrontal cortex (OFC) and ventral striatum (VS) are implicated. Several compelling reasons support a relationship between low monoamine oxidase-A (MAO-A), an enzyme that regulates neurotransmitters, and ASPD. These include MAO-A knockout models in rodents evidencing impulsive aggression and positron emission tomography (PET) studies of healthy subjects reporting associations between low brain MAO-A levels and greater impulsivity or aggression. However, a fundamental gap in the literature is that it is unknown whether brain MAO-A levels are low in more severe, clinical disorders of impulsivity, such as ASPD. To address this issue, we applied [(11)C] harmine PET to measure MAO-A total distribution volume (MAO-A VT), an index of MAO-A density, in 18 male ASPD participants and 18 age- and sex-matched controls. OFC and VS MAO-A VT were lower in ASPD compared with controls (multivariate analysis of variance (MANOVA): F2,33=6.8, P=0.003; OFC and VS MAO-A VT each lower by 19%). Similar effects were observed in other brain regions: prefrontal cortex, anterior cingulate cortex, dorsal putamen, thalamus, hippocampus, and midbrain (MANOVA: F7,28=2.7, P=0.029). In ASPD, VS MAO-A VT was consistently negatively correlated with self-report and behavioral measures of impulsivity (r=-0.50 to -0.52, all P-values<0.05). This study is the first to demonstrate lower brain MAO-A levels in ASPD. Our results support an important extension of preclinical models of impulsive aggression into a human disorder marked by pathological aggression and impulsivity.

  9. Lower Monoamine Oxidase-A Total Distribution Volume in Impulsive and Violent Male Offenders with Antisocial Personality Disorder and High Psychopathic Traits: An [11C] Harmine Positron Emission Tomography Study

    Science.gov (United States)

    Kolla, Nathan J; Matthews, Brittany; Wilson, Alan A; Houle, Sylvain; Michael Bagby, R; Links, Paul; Simpson, Alexander I; Hussain, Amina; Meyer, Jeffrey H

    2015-01-01

    Antisocial personality disorder (ASPD) often presents with highly impulsive, violent behavior, and pathological changes in the orbitofrontal cortex (OFC) and ventral striatum (VS) are implicated. Several compelling reasons support a relationship between low monoamine oxidase-A (MAO-A), an enzyme that regulates neurotransmitters, and ASPD. These include MAO-A knockout models in rodents evidencing impulsive aggression and positron emission tomography (PET) studies of healthy subjects reporting associations between low brain MAO-A levels and greater impulsivity or aggression. However, a fundamental gap in the literature is that it is unknown whether brain MAO-A levels are low in more severe, clinical disorders of impulsivity, such as ASPD. To address this issue, we applied [11C] harmine PET to measure MAO-A total distribution volume (MAO-A VT), an index of MAO-A density, in 18 male ASPD participants and 18 age- and sex-matched controls. OFC and VS MAO-A VT were lower in ASPD compared with controls (multivariate analysis of variance (MANOVA): F2,33=6.8, P=0.003; OFC and VS MAO-A VT each lower by 19%). Similar effects were observed in other brain regions: prefrontal cortex, anterior cingulate cortex, dorsal putamen, thalamus, hippocampus, and midbrain (MANOVA: F7,28=2.7, P=0.029). In ASPD, VS MAO-A VT was consistently negatively correlated with self-report and behavioral measures of impulsivity (r=−0.50 to −0.52, all P-values<0.05). This study is the first to demonstrate lower brain MAO-A levels in ASPD. Our results support an important extension of preclinical models of impulsive aggression into a human disorder marked by pathological aggression and impulsivity. PMID:26081301

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

    Science.gov (United States)

    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

  11. Azure B, a metabolite of methylene blue, is a high-potency, reversible inhibitor of monoamine oxidase

    OpenAIRE

    Petzer, Anél; Harvey, Brian H; Wegener, Gregers; Petzer, Jacobus P.

    2012-01-01

    Methylene blue (MB) has been shown to act at multiple cellular and molecular targets and as a result possesses diverse medical applications. Among these is a high potency reversible inhibition of monoamine oxidase A (MAO-A) that may, at least in part, underlie its adverse effects but also its psycho- and neuromodulatory actions. MB is metabolized to yield N-demethylated products of which azure B, the monodemethyl species, is the major metabolite. Similar to MB, azure B also displa...

  12. Comparison of time-dependent effects of (+-methamphetamine or forced swim on monoamines, corticosterone, glucose, creatine, and creatinine in rats

    Directory of Open Access Journals (Sweden)

    Gudelsky Gary A

    2008-05-01

    Full Text Available Abstract Background Methamphetamine (MA use is a worldwide problem. Abusers can have cognitive deficits, monoamine reductions, and altered magnetic resonance spectroscopy findings. Animal models have been used to investigate some of these effects, however many of these experiments have not examined the impact of MA on the stress response. For example, numerous studies have demonstrated (+-MA-induced neurotoxicity and monoamine reductions, however the effects of MA on other markers that may play a role in neurotoxicity or cell energetics such as glucose, corticosterone, and/or creatine have received less attention. In this experiment, the effects of a neurotoxic regimen of (+-MA (4 doses at 2 h intervals on brain monoamines, neostriatal GFAP, plasma corticosterone, creatinine, and glucose, and brain and muscle creatine were evaluated 1, 7, 24, and 72 h after the first dose. In order to compare MA's effects with stress, animals were subjected to a forced swim test in a temporal pattern similar to MA administration [i.e., (30 min/session 4 times at 2 h intervals]. Results MA increased corticosterone from 1–72 h with a peak 1 h after the first treatment, whereas glucose was only increased 1 h post-treatment. Neostriatal and hippocampal monoamines were decreased at 7, 24, and 72 h, with a concurrent increase in GFAP at 72 h. There was no effect of MA on regional brain creatine, however plasma creatinine was increased during the first 24 h and decreased by 72 h. As with MA treatment, forced swim increased corticosterone more than MA initially. Unlike MA, forced swim reduced creatine in the cerebellum with no change in other brain regions while plasma creatinine was decreased at 1 and 7 h. Glucose in plasma was decreased at 7 h. Conclusion Both MA and forced swim increase demand on energy substrates but in different ways, and MA has persistent effects on corticosterone that are not attributable to stress alone.

  13. Neurotransmitter matters

    DEFF Research Database (Denmark)

    Gerlach, Christian

    2004-01-01

    It weighs like half a bag of flour and has more holes than a sponge, but if we look closely, we find that the brain is also a complex and vibrant part of our body, one that undergoes physical changes as we learn. Join neuroscience for a brief sojourn into the realm of memory ? a world of neurons...

  14. Taltirelin improves motor ataxia independently of monoamine levels in rolling mouse nagoya, a model of spinocerebellar atrophy.

    Science.gov (United States)

    Nakamura, Tomoka; Honda, Motoko; Kimura, Satoko; Tanabe, Mitsuo; Oda, Sen-ichi; Ono, Hideki

    2005-12-01

    To examine the relationship between motor ataxia and monoamine levels in the central nervous system, the contents and concentrations of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the cerebellum, brain stem and spinal cord were measured in rolling mouse Nagoya (RMN), a murine model of spinocerebellar atrophy. The tissue weight of the cerebellum and spinal cord, but not that of the brain stem was significantly lower in RMN than in the control group. In RMN, the NA content of the brain stem and spinal cord, but not the cerebellum were decreased relative to the control, and the concentration of NA in the spinal cord was also lower, but not significant. The DA and 5-HT contents in each tissue did not differ from those of the control, but the concentrations of monoamines, except for DA, were elevated in the brain stem and spinal cord in RMN. In particular, the concentrations of NA, DA and 5-HT in the cerebellum were significantly increased in RMN. Repeated administration of tartilerin hydrate, an analog of thyrotropin-releasing hormone, improved the ataxia of RMN, and elicited no obvious changes in either monoamine content or concentration of cerebellum, brain stem and spinal cord. These results indicate that the concentration of DA, as well as NA and 5-HT, increased in the RMN cerebellum, and that tartilerin improves the motor function of these mice via mechanisms other than changes in the levels of NA, DA and 5-HT in the central nervous system.

  15. CSF monoamine metabolites, cholinesterases and lactate in the adult hydrocephalus syndrome (normal pressure hydrocephalus) related to CSF hydrodynamic parameters.

    Science.gov (United States)

    Malm, J; Kristensen, B; Ekstedt, J; Adolfsson, R; Wester, P

    1991-03-01

    Monoamine metabolites, cholinesterases and lactic acid in lumbar cerebrospinal fluid (CSF) were investigated on patients with the adult hydrocephalus syndrome (idiopathic normal pressure syndrome; AHS, n = 15), Alzheimer's disease (AD, n = 14), multi-infarct dementia (MID, n = 13) and controls (n = 21). Patients had clinical and CSF hydrodynamic investigations. Monoamine concentrations were determined by reversed-phase liquid chromatography, cholinesterases and lactate were determined photometrically. In the AHS patients, CSF monoamine concentrations were not significantly different compared with controls, AD or MID patients. AHS and AD patients showed a similar reduction of CSF acetylcholinesterase activity compared with controls. Positive correlations were found in concentrations of CSF homovanillic acid, CSF 5-hydroxyindoleacetic acid and CSF lactic acid versus CSF outflow conductance (that is, resistance against CSF outflow) in the AHS patients. A similar pattern was observed in a subgroup of MID patients characterised by dilated ventricles and disturbed CSF hydrodynamics. These data suggest that a low CSF outflow conductance may facilitate the clearance of acidic substances from the arachnoid space at the probenecid sensitive active transport site. Alternative explanations would be that a pathologically low CSF outflow conductance is accompanied by an inverse caudorostral flow of CSF or a compromised trans-ependymal diffusion.

  16. Changes in Brain Monoamines Underlie Behavioural Disruptions after Zebrafish Diet Exposure to Polycyclic Aromatic Hydrocarbons Environmental Mixtures

    Science.gov (United States)

    Vignet, Caroline; Trenkel, Verena M.; Vouillarmet, Annick; Bricca, Giampiero; Bégout, Marie-Laure; Cousin, Xavier

    2017-01-01

    Zebrafish were exposed through diet to two environmentally relevant polycyclic aromatic hydrocarbons (PAHs) mixtures of contrasted compositions, one of pyrolytic (PY) origin and one from light crude oil (LO). Monoamine concentrations were quantified in the brains of the fish after six month of exposure. A significant decrease in noradrenaline (NA) was observed in fish exposed to both mixtures, while a decrease in serotonin (5HT) and dopamine (DA) was observed only in LO-exposed fish. A decrease in metabolites of 5HT and DA was observed in fish exposed to both mixtures. Several behavioural disruptions were observed that depended on mixtures, and parallels were made with changes in monoamine concentrations. Indeed, we observed an increase in anxiety in fish exposed to both mixtures, which could be related to the decrease in 5HT and/or NA, while disruptions of daily activity rhythms were observed in LO fish, which could be related to the decrease in DA. Taken together, these results showed that (i) chronic exposures to PAHs mixtures disrupted brain monoamine contents, which could underlie behavioural disruptions, and that (ii) the biological responses depended on mixture compositions. PMID:28273853

  17. Mild traumatic brain injury with social defeat stress alters anxiety, contextual fear extinction, and limbic monoamines in adult rats

    Directory of Open Access Journals (Sweden)

    Daniel eDavies

    2016-04-01

    Full Text Available Mild traumatic brain injury (mTBI produces symptoms similar to those typifying posttraumatic stress disorder (PTSD in humans. We sought to determine whether a rodent model of stress concurrent with mTBI produces characteristics of PTSD such as impaired contextual fear extinction, while also examining concurrent alterations to limbic monoamine activity in brain regions relevant to fear and anxiety states. Male rats were exposed to social stress or control conditions immediately prior to mTBI induction, and 6 days later were tested either for anxiety-like behavior using the elevated plus maze (EPM, or for contextual fear conditioning and extinction. Brains were collected 24 hr after EPM testing, and tissue from various limbic regions analyzed for content of monoamines, their precursors and metabolites using HPLC with electrochemical detection. Either social defeat or mTBI alone decreased time spent in open arms of the EPM, indicating greater anxiety-like behavior. However, this effect was enhanced by the combination of treatments. Further, rats exposed to both social defeat and mTBI exhibited greater freezing within extinction sessions compared to all other groups, suggesting impaired contextual fear extinction. Social defeat combined with mTBI also had greater effects on limbic monoamines than either insult alone, particularly with respect to serotonergic effects associated with anxiety and fear learning. The results suggest social stress concurrent with mTBI produces provides a relevant animal model for studying the prevention and treatment of post-concussive psychobiological outcomes.

  18. Neurotransmitter mechanisms of the action of the antihistamine dimebon on the brain

    Energy Technology Data Exchange (ETDEWEB)

    Shadurskaya, S.K.; Khomenko, A.I.; Pereverzev, V.A.; Balakeevskii, A.I.

    1986-11-01

    To discover the possible mechanism of the stimulating effect of dimebon on the CNS, the action of the drug was studied on catecholamine concentrations and turnover and activity of forms of monoamine oxidase (MAO), differing in the substrate metabolized, in brain structures involved in the regulation of the emotional state and in the regulation of motor activity in rats. /sup 3/H-serotonin creatinine-sulfate, /sup 3/H-dopamine hydrochloride, and /sup 14/C- benzylamine hydrochloride were used as substrates. The results show that dimebon can inhibit MAO activity in the basal ganglia and other brain structures both in vitro and in vivo, and can cause changes in DA and NA metabolism and in functional activity of catecholaminergic neuronal structures of the brain.

  19. Coupled Global and Local Changes Direct Substrate Translocation by Neurotransmitter-Sodium Symporter Ortholog LeuT

    OpenAIRE

    Cheng, Mary Hongying; Bahar, Ivet

    2013-01-01

    Significant advances have been made in recent years in characterizing neurotransmitter:sodium symporter (NSS) family structure and function. Yet, many time-resolved events and intermediates that control the various stages of transport cycle remain to be elucidated. Whether NSSs harbor one or two sites for binding their substrates (neurotransmitters or amino acids), and what the role of the secondary site S2 is, if any, are still unresolved. Using molecular modeling and simulations for LeuT, a...

  20. Microtransplantation of membranes from cultured cells to Xenopus oocytes: A method to study neurotransmitter receptors embedded in native lipids

    OpenAIRE

    Palma, Eleonora; Trettel, Flavia; Fucile, Sergio; Renzi, Massimiliano; Miledi, Ricardo; Eusebi, Fabrizio

    2003-01-01

    The Xenopus oocyte is used as a convenient cell expression system to study the structure and function of heterogenic transmitter receptors and ion channels. Recently, we introduced a method to microtransplant already assembled neurotransmitter receptors from the human brain to the plasma membrane of Xenopus oocytes. The same approach was used here to transplant neurotransmitter receptors expressed from cultured cells to the oocytes. Membrane vesicles prepared from a human embryonic kidney cel...

  1. Effects of multiparity on recognition memory, monoaminergic neurotransmitters, and brain-derived neurotrophic factor (BDNF).

    Science.gov (United States)

    Macbeth, Abbe H; Scharfman, Helen E; Maclusky, Neil J; Gautreaux, Claris; Luine, Victoria N

    2008-06-01

    Recognition memory and anxiety were examined in nulliparous (NP: 0 litters) and multiparous (MP: 5-6 litters) middle-aged female rats (12 months old) to assess possible enduring effects of multiparity at least 3 months after the last litter was weaned. MP females performed significantly better than NP females on the non-spatial memory task, object recognition, and the spatial memory task, object placement. Anxiety as measured on the elevated plus maze did not differ between groups. Monoaminergic activity and levels were measured in prefrontal cortex, CA1 hippocampus, CA3 hippocampus, and olfactory bulb (OB). NP and MP females differed in monoamine concentrations in the OB only, with MP females having significantly greater concentrations of dopamine and metabolite DOPAC, norepinephrine and metabolite MHPG, and the serotonin metabolite 5-HIAA, as compared to NP females. These results indicate a long-term change in OB neurochemistry as a result of multiparity. Brain-derived neurotrophic factor (BDNF) was also measured in hippocampus (CA1, CA3, dentate gyrus) and septum. MP females had higher BDNF levels in both CA1 and septum; as these regions are implicated in memory performance, elevated BDNF may underlie the observed memory task differences. Thus, MP females (experiencing multiple bouts of pregnancy, birth, and pup rearing during the first year of life) displayed enhanced memory task performance but equal anxiety responses, as compared to NP females. These results are consistent with previous studies showing long-term changes in behavioral function in MP, as compared to NP, rats and suggest that alterations in monoamines and a neurotrophin, BDNF, may contribute to the observed behavioral changes.

  2. Effect of novel atypical antipsychotic, blonanserin, on extracellular neurotransmitter level in rat prefrontal cortex.

    Science.gov (United States)

    Ohoyama, Keiko; Yamamura, Satoshi; Hamaguchi, Tatsuya; Nakagawa, Masanori; Motomura, Eishi; Shiroyama, Takashi; Tanii, Hisashi; Okada, Motohiro

    2011-02-25

    To clarify the mechanisms of action of blonanserin, an atypical antipsychotic drug, we studied the effects of systemic administration of blonanserin and risperidone on extracellular levels of norepinephrine, dopamine, serotonin, GABA and glutamate in the medial prefrontal cortex using microdialysis, and neuronal firing in the ventral tegmental area, locus coeruleus, dorsal raphe nucleus and mediodorsal thalamic nucleus using radiotelemetry. The binding affinities of blonanserin to D(2) and 5-HT(2A) receptors in the rat brain were confirmed and found to be similar. Blonanserin transiently increased neuronal firing in locus coeruleus and ventral tegmental area but not in dorsal raphe nucleus or mediodorsal thalamic nucleus, whereas risperidone increased the firing in locus coeruleus, ventral tegmental area and dorsal raphe nucleus but not in mediodorsal thalamic nucleus. Blonanserin persistently increased frontal extracellular levels of norepinephrine and dopamine but not serotonin, GABA or glutamate, whereas risperidone persistently increased those of norepinephrine, dopamine and serotonin but not GABA or glutamate. These results suggest a pharmacological correlation between the stimulatory effects of these antipsychotics on frontal monoamine release and neuronal activity in monoaminergic nuclei. Inhibition of the α(2) adrenoceptor increased extracellular monoamine levels and enhanced blonanserin-induced increase in extracellular serotonin level. These results indicated that the combination of antagonism of D(2) and 5-HT(2A) receptors contribute to the rise in extracellular levels of norepinephrine and dopamine, and that α(2) adrenoceptors play important roles in frontal serotonin release. They also suggest that blonanserin-induced activation of monoaminergic transmission could be, at least partially, involved in atypical antipsychotic properties of blonanserin. Copyright © 2010 Elsevier B.V. All rights reserved.

  3. Genetic KCa3.1-deficiency produces locomotor hyperactivity and alterations in cerebral monoamine levels.

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    Kate Lykke Lambertsen

    Full Text Available BACKGROUND: The calmodulin/calcium-activated K(+ channel KCa3.1 is expressed in red and white blood cells, epithelia and endothelia, and possibly central and peripheral neurons. However, our knowledge about its contribution to neurological functions and behavior is incomplete. Here, we investigated whether genetic deficiency or pharmacological activation of KCa3.1 change behavior and cerebral monoamine levels in mice. METHODOLOGY/PRINCIPAL FINDINGS: In the open field test, KCa3.1-deficiency increased horizontal activity, as KCa3.1(-/- mice travelled longer distances (≈145% of KCa3.1(+/+ and at higher speed (≈1.5-fold of KCa3.1(+/+. Working memory in the Y-maze was reduced by KCa3.1-deficiency. Motor coordination on the rotarod and neuromuscular functions were unchanged. In KCa3.1(-/- mice, HPLC analysis revealed that turn-over rates of serotonin were reduced in frontal cortex, striatum and brain stem, while noradrenalin turn-over rates were increased in the frontal cortex. Dopamine turn-over rates were unaltered. Plasma catecholamine and corticosterone levels were unaltered. Intraperitoneal injections of 10 mg/kg of the KCa3.1/KCa2-activator SKA-31 reduced rearing and turning behavior in KCa3.1(+/+ but not in KCa3.1(-/- mice, while 30 mg/kg SKA-31 caused strong sedation in 50% of the animals of either genotypes. KCa3.1(-/- mice were hyperactive (≈+60% in their home cage and SKA-31-administration reduced nocturnal physical activity in KCa3.1(+/+ but not in KCa3.1(-/- mice. CONCLUSIONS/SIGNIFICANCE: KCa3.1-deficiency causes locomotor hyperactivity and altered monoamine levels in selected brain regions, suggesting a so far unknown functional link of KCa3.1 channels to behavior and monoaminergic neurotransmission in mice. The tranquilizing effects of low-dose SKA-31 raise the possibility to use KCa3.1/KCa2 channels as novel pharmacological targets for the treatment of neuropsychiatric hyperactivity disorders.

  4. Blood Levels of Monoamine Precursors and Smoking in Patients with Schizophrenia

    Directory of Open Access Journals (Sweden)

    Ashwin Jacob Mathai

    2016-08-01

    Full Text Available Smoking is highly prevalent in patients with schizophrenia and exerts a negative impact on cardiovascular mortality in these patients. Smoking has complex interactions with monoamine metabolism through the ability of cigarette smoke to suppress Type 1 T helper cell (Th1 type immunity, the immunophenotype that is implicated in phenylalanine hydroxylase (PAH dysfunction and tryptophan breakdown to kynurenine via indoleamine 2,3-dioxygenase (IDO. Nicotine also induces tyrosine hydroxylase gene (TH expression, leading to increased synthesis of catecholamines. Furthermore, there is evidence for PAH dysfunction in schizophrenia. This study aimed to compare the plasma levels of selected monoamine precursors and their metabolites in smokers vs non-smokers in a large sample of patients with schizophrenia. We measured plasma phenylalanine, tyrosine, tryptophan and kynurenine levels using high-performance liquid chromatography (HPLC and calculated phenylalanine: tyrosine (Phe: Tyr and kynurenine: tryptophan (Kyn: Trp ratios in 920 patients with schizophrenia. Analysis of variance (ANOVA and linear regression analyses were used to compare these endpoints between 3 groups of patients with schizophrenia; 1 current smokers, 2 past smokers and 3 non-smokers. There were significant differences among the three groups with regards to tyrosine levels [F(2,789=3.77, p=0.02], with current smokers having lower tyrosine levels when compared to non-smokers (p=0.02. Kynurenine levels and Kyn :Trp ratio were different among the 3 groups [F (2,738=3.17, p=0.04, F(2,738=3.61, p=0.03] with current smokers having lower kynurenine levels (p=0.04 and higher Kyn: Trp ratio (p=0.02 when compared to past smokers. These findings need to be replicated with protocols that include healthy controls to further elucidate the neurobiological underpinnings of altered tyrosine and kynurenine levels in smokers. Results do suggest potential molecular links between schizophrenia and smoking

  5. Antidepressant-like effect of ethanol extract from Zuojin Pill, containing two herbal drugs of Rhizoma Coptidis and Fructus Evodiae, is explained by modulating the monoaminergic neurotransmitter system in mice.

    Science.gov (United States)

    Wang, Qiang-Song; Ding, Shi-Lan; Mao, Hao-Ping; Cui, Yuan-Lu; Qi, Xue-Jie

    2013-07-09

    Zuojin Pill (ZJP), a traditional Chinese medicinal decoction, contains two herbal drugs: Coptis chinensis Franch. and Evodia rutaecarpa (Juss.) Benth. in the ratio of 6:1 (w/w). Previous pharmacological studies have shown that two herbs in ZJP have the antagonistic effects on catecholamine secretion in bovine adrenal medullary cells. Furthermore, the alkaloids from the two herbs in ZJP may provide a protective effect for depression in individuals with a low expressing 5-HTT allele by increasing receptor concentration in serotonergic neurons. However, antidepressant effect has not been reported before and has not been fully clarified. The present study aimed to investigate the antidepressant potential of ethanol extract from ZJP and its monoaminergic mechanism in mice. Seven alkaloids were determined from the ethanol extract of ZJP using High Performance Liquid Chromatography (HPLC) with the gradient mobile phase. The ethanol extract from ZJP was used to evaluate the antidepressant potential in mice. Mouse models of depression including the tail suspension test (TST) and the forced swim test (FST) were used to evaluate the effects of the ethanol extract from ZJP. A possible mechanism was explored in the tests of antagonism of reserpine-induced ptosis and hypothermia, and 5-HTP induced head twitch response in mice. The contents of monoamine neurotransmitters including norepinephrine (NE), serotonin (5-hydroxytryptamine or 5-HT) in hippocampus of mice and NE, 5-HT, dopamine (DA) in striatum of mice were determined by HPLC system with Electrochemical Detector (ECD). The results showed that intragastric administration of the ethanol extract from ZJP (5, 10, 20mg/kg) or fluoxetine (7.5mg/kg) significantly reduced the duration of immobility in TST and FST. However, the effect was not dose-dependent. Ethanol extract from ZJP (5, 10, 20mg/kg) also increased the accumulative number of the 5-HTP-induced head twitch response in mice. The mice were treated with the ethanol

  6. Biosensor based on inhibition of monoamine oxidases A and B for detection of β-carbolines.

    Science.gov (United States)

    Radulescu, Maria-Cristina; Bucur, Madalina-Petruta; Bucur, Bogdan; Radu, Gabriel Lucian

    2015-05-01

    β-Carbolines are inhibitors of monoamine oxidases (MAO-A and MAO-B) and can be found in foods, hallucinogenic plant or various drugs. We have developed a fast analysis method for β-carbolines based on the inhibition of MAO. The enzymes were immobilized on screen-printed electrodes modified with a stabilized film of Prussian blue that contain also copper. We have used benzylamine as substrate for the enzymatic reaction and the hydrogen peroxide was measured amperometrically at -50 mV. The detection limits obtained were 5.0 µM for harmane and 2.5 µM for both harmaline and norharmane. The MAO-A is inhibited by all three tested β-carbolines (harmane, norharmane, and harmaline) while MAO-B is inhibited only by norharmane. The presence of norharmane in mixtures of β-carbolines can be identified based on the difference between the cumulative inhibition of MAO-A by all β-carbolines and MAO-B inhibition. The developed biosensors were used for food analysis.

  7. The properties of B-form monoamine oxidase in mitochondria from monkey platelet.

    Science.gov (United States)

    Obata, Toshio; Aomine, Masahiro

    The present study was examined the effect of the properties of monkey platelet monoamine oxidase (MAO) based on inhibitor sensitivity. Monkey platelet showed a high MAO activity with beta-phenylethylamine (beta-PEA) as substrate and a very low A-form MAO activity with 5 hydroxytryptamine (5-HT) as substrate. Moreover, monkey platelet MAO was sensitive to the drugs deprenyl as B-form MAO inhibitor and less sensitive to clorgyline and harmaline as A form MAO inhibitor with beta-PEA as the B-form MAO substrate. B-form MAO from monkey platelet was more stable against heat treatment at 55 degrees C than B-form MAO in brain. After digestion with trypsin at 37 degrees C for 4 hrs, it was found that MAO from platelet was inhibited about 70% with beta-PEA as substrate with brain. The tricyclic antidepressant imipramine and nortriptyline inhibited B-form MAO activity more potency than B-form MAO in brain. However, when the noncyclic antidepressant nomifensine was used, monkey platelet B-form MAO activities were less potently inhibited. All these reagents were noncompetitive inhibitors of B form MAO in monkey platelet. The present studies demonstrated that monkey platelet MAO is a single of B-form MAO and sensitive to tricyclic antidepressants.

  8. In vitro evaluation of Bacopa monniera extract and individual constituents on human recombinant monoamine oxidase enzymes.

    Science.gov (United States)

    Singh, Rajbir; Ramakrishna, Rachumallu; Bhateria, Manisha; Bhatta, Rabi Sankar

    2014-09-01

    Bacopa monniera is a traditional Ayurvedic medicinal plant that has been used worldwide for its nootropic action. Chemically standardized extract of B. monniera is now available as over the counter herbal remedy to enhance memory in children and adults. Considering the nootropic action of B. monniera, we evaluated the effect of clinically available B. monniera extract and six of B. monniera constituents (bacoside A3, bacopaside I, bacopaside II, bacosaponin C, bacosine, and bacoside A mixture) on recombinant human monoamine oxidase (MAO) enzymes. The effect of B. monniera extract and individual constituents on human recombinant MAO-A and MAO-B enzymes was evaluated using MAO-Glo(TM) assay kit (Promega Corporation, USA), following the instruction manual. IC50 and mode of inhibition were measured for MAO enzymes. Bacopaside I and bacoside A mixture inhibited the MAO-A and MAO-B enzymes. Bacopaside I exhibited mixed mode of inhibition with IC50 and Ki values of 17.08 ± 1.64 and 42.5 ± 3.53 µg/mL, respectively, for MAO-A enzyme. Bacopaside I is the major constituent of B. monniera, which inhibited the MAO-A enzyme selectively.

  9. Effects of K. Lysolecithin on Blood Levels of Monoamines in Mice

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    In this research, Lysolecithin - a substance made with 100% natural ingredients - was given to ICR mice as medication to measure its periodic effect on the noradrenalin (NA), dopamine (DA), and serotonin (5-HT) levels of the brain. Both ICR and SAM mice were separated into two groups - control group and Lysolecithin (K. Lysolecithin: hydrolytic lysolecithin) medicated group, and given 1-week preparation period. The K. Lysolecithin group was given 500mg/kg of K. Lysolecithin at 0.2mL per dosage for 4 weeks, and the control group was given the same amount of dosage of water during the same period. NA, DA and 5-HT concentrations were measured from the blood before medication and 8 weeks / 12 weeks / 16 weeks after the first medication. For the SAM mice, 8 weeks after they were medicated with K .Lysolecithin, Morris Water Maze Test was conducted for 7 consecutive days and then the concentrations were measured by drawing blood from the heart. The K. Lysolecithin medicated group showed a tendency to have a statistically significant higher concentrations of 5-HT and NA in the blood. Also, periodic examination showed that the monoamine levels were highest in the 12th week and declined thereafter.

  10. Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity.

    Science.gov (United States)

    Williard, Robin L; Middaugh, Lawrence D; Zhu, Hao-Jie B; Patrick, Kennerly S

    2007-02-01

    Ethylphenidate is formed by metabolic transesterification of methylphenidate and ethanol. Study objectives were to (a) establish that ethylphenidate is formed in C57BL/6 (B6) mice; (b) compare the stimulatory effects of ethylphenidate and methylphenidate enantiomers; (c) determine methylphenidate and ethylphenidate plasma and brain distribution and (d) establish in-vitro effects of methylphenidate and ethylphenidate on monoamine transporter systems. Experimental results were that: (a) coadministration of ethanol with the separate methylphenidate isomers enantioselectively produced l-ethylphenidate; (b) d and dl-forms of methylphenidate and ethylphenidate produced dose-responsive increases in motor activity with stimulation being less for ethylphenidate; (c) plasma and whole-brain concentrations were greater for ethylphenidate than methylphenidate and (d) d and DL-methylphenidate and ethylphenidate exhibited comparably potent low inhibition of the dopamine transporter, whereas ethylphenidate was a less potent norepinephrine transporter inhibitor. These experiments establish the feasibility of the B6 mouse model for examining the interactive effects of ethanol and methylphenidate. As reported for humans, concurrent exposure of B6 mice to methylphenidate and ethanol more readily formed l-ethylphenidate than d-ethylphenidate, and the l-isomers of both methylphenidate and ethylphenidate were biologically inactive. The observed reduced stimulatory effect of d-ethylphenidate relative to d-methylphenidate appears not to be the result of brain dispositional factors, but rather may be related to its reduced inhibition of the norepinephrine transporter, perhaps altering the interaction of dopaminergic and noradrenergic neural systems.

  11. Psychological traits and platelet monoamine oxidase activity in eating disorder patients: their relationship and stability.

    Science.gov (United States)

    Podar, Iris; Jaanisk, Maiken; Allik, Jüri; Harro, Jaanus

    2007-01-30

    Self-reported behavior and attitudes towards eating [Eating Disorder Inventory-2; Garner DM (1991). Eating Disorder Inventory-2: Professional Manual. Odessa, Fl.: Psychological Assessment Resources; Estonian version Podar I, Hannus A, Allik J (1999). Personality and Affectivity Characteristics Associated With Eating Disorders: a Comparison of Eating Disordered, Weight-Preoccupied, and Normal Samples. J Pers Assess; 73(1), 133-147] and the activity of platelet monoamine oxidase (MAO) was studied in 11 patients with anorexia nervosa (AN), 43 patients with bulimia nervosa (BN) and a healthy control group (n=138). Nineteen patients filled in the EDI-2 questionnaire and donated blood samples three times with three month intervals in order to determine platelet MAO activity. Eating disordered (ED) patients scored higher on all EDI-2 subscales and had lower MAO activity compared to the control group. They also scored higher than the control group on the Neuroticism domain but lower on the Extraversion, Openness, and Conscientiousness domains of the NEO-PI-R questionnaire. The average stability of MAO on different occasions (r=.56) was slightly smaller than the stability of the EDI-2 scores (r=.70). The lack of correlations between personality dispositions and MAO activity indicates that they have independent influence on eating disorders. A possible relationship between neurochemical mechanisms and psychological symptoms of eating disordered behavior is discussed.

  12. CT scanning of the brain and lumbar CSF monoamine metabolites in spinocerebellar degenerative disorders

    Energy Technology Data Exchange (ETDEWEB)

    Sasaki, Hidenao; Kanazawa, Ichiro; Nakanishi, Takao; Kuramoto, Kenmei (Tsukuba Univ., Sakura, Ibaraki (Japan))

    1984-08-01

    Eight patients with parenchymatous cerebellar degeneration (PCD) group (3 with late cortical cerebellar atrophy and 5 with Holmes' hereditary ataxia), 14 with olivo-ponto-cerebellar atrophy (OPCA) group (4 with Shy-Drager syndrome, 6 with OPCA without family history and 4 with Menzel type SCS), 15 with Parkinson's disease and 44 control with other neurological diseases were studied. In all the spinocerebellar degenerative disorders (SCD) cases, CVI values corresponding to the cerebellar atrophy were definitely reduced. On the other hand, PVI values corresponding to the pontine atrophy were only significantly decreased in OPCA group. However, since there were several cases showing only questionable pontine atrophy, it seems difficult to clearly differentiate individual OPCA cases from other SCD cases on CT films alone. Concerning monoamine metabolites in CSF, it was noted that a significant reduction of HVA and total MHPG was found in the OPCA group. Among them, the patients with overt autonomic failure showed the lowest HVA level and the cases of Menzel type of SCD showed a slight reduction of HVA but an unexpected elevation of free MHPG values. The cases of Parkinson's disease showed a definite reduction of HVA. On the other hand, the cases of PCD group showed no significant difference against controls. 5-HIAA levels were not significantly different among the SCD subgroups.

  13. Monoamine oxidase A genotype is associated with gang membership and weapon use.

    Science.gov (United States)

    Beaver, Kevin M; DeLisi, Matt; Vaughn, Michael G; Barnes, J C

    2010-01-01

    A functional polymorphism in the promoter region of the monoamine oxidase A (MAOA) gene has been found to be associated with a broad range of antisocial phenotypes, including physical violence. At the same time, it is well known that gang members represent some of the most serious violent offenders. Even so, no research has ever examined the association between MAOA and gang membership. The aim of this study is to examine the association between MAOA and gang membership and between MAOA and weapon use. We examined the effects of MAOA by using a molecular genetic association research design. A nonclinical sample was used in this study. Participants were drawn from the National Longitudinal Study of Adolescent Health (1155 females, 1041 males). The outcome measures of this study are gang membership and weapon use. The low MAOA activity alleles conferred an increased risk of joining a gang and using a weapon in a fight for males but not for females. Moreover, among male gang members, those who used weapons in a fight were more likely to have a low MAOA activity allele when compared with male gang members who do not use weapons in a fight. Male carriers of low MAOA activity alleles are at risk for becoming a gang member and, once a gang member, are at risk for using weapons in a fight. Copyright 2010 Elsevier Inc. All rights reserved.

  14. Monoamine oxidase A gene DNA hypomethylation - a risk factor for panic disorder?

    Science.gov (United States)

    Domschke, Katharina; Tidow, Nicola; Kuithan, Henriette; Schwarte, Kathrin; Klauke, Benedikt; Ambrée, Oliver; Reif, Andreas; Schmidt, Hartmut; Arolt, Volker; Kersting, Anette; Zwanzger, Peter; Deckert, Jürgen

    2012-10-01

    The monoamine oxidase A (MAOA) gene has been suggested as a prime candidate in the pathogenesis of panic disorder. In the present study, DNA methylation patterns in the MAOA regulatory and exon 1/intron 1 region were investigated for association with panic disorder with particular attention to possible effects of gender and environmental factors. Sixty-five patients with panic disorder (44 females, 21 males) and 65 healthy controls were analysed for DNA methylation status at 42 MAOA CpG sites via direct sequencing of sodium bisulfate treated DNA extracted from blood cells. The occurrence of recent positive and negative life events was ascertained. Male subjects showed no or only very minor methylation with some evidence for relative hypomethylation at one CpG site in intron 1 in patients compared to controls. Female patients exhibited significantly lower methylation than healthy controls at 10 MAOA CpG sites in the promoter as well as in exon/intron 1, with significance surviving correction for multiple testing at four CpG sites (p≤0.001). Furthermore, in female subjects the occurrence of negative life events was associated with relatively decreased methylation, while positive life events were associated with increased methylation. The present pilot data suggest a potential role of MAOA gene hypomethylation in the pathogenesis of panic disorder particularly in female patients, possibly mediating a detrimental influence of negative life events. Future studies are warranted to replicate the present finding in independent samples, preferably in a longitudinal design.

  15. Assessment of Mitochondrial Dysfunction and Monoamine Oxidase Contribution to Oxidative Stress in Human Diabetic Hearts

    Directory of Open Access Journals (Sweden)

    O. M. Duicu

    2016-01-01

    Full Text Available Mitochondria-related oxidative stress is a pathomechanism causally linked to coronary heart disease (CHD and diabetes mellitus (DM. Recently, mitochondrial monoamine oxidases (MAOs have emerged as novel sources of oxidative stress in the cardiovascular system and experimental diabetes. The present study was purported to assess the mitochondrial impairment and the contribution of MAOs-related oxidative stress to the cardiovascular dysfunction in coronary patients with/without DM. Right atrial appendages were obtained from 75 patients randomized into 3 groups: (1 Control (CTRL, valvular patients without CHD; (2 CHD, patients with confirmed CHD; and (3 CHD-DM, patients with CHD and DM. Mitochondrial respiration was measured by high-resolution respirometry and MAOs expression was evaluated by RT-PCR and immunohistochemistry. Hydrogen peroxide (H2O2 emission was assessed by confocal microscopy and spectrophotometrically. The impairment of mitochondrial respiration was substrate-independent in CHD-DM group. MAOs expression was comparable among the groups, with the predominance of MAO-B isoform but no significant differences regarding oxidative stress were detected by either method. Incubation of atrial samples with MAOs inhibitors significantly reduced the H2O2 in all groups. In conclusion, abnormal mitochondrial respiration occurs in CHD and is more severe in DM and MAOs contribute to oxidative stress in human diseased hearts with/without DM.

  16. Inhibition of monoamine oxidase by selected C6-substituted chromone derivatives.

    Science.gov (United States)

    Legoabe, Lesetja J; Petzer, Anél; Petzer, Jacobus P

    2012-03-01

    Chromone has been reported to be a useful scaffold for the design of monoamine oxidase (MAO) inhibitors. In an attempt to discover highly potent MAO inhibitors and to contribute to the known structure-activity relationships (SAR) of MAO inhibition by chromones, in the present study, we have synthesized a series of chromone derivatives substituted at C6 with a variety of alkyloxy substituents, and evaluated the resulting compounds as inhibitors of recombinant human MAO-A and -B. The results document that the C6-substituted chromones are potent reversible MAO-B inhibitors with IC(50) values in the low nM range (2-76 nM). The chromones were also found to bind reversibly to MAO-A, but with lower affinities compared to MAO-B. It may therefore be concluded that C6-substituted chromones are highly potent MAO-B selective inhibitors and promising lead compounds for the development of therapy for neurodegenerative disorders such as Parkinson's disease. The results of this study are discussed with reference to possible binding orientations of a selected C6-substituted chromone in the active site cavities of MAO-A and -B. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  17. Chromone, a privileged scaffold for the development of monoamine oxidase inhibitors.

    Science.gov (United States)

    Gaspar, Alexandra; Silva, Tiago; Yáñez, Matilde; Vina, Dolores; Orallo, Franscisco; Ortuso, Francesco; Uriarte, Eugenio; Alcaro, Stefano; Borges, Fernanda

    2011-07-28

    Two series of novel chromone derivatives were synthesized and investigated for their ability to inhibit the activity of monoamine oxidase. The SAR data indicate that chromone derivatives with substituents in position 3 of γ-pyrone nucleus act preferably as MAO-B inhibitors, with IC(50) values in the nanomolar to micromolar range. Almost all chromone 3-carboxamides display selectivity toward MAO-B. Identical substitutions on position 2 of γ-pyrone nucleus result in complete loss of activity in both isoforms (chromones 2-12 except 3 and 5). Notably, chromone (19) exhibits an MAO-B IC(50) of 63 nM, greater than 1000-fold selectivity over MAO-A, and behaves as a quasi-reversible inhibitor. Docking experiments onto the MAO binding of the most active compound highlight different interaction patterns among the isoforms A and B. The differential analysis of the solvation effects among the chromone isomers gave additional insight about the superior outline of the 3-substituted chromone derivatives.

  18. Is fetal brain monoamine oxidase inhibition the missing link between maternal smoking and conduct disorders?

    Science.gov (United States)

    Baler, Ruben D; Volkow, Nora D; Fowler, Joanna S; Benveniste, Helene

    2008-05-01

    Smoking is the leading cause of preventable illness in the world today. Prenatal cigarette smoke exposure (PCSE) is a particularly insidious form because so many of its associated health effects befall the unborn child and produce behavioural outcomes that manifest themselves only years later. Among these are the associations between PCSE and conduct disorders, which have been mostly ascribed to the deleterious effects of nicotine on the fetal brain. Here we hypothesize that inhibition of brain monoamine oxidase (MAO) during fetal brain development, secondary to maternal cigarette smoking and in addition to nicotine, is a likely contributor to this association. MAOs play a central role in monoaminergic balance in the brain, and their inhibition during fetal development - but not during adult life - is known to result in an aggressive phenotype in laboratory animals. This paper provides theoretical and experimental support for the notion that cigarette smoke-induced inhibition of MAO in the fetal brain, particularly when it occurs in combination with polymorphisms in the MAOA gene that lead to lower enzyme concentration in the brain, may result in brain morphologic and functional changes that enhance the risk of irritability, poor self-control and aggression in the offspring. It also encourages research to evaluate whether the interaction of smoking exposure during fetal development and MAOA genotype increases the risk for conduct disorder over that incurred by mere fetal exposure to tobacco smoke.

  19. Simultaneous determination of cadaverine and putrescine using a disposable monoamine oxidase based biosensor.

    Science.gov (United States)

    Henao-Escobar, Wilder; Domínguez-Renedo, Olga; Asunción Alonso-Lomillo, M; Julia Arcos-Martínez, M

    2013-12-15

    The selective and simultaneous amperometric determination of putrescine (Put) and cadaverine (Cad) has been carried out using a novel design of screen-printed carbon electrode (SPCE) with two working electrodes connected in array mode. A mixture of 3% of tetrathiafulvalene (TTF), as mediator, and carbon ink was used for the construction of the screen-printed working electrode. The employment of different amounts of monoamine oxidase (MAO) enzyme on these modified TTF/SPCEs and the use of gold nanoparticles (AuNPs) allowed performing the simultaneous determination of both analytes. The amperometric detection has been performed by measuring the oxidation current of the mediator at a potential of+250 mV vs. screen-printed Ag/AgCl reference electrode. A linear response in the Cad concentration range from 19.6 till 107.1 µM and from 9.9 till 74.1 μM for Put was obtained at the MAO/AuNPs/TTF/SPCE biosensor. This device showed a capability of detection of 9.9 and 19.9±0.9 µM (n=4 α=β=0.05) and a precision of 4.9% and 10.3% in terms of relative standard deviation for Put and Cad, respectively. The developed biosensor was successfully applied to the simultaneous determination of Put and Cad in octopus samples.

  20. Oxidative stress by monoamine oxidases is causally involved in myofiber damage in muscular dystrophy.

    Science.gov (United States)

    Menazza, Sara; Blaauw, Bert; Tiepolo, Tania; Toniolo, Luana; Braghetta, Paola; Spolaore, Barbara; Reggiani, Carlo; Di Lisa, Fabio; Bonaldo, Paolo; Canton, Marcella

    2010-11-01

    Several studies documented the key role of oxidative stress and abnormal production of reactive oxygen species (ROS) in the pathophysiology of muscular dystrophies (MDs). The sources of ROS, however, are still controversial as well as their major molecular targets. This study investigated whether ROS produced in mitochondria by monoamine oxidase (MAO) contributes to MD pathogenesis. Pargyline, an MAO inhibitor, reduced ROS accumulation along with a beneficial effect on the dystrophic phenotype of Col6a1(-/-) mice, a model of Bethlem myopathy and Ullrich congenital MD, and mdx mice, a model of Duchenne MD. Based on our previous observations on oxidative damage of myofibrillar proteins in heart failure, we hypothesized that MAO-dependent ROS might impair contractile function in dystrophic muscles. Indeed, oxidation of myofibrillar proteins, as probed by formation of disulphide cross-bridges in tropomyosin, was detected in both Col6a1(-/-) and mdx muscles. Notably, pargyline significantly reduced myofiber apoptosis and ameliorated muscle strength in Col6a1(-/-) mice. This study demonstrates a novel and determinant role of MAO in MDs, adding evidence of the pivotal role of mitochondria and suggesting a therapeutic potential for MAO inhibition.

  1. Carnosine: effect on aging-induced increase in brain regional monoamine oxidase-A activity.

    Science.gov (United States)

    Banerjee, Soumyabrata; Poddar, Mrinal K

    2015-03-01

    Aging is a natural biological process associated with several neurological disorders along with the biochemical changes in brain. Aim of the present investigation is to study the effect of carnosine (0.5-2.5μg/kg/day, i.t. for 21 consecutive days) on aging-induced changes in brain regional (cerebral cortex, hippocampus, hypothalamus and pons-medulla) mitochondrial monoamine oxidase-A (MAO-A) activity with its kinetic parameters. The results of the present study are: (1) The brain regional mitochondrial MAO-A activity and their kinetic parameters (except in Km of pons-medulla) were significantly increased with the increase of age (4-24 months), (2) Aging-induced increase of brain regional MAO-A activity including its Vmax were attenuated with higher dosages of carnosine (1.0-2.5μg/kg/day) and restored toward the activity that observed in young, though its lower dosage (0.5μg/kg/day) were ineffective in these brain regional MAO-A activity, (3) Carnosine at higher dosage in young rats, unlike aged rats significantly inhibited all the brain regional MAO-A activity by reducing their only Vmax excepting cerebral cortex, where Km was also significantly enhanced. These results suggest that carnosine attenuated the aging-induced increase of brain regional MAO-A activity by attenuating its kinetic parameters and restored toward the results of MAO-A activity that observed in corresponding brain regions of young rats.

  2. Methadone, monoamine oxidase, and depression: opioid distribution and acute effects on enzyme activity

    Energy Technology Data Exchange (ETDEWEB)

    Kaufmann, C.A.; Kreek, M.J.; Raghunath, J.; Arns, P.

    1983-09-01

    Narcotic withdrawal is often accompanied by an atypical depression which responds to resumption of narcotics. It was hypothesized that methadone might exert its antidepressant effects through monoamine oxidase (MAO) inhibition. The current study examined /sub 3/H-methadone distribution in rat brain and effects on regional MAO activity with acute doses (2.5 mg/kg) which approximate those found during chronic methadone maintenance in man. Limbic areas (amygdala, basomedial hypothalamus, caudate-putamen, hippocampus, preoptic nucleus), as well as pituitary and liver were assayed for MAO activity and methadone concentration. MAO activities did not differ significantly in acute methadone or saline-treated cage-mates at 1 or 24 hr. The concentrations of methadone at 1 hr ranged between 17 and 223 ng/100 mg wet wt tissue in the preoptic nucleus and pituitary, respectively. No significant correlation was found between change in MAO activity (MAO methadone/MAO saline) and methadone concentration in any region at 1 or 24 hr. This study does not support the hypothesis that methadone acts as an antidepressant through MAO inhibition, at least not following acute administration of this exogenous opioid.

  3. Potent and Selective Monoamine Oxidase-B Inhibitory Activity: Fluoro- vs. Trifluoromethyl-4-hydroxylated Chalcone Derivatives.

    Science.gov (United States)

    Mathew, Bijo; Mathew, Githa Elizabeth; Uçar, Gülberk; Baysal, Ipek; Suresh, Jerad; Mathew, Sincy; Haridas, Abitha; Jayaprakash, Venkatesan

    2016-08-01

    For various neurodegenerative disorders like Alzheimer's and Parkinson's diseases, selective and reversible MAO-B inhibitors have a great therapeutic value. In our previous study, we have shown that a series of methoxylated chalcones with F functional group exhibited high binding affinity toward human monoamine oxidase-B (hMAO-B). In continuation of our earlier study and to extend the understanding of the structure-activity relationships, a series of five new chalcones were studied for their inhibition of hMAO. The results demonstrated that these compounds are reversible and selective hMAO-B inhibitors with a competitive mode of inhibition. The most active compound, (2E)-1-(4-hydroxyphenyl)-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-one, exhibited a Ki value of 0.33 ± 0.01 μm toward hMAO-B with a selectivity index of 26.36. A molecular docking study revealed that the presence of a H-bond network in hydroxylated chalcone with the N(5) atom of FAD is crucial for MAO-B selectivity and potency.

  4. Monoamine Oxidases, Oxidative Stress, and Altered Mitochondrial Dynamics in Cardiac Ageing

    Directory of Open Access Journals (Sweden)

    Damien Maggiorani

    2017-01-01

    Full Text Available The advances in healthcare over the past several decades have resulted in populations now living longer. With this increase in longevity, a wider prevalence of cardiovascular diseases is more common and known to be a major factor in rising healthcare costs. A wealth of scientific evidence has implicated cell senescence as an important component in the etiology of these age-dependent pathologies. A number of studies indicate that an excess of reactive oxygen species (ROS contributes to trigger and accelerate the cardiac senescence processes, and a new role of monoamine oxidases, MAO-A and MAO-B, is emerging in this context. These mitochondrial enzymes regulate the level of catecholamines and serotonin by catalyzing their oxidative deamination in the heart. MAOs’ expression substantially increases with ageing (6-fold MAO-A in the heart and 4-fold MAO-B in neuronal tissue, and their involvement in cardiac diseases is supposedly related to the formation of ROS, via the hydrogen peroxide produced during the substrate degradation. Here, we will review the most recent advances in this field and describe why MAOs could be effective targets in order to prevent age-associated cardiovascular disease.

  5. Switching antipsychotics to aripiprazole or blonanserin and plasma monoamine metabolites levels in patients with schizophrenia.

    Science.gov (United States)

    Miura, Itaru; Shiga, Tetsuya; Katsumi, Akihiko; Kanno-Nozaki, Keiko; Mashiko, Hirobumi; Niwa, Shin-Ichi; Yabe, Hirooki

    2014-03-01

    Blonanserin is a novel atypical antipsychotic drug that has efficacy equal to risperidone. We investigated the effects of aripiprazole and blonanserin on clinical symptoms and plasma levels of homovanillic acid (pHVA) and 3-methoxy-4hydroxyphenylglycol in the switching strategy of schizophrenia. Twenty two Japanese patients with schizophrenia were enrolled into this open study. The antipsychotics of all patients were switched to aripiprazole or blonanserin for the improvement of clinical symptoms or side effects. Plasma monoamine metabolites levels were analyzed with high-performance liquid chromatography. There were no significant effects for time (p = 0.346) or time × group interaction (p = 0.27) on the changes of positive and negative syndrome scale (PANSS) total score, although blonanserin decreased PANSS scores. We observed negative correlation between pHVA at baseline and the change in PANSS total score (rs = -0.450, p = 0.046). We also found positive correlation between the changes in pHVA and the changes in PANSS total (rs = 0.536, p = 0.015) and positive (rs = 0.572, p = 0.008) scores. There were no differences between blonanserin and aripiprazole in the improvement of clinical symptoms. Our results suggest that pHVA may be useful indicator for the switching strategy to aripiprazole or blonanserin in schizophrenia. Copyright © 2014 John Wiley & Sons, Ltd.

  6. Cofactor-dependent conformational heterogeneity of GAD65 and its role in autoimmunity and neurotransmitter homeostasis.

    Science.gov (United States)

    Kass, Itamar; Hoke, David E; Costa, Mauricio G S; Reboul, Cyril F; Porebski, Benjamin T; Cowieson, Nathan P; Leh, Hervé; Pennacchietti, Eugenia; McCoey, Julia; Kleifeld, Oded; Borri Voltattorni, Carla; Langley, David; Roome, Brendan; Mackay, Ian R; Christ, Daniel; Perahia, David; Buckle, Malcolm; Paiardini, Alessandro; De Biase, Daniela; Buckle, Ashley M

    2014-06-24

    The human neuroendocrine enzyme glutamate decarboxylase (GAD) catalyses the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) using pyridoxal 5'-phosphate as a cofactor. GAD exists as two isoforms named according to their respective molecular weights: GAD65 and GAD67. Although cytosolic GAD67 is typically saturated with the cofactor (holoGAD67) and constitutively active to produce basal levels of GABA, the membrane-associated GAD65 exists mainly as the inactive apo form. GAD65, but not GAD67, is a prevalent autoantigen, with autoantibodies to GAD65 being detected at high frequency in patients with autoimmune (type 1) diabetes and certain other autoimmune disorders. The significance of GAD65 autoinactivation into the apo form for regulation of neurotransmitter levels and autoantibody reactivity is not understood. We have used computational and experimental approaches to decipher the nature of the holo → apo conversion in GAD65 and thus, its mechanism of autoinactivation. Molecular dynamics simulations of GAD65 reveal coupling between the C-terminal domain, catalytic loop, and pyridoxal 5'-phosphate-binding domain that drives structural rearrangement, dimer opening, and autoinactivation, consistent with limited proteolysis fragmentation patterns. Together with small-angle X-ray scattering and fluorescence spectroscopy data, our findings are consistent with apoGAD65 existing as an ensemble of conformations. Antibody-binding kinetics suggest a mechanism of mutually induced conformational changes, implicating the flexibility of apoGAD65 in its autoantigenicity. Although conformational diversity may provide a mechanism for cofactor-controlled regulation of neurotransmitter biosynthesis, it may also come at a cost of insufficient development of immune self-tolerance that favors the production of GAD65 autoantibodies.

  7. Acute Exposure to Pacific Ciguatoxin Reduces Electroencephalogram Activity and Disrupts Neurotransmitter Metabolic Pathways in Motor Cortex.

    Science.gov (United States)

    Kumar, Gajendra; Au, Ngan Pan Bennett; Lei, Elva Ngai Yu; Mak, Yim Ling; Chan, Leanne Lai Hang; Lam, Michael Hon Wah; Chan, Leo Lai; Lam, Paul Kwan Sing; Ma, Chi Him Eddie

    2016-09-10

    Ciguatera fish poisoning (CFP) is a common human food poisoning caused by consumption of ciguatoxin (CTX)-contaminated fish affecting over 50,000 people worldwide each year. CTXs are classified depending on their origin from the Pacific (P-CTXs), Indian Ocean (I-CTXs), and Caribbean (C-CTXs). P-CTX-1 is the most toxic CTX known and the major source of CFP causing an array of neurological symptoms. Neurological symptoms in some CFP patients last for several months or years; however, the underlying electrophysiological properties of acute exposure to CTXs remain unknown. Here, we used CTX purified from ciguatera fish sourced in the Pacific Ocean (P-CTX-1). Delta and theta electroencephalography (EEG) activity was reduced remarkably in 2 h and returned to normal in 6 h after a single exposure. However, second exposure to P-CTX-1 induced not only a further reduction in EEG activities but also a 2-week delay in returning to baseline EEG values. Ciguatoxicity was detected in the brain hours after the first and second exposure by mouse neuroblastoma assay. The spontaneous firing rate of single motor cortex neuron was reduced significantly measured by single-unit recording with high spatial resolution. Expression profile study of neurotransmitters using targeted profiling approach based on liquid chromatography-tandem mass spectrometry revealed an imbalance between excitatory and inhibitory neurotransmitters in the motor cortex. Our study provides a possible link between the brain oscillations and neurotransmitter release after acute exposure to P-CTX-1. Identification of EEG signatures and major metabolic pathways affected by P-CTX-1 provides new insight into potential biomarker development and therapeutic interventions.

  8. Chemical stimulation of rat retinal neurons: feasibility of an epiretinal neurotransmitter-based prosthesis

    Science.gov (United States)

    Inayat, Samsoon; Rountree, Corey M.; Troy, John B.; Saggere, Laxman

    2015-02-01

    Objective. No cure currently exists for photoreceptor degenerative diseases, which cause partial or total blindness in millions of people worldwide. Electrical retinal prostheses have been developed by several groups with the goal of restoring vision lost to these diseases, but electrical stimulation has limitations. It excites both somas and axons, activating retinal pathways nonphysiologically, and limits spatial resolution because of current spread. Chemical stimulation of retinal ganglion cells (RGCs) using the neurotransmitter glutamate has been suggested as an alternative to electrical stimulation with some significant advantages. However, sufficient scientific data to support developing a chemical-based retinal prosthesis is lacking. The goal of this study was to investigate the feasibility of a neurotransmitter-based retinal prosthesis and determine therapeutic stimulation parameters. Approach. We injected controlled amounts of glutamate into rat retinas from the epiretinal side ex vivo via micropipettes using a pressure injection system and recorded RGC responses with a multielectrode array. Responsive units were identified using a spike rate threshold of 3 Hz. Main results. We recorded both somal and axonal units and demonstrated successful glutamatergic stimulation across different RGC subtypes. Analyses show that exogenous glutamate acts on RGC synapses similar to endogenous glutamate and, unlike electrical prostheses, stimulates only RGC somata. The spatial spread of glutamate stimulation was ˜ 290 μm from the injection site, comparable to current electrical prostheses. Further, the glutamate injections produced spatially differential responses in OFF, ON, and ON-OFF RGC subtypes, suggesting that differential stimulation of the OFF and ON systems may be possible. A temporal resolution of 3.2 Hz was obtained, which is a rate suitable for spatial vision. Significance. We provide strong support for the feasibility of an epiretinal neurotransmitter

  9. Neurotransmitter/sodium symporter orthologue LeuT has a single high-affinity substrate site.

    Science.gov (United States)

    Piscitelli, Chayne L; Krishnamurthy, Harini; Gouaux, Eric

    2010-12-23

    Neurotransmitter/sodium symporters (NSSs) couple the uptake of neurotransmitter with one or more sodium ions, removing neurotransmitter from the synaptic cleft. NSSs are essential to the function of chemical synapses, are associated with multiple neurological diseases and disorders, and are the targets of therapeutic and illicit drugs. LeuT, a prokaryotic orthologue of the NSS family, is a model transporter for understanding the relationships between molecular mechanism and atomic structure in a broad range of sodium-dependent and sodium-independent secondary transporters. At present there is a controversy over whether there are one or two high-affinity substrate binding sites in LeuT. The first-reported crystal structure of LeuT, together with subsequent functional and structural studies, provided direct evidence for a single, high-affinity, centrally located substrate-binding site, defined as the S1 site. Recent binding, flux and molecular simulation studies, however, have been interpreted in terms of a model where there are two high-affinity binding sites: the central, S1, site and a second, the S2 site, located within the extracellular vestibule. Furthermore, it was proposed that the S1 and S2 sites are allosterically coupled such that occupancy of the S2 site is required for the cytoplasmic release of substrate from the S1 site. Here we address this controversy by performing direct measurement of substrate binding to wild-type LeuT and to S2 site mutants using isothermal titration calorimetry, equilibrium dialysis and scintillation proximity assays. In addition, we perform uptake experiments to determine whether the proposed allosteric coupling between the putative S2 site and the S1 site manifests itself in the kinetics of substrate flux. We conclude that LeuT harbours a single, centrally located, high-affinity substrate-binding site and that transport is well described by a simple, single-substrate kinetic mechanism.

  10. In Vivo Assessment of Neurotransmitters and Modulators with Magnetic Resonance Spectroscopy: Application to Schizophrenia

    Science.gov (United States)

    Wijtenburg, S. Andrea; Yang, Shaolin; Fischer, Bernard A.; Rowland, Laura M.

    2015-01-01

    In vivo measurement of neurotransmitters and modulators is now feasible with advanced proton magnetic resonance spectroscopy (1H-MRS) techniques. This review provides a basic tutorial of MRS, describes the methods available to measure brain glutamate, glutamine, γ-aminobutyric acid, glutathione, N-acetylaspartylglutamate, glycine, and serine at magnetic field strengths of 3Tesla or higher, and summarizes the neurochemical findings in schizophrenia. Overall, 1H-MRS holds great promise for producing biomarkers that can serve as treatment targets, prediction of disease onset, or illness exacerbation in schizophrenia and other brain diseases. PMID:25614132

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

    Science.gov (United States)

    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.

  12. Role of putative neurotransmitters in the central gastric antisecretory effect of prostaglandin E2 in rats.

    OpenAIRE

    Puurunen, J.

    1985-01-01

    The role of putative neurotransmitters of the central nervous system in the central gastric antisecretory effect of prostaglandin E2 (PGE2) was investigated in pylorus-ligated rats. Pretreatment of the rats with an intracerebroventricular (i.c.v.) injection of 6-hydroxydopamine (6-OHDA) prevented the antisecretory effect of the i.c.v. administration of PGE2, whereas pretreatment with 5,6-dihydroxytryptamine (5,6-DHT) plus p-chlorophenylalanine (PCPA) had no effect. I.c.v.-administered phentol...

  13. Galactorrhea-a strong clinical clue towards the diagnosis of neurotransmitter disease.

    Science.gov (United States)

    Yeung, Wai Lan; Lam, Ching Wan; Hui, Joannie; Tong, Sui Fan; Wu, Shun Ping

    2006-07-01

    Two siblings from a Hong Kong Chinese family are diagnosed to have heterozygous mutation in tyrosine hydroxylase gene-a novel mutation R169X and the common Dutch mutation R233H. Presented with developmental delay and dystonia before 6 months of age, both had hyperprolactinemia with persistent galactorrhea present in the elder brother since birth. Serum prolactin level is a good screening test for those suspected of underlying neurotransmitter diseases. To our knowledge, this is the first Chinese family diagnosed with such condition. Clinicians must be aware of this rare disease especially in those unexplained 'cerebral palsy' like children.

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

    Energy Technology Data Exchange (ETDEWEB)

    Ozel, Rifat Emrah [Department of Chemistry and Biomolecular Science, 8 Clarkson Ave, Potsdam, NY 136995810 (United States); Wallace, Kenneth N. [Department of Biology, Clarkson University, Potsdam, NY 136995810 (United States); Andreescu, Silvana, E-mail: eandrees@clarkson.edu [Department of Chemistry and Biomolecular Science, 8 Clarkson Ave, Potsdam, NY 136995810 (United States)

    2011-06-10

    Graphical abstract: Chitosan coated fiber electrodes are sensitive to serotonin detection while rejecting physiological levels of ascorbic acid interferences. - Abstract: 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/{mu}M, 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.

  15. FMRP Regulates Neurotransmitter Release and Synaptic Information Transmission by Modulating Action Potential Duration via BK channels

    Science.gov (United States)

    Deng, Pan-Yue; Rotman, Ziv; Blundon, Jay A.; Cho, Yongcheol; Cui, Jianmin; Cavalli, Valeria; Zakharenko, Stanislav S.; Klyachko, Vitaly A.

    2013-01-01

    SUMMARY Loss of FMRP causes Fragile X syndrome (FXS), but the physiological functions of FMRP remain highly debatable. Here we show that FMRP regulates neurotransmitter release in CA3 pyramidal neurons by modulating action potential (AP) duration. Loss of FMRP leads to excessive AP broadening during repetitive activity, enhanced presynaptic calcium influx and elevated neurotransmitter release. The AP broadening defects caused by FMRP loss have a cell-autonomous presynaptic origin and can be acutely rescued in postnatal neurons. These presynaptic actions of FMRP are translation-independent and are mediated selectively by BK channels via interaction of FMRP with BK channel’s regulatory β4 subunits. Information-theoretical analysis demonstrates that loss of these FMRP functions causes marked dysregulation of synaptic information transmission. FMRP-dependent AP broadening is not limited to the hippocampus, but also occurs in cortical pyramidal neurons. Our results thus suggest major translation-independent presynaptic functions of FMRP that may have important implications for understanding FXS neuropathology. PMID:23439122

  16. The role of amino acid neurotransmitters in the descending control of electroreception.

    Science.gov (United States)

    Bastian, J

    1993-05-01

    The roles of amino acid neurotransmitters in determining the processing characteristics of the electrosensory lateral line lobe (ELL) in Apteronotus leptorhynchus were investigated by studying the responses of ELL output neurons to pressure ejection of various neurotransmitter agonists and antagonists alone and in combination with simple electrosensory stimuli. 1. Pressure ejection of L-glutamate into the ELL dorsal molecular layer caused either excitation or inhibition of ELL efferent neurons (pyramidal cells). The sign of these responses reversed with changes in the position of the pressure pipette. Histological verification of drug ejection sites relative to recorded cells and diffusion estimates indicate that excitatory and inhibitory responses result from glutamate activation of pyramidal cells and of inhibitory interneurons, respectively. 2. ELL output cells respond to both NMDA and non-NMDA glutamate agonists and the responses are attenuated by co-ejection of specific antagonists indicating that both AMPA/kainate and NMDA receptors exist on pyramidal cell apical dendrites. 3. Gamma-aminobutyric acid inhibits basilar and nonbasilar pyramidal cells when ejected near their apical dendrites and disinhibits them when ejected near surrounding inhibitory interneurons confirming the presence of GABA receptors on these cell types. 4. An NMDA antagonist did not alter pyramidal cell responses to electrosensory stimuli but a non-NMDA antagonist altered both responses to the stimuli and firing frequency shortly following stimulus cessation.

  17. Fine-tuning of defensive behaviors in the dorsal periaqueductal gray by atypical neurotransmitters

    Directory of Open Access Journals (Sweden)

    M.V. Fogaça

    2012-04-01

    Full Text Available This paper presents an up-to-date review of the evidence indicating that atypical neurotransmitters such as nitric oxide (NO and endocannabinoids (eCBs play an important role in the regulation of aversive responses in the periaqueductal gray (PAG. Among the results supporting this role, several studies have shown that inhibitors of neuronal NO synthase or cannabinoid receptor type 1 (CB1 receptor agonists cause clear anxiolytic responses when injected into this region. The nitrergic and eCB systems can regulate the activity of classical neurotransmitters such as glutamate and γ-aminobutyric acid (GABA that control PAG activity. We propose that they exert a ‘fine-tuning’ regulatory control of defensive responses in this area. This control, however, is probably complex, which may explain the usually bell-shaped dose-response curves observed with drugs that act on NO- or CB1-mediated neurotransmission. Even if the mechanisms responsible for this complex interaction are still poorly understood, they are beginning to be recognized. For example, activation of transient receptor potential vanilloid type-1 channel (TRPV1 receptors by anandamide seems to counteract the anxiolytic effects induced by CB1 receptor activation caused by this compound. Further studies, however, are needed to identify other mechanisms responsible for this fine-tuning effect.

  18. Vitis vinifera juice ameliorates depression-like behavior in mice by modulating biogenic amine neurotransmitters

    Directory of Open Access Journals (Sweden)

    Muhammad Aslam

    2015-12-01

    Full Text Available The advantageous effects of Vitis vinifera juice on depressive model mice were examined utilizing a blend of behavioral evaluations and biogenic amine neurotransmitter estimations. During the behavioral evaluations, immobility time on the forced swimming test and tail suspension test were measured in unstressed and immobilization-induced stressed mice. V. vinifera juice (4 mL/kg and 8 mL/kg and fluoxetine (20 mg/kg produced a significant decrease in immobility time of both unstressed and stressed mice when compared with their respective saline-treated control groups in both paradigms. Neurotransmitters were measured using high-performance liquid chromatography with electrochemical detector. V. vinifera juice raised the levels of both serotonin (p<0.001 and noradrenalin (p<0.001 in brain tissue. These outcomes give significant mechanistic insights into the protective effect of V. vinifera juice against depressive disorders. Our results showed that V. vinifera juice could relieve depressive manifestations in the rodent model of depression.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    Singh, Satinder K; Pal, Aritra

    2015-01-01

    Ion-coupled secondary transport is utilized by multiple integral membrane proteins as a means of achieving the thermodynamically unfavorable translocation of solute molecules across the lipid bilayer. The chemical nature of these molecules is diverse and includes sugars, amino acids, neurotransmitters, and other ions. LeuT is a sodium-coupled, nonpolar amino acid symporter and eubacterial member of the solute carrier 6 (SLC6) family of Na(+)/Cl(-)-dependent neurotransmitter transporters. Eukaryotic counterparts encompass the clinically and pharmacologically significant transporters for γ-aminobutyric acid (GABA), glycine, serotonin (5-hydroxytryptamine, 5-HT), dopamine (DA), and norepinephrine (NE). Since the crystal structure of LeuT was first solved in 2005, subsequent crystallographic, binding, flux, and spectroscopic studies, complemented with homology modeling and molecular dynamic simulations, have allowed this protein to emerge as a remarkable mechanistic paradigm for both the SLC6 class as well as several other sequence-unrelated SLCs whose members possess astonishingly similar architectures. Despite yielding groundbreaking conceptual advances, this vast treasure trove of data has also been the source of contentious hypotheses. This chapter will present a historical scientific overview of SLC6s; recount how the initial and subsequent LeuT structures were solved, describing the insights they each provided; detail the accompanying functional techniques, emphasizing how they either supported or refuted the static crystallographic data; and assemble these individual findings into a mechanism of transport and inhibition. © 2015 Elsevier Inc. All rights reserved.

  1. Cholinergic and other neurotransmitter mechanisms in Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies.

    Science.gov (United States)

    Francis, Paul T; Perry, Elaine K

    2007-09-01

    It is now 30 years since the beginning of intensive efforts to understand the neurotransmitter biochemistry of dementia as exemplified by Alzheimer's disease and such studies have led to the development of rational treatment strategies, which are continuing to benefit patients. However, as studies became more sophisticated and clinicians rediscovered an interest in dementia, because of the potential for symptomatic treatment, it has become clear that there are several different neurodegenerative conditions that gives rise to dementia syndromes and that each has distinct neurochemical pathology. This has important treatment implications since what works for one may not work for another or at the extreme, may make matters worse. Therefore it is clear that a detailed understanding of the neurotransmitter function in each condition is not merely academic but can lead to rationale drug design and treatment strategies appropriate for that group of patients. Dementia with Lewy bodies (DLB) has clinico-pathological features, which overlap with either AD or Parkinson's disease (PD) as well as features that help to distinguish it, such as fluctuations in cognitive impairment and a higher prevalence of visual hallucinations. On this basis, it would be expected that the neurochemistry would have some similarities with both disorders.

  2. 白质内的神经递质信号%Neurotransmitter signaling in white matter

    Institute of Scientific and Technical Information of China (English)

    唐颖馨(编译)

    2014-01-01

    脑白质是由许多有髓鞘的轴突组成,白质和灰质共同组成中枢神经系统,白质是中枢神经系统内信息快速传递的基础。有髓神经通路主要是由少突胶质细胞、星形胶质细胞及少量的小胶质细胞和少突胶质前体细胞构成。大部分白质内的神经递质信号主要存在于神经细胞胞体外,这提示这些神经递质除了具有完成神经元与神经元之间信息传递的功能外,还有其他生理功能。白质中的神经递质信号种类很多,已经证实的有谷氨酸能、嘌呤能(ATP和腺苷)、GABA能、甘氨酸能、肾上腺素能、胆碱能、多巴胺能、血清素能等信号递质,通过与各种离子型或代谢型受体结合发挥作用。轴突和胶质细胞都可以释放神经递质,也可以表达相应的受体。白质内神经递质信号的生理功能还需进一步研究,但研究已经证实谷氨酸和ATP介导的信号可激活胶质细胞上的钙离子通道,并调节轴突的传导功能。某项研究显示,在动作电位传播的过程中,轴突释放神经递质并与胶质细胞上的受体结合,通过少突胶质细胞来调节星形胶质细胞的稳态和髓鞘形成。星形胶质细胞也释放神经递质,与轴突上的受体相结合,增强动作电位的传播,维持信号电位沿长的轴突传播。白质内神经递质种类的多样性,提示它们有多种功能,对信号的传递有重要作用。白质内的神经递质信号现象很有可能也存在于大脑皮质和灰质,在这些部位的神经递质对于大脑的高级认知功能有更重要的作用。%White matter (WM) tracts are bundles of myelinated axons that provide for rapid communication throughout the CNS and integration in grey matter (GM). The main cells in myelinated tracts are oligodendrocytes and astrocytes, with small populations of microglia and oligodendrocyte precursor cells. The prominence of neurotransmitter

  3. Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior.

    Science.gov (United States)

    Huang, Fei; Wang, Tingting; Lan, Yunyi; Yang, Li; Pan, Weihong; Zhu, Yonghui; Lv, Boyang; Wei, Yuting; Shi, Hailian; Wu, Hui; Zhang, Beibei; Wang, Jie; Duan, Xiaofeng; Hu, Zhibi; Wu, Xiaojun

    2015-01-01

    Farnesoid X receptor (FXR) is a nuclear hormone receptor involved in bile acid synthesis and homeostasis. Dysfunction of FXR is involved in cholestasis and atherosclerosis. FXR is prevalent in liver, gallbladder, and intestine, but it is not yet clear whether it modulates neurobehavior. In the current study, we tested the hypothesis that mouse FXR deficiency affects a specific subset of neurotransmitters and results in an unique behavioral phenotype. The FXR knockout mice showed less depressive-like and anxiety-related behavior, but increased motor activity. They had impaired memory and reduced motor coordination. There were changes of glutamatergic, GABAergic, serotoninergic, and norepinephrinergic neurotransmission in either hippocampus or cerebellum. FXR deletion decreased the amount of the GABA synthesis enzyme GAD65 in hippocampus but increased GABA transporter GAT1 in cerebral cortex. FXR deletion increased serum concentrations of many bile acids, including taurodehydrocholic acid, taurocholic acid, deoxycholic acid (DCA), glycocholic acid (GCA), tauro-α-muricholic acid, tauro-ω-muricholic acid, and hyodeoxycholic acid (HDCA). There were also changes in brain concentrations of taurocholic acid, taurodehydrocholic acid, tauro-ω-muricholic acid, tauro-β-muricholic acid, deoxycholic acid, and lithocholic acid (LCA). Taken together, the results from studies with FXR knockout mice suggest that FXR contributes to the homeostasis of multiple neurotransmitter systems in different brain regions and modulates neurobehavior. The effect appears to be at least partially mediated by bile acids that are known to cross the blood-brain barrier (BBB) inducing potential neurotoxicity.

  4. Near-future carbon dioxide levels alter fish behaviour by interfering with neurotransmitter function

    Science.gov (United States)

    Nilsson, Göran E.; Dixson, Danielle L.; Domenici, Paolo; McCormick, Mark I.; Sørensen, Christina; Watson, Sue-Ann; Munday, Philip L.

    2012-03-01

    Predicted future CO2 levels have been found to alter sensory responses and behaviour of marine fishes. Changes include increased boldness and activity, loss of behavioural lateralization, altered auditory preferences and impaired olfactory function. Impaired olfactory function makes larval fish attracted to odours they normally avoid, including ones from predators and unfavourable habitats. These behavioural alterations have significant effects on mortality that may have far-reaching implications for population replenishment, community structure and ecosystem function. However, the underlying mechanism linking high CO2 to these diverse responses has been unknown. Here we show that abnormal olfactory preferences and loss of behavioural lateralization exhibited by two species of larval coral reef fish exposed to high CO2 can be rapidly and effectively reversed by treatment with an antagonist of the GABA-A receptor. GABA-A is a major neurotransmitter receptor in the vertebrate brain. Thus, our results indicate that high CO2 interferes with neurotransmitter function, a hitherto unrecognized threat to marine populations and ecosystems. Given the ubiquity and conserved function of GABA-A receptors, we predict that rising CO2 levels could cause sensory and behavioural impairment in a wide range of marine species, especially those that tightly control their acid-base balance through regulatory changes in HCO3- and Cl- levels.

  5. Expression of functional neurotransmitter receptors in Xenopus oocytes after injection of human brain membranes

    Science.gov (United States)

    Miledi, Ricardo; Eusebi, Fabrizio; Martínez-Torres, Ataúlfo; Palma, Eleonora; Trettel, Flavia

    2002-01-01

    The Xenopus oocyte is a very powerful tool for studies of the structure and function of membrane proteins, e.g., messenger RNA extracted from the brain and injected into oocytes leads to the synthesis and membrane incorporation of many types of functional receptors and ion channels, and membrane vesicles from Torpedo electroplaques injected into oocytes fuse with the oocyte membrane and cause the appearance of functional Torpedo acetylcholine receptors and Cl− channels. This approach was developed further to transplant already assembled neurotransmitter receptors from human brain cells to the plasma membrane of Xenopus oocytes. Membranes isolated from the temporal neocortex of a patient, operated for intractable epilepsy, were injected into oocytes and, within a few hours, the oocyte membrane acquired functional neurotransmitter receptors to γ-aminobutyric acid, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, and glycine. These receptors were also expressed in the plasma membrane of oocytes injected with mRNA extracted from the temporal neocortex of the same patient. All of this makes the Xenopus oocyte a more useful model than it already is for studies of the structure and function of many human membrane proteins and opens the way to novel pathophysiological investigations of some human brain disorders. PMID:12237406

  6. Transition metal ion FRET uncovers K+ regulation of a neurotransmitter/sodium symporter

    Science.gov (United States)

    Billesbølle, Christian B.; Mortensen, Jonas S.; Sohail, Azmat; Schmidt, Solveig G.; Shi, Lei; Sitte, Harald H.; Gether, Ulrik; Loland, Claus J.

    2016-01-01

    Neurotransmitter/sodium symporters (NSSs) are responsible for Na+-dependent reuptake of neurotransmitters and represent key targets for antidepressants and psychostimulants. LeuT, a prokaryotic NSS protein, constitutes a primary structural model for these transporters. Here we show that K+ inhibits Na+-dependent binding of substrate to LeuT, promotes an outward-closed/inward-facing conformation of the transporter and increases uptake. To assess K+-induced conformational dynamics we measured fluorescence resonance energy transfer (FRET) between fluorescein site-specifically attached to inserted cysteines and Ni2+ bound to engineered di-histidine motifs (transition metal ion FRET). The measurements supported K+-induced closure of the transporter to the outside, which was counteracted by Na+ and substrate. Promoting an outward-open conformation of LeuT by mutation abolished the K+-effect. The K+-effect depended on an intact Na1 site and mutating the Na2 site potentiated K+ binding by facilitating transition to the inward-facing state. The data reveal an unrecognized ability of K+ to regulate the LeuT transport cycle. PMID:27678200

  7. Effect of Dimerization on the Dynamics of Neurotransmitter:Sodium Symporters.

    Science.gov (United States)

    Gur, Mert; Cheng, Mary Hongying; Zomot, Elia; Bahar, Ivet

    2017-02-07

    Dimerization is a common feature among the members of the neurotransmitter:sodium symporter (NSS) family of membrane proteins. Yet, the effect of dimerization on the mechanism of action of NSS members is not fully understood. In this study, we examined the collective dynamics of two members of the family, leucine transporter (LeuT) and dopamine transporter (DAT), to assess the significance of dimerization in modulating the functional motions of the monomers. We used to this aim the anisotropic network model (ANM), an efficient and robust method for modeling the intrinsic motions of proteins and their complexes. Transporters belonging to the NSS family are known to alternate between outward-facing (OF) and inward-facing (IF) states, which enables the uptake and release of their substrate (neurotransmitter) respectively, as the substrate is transported from the exterior to the interior of the cell. In both LeuT and DAT, dimerization is found to alter the collective motions intrinsically accessible to the individual monomers in favor of the functional transitions (OF ↔ IF), suggesting that dimerization may play a role in facilitating transport.

  8. Transition metal ion FRET uncovers K(+) regulation of a neurotransmitter/sodium symporter.

    Science.gov (United States)

    Billesbølle, Christian B; Mortensen, Jonas S; Sohail, Azmat; Schmidt, Solveig G; Shi, Lei; Sitte, Harald H; Gether, Ulrik; Loland, Claus J

    2016-09-28

    Neurotransmitter/sodium symporters (NSSs) are responsible for Na(+)-dependent reuptake of neurotransmitters and represent key targets for antidepressants and psychostimulants. LeuT, a prokaryotic NSS protein, constitutes a primary structural model for these transporters. Here we show that K(+) inhibits Na(+)-dependent binding of substrate to LeuT, promotes an outward-closed/inward-facing conformation of the transporter and increases uptake. To assess K(+)-induced conformational dynamics we measured fluorescence resonance energy transfer (FRET) between fluorescein site-specifically attached to inserted cysteines and Ni(2+) bound to engineered di-histidine motifs (transition metal ion FRET). The measurements supported K(+)-induced closure of the transporter to the outside, which was counteracted by Na(+) and substrate. Promoting an outward-open conformation of LeuT by mutation abolished the K(+)-effect. The K(+)-effect depended on an intact Na1 site and mutating the Na2 site potentiated K(+) binding by facilitating transition to the inward-facing state. The data reveal an unrecognized ability of K(+) to regulate the LeuT transport cycle.

  9. Modulation of electrogenic transport processes in the porcine proximal colon by enteric neurotransmitters.

    Science.gov (United States)

    Pfannkuche, H; Mauksch, A; Gäbel, G

    2012-06-01

    The aim of our study was to evaluate the involvement of essential pro- and antisecretory neurotransmitters in regulation of secretion in porcine proximal colon. Choline acetyltransferase (ChAT), nitric oxide synthase (NOS), vasoactive intestinal peptide (VIP), substance P (SP), somatostatin (SOM) and neuropeptide Y (NPY) were located immunohistochemically in the epithelium and subepithelial layer. Modulation of epithelial secretion was studied in Ussing chambers. Application of carbachol (CA), sodium nitroprussid (SNP), VIP and SP but not of NPY or SOM resulted in a chloride dependent increase in short circuit current (I(sc) ). I(sc) increase induced by CA, VIP or SNP was not altered by preincubation with tetrodotoxin or indomethacin. In contrast, SP-induced I(sc) increase was diminished by preincubation with tetrodotoxin, indomethacin, L-nitro-arginin-methyl-ester, and atropine but not hexamethonium. Simultaneous application of CA and VIP, or CA and SNP increased the I(sc) stronger as expected. Applying SP/CA led to a smaller increase in I(sc) as calculated. It is concluded that mainly prosecretory neurotransmitters are involved in regulation of colonic secretion. Cross-potentiations of acetylcholine and nitric oxide and acetylcholine and VIP suggest activation of different intracellular cascades. Similar intracellular pathways may be stimulated by acetylcholine and SP, thus preventing an additive effect of the transmitters.

  10. The fax-1 nuclear hormone receptor regulates axon pathfinding and neurotransmitter expression.

    Science.gov (United States)

    Much, J W; Slade, D J; Klampert, K; Garriga, G; Wightman, B

    2000-02-01

    Specification of neuron identity requires the activation of a number of discrete developmental programs. Among these is pathway selection by growth cones: in order for a neuron's growth cone to respond appropriately to guidance cues presented by other cells or the extracellular matrix, the neuron must express genes to mediate the response. The fax-1 gene of C. elegans is required for pathfinding of axons that extend along the ventral nerve cord. We show that fax-1 is also required for pathfinding of axons in the nerve ring, the largest nerve bundle in the nematode, and for normal expression of FMRFamide-like neurotransmitters in the AVK interneurons. The fax-1 gene encodes a member of the superfamily of nuclear hormone receptors and has a DNA-binding domain related to the human PNR and Drosophila Tailless proteins. We observe fax-1 expression in embryonic neurons, including the AVK interneurons, just prior to axon extension, but after neurogenesis. These data suggest that fax-1 coordinately regulates the transcription of genes that function in the selection of axon pathways, neurotransmitter expression and, perhaps, other aspects of the specification of neuron identity.

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

    Science.gov (United States)

    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

  12. Evolution of neurotransmitter gamma-aminobutyric acid,glutamate and their receptors

    Institute of Scientific and Technical Information of China (English)

    Zhiheng GOU; Xiao WANG; Wen WANG

    2012-01-01

    Gamma-aminobutyric acid (GABA) and glutamate are two important amino acid neurotransmitters widely present in the nervous systems of ammals,insects,round worm,and platyhelminths,while their receptors are quite diversified across different animal phyla.However,the evolutionary mechanisms between the two conserved neurotransmitters and their diversified receptors remain elusive,and antagonistic interactions between GABA and glutamate signal transduction systems,in particular,have begun to attract significant attention.In this review,we summarize the extant results on the origin and evolution of GABA and glutamate,as well as their receptors,and analyze possible evolutionary processes and phylogenetic relationships of various GABAs and glutamate receptors.We further discuss the evolutionary history of Excitatory/Neutral Amino Acid Transporter (EAAT),a transport protein,which plays an important role in the GABA-glutamate "yin and yang" balanced regulation.Finally,based on current advances,we propose several potential directions of future research.

  13. Probing interactions of neurotransmitters with twin tailed anionic surfactant: A detailed physicochemical study.

    Science.gov (United States)

    Kaur, Rajwinder; Sanan, Reshu; Mahajan, Rakesh Kumar

    2016-05-01

    Keeping in view the role of neurotransmitters (NTs) in central nervous system diseases and in controlling various physiological processes, present study is aimed to study the binding of neurotransmitters (NTs) such as norepinephrine hydrochloride (NE) and serotonin hydrochloride (5-HT) with twin tailed surfactant sodium bis(2-ethylhexyl)sulfosuccinate (AOT). Spectroscopic and electrochemical measurements combined with microcalorimetric measurements were used to characterize the interactions between AOT and NTs. Meteoric modifications to emission profile and absorption spectra of NTs upon addition of AOT are indicative of the binding of NTs with AOT. Distinct interactional states such as formation of ion-pairs, induced and regular micelles with adsorbed NTs molecules have been observed in different concentration regimes of AOT. The formation of ion-pairs from oppositely charged NTs and AOT is confirmed by the reduced absorbance, quenched fluorescence intensity and decrease in peak current (ipa) as well as shifts in peak potential (Epa) values. The stoichiometry and formation of the NTs-AOT complexes has been judged and the extent of interactions is quantitatively discussed in terms of binding constant (K) and free energy of binding (ΔG°). The enthalpy (ΔH°mic) and free energy of micellization (ΔG°mic) for AOT in presence and absence of NTs are determined from the enthalpy curves.

  14. A putative vesicular transporter expressed in Drosophila mushroom bodies that mediates sexual behavior may define a neurotransmitter system.

    Science.gov (United States)

    Brooks, Elizabeth S; Greer, Christina L; Romero-Calderón, Rafael; Serway, Christine N; Grygoruk, Anna; Haimovitz, Jasmine M; Nguyen, Bac T; Najibi, Rod; Tabone, Christopher J; de Belle, J Steven; Krantz, David E

    2011-10-20

    Vesicular transporters are required for the storage of all classical and amino acid neurotransmitters in synaptic vesicles. Some neurons lack known vesicular transporters, suggesting additional neurotransmitter systems remain unidentified. Insect mushroom bodies (MBs) are critical for several behaviors, including learning, but the neurotransmitters released by the intrinsic Kenyon cells (KCs) remain unknown. Likewise, KCs do not express a known vesicular transporter. We report the identification of a novel Drosophila gene portabella (prt) that is structurally similar to known vesicular transporters. Both larval and adult brains express PRT in the KCs of the MBs. Additional PRT cells project to the central complex and optic ganglia. prt mutation causes an olfactory learning deficit and an unusual defect in the male's position during copulation that is rescued by expression in KCs. Because prt is expressed in neurons that lack other known vesicular transporters or neurotransmitters, it may define a previously unknown neurotransmitter system responsible for sexual behavior and a component of olfactory learning. Copyright © 2011 Elsevier Inc. All rights reserved.

  15. Group IIA secretory phospholipase A2 stimulates exocytosis and neurotransmitter release in pheochromocytoma-12 cells and cultured rat hippocampal neurons.

    Science.gov (United States)

    Wei, S; Ong, W Y; Thwin, M M; Fong, C W; Farooqui, A A; Gopalakrishnakone, P; Hong, W

    2003-01-01

    Recent evidence shows that secretory phospholipase A2 (sPLA2) may play a role in membrane fusion and fission, and may thus affect neurotransmission. The present study therefore aimed to elucidate the effects of sPLA2 on vesicle exocytosis. External application of group IIA sPLA2 (purified crotoxin subunit B or purified human synovial sPLA2) caused an immediate increase in exocytosis and neurotransmitter release in pheochromocytoma-12 (PC12) cells, detected by carbon fiber electrodes placed near the cells, or by changes in membrane capacitance of the cells. EGTA and a specific inhibitor of sPLA2 activity, 12-epi-scalaradial, abolished the increase in neurotransmitter release, indicating that the effect of sPLA2 was dependent on calcium and sPLA2 enzymatic activity. A similar increase in neurotransmitter release was also observed in hippocampal neurons after external application of sPLA2, as detected by changes in membrane capacitance of the neurons. In contrast to external application, internal application of sPLA2 to PC12 cells and neurons produced blockade of neurotransmitter release. Our recent studies showed high levels of sPLA2 activity in the normal rat hippocampus, medulla oblongata and cerebral neocortex. The sPLA2 activity in the hippocampus was significantly increased, after kainate-induced neuronal injury. The observed effects of sPLA2 on neurotransmitter release in this study may therefore have a physiological, as well as a pathological role.

  16. LKB1 Regulates Mitochondria-Dependent Presynaptic Calcium Clearance and Neurotransmitter Release Properties at Excitatory Synapses along Cortical Axons.

    Directory of Open Access Journals (Sweden)

    Seok-Kyu Kwon

    2016-07-01

    Full Text Available Individual synapses vary significantly in their neurotransmitter release properties, which underlie complex information processing in neural circuits. Presynaptic Ca2+ homeostasis plays a critical role in specifying neurotransmitter release properties, but the mechanisms regulating synapse-specific Ca2+ homeostasis in the mammalian brain are still poorly understood. Using electrophysiology and genetically encoded Ca2+ sensors targeted to the mitochondrial matrix or to presynaptic boutons of cortical pyramidal neurons, we demonstrate that the presence or absence of mitochondria at presynaptic boutons dictates neurotransmitter release properties through Mitochondrial Calcium Uniporter (MCU-dependent Ca2+ clearance. We demonstrate that the serine/threonine kinase LKB1 regulates MCU expression, mitochondria-dependent Ca2+ clearance, and thereby, presynaptic release properties. Re-establishment of MCU-dependent mitochondrial Ca2+ uptake at glutamatergic synapses rescues the altered neurotransmitter release properties characterizing LKB1-null cortical axons. Our results provide novel insights into the cellular and molecular mechanisms whereby mitochondria control neurotransmitter release properties in a bouton-specific way through presynaptic Ca2+ clearance.

  17. LKB1 Regulates Mitochondria-Dependent Presynaptic Calcium Clearance and Neurotransmitter Release Properties at Excitatory Synapses along Cortical Axons

    Science.gov (United States)

    Kwon, Seok-Kyu; Sando, Richard; Maximov, Anton; Polleux, Franck

    2016-01-01

    Individual synapses vary significantly in their neurotransmitter release properties, which underlie complex information processing in neural circuits. Presynaptic Ca2+ homeostasis plays a critical role in specifying neurotransmitter release properties, but the mechanisms regulating synapse-specific Ca2+ homeostasis in the mammalian brain are still poorly understood. Using electrophysiology and genetically encoded Ca2+ sensors targeted to the mitochondrial matrix or to presynaptic boutons of cortical pyramidal neurons, we demonstrate that the presence or absence of mitochondria at presynaptic boutons dictates neurotransmitter release properties through Mitochondrial Calcium Uniporter (MCU)-dependent Ca2+ clearance. We demonstrate that the serine/threonine kinase LKB1 regulates MCU expression, mitochondria-dependent Ca2+ clearance, and thereby, presynaptic release properties. Re-establishment of MCU-dependent mitochondrial Ca2+ uptake at glutamatergic synapses rescues the altered neurotransmitter release properties characterizing LKB1-null cortical axons. Our results provide novel insights into the cellular and molecular mechanisms whereby mitochondria control neurotransmitter release properties in a bouton-specific way through presynaptic Ca2+ clearance. PMID:27429220

  18. [{sup 11}C]S.L.(25.1188), a new radioligand to study the monoamine oxidase type B with PET: preclinical characterisation

    Energy Technology Data Exchange (ETDEWEB)

    Saba, W.; Valette, H.; Peyronneau, M.A.; Bramoulle, Y.; Coulon, C.; Dolle, F.; Bottlaender, M. [Service Hospitalier Frederic Joliot, IIBM/DSV, 91 - Orsay (France); Curet, O.; George, P. [Sanofi-Aventis, 92 - Bagneux (France)

    2008-02-15

    Introduction. - Monoamine oxidase (M.A.O.) is a flavin containing enzyme, that catalyzes the oxidative deamination of various amines and neurotransmitters. Two isoforms exist, M.A.O.-A and M.A.O.-B. Variations in M.A.O. activity may be associated to human disease such as Parkinson and Alzheimer disease. Few radiotracers have been developed for M.A.O. PET studies such as [{sup 11}C]deprenyl, an irreversible M.A.O.-B inhibitor. Recently an oxazolidinone derivative, S.L.- 25.1188 ((S)-5-methoxy-methyl-3-[6-(4,4,4-tri-fluoro butoxy)- benzo[d]isoxazol-3-yl]-oxazolidin-2-one), belonging to a new generation of selective and reversible M.A.O.-B inhibitors was developed and showed in vitro a high selectivity for M.A.O.B. [1]. The aim of this study was to characterize [{sup 11}C]S.L.- 25.1188 as radioligand for in vivo PET examination of M.A.O.-B. Materials and methods. - PET studies of the brain distribution were carried out in male Papio anubis baboons. Selectivity and reversibility of [{sup 11}C]S.L.-25.1188 binding for M.A.O.-B was assessed by pre-treatment or displacement experiments (30 min before and after tracer injection, respectively) using reference ligands for M.A.O.-B (deprenyl: 2 mg/kg i.v. and lazabemide: 0.5 mg/kg i.v.) or by displacement experiments using unlabelled S.L.-25.1188 (1 mg/kg, i.v., 30 min after tracer injection). Distribution volume (D.V.) was calculated using 2-tissue-compartment model. The saturable binding following pre-treatment with deprenyl was considered as the specific binding. Results. - After injection, [1{sup 1C}]S.L.-25.1188 presents a rapid phase of distribution in blood (about 5 min), followed by a elimination with T1/2 of 75 min. The Blood to plasma concentration ratio was constant during the experimentation (0.9 {+-} .04) consistent with a similar kinetic of [{sup 11}C]S.L.- 25.1188 in both blood and plasma. Metabolism analysis showed that [{sup 11}C]S.L.-25.1188 is stable in vivo. In the brain, uptake in different areas was

  19. The monoamine oxidase inhibition properties of selected structural analogues of methylene blue.

    Science.gov (United States)

    Delport, Anzelle; Harvey, Brian H; Petzer, Anél; Petzer, Jacobus P

    2017-06-15

    The thionine dye, methylene blue (MB), is a potent inhibitor of monoamine oxidase (MAO) A, a property that may, at least in part, mediate its antidepressant effects in humans and animals. The central inhibition of MAO-A by MB has also been linked to serotonin toxicity (ST) which may arise when MB is used in combination with serotonergic drugs. Structural analogues and the principal metabolite of MB, azure B, have also been reported to inhibit the MAO enzymes, with all compounds exhibiting specificity for the MAO-A isoform. To expand on the structure-activity relationships (SARs) of MAO inhibition by MB analogues, the present study investigates the human MAO inhibition properties of five MB analogues: neutral red, Nile blue, new methylene blue, cresyl violet and 1,9-dimethyl methylene blue. Similar to MB, these analogues also are specific MAO-A inhibitors with cresyl violet (IC50=0.0037μM), Nile blue (IC50=0.0077μM) and 1,9-dimethyl methylene blue (IC50=0.018μM) exhibiting higher potency inhibition compared to MB (IC50=0.07μM). Nile blue also represents a potent MAO-B inhibitor with an IC50 value of 0.012μM. From the results it may be concluded that non-thionine MB analogues (e.g. cresyl violet and Nile blue) also may exhibit potent MAO inhibition, a property which should be considered when using these compounds in pharmacological studies. Benzophenoxazines such as cresyl violet and Nile blue are, similar to phenothiazines (e.g. MB), representative of high potency MAO-A inhibitors with a potential risk of ST. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Monoamine oxidase A polymorphism moderates stability of attention problems and susceptibility to life stress during adolescence.

    Science.gov (United States)

    Zohsel, K; Bianchi, V; Mascheretti, S; Hohm, E; Schmidt, M H; Esser, G; Brandeis, D; Banaschewski, T; Nobile, M; Laucht, M

    2015-11-01

    Attention problems affect a substantial number of children and adolescents and are predictive of academic underachievement and lower global adaptive functioning. Considerable variability has been observed with regard to the individual development of attention problems over time. In particular, the period of adolescence is characterized by substantial maturation of executive functioning including attentional processing, with the influence of genetic and environmental factors on individual trajectories not yet well understood. In the present investigation, we evaluated whether the monoamine oxidase A functional promoter polymorphism, MAOA-LPR, plays a role in determining continuity of parent-rated attention problems during adolescence. At the same time, a potential effect of severe life events (SLEs) was taken into account. A multi-group path analysis was used in a sample of 234 adolescents (149 males, 85 females) who took part in an epidemiological cohort study at the ages of 11 and 15 years. Attention problems during early adolescence were found to be a strong predictor of attention problems in middle adolescence. However, in carriers of the MAOA-LPR low-activity variant (MAOA-L), stability was found to be significantly higher than in carriers of the high-activity variant (MAOA-H). Additionally, only in MAOA-L carriers did SLEs during adolescence significantly impact on attention problems at the age of 15 years, implying a possible gene × environment interaction. To conclude, we found evidence that attention problems during adolescence in carriers of the MAOA-L allele are particularly stable and malleable to life stressors. The present results underline the usefulness of applying a more dynamic GxE perspective. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  1. Lobelane inhibits methamphetamine-evoked dopamine release via inhibition of the vesicular monoamine transporter-2.

    Science.gov (United States)

    Nickell, Justin R; Krishnamurthy, Sairam; Norrholm, Seth; Deaciuc, Gabriela; Siripurapu, Kiran B; Zheng, Guangrong; Crooks, Peter A; Dwoskin, Linda P

    2010-02-01

    Lobeline is currently being evaluated in clinical trials as a methamphetamine abuse treatment. Lobeline interacts with nicotinic receptor subtypes, dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Methamphetamine inhibits VMAT2 and promotes dopamine (DA) release from synaptic vesicles, resulting ultimately in increased extracellular DA. The present study generated structure-activity relationships by defunctionalizing the lobeline molecule and determining effects on [(3)H]dihydrotetrabenazine binding, inhibition of [(3)H]DA uptake into striatal synaptic vesicles and synaptosomes, the mechanism of VMAT2 inhibition, and inhibition of methamphetamine-evoked DA release. Compared with lobeline, the analogs exhibited greater potency inhibiting DA transporter (DAT) function. Saturated analogs, lobelane and nor-lobelane, exhibited high potency (K(i) = 45 nM) inhibiting vesicular [(3)H]DA uptake, and lobelane competitively inhibited VMAT2 function. Lobeline and lobelane exhibited 67- and 35-fold greater potency, respectively, in inhibiting VMAT2 function compared to DAT function. Lobelane potently decreased (IC(50) = 0.65 microM; I(max) = 73%) methamphetamine-evoked DA overflow, and with a greater maximal effect compared with lobeline (IC(50) = 0.42 microM, I(max) = 56.1%). These results provide support for VMAT2 as a target for inhibition of methamphetamine effects. Both trans-isomers and demethylated analogs of lobelane had reduced or unaltered potency inhibiting VMAT2 function and lower maximal inhibition of methamphetamine-evoked DA release compared with lobelane. Thus, defunctionalization, cis-stereochemistry of the side chains, and presence of the piperidino N-methyl are structural features that afford greatest inhibition of methamphetamine-evoked DA release and enhancement of selectivity for VMAT2. The current results reveal that lobelane, a selective VMAT2 inhibitor, inhibits methamphetamine-evoked DA release and is a promising lead for

  2. Lobelane Inhibits Methamphetamine-Evoked Dopamine Release via Inhibition of the Vesicular Monoamine Transporter-2S⃞

    Science.gov (United States)

    Nickell, Justin R.; Krishnamurthy, Sairam; Norrholm, Seth; Deaciuc, Gabriela; Siripurapu, Kiran B.; Zheng, Guangrong; Crooks, Peter A.

    2010-01-01

    Lobeline is currently being evaluated in clinical trials as a methamphetamine abuse treatment. Lobeline interacts with nicotinic receptor subtypes, dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Methamphetamine inhibits VMAT2 and promotes dopamine (DA) release from synaptic vesicles, resulting ultimately in increased extracellular DA. The present study generated structure-activity relationships by defunctionalizing the lobeline molecule and determining effects on [3H]dihydrotetrabenazine binding, inhibition of [3H]DA uptake into striatal synaptic vesicles and synaptosomes, the mechanism of VMAT2 inhibition, and inhibition of methamphetamine-evoked DA release. Compared with lobeline, the analogs exhibited greater potency inhibiting DA transporter (DAT) function. Saturated analogs, lobelane and nor-lobelane, exhibited high potency (Ki = 45 nM) inhibiting vesicular [3H]DA uptake, and lobelane competitively inhibited VMAT2 function. Lobeline and lobelane exhibited 67- and 35-fold greater potency, respectively, in inhibiting VMAT2 function compared to DAT function. Lobelane potently decreased (IC50 = 0.65 μM; Imax = 73%) methamphetamine-evoked DA overflow, and with a greater maximal effect compared with lobeline (IC50 = 0.42 μM, Imax = 56.1%). These results provide support for VMAT2 as a target for inhibition of methamphetamine effects. Both trans-isomers and demethylated analogs of lobelane had reduced or unaltered potency inhibiting VMAT2 function and lower maximal inhibition of methamphetamine-evoked DA release compared with lobelane. Thus, defunctionalization, cis-stereochemistry of the side chains, and presence of the piperidino N-methyl are structural features that afford greatest inhibition of methamphetamine-evoked DA release and enhancement of selectivity for VMAT2. The current results reveal that lobelane, a selective VMAT2 inhibitor, inhibits methamphetamine-evoked DA release and is a promising lead for the development of a

  3. Antidepressant stimulation of CDP-diacylglycerol synthesis does not require monoamine reuptake inhibition

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    Aboukhatwa Marwa A

    2010-01-01

    Full Text Available Abstract Background Recent studies demonstrate that diverse antidepressant agents increase the cellular production of the nucleolipid CDP-diacylglycerol and its synthetic derivative, phosphatidylinositol, in depression-relevant brain regions. Pharmacological blockade of downstream phosphatidylinositide signaling disrupted the behavioral antidepressant effects in rats. However, the nucleolipid responses were resistant to inhibition by serotonin receptor antagonists, even though antidepressant-facilitated inositol phosphate accumulation was blocked. Could the neurochemical effects be additional to the known effects of the drugs on monoamine transmitter transporters? To examine this question, we tested selected agents in serotonin-depleted brain tissues, in PC12 cells devoid of serotonin transporters, and on the enzymatic activity of brain CDP-diacylglycerol synthase - the enzyme that catalyzes the physiological synthesis of CDP-diacylglycerol. Results Imipramine, paroxetine, and maprotiline concentration-dependently increased the levels of CDP-diacylglycerol and phosphatidylinositides in PC12 cells. Rat forebrain tissues depleted of serotonin by pretreatment with p-chlorophenylalanine showed responses to imipramine or maprotiline that were comparable to respective responses from saline-injected controls. With fluoxetine, nucleolipid responses in the serotonin-depleted cortex or hippocampus were significantly reduced, but not abolished. Each drug significantly increased the enzymatic activity of CDP-diacylglycerol synthase following incubations with cortical or hippocampal brain tissues. Conclusion Antidepressants probably induce the activity of CDP-diacylglycerol synthase leading to increased production of CDP-diacylglycerol and facilitation of downstream phosphatidylinositol synthesis. Phosphatidylinositol-dependent signaling cascades exert diverse salutary effects in neural cells, including facilitation of BDNF signaling and neurogenesis. Hence

  4. Evaluation of the Inhibitory Effects of Bavachinin and Bavachin on Human Monoamine Oxidases A and B

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    Najla O. Zarmouh

    2015-01-01

    Full Text Available Monoamine oxidase B inhibitors (MAO-BIs are used in the early management of Parkinson’s disease (PD. Long-term suspected side effects of MAO-B classical inhibitors established the need for safer alternative therapeutic agents. In our study, the flavanone bavachinin (BNN and its analog bavachin (BVN found in the seeds of Psoralea corylifolia L. ethanolic extract (PCSEE were investigated for their human MAO-A and MAO-B (hMAO-A and hMAO-B inhibition. Both PCSEE and BNN effectively reduced hMAO-B activity more than hMAO-A while BVN had activating effects. BNN showed selective hMAO-B inhibition (IC50 ~ 8.82 μM more than hMAO-A (IC502009;~ 189.28 μM. BNN in the crude extract was determined by HPLC, also validated by TLC showing a yield of 0.21% PCSEE dry weight. BNN competitively inhibited hMAO-A and hMAO-B, with a lower hMAO-B Ki than hMAO-A Ki by 10.33-fold, and reduced hMAO-B Km/Vmax efficiency ratio to be comparable to the standard selegiline. Molecular docking examination of BNN and BVN predicted an indirect role of BNN C7-methoxy group for its higher affinity, selectivity, and reversibility as an MAO-BI. These findings suggest that BNN, which is known to be a potent PPAR-γ agonist, is a selective and competitive hMAO-B inhibitor and could be used in the management of PD.

  5. Sex-dependent changes in anxiety, memory, and monoamines following one week of stress.

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    Bowman, R E; Micik, R; Gautreaux, C; Fernandez, L; Luine, V N

    2009-04-20

    Chronic restraint stress alters performance of rats on cognitive tasks, and anxiety measurements, and these stress-induced behavioral alterations are sexually dimorphic. Following a long stress period (21 days restraint) males show cognitive impairments while females are either not affected or enhanced on the same tasks. The current study examined whether sexually differentiated responses are also induced following shorter restraint stress durations. Male and female Sprague Dawley rats, aged 2.5 months, served as controls or received restraint stress (6 h/day, 7 days) and were tested for anxiety (plus maze), non-spatial memory (object recognition), and spatial memory (object placement). Plus maze performance was altered by sex and stress exposure. Stress impaired male object recognition but did not affect female performance. Stress did not affect male spatial memory; however, control females could not significantly discriminate between the old and new locations, but stress exposure enhanced female performance. Following behavioral testing, monoamines and metabolites were measured in prefrontal cortex (PFC), hippocampus (CA1, CA3), and amygdala. Notably, PFC and CA3 indices for noradrenergic activity (MHPG levels and MHPG/NE ratios) were increased in stress females, but decreased in males, and similar changes were found in CA1 and BLA dopaminergic indices. Thus, these sexually dimorphic neurochemical changes following stress may underlie the behavioral differences. Current results show that short-term restraint elicits sex-dependent behavioral and neural changes different from those previously reported for longer term stresses and suggest that the temporal relationship between the change from adaptive to maladaptive responses to stress is shorter in male than female rats.

  6. The N terminus of monoamine transporters is a lever required for the action of amphetamines.

    Science.gov (United States)

    Sucic, Sonja; Dallinger, Stefan; Zdrazil, Barbara; Weissensteiner, René; Jørgensen, Trine N; Holy, Marion; Kudlacek, Oliver; Seidel, Stefan; Cha, Joo Hwan; Gether, Ulrik; Newman, Amy H; Ecker, Gerhard F; Freissmuth, Michael; Sitte, Harald H

    2010-04-02

    The serotonin transporter (SERT) terminates neurotransmission by removing serotonin from the synaptic cleft. In addition, it is the site of action of antidepressants (which block the transporter) and of amphetamines (which induce substrate efflux). We explored the functional importance of the N terminus in mediating the action of amphetamines by focusing initially on the highly conserved threonine residue at position 81, a candidate site for phosphorylation by protein kinase C. Molecular dynamics simulations of the wild type SERT, compared with its mutations SERT(T81A) and SERT(T81D), suggested structural changes in the inner vestibule indicative of an opening of the inner vestibule. Predictions from this model (e.g. the preferential accumulation of SERT(T81A) in the inward conformation, its reduced turnover number, and a larger distance between its N and C termini) were verified. Most importantly, SERT(T81A) (and the homologous mutations in noradrenaline and dopamine) failed to support amphetamine-induced efflux, and this was not remedied by aspartate at this position. Amphetamine-induced currents through SERT(T81A) were comparable with those through the wild type transporter. Both abundant Na(+) entry and accumulation of SERT(T81A) in the inward facing conformation ought to favor amphetamine-induced efflux. Thus, we surmised that the N terminus must play a direct role in driving the transporter into a state that supports amphetamine-induced efflux. This hypothesis was verified by truncating the first 64 amino acids and by tethering the N terminus to an additional transmembrane helix. Either modification abolished amphetamine-induced efflux. We therefore conclude that the N terminus of monoamine transporters acts as a lever that sustains reverse transport.

  7. Adipogenesis-related increase of semicarbazide-sensitive amine oxidase and monoamine oxidase in human adipocytes.

    Science.gov (United States)

    Bour, Sandy; Daviaud, Danièle; Gres, Sandra; Lefort, Corinne; Prévot, Danielle; Zorzano, Antonio; Wabitsch, Martin; Saulnier-Blache, Jean-Sébastien; Valet, Philippe; Carpéné, Christian

    2007-08-01

    A strong induction of semicarbazide-sensitive amine oxidase (SSAO) has previously been reported during murine preadipocyte lineage differentiation but it remains unknown whether this emergence also occurs during adipogenesis in man. Our aim was to compare SSAO and monoamine oxidase (MAO) expression during in vitro differentiation of human preadipocytes and in adipose and stroma-vascular fractions of human fat depots. A human preadipocyte cell strain from a patient with Simpson-Golabi-Behmel syndrome was first used to follow amine oxidase expression during in vitro differentiation. Then, human preadipocytes isolated from subcutaneous adipose tissues were cultured under conditions promoting ex vivo adipose differentiation and tested for MAO and SSAO expression. Lastly, human adipose tissue was separated into mature adipocyte and stroma-vascular fractions for analyses of MAO and SSAO at mRNA, protein and activity levels. Both SSAO and MAO were increased from undifferentiated preadipocytes to lipid-laden cells in all the models: 3T3-F442A and 3T3-L1 murine lineages, human SGBS cell strain or human preadipocytes in primary culture. In human subcutaneous adipose tissue, the adipocyte-enriched fraction exhibited seven-fold higher amine oxidase activity and contained three- to seven-fold higher levels of mRNAs encoded by MAO-A, MAO-B, AOC3 and AOC2 genes than the stroma-vascular fraction. MAO-A and AOC3 genes accounted for the majority of their respective MAO and SSAO activities in human adipose tissue. Most of the SSAO and MAO found in adipose tissue originated from mature adipocytes. Although the mechanism and role of adipogenesis-related increase in amine oxidase expression remain to be established, the resulting elevated levels of amine oxidase activities found in human adipocytes may be of potential interest for therapeutic intervention in obesity.

  8. Comparative modeling of the human monoamine transporters: similarities in substrate binding.

    Science.gov (United States)

    Koldsø, Heidi; Christiansen, Anja B; Sinning, Steffen; Schiøtt, Birgit

    2013-02-20

    The amino acid compositions of the substrate binding pockets of the three human monoamine transporters are compared as is the orientation of the endogenous substrates, serotonin, dopamine, and norepinephrine, bound in these. Through a combination of homology modeling, induced fit dockings, molecular dynamics simulations, and uptake experiments in mutant transporters, we propose a common binding mode for the three substrates. The longitudinal axis of the substrates is similarly oriented with these, forming an ionic interaction between the ammonium group and a highly conserved aspartate, Asp98 (serotonin transporter, hSERT), Asp79 (dopamine transporter, hDAT), and Asp75 (norepinephrine transporter, hNET). The 6-position of serotonin and the para-hydroxyl groups of dopamine and norepinephrine were found to face Ala173 in hSERT, Gly153 in hDAT, and Gly149 in hNET. Three rotations of the substrates around the longitudinal axis were identified. In each mode, an aromatic hydroxyl group of the substrates occupied equivalent volumes of the three binding pockets, where small changes in amino acid composition explains the differences in selectivity. Uptake experiments support that the 5-hydroxyl group of serotonin and the meta-hydroxyl group norepinephrine and dopamine are placed in the hydrophilic pocket around Ala173, Ser438, and Thr439 in hSERT corresponding to Gly149, Ser419, Ser420 in hNET and Gly153 Ser422 and Ala423 in hDAT. Furthermore, hDAT was found to possess an additional hydrophilic pocket around Ser149 to accommodate the para-hydroxyl group. Understanding these subtle differences between the binding site compositions of the three transporters is imperative for understanding the substrate selectivity, which could eventually aid in developing future selective medicines.

  9. A new stress model, a scream sound, alters learning and monoamine levels in rat brain.

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    Hu, Lili; Yang, Juan; Song, Tusheng; Hou, Ni; Liu, Yong; Zhao, Xiaoge; Zhang, Dianzeng; Wang, Lumin; Wang, Tao; Huang, Chen

    2014-01-17

    Most existing animal models for stress involve the simultaneous application of physical and psychological stress factors. In the current study, we described and used a novel psychological stress model (scream sound stress). To study the validity of it, we carried out acute and chronic scream sound stress. First, adult Sprague-Dawley (SD) rats were randomly divided into white noise, stress and background groups. The white noise group and stress group were treated with white noise and scream sound for 4h in the morning respectively. Compared with white noise and background groups, exposure to acute scream sound increased corticosterone (CORT) level and decreased latency in Morris water maze (MWM) test. The levels of noradrenaline (NE), dopamine (DA), 5-hydroxytryptamine (5-HT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were altered in the striatum, hypothalamus and hippocampus of stress rats. Second, adult SD rats were randomly divided into background and stress groups, which were treated with scream sound for three weeks. Exposure to chronic scream sound suppressed body weight gain, increased corticosterone (CORT) level, influenced the morphology of adrenal gland, improved spleen and thymus indices, and decreased latency in MWM test. NE, DA, DOPAC, HVA and 5-HIAA levels were also altered in the brain of stress rats. Our results suggested that scream sound, as a novel stressor, facilitated learning ability, as well as altered monoamine levels in the rat brain. Moreover, scream sound is easy to apply and can be applied in more animals at the same time.

  10. Behavioral and plasma monoamine responses to high-speed railway noise stress in mice

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    Guoqing Di

    2013-01-01

    Full Text Available Studies have reported that railway noise causes stress responses. To evaluate the effects of high-speed railway (HSR noise on behaviors and plasma monoamines. Institute of cancer research mice were exposed to previously recorded HSR noise for 53 days. The noise was arranged according to the HSR′s 24-h traffic number and adjusted to a day-night equivalent continuous A-weighted sound pressure level (Ldn of 70 dB (A. The open field test (OFT and the light/dark box test were applied to observe mice behaviors. High performance liquid chromatography-fluorimetric detection was performed to determine the concentrations of plasma norepinephrine (NE, dopamine (DA, serotonin (5-hydroxytryptamine, 5-HT. Data were analyzed by two-way analysis of variance using SPSS 16.0. After 53 days of noise exposure, center time and the frequency of line crossing of the exposed mice decreased significantly in the OFT compared with the control group. Meanwhile, transitions and the time spent in the lit compartment of the exposed group decreased significantly in the light/dark box test. After 40 days of HSR noise exposure, the concentrations of plasma DA of the exposed group were significantly higher than those of the control group, while the plasma NE and 5-HT concentrations showed no significant difference between the two groups. The behavioral tests indicate that 70 dB (A HSR noise can result in anxiety-like behaviors in mice. The physiological results show that plasma DA is more sensitive to HSR noise compared with NE and 5-HT.

  11. Sudden infant death syndrome (SIDS) and polymorphisms in Monoamine oxidase A gene (MAOA): a revisit.

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    Groß, Maximilian; Bajanowski, Thomas; Vennemann, Mechtild; Poetsch, Micaela

    2014-01-01

    Literature describes multiple possible links between genetic variations in the neuroadrenergic system and the occurrence of sudden infant death syndrome. The X-chromosomal Monoamine oxidase A (MAOA) is one of the genes with regulatory activity in the noradrenergic and serotonergic neuronal systems and a polymorphism of the promoter which affects the activity of this gene has been proclaimed to contribute significantly to the prevalence of sudden infant death syndrome (SIDS) in three studies from 2009, 2012 and 2013. However, these studies described different significant correlations regarding gender or age of children. Since several studies, suggesting associations between genetic variations and SIDS, were disproved by follow-up analysis, this study was conducted to take a closer look at the MAOA gene and its polymorphisms. The functional MAOA promoter length polymorphism was investigated in 261 SIDS cases and 93 control subjects. Moreover, the allele distribution of 12 coding and non-coding single nucleotide polymorphisms (SNPs) of the MAOA gene was examined in 285 SIDS cases and 93 controls by a minisequencing technique. In contrast to prior studies with fewer individuals, no significant correlations between the occurrence of SIDS and the frequency of allele variants of the promoter polymorphism could be demonstrated, even including the results from the abovementioned previous studies. Regarding the SNPs, three statistically significant associations were observed which had not been described before. This study clearly disproves interactions between MAOA promoter polymorphisms and SIDS, even if variations in single nucleotide polymorphisms of MAOA should be subjected to further analysis to clarify their impact on SIDS.

  12. The role of monoamines in the actions of established and "novel" antidepressant agents: a critical review.

    Science.gov (United States)

    Millan, Mark J

    2004-10-01

    Monoaminergic pathways are highly responsive to aversive stimuli and play a crucial role in the control of affect, cognition, endocrine secretion, chronobiotic rhythms, appetite, and motor function, all of which are profoundly disrupted in depressive states. Accordingly, a perturbation of monoaminergic transmission is implicated in the aetiology of depressive disorders, and all clinically available antidepressants increase corticolimbic availability of monoamines. However, their limited efficacy, delayed onset of action, and undesirable side effects underlie ongoing efforts to identify improved therapeutic agents. Sequencing the human genome has raised the hope not only of better symptomatic control of depression, but even of the prevention or cure of depressive states. In the pursuit of these goals, there is currently a tendency to focus on selective ligands of "novel" nonmonoaminergic targets. However, certain classes of novel agent (such as neurokinin(1) receptor antagonists) indirectly modulate the activity of monoaminergic networks. Others may act "downstream" of them, converging onto common cellular substrates controlling gene expression, synaptic plasticity, and neurogenesis. Further, by analogy to the broad-based actions of currently employed drugs, multitarget agents may be better adapted than selective agents to the management of depression-a complex disorder with hereditary, developmental, and environmental origins. It is, thus, important to continue the creative exploration of clinically validated and innovative monoaminergic strategies within a multitarget framework. In this light, drugs combining monoaminergic and nonmonoaminergic mechanisms of action may be of particular interest. The present article provides a critical overview of monoaminergic strategies for the treatment of depressive states, both established and under development, and discusses interactions of novel "nonmonoaminergic" antidepressants with monoaminergic mechanisms.

  13. Intoxications with the monoamine oxidase inhibitor tranylcypromine: an analysis of fatal and non-fatal events.

    Science.gov (United States)

    Gahr, Maximilian; Schönfeldt-Lecuona, Carlos; Kölle, Markus A; Freudenmann, Roland W

    2013-11-01

    Tranylcypromine (TCP) is a non-selective and irreversible monoamine oxidase inhibitor and an effective agent in the treatment of major depression. It features a complex pharmacologic profile and overdoses might induce severe intoxications. To identify typical clinical presentations of TCP-intoxications, range of associated TCP-dosages and possible differences between fatal and non-fatal intoxications a systematic review of all previously published cases of TCP-intoxications was conducted. We detected n=20 reports of TCP-intoxications in the literature (fatalities n=10). Mean age was 36.7 years (median 37); the majority of patients were female (60%). Frequent findings in patients with TCP-intoxications were disturbance of consciousness/cognitive dysfunction (90%), cardio-vascular symptoms (55%), hyperthermia (50%), respiratory distress (45%), delirium (45%), muscular rigidity (30%) and renal failure (20%). Suicidal intent was present in n=18 (90%) patients. First clinical symptoms related to TCP-intoxication developed on average in less than 1 day. The average dosage related to TCP-intoxication was 677 mg. The highest survived TCP-dosage was 4000 mg and the lowest fatal dosage was 170 mg. Patients with fatal intoxications were on average older (40.5 vs. 32.8 years) and developed a more rapid onset of symptoms (0.2 vs. 0.8 days). Death occurred after a mean time of 0.6 days; symptom relief in patients with non-fatal intoxications developed on average after 3.2 days. Considering the large dose spectrum between survived and lethal TCP-dosages individual susceptibility factors might play a role regarding the severity of clinical symptoms independently of the ingested dosage.

  14. Carrier-mediated release of monoamines induced by the nicotinic acetylcholine receptor agonist DMPP.

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    Szász, Bernadett K; Mayer, Aliz; Zsilla, Gabriella; Lendvai, Balázs; Vizi, E Sylvester; Kiss, János P

    2005-09-01

    We have previously shown that dimethylphenylpiperazinium (DMPP) increases the release of noradrenaline (NA) from rat hippocampal slices via two distinct mechanisms: a nicotinic acetylcholine receptor (nAChR)-mediated exocytosis and a carrier-mediated release induced by the reversal of NA transporters. Our aim was to investigate whether other monoaminergic systems are also affected by the multiple actions of DMPP. In our experiments DMPP dose-dependently increased the release of dopamine (DA) and serotonin (5-HT) from rat striatal and hippocampal slices, respectively. The dual effect was observed, however, only in case of DA at a lower DMPP concentration (30 microM), where the response was partly inhibited by mecamylamine, TTX and Ca2+-free medium (nAChR-mediated exocytosis) while the other part of the response was blocked only by the DA uptake inhibitor nomifensine (carrier-mediated release). In contrast, the DMPP-evoked 5-HT release and the DA release induced by high concentration DMPP was not inhibited by nicotinic antagonists, TTX and Ca2+-free medium but only by selective uptake inhibitors. In addition, DMPP dose-dependently inhibited the [3H]DA and [3H]5-HT uptake in striatal and hippocampal synaptosome preparation with an IC50 of 3.18 and 0.49 microM, respectively. Our data show that DMPP interacts with monoamine transporters and induces a substantial carrier-mediated release of DA and 5-HT, therefore caution is needed for the interpretation of data, when this drug is used as a nAChR agonist.

  15. Effects of developmental manganese, stress, and the combination of both on monoamines, growth, and corticosterone

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    Charles V. Vorhees

    2014-01-01

    Full Text Available Developmental exposure to manganese (Mn or stress can each be detrimental to brain development. Here, Sprague-Dawley rats were exposed to two housing conditions and Mn from postnatal day (P4–28. Within each litter two males and two females were assigned to the following groups: 0 (vehicle, 50, or 100 mg/kg Mn by gavage every other day. Half the litters were reared in cages with standard bedding and half with no bedding. One pair/group in each litter had an acute shallow water stressor before tissue collection (i.e., standing in shallow water. Separate litters were assessed at P11, 19, or 29. Mn-treated rats raised in standard cages showed no change in baseline corticosterone but following acute stress increased more than controls on P19; no Mn effects were seen on P11 or P29. Mn increased neostriatal dopamine in females at P19 and norepinephrine at P11 and P29. Mn increased hippocampal dopamine at P11 and P29 and 5-HT at P29 regardless of housing or sex. Mn had no effect on hypothalamic dopamine, but increased norepinephrine in males at P29 and 5-HT in males at all ages irrespective of rearing condition. Barren reared rats showed no or opposite effects of Mn, i.e., barren rearing + Mn attenuated corticosterone increases to acute stress. Barren rearing also altered the Mn-induced changes in dopamine and norepinephrine in the neostriatum, but not in the hippocampus. Barren rearing caused a Mn-associated increase in hypothalamic dopamine at P19 and P29 not seen in standard reared Mn-treated groups. Developmental Mn alters monoamines and corticosterone as a function of age, stress (acute and chronic, and sex.

  16. Catechol O-methyltransferase and monoamine oxidase A genotypes, and plasma catecholamine metabolites in bipolar and schizophrenic patients.

    Science.gov (United States)

    Zumárraga, Mercedes; Dávila, Ricardo; Basterreche, Nieves; Arrue, Aurora; Goienetxea, Biotza; Zamalloa, María I; Erkoreka, Leire; Bustamante, Sonia; Inchausti, Lucía; González-Torres, Miguel A; Guimón, José

    2010-01-01

    Metabolites of dopamine and norepinephrine measured in the plasma have long been associated with symptomatic severity and response to treatment in schizophrenic, bipolar and other psychiatric patients. Plasma concentrations of catecholamine metabolites are genetically regulated. The genes encoding enzymes that are involved in the synthesis and degradation of these monoamines are candidate targets for this genetic regulation. We have studied the relationship between the Val158Met polymorphism in catechol O-methyltransferase gene, variable tandem repeat polymorphisms in the monoamine oxidase A gene promoter, and plasma concentrations of 3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxyphenylacetic acid and homovanillic acid in healthy control subjects as well as in untreated schizophrenic and bipolar patients. We found that the Val158Met substitution in catechol O-methyltransferase gene influences the plasma concentrations of homovanillic and 3,4-dihydroxyphenylacetic acids. Although higher concentrations of plasma homovanillic acid were found in the high-activity ValVal genotype, this mutation did not affect the plasma concentration of 3-methoxy-4-hydroxyphenylglycol. 3,4-dihydroxyphenylacetic acid concentrations were higher in the low-activity MetMet genotype. Interestingly, plasma values 3-methoxy-4-hydroxyphenylglycol were greater in schizophrenic patients and in bipolar patients than in healthy controls. Our results are compatible with the previously reported effect of the Val158Met polymorphism on catechol O-methyltransferase enzymatic activity. Thus, our results suggest that this polymorphism, alone or associated with other polymorphisms, could have an important role in the genetic control of monoamine concentration and its metabolites.

  17. Song competition affects monoamine levels in sensory and motor forebrain regions of male Lincoln's sparrows (Melospiza lincolnii.

    Directory of Open Access Journals (Sweden)

    Kendra B Sewall

    Full Text Available Male animals often change their behavior in response to the level of competition for mates. Male Lincoln's sparrows (Melospiza lincolnii modulate their competitive singing over the period of a week as a function of the level of challenge associated with competitors' songs. Differences in song challenge and associated shifts in competitive state should be accompanied by neural changes, potentially in regions that regulate perception and song production. The monoamines mediate neural plasticity in response to environmental cues to achieve shifts in behavioral state. Therefore, using high pressure liquid chromatography with electrochemical detection, we compared levels of monoamines and their metabolites from male Lincoln's sparrows exposed to songs categorized as more or less challenging. We compared levels of norepinephrine and its principal metabolite in two perceptual regions of the auditory telencephalon, the caudomedial nidopallium and the caudomedial mesopallium (CMM, because this chemical is implicated in modulating auditory sensitivity to song. We also measured the levels of dopamine and its principal metabolite in two song control nuclei, area X and the robust nucleus of the arcopallium (RA, because dopamine is implicated in regulating song output. We measured the levels of serotonin and its principal metabolite in all four brain regions because this monoamine is implicated in perception and behavioral output and is found throughout the avian forebrain. After controlling for recent singing, we found that males exposed to more challenging song had higher levels of norepinephrine metabolite in the CMM and lower levels of serotonin in the RA. Collectively, these findings are consistent with norepinephrine in perceptual brain regions and serotonin in song control regions contributing to neuroplasticity that underlies socially-induced changes in behavioral state.

  18. Monoamine transporter and receptor interaction profiles of novel psychoactive substances: para-halogenated amphetamines and pyrovalerone cathinones.

    Science.gov (United States)

    Rickli, Anna; Hoener, Marius C; Liechti, Matthias E

    2015-03-01

    The pharmacology of novel psychoactive substances is mostly unknown. We evaluated the transporter and receptor interaction profiles of a series of para-(4)-substituted amphetamines and pyrovalerone cathinones. We tested the potency of these compounds to inhibit the norepinephrine (NE), dopamine (DA), and serotonin (5-HT) transporters (NET, DAT, and SERT, respectively) using human embryonic kidney 293 cells that express the respective human transporters. We also tested the substance-induced efflux of NE, DA, and 5-HT from monoamine-loaded cells, binding affinities to monoamine receptors, and 5-HT2B receptor activation. Para-(4)-substituted amphetamines, including 4-methylmethcathinone (mephedrone), 4-ethylmethcathinone, 4-fluoroamphetamine, 4-fluoromethamphetamine, 4-fluoromethcatinone (flephedrone), and 4-bromomethcathinone, were relatively more serotonergic (lower DAT:SERT ratio) compared with their analogs amphetamine, methamphetamine, and methcathinone. The 4-methyl, 4-ethyl, and 4-bromo groups resulted in enhanced serotonergic properties compared with the 4-fluoro group. The para-substituted amphetamines released NE and DA. 4-Fluoramphetamine, 4-flouromethamphetamine, 4-methylmethcathinone, and 4-ethylmethcathinone also released 5-HT similarly to 3,4-methylenedioxymethamphetamine. The pyrovalerone cathinones 3,4-methylenedioxypyrovalerone, pyrovalerone, α-pyrrolidinovalerophenone, 3,4-methylenedioxy-α-pyrrolidinopropiophenone, and 3,4-methylenedioxy-α-pyrrolidinobutiophenone potently inhibited the NET and DAT but not the SERT. Naphyrone was the only pyrovalerone that also inhibited the SERT. The pyrovalerone cathinones did not release monoamines. Most of the para-substituted amphetamines exhibited affinity for the 5-HT2A receptor but no relevant activation of the 5-HT2B receptor. All the cathinones exhibited reduced trace amine-associated receptor 1 binding compared with the non-β-keto-amphetamines. In conclusion, para-substituted amphetamines exhibited

  19. Song competition affects monoamine levels in sensory and motor forebrain regions of male Lincoln's sparrows (Melospiza lincolnii).

    Science.gov (United States)

    Sewall, Kendra B; Caro, Samuel P; Sockman, Keith W

    2013-01-01

    Male animals often change their behavior in response to the level of competition for mates. Male Lincoln's sparrows (Melospiza lincolnii) modulate their competitive singing over the period of a week as a function of the level of challenge associated with competitors' songs. Differences in song challenge and associated shifts in competitive state should be accompanied by neural changes, potentially in regions that regulate perception and song production. The monoamines mediate neural plasticity in response to environmental cues to achieve shifts in behavioral state. Therefore, using high pressure liquid chromatography with electrochemical detection, we compared levels of monoamines and their metabolites from male Lincoln's sparrows exposed to songs categorized as more or less challenging. We compared levels of norepinephrine and its principal metabolite in two perceptual regions of the auditory telencephalon, the caudomedial nidopallium and the caudomedial mesopallium (CMM), because this chemical is implicated in modulating auditory sensitivity to song. We also measured the levels of dopamine and its principal metabolite in two song control nuclei, area X and the robust nucleus of the arcopallium (RA), because dopamine is implicated in regulating song output. We measured the levels of serotonin and its principal metabolite in all four brain regions because this monoamine is implicated in perception and behavioral output and is found throughout the avian forebrain. After controlling for recent singing, we found that males exposed to more challenging song had higher levels of norepinephrine metabolite in the CMM and lower levels of serotonin in the RA. Collectively, these findings are consistent with norepinephrine in perceptual brain regions and serotonin in song control regions contributing to neuroplasticity that underlies socially-induced changes in behavioral state.

  20. Exposure to (12)C particles alters the normal dynamics of brain monoamine metabolism and behaviour in rats.

    Science.gov (United States)

    Belov, Oleg V; Belokopytova, Ksenia V; Bazyan, Ara S; Kudrin, Vladimir S; Narkevich, Viktor B; Ivanov, Aleksandr A; Severiukhin, Yury S; Timoshenko, Gennady N; Krasavin, Eugene A

    2016-09-01

    Planning of the deep-space exploration missions raises a number of questions on the radiation protection of astronauts. One of the medical concerns is associated with exposure of a crew to highly energetic particles of galactic cosmic rays. Among many other health disorders, irradiation with these particles has a substantial impact on the central nervous system (CNS). Although radiation damage to CNS has been addressed extensively during the last years, the mechanisms underlying observed impairments remain mostly unknown. The present study reveals neurochemical and behavioural alterations induced in rats by 1Gy of 500MeV/u (12)C particles with a relatively moderate linear energy transfer (10.6keV/μm). It is found that exposure to carbon ions leads to significant modification of the normal monoamine metabolism dynamics as well as the locomotor, exploratory, and anxiety-like behaviours during a two-month period. The obtained results indicate an abnormal redistribution of monoamines and their metabolites in different brain regions after exposure. The most pronounced impairments are detected in the prefrontal cortex, nucleus accumbens, and hypothalamus that illustrate the sensitivity of these brain regions to densely ionizing radiations. It is also shown that exposure to (12)C particles enhances the anxiety in animals and accelerates the age-related reduction in their exploratory capability. The observed monoamine metabolism pattern may indicate the presence of certain compensatory mechanisms being induced in response to irradiation and capable of partial restoration of monoaminergic systems' functions. Overall, these findings support a possibility of CNS damage by space-born particles of a relatively moderate linear energy transfer.

  1. Influence of parenting style on the offspring's behaviour and CSF monoamine metabolite levels in crossfostered and noncrossfostered female rhesus macaques.

    Science.gov (United States)

    Maestripieri, Dario; McCormack, Kai; Lindell, Stephen G; Higley, J Dee; Sanchez, Mar M

    2006-11-25

    We investigated the association between variation in parenting style and the offspring's behaviour and CSF monoamine metabolite (5-HIAA, HVA, and MHPG) levels in rhesus monkeys. Study subjects were 25 two-year-old females reared by their biological mothers and 15 same-aged females that were crossfostered at birth and reared by unrelated mothers. Subjects that were rejected more by their mothers in the first 6 months of life engaged in more solitary play and had lower CSF concentrations of 5-HIAA than subjects that were rejected less. The relation between these variables was generally similar in crossfostered and noncrossfostered females. CSF levels of 5-HIAA were negatively correlated with rates of scratching, a behavioural indicator of anxiety. These results suggest that that early exposure to high rates of maternal rejection can result in higher anxiety later in life, and that this effect may be mediated by serotonergic mechanisms. Variation in maternal protectiveness did not affect offspring behaviour and neither protectiveness nor rejection affected CSF levels of HVA and MHPG. CSF levels of MHPG, however, were negatively correlated with solitary play behaviour and avoidance of other individuals, suggesting that individuals with lower CSF MHPG were more fearful and socially phobic than those with higher CSF MHPG. Taken together, these findings suggest that individual differences in anxiety and fearfulness in young rhesus monkeys are accounted for, at least in part, by variation in CSF levels of monoamine metabolites, and that the development of brain monoamine systems, particularly serotonin, can be affected by early exposure to variable maternal behaviour.

  2. Kinetics of Inhibition of Monoamine Oxidase Using Cymbopogon martinii (Roxb.) Wats.: A Potential Antidepressant Herbal Ingredient with Antioxidant Activity.

    Science.gov (United States)

    Gacche, R N; Shaikh, R U; Chapole, S M; Jadhav, A D; Jadhav, S G

    2011-07-01

    The study was designed to evaluate the antioxidant activity and effect of Cymbopogon martinii (Roxb.) Wats. (Poaceae) leaves on the activity of monoamine oxidase and kinetics of enzyme inhibition. Ethanol extract of C. martinii and rat brain mitochondrial monoamine oxidase preparation ware used to study the kinetics of enzyme inhibition using double reciprocal Lineweaver-Burk plot. The DPPH was used as a source of free radical to evaluate antioxidant potential. It is observed that, the ethanolic extract of C. martinii inhibits the monoamine oxidase activity with competitive mode of inhibition. The V(max) (0.01 mM/min) remained constant while, K(m) varied from 21.00 ± 1.1, 43.33 ± 1.5 and 83.33 ± 1.4 mM for 100-500 μg/ml concentration of C. martinii. The K(i) values were calculated to be 90.00 ± 0.87, 75.00 ± 0.69, 68.18 ± 0.68 μg for 100-500 μg/ml concentration of C. martini. It also shows a significant DPPH (1,1-diphenyl-2-picryl hydrazine) radical scavenging (IC(50) = 0.34 ± 0.05 mg/ml) and reducing activity (IC(50) = 0.70 ± 0.22 mg/ml). The C. martini can be considered as a possible source of MAO inhibitor used in the treatment of depression and other neurological disorders.

  3. Monoamine Oxidases as Potential Contributors to Oxidative Stress in Diabetes: Time for a Study in Patients Undergoing Heart Surgery

    Directory of Open Access Journals (Sweden)

    Oana M. Duicu

    2015-01-01

    Full Text Available Oxidative stress is a pathomechanism causally linked to the progression of chronic cardiovascular diseases and diabetes. Mitochondria have emerged as the most relevant source of reactive oxygen species, the major culprit being classically considered the respiratory chain at the inner mitochondrial membrane. In the past decade, several experimental studies unequivocally demonstrated the contribution of monoamine oxidases (MAOs at the outer mitochondrial membrane to the maladaptative ventricular hypertrophy and endothelial dysfunction. This paper addresses the contribution of mitochondrial dysfunction to the pathogenesis of heart failure and diabetes together with the mounting evidence for an emerging role of MAO inhibition as putative cardioprotective strategy in both conditions.

  4. Inhibition of monoamine oxidase by furazolidone in the chicken and the influence of the alimentary flora thereon.

    OpenAIRE

    Ali, B. H.; Bartlet, A. L.

    1980-01-01

    1 The addition of furazolidone to the feed at the therapeutic level (0.04% w/w, 10 days) inhibited monoamine oxidase (MAO) activity by 47 to 72% in chicken duodenal mucosa, heart and brain, but in the liver the enzyme activity was unaffected by the treatment. 2 Furazolidone (200 mg/kg) administered by crop tube inhibited MAO activities in duodenal mucosa, liver, heart and brain. 3 Furazolidone (200 mg/kg) injected intramuscularly did not inhibit MAO activity in the chicken. 4 Pretreatment of ...

  5. Stimulation of vesicular monoamine transporter 2 activity by DJ-1 in SH-SY5Y cells

    OpenAIRE

    Ishikawa, Shizuma; Tanaka, Yuki; Takahashi-Niki, Kazuko; Niki, Takeshi; Ariga, Hiroyoshi; Iguchi-Ariga, Sanae M. M.

    2012-01-01

    Loss-of-functional mutation in the DJ-1 gene causes a subset of familial Parkinson's disease. The mechanism underlying DJ-1-related selective vulnerability in the dopaminergic pathway is, however, not known. Dopamine is synthesized by two enzymes and then packed into synaptic vesicles by vesicular monoamine transporter 2 (VMAT2). In this study, we found that knockdown of DJ-1 expression reduced the levels of mRNA and protein of VMAT2, resulting in reduced VMAT2 activity. Co-immunoprecipitatio...

  6. [Association between the canine monoamine oxidase B (MAOB) gene polymorphisms and behavior of puppies in open-field test].

    Science.gov (United States)

    Li, Xiao-Hui; Xu, Han-Kun; Mao, Da-Gan; Ma, Da-Jun; Chen, Peng; Yang, Li-Guo

    2006-11-01

    Excitability, activity and exploration behavior of puppies in a novel open-field were tested in a total of 204 two-month-old German shepherd dog, labrador retriever or English springer spaniel puppies. The polymorphisms of monoamine oxidase B gene (MAOB) were detected by PCR-RFLP. Statistics analysis indicated that genotype and allele frequencies of the polymorphisms were significantly different among three breeds (P open-field test. The results showed that MAOB gene polymorphisms had a significant effect on walking time, squares crossed, lying time, the times of standing up against walls(P open-field test and TT genotype has favorable effects in these behavior traits.

  7. Relative contributions of norepinephrine and serotonin transporters to antinociceptive synergy between monoamine reuptake inhibitors and morphine in the rat formalin model.

    Directory of Open Access Journals (Sweden)

    Fei Shen

    Full Text Available Multimodal analgesia is designed to optimize pain relief by coadministering drugs with distinct mechanisms of action or by combining multiple pharmacologies within a single molecule. In clinical settings, combinations of monoamine reuptake inhibitors and opioid receptor agonists have been explored and one currently available analgesic, tapentadol, functions as both a µ-opioid receptor agonist and a norepinephrine transporter inhibitor. However, it is unclear whether the combination of selective norepinephrine reuptake inhibition and µ-receptor agonism achieves an optimal antinociceptive synergy. In this study, we assessed the pharmacodynamic interactions between morphine and monoamine reuptake inhibitors that possess different affinities and selectivities for norepinephrine and serotonin transporters. Using the rat formalin model, in conjunction with measurements of ex vivo transporter occupancy, we show that neither the norepinephrine-selective inhibitor, esreboxetine, nor the serotonin-selective reuptake inhibitor, fluoxetine, produce antinociceptive synergy with morphine. Atomoxetine, a monoamine reuptake inhibitor that achieves higher levels of norepinephrine than serotonin transporter occupancy, exhibited robust antinociceptive synergy with morphine. Similarly, a fixed-dose combination of esreboxetine and fluoxetine which achieves comparable levels of transporter occupancy potentiated the antinociceptive response to morphine. By contrast, duloxetine, a monoamine reuptake inhibitor that achieves higher serotonin than norepinephrine transporter occupancy, failed to potentiate the antinociceptive response to morphine. However, when duloxetine was coadministered with the 5-HT3 receptor antagonist, ondansetron, potentiation of the antinociceptive response to morphine was revealed. These results support the notion that inhibition of both serotonin and norepinephrine transporters is required for monoamine reuptake inhibitor and opioid

  8. Aquatic contaminants alter genes involved in neurotransmitter synthesis and gonadotropin release in largemouth bass

    Energy Technology Data Exchange (ETDEWEB)

    Martyniuk, Christopher J. [Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 32611 (United States); Sanchez, Brian C. [Department of Forestry and Natural Resources and School of Civil Engineering, 195 Marsteller St., Purdue University, West Lafayette, IN 47907 (United States); Szabo, Nancy J.; Denslow, Nancy D. [Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 32611 (United States); Sepulveda, Maria S., E-mail: mssepulv@purdue.edu [Department of Forestry and Natural Resources and School of Civil Engineering, 195 Marsteller St., Purdue University, West Lafayette, IN 47907 (United States)

    2009-10-19

    Many aquatic contaminants potentially affect the central nervous system, however the underlying mechanisms of how toxicants alter normal brain function are not well understood. The objectives of this study were to compare the effects of emerging and prevalent environmental contaminants on the expression of brain transcripts with a role in neurotransmitter synthesis and reproduction. Adult male largemouth bass (Micropterus salmoides) were injected once for a 96 h duration with control (water or oil) or with one of two doses of a single chemical to achieve the following body burdens ({mu}g/g): atrazine (0.3 and 3.0), toxaphene (10 and 100), cadmium (CdCl{sub 2}) (0.000067 and 0.00067), polychlorinated biphenyl (PCB) 126 (0.25 and 2.5), and phenanthrene (5 and 50). Partial largemouth bass gene segments were cloned for enzymes involved in neurotransmitter (glutamic acid decarboxylase 65, GAD65; tyrosine hydroxylase) and estrogen (brain aromatase; CYP19b) synthesis for real-time PCR assays. In addition, neuropeptides regulating feeding (neuropeptide Y) and reproduction (chicken GnRH-II, cGnRH-II; salmon GnRH, sGnRH) were also investigated. Of the chemicals tested, only cadmium, PCB 126, and phenanthrene showed any significant effects on the genes tested, while atrazine and toxaphene did not. Cadmium (0.000067 {mu}g/g) significantly increased cGnRH-II mRNA while PCB 126 (0.25 {mu}g/g) decreased GAD65 mRNA. Phenanthrene decreased GAD65 and tyrosine hydroxylase mRNA levels at the highest dose (50 {mu}g/g) but increased cGnRH-II mRNA at the lowest dose (5 {mu}g/g). CYP19b, NPY, and sGnRH mRNA levels were unaffected by any of the treatments. A hierarchical clustering dendrogram grouped PCB 126 and phenanthrene more closely than other chemicals with respect to the genes tested. This study demonstrates that brain transcripts important for neurotransmitter synthesis neuroendocrine function are potential targets for emerging and prevalent aquatic contaminants.

  9. Development of radioiodinated ligands for exploration of brain monoamine oxidase by tomo-scintigraphy; Developpement de ligands radioactifs pour l'exploration des monoamines oxydases cerebrales en tomoscintigraphie

    Energy Technology Data Exchange (ETDEWEB)

    Rafii, H

    1996-07-01

    Monoamine oxidases, MAO, are important in the regulation of monoaminergic neuro-transmissions. The fluctuations in MAO activities has been observed in some psychiatric and neuro-degenerative diseases. Thus, quantification of cerebral MAO activity would be useful for diagnosis and the therapeutic follow-up of these disorders. With the object of doing an in vivo scintigraphic exploration of cerebral MAO by SPECT, we have undertaken to synthesize some radioiodinated MAO inhibitors. In the first part of this work, we have discussed the general properties of the monoamine oxidases and their inhibitors. In the second part we have described the scintigraphic methods. the ligands to be used for MAO exploration, and the radioiodination methods. At last in the third part, the development of three radioiodinated ligands has been presented: - [{sup 125}I]3-iodopargyline. In vivo results showed that, this radioligand blocked the cerebral MAO-B with moderate selectivity. However, complementary in vivo studies would be needed to define precisely its activity.- [{sup 125}I]Ro 16-6491. The cerebral fixation of this radioligand was in accordance with the MAO-B sites in the rat brains, but its fixation was too low for scintigraphic exploration in vivo with iodine-123. - [{sup 125}I]Ro 11-9900. In vivo studies of rat brains showed that the MAO-A sites were bound preferentially by this radioligand. The cerebral biodistribution of this ligand labelled with iodine-123 is considered for use in a model animal nearest to human pathology. (author)

  10. Spintronic characteristics of self-assembled neurotransmitter acetylcholine molecular complexes enable quantum information processing in neural networks and brain

    Science.gov (United States)

    Tamulis, Arvydas; Majauskaite, Kristina; Kairys, Visvaldas; Zborowski, Krzysztof; Adhikari, Kapil; Krisciukaitis, Sarunas

    2016-09-01

    Implementation of liquid state quantum information processing based on spatially localized electronic spin in the neurotransmitter stable acetylcholine (ACh) neutral molecular radical is discussed. Using DFT quantum calculations we proved that this molecule possesses stable localized electron spin, which may represent a qubit in quantum information processing. The necessary operating conditions for ACh molecule are formulated in self-assembled dimer and more complex systems. The main quantum mechanical research result of this paper is that the neurotransmitter ACh systems, which were proposed, include the use of quantum molecular spintronics arrays to control the neurotransmission in neural networks.

  11. Polymeric bilayer modified microelectrodes for in-vivo determi nation of neurotransmitter dopamine

    Institute of Scientific and Technical Information of China (English)

    YANG, Li-Jua; PENG, Tu-Zhi; YANG, F. Catherine

    2000-01-01

    A composite polymer carbon fiber electrode modified with Nafion and cellulose acetate is described. The modified elec trode discriminates agninst both anionic reactants and big molecular organic compounds. The bilayer configuration is prepared in two steps, First, the carbon fiber electrode is coated with Nafion, then followed by air evaporation of the solvent, the electrode is dipped in a cellulose acetate solution and hydrolyzed for a selected time. The permeability of the film is explored by use of rotating disk electrode measure ments. Parameters affecting the fihm electrochemistry are in vestigated. The resulting electrodes show high selectivity and stability in body fluids. For in-vivo voltammetry, the com posite polymer modified electrode has been used for detection of the oxidative current of neurotransmitter dopamine in rat brain, while it inhabits the oxidation of anionic neurotransmit ter metabolites and some electroactive compounds.

  12. Microelectronics-Based Biosensors Dedicated to the Detection of Neurotransmitters: A Review

    Directory of Open Access Journals (Sweden)

    Maryam Mirzaei

    2014-09-01

    Full Text Available Dysregulation of neurotransmitters (NTs in the human body are related to diseases such as Parkinson’s and Alzheimer’s. The mechanisms of several neurological disorders, such as epilepsy, have been linked to NTs. Because the number of diagnosed cases is increasing, the diagnosis and treatment of such diseases are important. To detect biomolecules including NTs, microtechnology, micro and nanoelectronics have become popular in the form of the miniaturization of medical and clinical devices. They offer high-performance features in terms of sensitivity, as well as low-background noise. In this paper, we review various devices and circuit techniques used for monitoring NTs in vitro and in vivo and compare various methods described in recent publications.

  13. Neurotransmitter CART as a New Therapeutic Candidate for Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Philippe Thuillier

    2013-01-01

    Full Text Available Parkinson’s disease (PD is one of the most common neurodegenerative diseases. To date, there is no effective treatment that halts its progression. Increasing evidence indicates that mitochondria play an important role in the development of PD. Hence mitochondria-targeted approaches or agents may have therapeutic promise for treatment of the disease. Neuropeptide CART (cocaine-amphetamine-regulated transcript, a hypothalamus and midbrain enriched neurotransmitter with an antioxidant property, can be found in mitochondria, which is the main source of reactive oxygen species. Systemic administration of CART has been found to ameliorate dopaminergic neuronal loss and improve motor functions in a mouse model of PD. In this article, we summarize recent progress in studies investigating the relationship between CART, dopamine, and the pathophysiology of PD, with a focus on mitochondria-related topics.

  14. PRRT2 Is a Key Component of the Ca2+-Dependent Neurotransmitter Release Machinery

    Directory of Open Access Journals (Sweden)

    Pierluigi Valente

    2016-04-01

    Full Text Available Heterozygous mutations in proline-rich transmembrane protein 2 (PRRT2 underlie a group of paroxysmal disorders, including epilepsy, kinesigenic dyskinesia, and migraine. Most of the mutations lead to impaired PRRT2 expression, suggesting that loss of PRRT2 function may contribute to pathogenesis. We show that PRRT2 is enriched in presynaptic terminals and that its silencing decreases the number of synapses and increases the number of docked synaptic vesicles at rest. PRRT2-silenced neurons exhibit a severe impairment of synchronous release, attributable to a sharp decrease in release probability and Ca2+ sensitivity and associated with a marked increase of the asynchronous/synchronous release ratio. PRRT2 interacts with the synaptic proteins SNAP-25 and synaptotagmin 1/2. The results indicate that PRRT2 is intimately connected with the Ca2+-sensing machinery and that it plays an important role in the final steps of neurotransmitter release.

  15. PRRT2 Is a Key Component of the Ca(2+)-Dependent Neurotransmitter Release Machinery.

    Science.gov (United States)

    Valente, Pierluigi; Castroflorio, Enrico; Rossi, Pia; Fadda, Manuela; Sterlini, Bruno; Cervigni, Romina Ines; Prestigio, Cosimo; Giovedì, Silvia; Onofri, Franco; Mura, Elisa; Guarnieri, Fabrizia C; Marte, Antonella; Orlando, Marta; Zara, Federico; Fassio, Anna; Valtorta, Flavia; Baldelli, Pietro; Corradi, Anna; Benfenati, Fabio

    2016-04-05

    Heterozygous mutations in proline-rich transmembrane protein 2 (PRRT2) underlie a group of paroxysmal disorders, including epilepsy, kinesigenic dyskinesia, and migraine. Most of the mutations lead to impaired PRRT2 expression, suggesting that loss of PRRT2 function may contribute to pathogenesis. We show that PRRT2 is enriched in presynaptic terminals and that its silencing decreases the number of synapses and increases the number of docked synaptic vesicles at rest. PRRT2-silenced neurons exhibit a severe impairment of synchronous release, attributable to a sharp decrease in release probability and Ca(2+) sensitivity and associated with a marked increase of the asynchronous/synchronous release ratio. PRRT2 interacts with the synaptic proteins SNAP-25 and synaptotagmin 1/2. The results indicate that PRRT2 is intimately connected with the Ca(2+)-sensing machinery and that it plays an important role in the final steps of neurotransmitter release.

  16. PRRT2 Is a Key Component of the Ca2+-Dependent Neurotransmitter Release Machinery

    Science.gov (United States)

    Valente, Pierluigi; Castroflorio, Enrico; Rossi, Pia; Fadda, Manuela; Sterlini, Bruno; Cervigni, Romina Ines; Prestigio, Cosimo; Giovedì, Silvia; Onofri, Franco; Mura, Elisa; Guarnieri, Fabrizia C.; Marte, Antonella; Orlando, Marta; Zara, Federico; Fassio, Anna; Valtorta, Flavia; Baldelli, Pietro; Corradi, Anna; Benfenati, Fabio

    2016-01-01

    Summary Heterozygous mutations in proline-rich transmembrane protein 2 (PRRT2) underlie a group of paroxysmal disorders, including epilepsy, kinesigenic dyskinesia, and migraine. Most of the mutations lead to impaired PRRT2 expression, suggesting that loss of PRRT2 function may contribute to pathogenesis. We show that PRRT2 is enriched in presynaptic terminals and that its silencing decreases the number of synapses and increases the number of docked synaptic vesicles at rest. PRRT2-silenced neurons exhibit a severe impairment of synchronous release, attributable to a sharp decrease in release probability and Ca2+ sensitivity and associated with a marked increase of the asynchronous/synchronous release ratio. PRRT2 interacts with the synaptic proteins SNAP-25 and synaptotagmin 1/2. The results indicate that PRRT2 is intimately connected with the Ca2+-sensing machinery and that it plays an important role in the final steps of neurotransmitter release. PMID:27052163

  17. VLSI Potentiostat Array With Oversampling Gain Modulation for Wide-Range Neurotransmitter Sensing.

    Science.gov (United States)

    Stanacevic, M; Murari, K; Rege, A; Cauwenberghs, G; Thakor, N V

    2007-03-01

    A 16-channel current-measuring very large-scale integration (VLSI) sensor array system for highly sensitive electrochemical detection of electroactive neurotransmiters like dopamine and nitric-oxide is presented. Each channel embeds a current integrating potentiostat within a switched-capacitor first-order single-bit delta-sigma modulator implementing an incremental analog-to-digital converter. The duty-cycle modulation of current feedback in the delta-sigma loop together with variable oversampling ratio provide a programmable digital range selection of the input current spanning over six orders of magnitude from picoamperes to microamperes. The array offers 100-fA input current sensitivity at 3.4-muW power consumption per channel. The operation of the 3 mm times3 mm chip fabricated in 0.5-mum CMOS technology is demonstrated with real-time multichannel acquisition of neurotransmitter concentration.

  18. Microelectronics-based biosensors dedicated to the detection of neurotransmitters: a review.

    Science.gov (United States)

    Mirzaei, Maryam; Sawan, Mohamad

    2014-09-26

    Dysregulation of neurotransmitters (NTs) in the human body are related to diseases such as Parkinson's and Alzheimer's. The mechanisms of several neurological disorders, such as epilepsy, have been linked to NTs. Because the number of diagnosed cases is increasing, the diagnosis and treatment of such diseases are important. To detect biomolecules including NTs, microtechnology, micro and nanoelectronics have become popular in the form of the miniaturization of medical and clinical devices. They offer high-performance features in terms of sensitivity, as well as low-background noise. In this paper, we review various devices and circuit techniques used for monitoring NTs in vitro and in vivo and compare various methods described in recent publications.

  19. Alzheimer-like neurotransmitter deficits in adult Down's syndrome brain tissue.

    Science.gov (United States)

    Godridge, H; Reynolds, G P; Czudek, C; Calcutt, N A; Benton, M

    1987-01-01

    Brain tissue taken at necropsy from five cases of Down's syndrome and six controls was analysed for changes in neurotransmitter markers. Concentrations of noradrenaline (NA), dopamine (DA) and its major metabolite homovanillic acid (HVA), 5-hydroxytryptamine (5HT) and its metabolite 5-hydroxyindoleacetic acid (5HIAA) were determined by means of HPLC, whilst choline acetyltransferase (ChAT) was measured by a radiochemical technique. Significant reductions in NA, 5HT and ChAT were found in most cortical and subcortical regions of the Down's syndrome tissue investigated. The neuropathological lesions were assessed using a fluorescent stain for neuritic plaques and neurofibrillary tangles. These were present to varying extents in every Down's syndrome case except the youngest but were not found in control tissue of comparable age. The results indicate profound transmitter deficits and neuropathological abnormalities in adult patients with Down's syndrome, which closely resemble those of Alzheimer's disease. PMID:2440994

  20. Activities of autonomic neurotransmitters in meibomian gland tissues are associated with menopausal dry eye

    Institute of Scientific and Technical Information of China (English)

    Lianxiang Li; Dongling Jin; Jinsheng Gao; Liguang Wang; Xianjun Liu; Jingzhang Wang; Zhongxin Xu

    2012-01-01

    The secretory activities of meibomian glands are regulated by the autonomic nervous system. The change in density and activity of autonomic nerves in meibomian glands during menopause play an important role in the pathogenesis of dry eye. In view of this, we established a dry eye rat model by removing the bilateral ovaries. We used neuropeptide Y and vasoactive intestinal polypeptide as markers of autonomic neurotransmitters. Our results showed that the concentration of estradiol in serum significantly decreased, the density of neuropeptide Y immunoreactivity in nerve fibers significantly increased, the density of vasoactive intestinal polypeptide immunoreactivity in nerve fibers significantly decreased, and the ratio of vasoactive intestinal polypeptide/neuropeptide Y positive staining significantly decreased. These results suggest that a decrease in ovary activity may lead to autonomic nervous system dysfunction, thereby affecting the secretory activity of the meibomian gland, which participates in sexual hormone imbalance-induced dry eye.

  1. In-capillary derivatization and capillary electrophoresis separation of amino acid neurotransmitters from brain microdialysis samples.

    Science.gov (United States)

    Denoroy, Luc; Parrot, Sandrine; Renaud, Louis; Renaud, Bernard; Zimmer, Luc

    2008-09-26

    A new in-capillary derivatization method with naphtalene-2,3-dicarboxyaldehyde (NDA)/CN(-) has been developed for capillary electrophoresis with laser-induced fluorescence detection of brain microdialysate amino acids. Samples are sandwiched between two plugs of reagent mixture at the capillary inlet and subsequently separated. Highest derivatization yields are obtained by using a reagent to sample plug length ratio equal to 4, performing a first electrophoretic mixing followed by a zero potential amplification step before applying the separation voltage and using a NaCN to NDA concentration ratio equal to 1. This new single-step methodology allows the analysis of amino acid neurotransmitters in rat brain microdialysis samples.

  2. Microtransplantation of neurotransmitter receptors from postmortem autistic brains to Xenopus oocytes

    Science.gov (United States)

    Limon, Agenor; Reyes-Ruiz, Jorge Mauricio; Miledi, Ricardo

    2008-01-01

    Autism is a complex disorder that arises from the pervasive action of genetic and epigenetic factors that alter synaptic connectivity of the brain. Although GABA and glutamate receptors seem to be two of those factors, very little is known about the functional properties of the autistic receptors. Autistic tissue samples stored in brain banks usually have relatively long postmortem times, and it is highly desirable to know whether neurotransmitter receptors in such tissues are still functional. Here we demonstrate that native receptors microtransplanted from autistic brains, as well as de novo mRNA-expressed receptors, are still functional and susceptible to detailed electrophysiological characterization even after long postmortem intervals. The opportunity to study the properties of human receptors present in diseased brains not only opens new avenues toward understanding autism and other neurological disorders, but it also makes the microtransplantation method a useful translational system to evaluate and develop novel medicinal drugs. PMID:18645182

  3. The influence of anesthetics, neurotransmitters and antibiotics on the relaxation processes in lipid membranes

    CERN Document Server

    Seeger, H M; Heimburg, T; Gudmundsson, Marie L.; Heimburg, Thomas; Seeger, Heiko M.

    2007-01-01

    In the proximity of melting transitions of artificial and biological membranes fluctuations in enthalpy, area, volume and concentration are enhanced. This results in domain formation, changes of the elastic constants, changes in permeability and slowing down of relaxation processes. In this study we used pressure perturbation calorimetry to investigate the relaxation time scale after a jump into the melting transition regime of artificial lipid membranes. This time corresponds to the characteristic rate of domain growth. The studies were performed on single-component large unilamellar and multilamellar vesicle systems with and without the addition of small molecules such as general anesthetics, neurotransmitters and antibiotics. These drugs interact with membranes and affect melting points and profiles. In all systems we found that heat capacity and relaxation times are related to each other in a simple manner. The maximum relaxation time depends on the cooperativity of the heat capacity profile and decreases...

  4. `Full fusion' is not ineluctable during vesicular exocytosis of neurotransmitters by endocrine cells

    Science.gov (United States)

    Oleinick, Alexander; Svir, Irina; Amatore, Christian

    2017-01-01

    Vesicular exocytosis is an essential and ubiquitous process in neurons and endocrine cells by which neurotransmitters are released in synaptic clefts or extracellular fluids. It involves the fusion of a vesicle loaded with chemical messengers with the cell membrane through a nanometric fusion pore. In endocrine cells, unless it closes after some flickering (`Kiss-and-Run' events), this initial pore is supposed to expand exponentially, leading to a full integration of the vesicle membrane into the cell membrane-a stage called `full fusion'. We report here a compact analytical formulation that allows precise measurements of the fusion pore expansion extent and rate to be extracted from individual amperometric spike time courses. These data definitively establish that, during release of catecholamines, fusion pores enlarge at most to approximately one-fifth of the radius of their parent vesicle, hence ruling out the ineluctability of `full fusion'.

  5. Agrin promotes synaptic differentiation by counteracting an inhibitory effect of neurotransmitter.

    Science.gov (United States)

    Misgeld, Thomas; Kummer, Terrance T; Lichtman, Jeff W; Sanes, Joshua R

    2005-08-02

    Synaptic organizing molecules and neurotransmission regulate synapse development. Here, we use the skeletal neuromuscular junction to assess the interdependence of effects evoked by an essential synaptic organizing protein, agrin, and the neuromuscular transmitter, acetylcholine (ACh). Mice lacking agrin fail to maintain neuromuscular junctions, whereas neuromuscular synapses differentiate extensively in the absence of ACh. We now demonstrate that agrin's action in vivo depends critically on cholinergic neurotransmission. Using double-mutant mice, we show that synapses do form in the absence of agrin provided that ACh is also absent. We provide evidence that ACh destabilizes nascent postsynaptic sites, and that one major physiological role of agrin is to counteract this "antisynaptogenic" influence. Similar interactions between neurotransmitters and synaptic organizing molecules may operate at synapses in the central nervous system.

  6. Phorbol esters and neurotransmitter release: more than just protein kinase C?

    Science.gov (United States)

    Silinsky, Eugene M; Searl, Timothy J

    2003-01-01

    This review focuses on the effects of phorbol esters and the role of phorbol ester receptors in the secretion of neurotransmitter substances. We begin with a brief background on the historical use of phorbol esters as tools to decipher the role of the enzyme protein kinase C in signal transduction cascades. Next, we illustrate the structural differences between active and inactive phorbol esters and the mechanism by which the binding of phorbol to its recognition sites (C1 domains) on a particular protein acts to translocate that protein to the membrane. We then discuss the evidence that the most important nerve terminal receptor for phorbol esters (and their endogenous counterpart diacylglycerol) is likely to be Munc13. Indeed, Munc13 and its invertebrate homologues are the main players in priming the secretory apparatus for its critical function in the exocytosis process. PMID:12711617

  7. 'Full fusion' is not ineluctable during vesicular exocytosis of neurotransmitters by endocrine cells.

    Science.gov (United States)

    Oleinick, Alexander; Svir, Irina; Amatore, Christian

    2017-01-01

    Vesicular exocytosis is an essential and ubiquitous process in neurons and endocrine cells by which neurotransmitters are released in synaptic clefts or extracellular fluids. It involves the fusion of a vesicle loaded with chemical messengers with the cell membrane through a nanometric fusion pore. In endocrine cells, unless it closes after some flickering ('Kiss-and-Run' events), this initial pore is supposed to expand exponentially, leading to a full integration of the vesicle membrane into the cell membrane-a stage called 'full fusion'. We report here a compact analytical formulation that allows precise measurements of the fusion pore expansion extent and rate to be extracted from individual amperometric spike time courses. These data definitively establish that, during release of catecholamines, fusion pores enlarge at most to approximately one-fifth of the radius of their parent vesicle, hence ruling out the ineluctability of 'full fusion'.

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

    Directory of Open Access Journals (Sweden)

    Lauren Faget

    2016-06-01

    Full Text Available 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.

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

    Science.gov (United States)

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

    1985-01-01

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

  10. Kv3 voltage-gated potassium channels regulate neurotransmitter release from mouse motor nerve terminals.

    Science.gov (United States)

    Brooke, Ruth E; Moores, Thomas S; Morris, Neil P; Parson, Simon H; Deuchars, Jim

    2004-12-01

    Voltage-gated potassium (Kv) channels are critical to regulation of neurotransmitter release throughout the nervous system but the roles and identity of the subtypes involved remain unclear. Here we show that Kv3 channels regulate transmitter release at the mouse neuromuscular junction (NMJ). Light- and electron-microscopic immunohistochemistry revealed Kv3.3 and Kv3.4 subunits within all motor nerve terminals of muscles examined [transversus abdominus, lumbrical and flexor digitorum brevis (FDB)]. To determine the roles of these Kv3 subunits, intracellular recordings were made of end-plate potentials (EPPs) in FDB muscle fibres evoked by electrical stimulation of tibial nerve. Tetraethylammonium (TEA) applied at low concentrations (0.05-0.5 mM), which blocks only a few known potassium channels including Kv3 channels, did not affect muscle fibre resting potential but significantly increased the amplitude of all EPPs tested. Significantly, this effect of TEA was still observed in the presence of the large-conductance calcium-activated potassium channel blockers iberiotoxin (25-150 nM) and Penitrem A (100 nM), suggesting a selective action on Kv3 subunits. Consistent with this, 15-microM 4-aminopyridine, which blocks Kv3 but not large-conductance calcium-activated potassium channels, enhanced evoked EPP amplitude. Unexpectedly, blood-depressing substance-I, a toxin selective for Kv3.4 subunits, had no effect at 0.05-1 microM. The combined presynaptic localization of Kv3 subunits and pharmacological enhancement of EPP amplitude indicate that Kv3 channels regulate neurotransmitter release from presynaptic terminals at the NMJ.

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

    Science.gov (United States)

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

    2016-12-01

    Chemical neurotransmitters (NT) are principal actors in all neuronal networks of animals. The central nervous system plays an important role in stress susceptibility and organizes the response to a stressful situation through the interaction of the dopaminergic and the serotonergic pathways, leading to the activation of the hypothalamus-pituitary-adrenal axis (HPA). This study was designed to investigate: a) the effects of stressful handling of pigs at the slaughterhouse on the neurotransmitter profile in four brain areas: amygdala, prefrontal cortex (PFC), hippocampus and hypothalamus, and b) whether the alterations in the brain NT profile after stressful handling were associated with fear, determined by the tonic immobility (TI) test. In the first place, the characterization of the NT profile allowed to distinguish the four brain areas in a principal component analysis. The most crucial pathway involved in the reaction of pigs to a stressful handling was the sero