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1

Synapsins Differentially Control Dopamine and Serotonin Release  

PubMed Central

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

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

2010-01-01

2

Synapsins differentially control dopamine and serotonin release.  

PubMed

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

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

2010-07-21

3

Optogenetic control of serotonin and dopamine release in Drosophila larvae.  

PubMed

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

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

2014-08-20

4

Antihistamine effect on synaptosomal uptake of serotonin, norepinephrine and dopamine  

NASA Technical Reports Server (NTRS)

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

Brown, P. A.; Vernikos, J.

1980-01-01

5

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

NASA Astrophysics Data System (ADS)

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

Chen, Zhengming; Yang, Ji; Skolnick, Phil

6

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

PubMed

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 ?-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 ?-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 ?-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 modulation of neurotransmitter networks. PMID:23671038

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

2014-05-01

7

Reproductive phase dependent circadian variation in hypothalamic concentration of serotonin, dopamine and peripheral thyroxine levels in Japanese Quail following 5-HTP and L-DOPA administration at specific time intervals  

Microsoft Academic Search

Temporal phase relations of circadian hypothalamic neurotransmitters are reported to regulate seasonal reproduction in some avian species. Present experiments were designed to study circadian variation in the hypothalamic concentration of neurotransmitters (serotonin and dopamine) and the plasma thyroxine level in sexually active (long day) and inactive (short day) Japanese Quail. A significant circadian cycle was noted in the hypothalamic content

A. C. Tiwari; P. Kumar; S. Singh; D. Sharma; C. M. Chaturvedi

2006-01-01

8

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

NASA Astrophysics Data System (ADS)

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

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

2013-11-01

9

Analysis of Glutamate, GABA, Noradrenaline, Dopamine, Serotonin, and Metabolites Using Microbore UHPLC with Electrochemical Detection  

PubMed Central

The applicability of microbore ultrahigh performance liquid chromatography (UHPLC) with electrochemical detection for offline analysis of a number of well-known neurotransmitters in less than 10 ?L microdialysis fractions is described. Two methods are presented for the analysis of monoamine or amino acid neurotransmitters, using the same UHPLC instrument. Speed of analysis of noradrenaline (NA), dopamine (DA), serotonin (5-HT), and the metabolites homovanillic acid (HVA), 5-hydroxyindole aceticacid (5-HIAA), and 3,4-dihydroxyphenylacetic acid (DOPAC) was predominated by the retention behavior of NA, the nonideal behavior of matrix components, and the loss in signal of 5-HT. This method was optimized to meet the requirements for detection sensitivity and minimizing the size of collected fractions, which determines temporal resolution in microdialysis. The amino acid neurotransmitters glutamate (Glu) and ?-aminobutyric acid (GABA) were analyzed after an automated derivatization procedure. Under optimized conditions, Glu was resolved from a number of early eluting system peaks, while the total runtime was decreased to 15 min by a 4-fold increase of the flow rate under UHPLC conditions. The detection limit for Glu and GABA was 10 nmol/L (15 fmol in 1.5 ?L); the monoamine neurotransmitters had a detection limit between 32 and 83 pmol/L (0.16–0.42 fmol in 5 ?L) in standard solutions. Using UHPLC, the analysis times varied from 15 min to less than 2 min depending on the complexity of the samples and the substances to be analyzed. PMID:23642417

2013-01-01

10

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

PubMed Central

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

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

2011-01-01

11

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

PubMed

The nucleus accumbens (NAc) is gaining interest as a target for deep brain stimulation (DBS) in refractory neuropsychiatric disorders with impulsivity as core symptom. The nucleus accumbens is composed of two subterritories, core and shell, which have different anatomical connections. In animal models, it has been shown that DBS of the NAc changes impulsive action. Here, we tested the hypothesis that a change in impulsive action by DBS of the NAc is associated with changes in dopamine levels. Rats received stimulating electrodes either in the NAc core or shell, and underwent behavioral testing in a reaction time task. In addition, in a second experiment, the effect of DBS of the NAc core and shell on extracellular dopamine and serotonin levels was assessed in the NAc and medial prefrontal cortex. Control subjects received sham surgery. We have found that DBS of the NAc shell stimulation induced more impulsive action but less perseverative checking. These effects were associated with increased levels of dopamine and serotonin in the NAc, but not in the medial prefrontal cortex. DBS of the NAc core had no effect on impulsive action, but decreased perseverative responses indicative of a better impulse control. In these subjects, no effects were found on neurotransmitter levels. Our data point out that DBS of the NAc shell has negative effects on impulsive action which is accompanied by increases of dopamine and serotonin levels in the NAc, whereas DBS of the NAc core has beneficial behavioral effects. PMID:20615406

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

2010-10-01

12

Ca 2+ channel blockade prevents lysergic acid diethylamide-induced changes in dopamine and serotonin metabolism  

Microsoft Academic Search

To investigate the effect of a single and multiple administration of lysergic acid diethylamide (LSD) on cerebral metabolism of dopamine and serotonin, male Wistar rats were treated with low and high doses (0.1 and 2.0 mg\\/kg i.p.) of LSD and the levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 3-methoxytyramine, serotonin and 5-hydroxyindoleacetic acid were assayed by HPLC in the nucleus

Lucyna Antkiewicz-Michaluk; Irena Roma?ska; Jerzy Vetulani

1997-01-01

13

Serotonin/Dopamine Interactions in a Hyperactive Mouse: Reduced Serotonin Receptor 1B Activity Reverses Effects of Dopamine Transporter Knockout  

PubMed Central

Knockout (KO) mice that lack the dopamine transporter (SL6A3; DAT) display increased locomotion that can be attenuated, under some circumstances, by administration of drugs that normally produce psychostimulant-like effects, such as amphetamine and methylphenidate. These results have led to suggestions that DAT KO mice may model features of attention deficit hyperactivity disorder (ADHD) and that these drugs may act upon serotonin (5-HT) systems to produce these unusual locomotor decreasing effects. Evidence from patterns of brain expression and initial pharmacologic studies led us to use genetic and pharmacologic approaches to examine the influence of altered 5-HT1B receptor activity on hyperactivity in DAT KO mice. Heterozygous 5-HT1B KO and pharmacologic 5-HT1B antagonism both attenuated locomotor hyperactivity in DAT KO mice. Furthermore, DAT KO mice with reduced, but not eliminated, 5-HT1B receptor expression regained cocaine-stimulated locomotion, which was absent in DAT KO mice with normal levels of 5-HT1B receptor expression. Further experiments demonstrated that the degree of habituation to the testing apparatus determined whether cocaine had no effect on locomotion in DAT KO or reduced locomotion, helping to resolve differences among prior reports. These findings of complementation of the locomotor effects of DAT KO by reducing 5-HT1B receptor activity underscore roles for interactions between specific 5-HT receptors and dopamine (DA) systems in basal and cocaine-stimulated locomotion and support evaluation of 5-HT1B antagonists as potential, non-stimulant ADHD therapeutics. PMID:25514162

Hall, Frank Scott; Sora, Ichiro; Hen, René; Uhl, George R.

2014-01-01

14

Microdialysis studies of brain norepinephrine, serotonin, and dopamine release during ingestive behavior. Theoretical and clinical implications.  

PubMed

This minireview deals with the possible roles of monoamines in feeding and feeding disorders. The introduction sketches the results of earlier studies with local drug injections and selective neurotoxins which provided pharmacological evidence that monoamines can influence food intake and body weight. A table summarizing this evidence is used to list monoamine changes that could underlie anorexia or hyperphagia. It is apparent that abnormalities in the monoamines, along with their cotransmitters, could cause many forms of feeding disorder. It is proposed as a working hypothesis that several varieties of hyperphagia leading to obesity have a common element. This common factor is a change in excitability of a lateral hypothalamic reinforcement system as manifested in self-stimulation at a stimulation-bound feeding site. Understanding this feeding reward-aversion system helps us understand hyperphagia and anorexia. The neurochemistry of reward and aversion involves the monoamines. This paper focuses on dopamine and serotonin. The data support the hypothesis that dopamine systems projecting to the nucleus accumbens and other forebrain areas from the mid-brain ventral tegmental area (VTA) are important for approach and positive reinforcement in ingestive behavior and self-stimulation. Serotonin is hypothesized to facilitate satiety and inhibition of feeding reward in the hypothalamus. The next section abstracts our recent experiments that measured pharmacological and physiological release of the monoamines in the hypothalamus and nucleus accumbens during ingestive behavior and self-stimulation. In vivo microdialysis in freely moving rats suggested the following: (1) Norepinephrine was released in the paraventricular nucleus during the active, feeding period of the circadian cycle. (2) The serotonin metabolite 5-HIAA also increased in the PVN at the same time if there was food to eat. (3) Amphetamine infused into the lateral hypothalamus (LH) by reverse dialysis increased synaptic dopamine, norepinephrine, and serotonin. (4) The anorectic drug d-fenfluramine increased synaptic serotonin in the LH and also increased the dopamine metabolite DOPAC, suggesting that serotonin and dopamine in the LH might contribute to fenfluramine-induced satiety. Local d-fenfluramine injection into the LH or local infusion by reverse dialysis again increased serotonin and decreased 5-HIAA and interfered with local dopamine metabolism as reflected in decreased DOPAC and HVA. (5) Tryptophan, a serotonin precursor, given systemically at an anorectic dose, increased extracellular serotonin in the LH, but this effect was only detectable in food-deprived rats. This was seemingly pH independent (between 5.8 and 8). The passage other cations through CFo is strictly suppressed (even at pH 8 and with 300 mM NaCl in the medium).(ABSTRACT TRUNCATED AT 400 WORDS) PMID:2699187

Hoebel, B G; Hernandez, L; Schwartz, D H; Mark, G P; Hunter, G A

1989-01-01

15

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

PubMed Central

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

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

2012-01-01

16

Distribution of serotonin and dopamine in the central nervous system of the female mud crab, Scylla olivacea (Herbst).  

PubMed

In crustaceans serotonin (5-HT) and dopamine (DA) are neurotransmitters that play roles in the modulation of numerous physiological functions, including reproduction. However, in the mud crab, Scylla olivacea, the distributions of 5-HT and DA in the CNS have not yet been investigated. The aim of our study was to map the distributions of these two neurotransmitters in the central nervous system (CNS) of the female of this crab during the late stage of ovarian development. We found 5-HT immunoreactivity (-ir) and DA-ir in many parts of the CNS, including the eyestalk, brain, and thoracic ganglia. In the eyestalk, 5-HT-ir was localized in the medulla terminalis (MT), hemi-ellipsoid body (HB), and protocerebral tract (PT), whereas DA-ir was present in neuronal cluster 1, the LG neuropils, and PT. In the brain, 5-HT-ir and DA-ir were detected in cells and fibers of neuronal clusters 6, 7, 8, 9, 10, 11, 14, and 15. In the ventral nerve cord, 5-HT-ir was present in neurons of the abdominal ganglia, whereas DA was only present in fibers. These spatial distributions of 5-HT and DA suggest that they may be involved in the neuromodulation of important physiological functions, including ovarian maturation, as shown in other non-crab decapods. PMID:25618422

Khornchatri, Kanjana; Kornthong, Napamanee; Saetan, Jirawat; Tinikul, Yotsawan; Chotwiwatthanakun, Charoonroj; Cummins, Scott F; Hanna, Peter J; Sobhon, Prasert

2015-03-01

17

Differential involvement of the norepinephrine, serotonin and dopamine reuptake transporter proteins in cocaine-induced taste aversion.  

PubMed

Despite the impact of cocaine's aversive effects on its abuse potential, the neurochemical basis of these aversive effects remains poorly understood. By blocking the reuptake of the monoamine neurotransmitters dopamine (DA), norepinephrine (NE) and serotonin (5-HT) into the presynaptic terminal, cocaine acts as a potent indirect agonist of each of these systems. The following studies attempted to assess the extent of monoaminergic mediation of cocaine's aversive effects using conditioned taste aversion (CTA) learning [Garcia, J., Kimeldorf, D.J., Koelling, R.A., Conditioned aversion to saccharin resulting from exposure to gamma radiation. Science 1955;122:157-158.]. Specifically, Experiment 1 assessed the ability of selective monoamine transporter inhibitors, e.g., DAT (vanoxerine), NET (nisoxetine) and SERT (fluoxetine), to induce taste aversions (relative to cocaine). Only the NET inhibitor approximated the aversive strength of cocaine. Experiment 2 compared the effects of pretreatment of each of these transport inhibitors on the development of a cocaine-induced CTA. Pretreatment with nisoxetine and fluoxetine both attenuated cocaine-induced aversions in a manner comparable to that produced by cocaine itself. The DAT inhibitor was without effect. Combined, the results of these investigations indicate little or no involvement of dopaminergic systems in cocaine's aversive effects while NE appears to contribute most substantially, with a possible modulatory involvement by serotonin. PMID:19376154

Jones, Jermaine D; Hall, F Scott; Uhl, George R; Rice, Kenner; Riley, Anthony L

2009-07-01

18

Dopamine Transporter Density in the Basal Ganglia in Obsessive-Compulsive Disorder, Measured with [123I]IPT SPECT before and after Treatment with Serotonin Reuptake Inhibitors  

Microsoft Academic Search

It has been suggested that dopamine as well as serotonin are associated with the pathophysiology of obsessive-compulsive disorder (OCD). 5-Hydroxytryptophan inhibits dopamine release in healthy persons as well as in patients with OCD, and serotonin tonic inhibition affects dopamine function in basal ganglia, indicating a close relationship between serotonin and the dopamine system. Using iodine-123-labeled N-(3-iodopropen-2-yl)-2?-carbomethoxy-3?-(4-chlorophenyl) tropane ([123I]IPT) single photon

C. H. Kim; K. A. Cheon; M.-S. Koo; Y. H. Ryu; J. D. Lee; J. W. Chang; H. S. Lee

2007-01-01

19

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

PubMed

Neurophysiological experiments in primates, alongside neuropsychological and functional magnetic resonance investigations in humans, have significantly enhanced our understanding of the neural architecture of decision making. In this review, I consider the more limited database of experiments that have investigated how dopamine and serotonin activity influences the choices of human adults. These include those experiments that have involved the administration of drugs to healthy controls, experiments that have tested genotypic influences upon dopamine and serotonin function, and, finally, some of those experiments that have examined the effects of drugs on the decision making of clinical samples. Pharmacological experiments in humans are few in number and face considerable methodological challenges in terms of drug specificity, uncertainties about pre- vs post-synaptic modes of action, and interactions with baseline cognitive performance. However, the available data are broadly consistent with current computational models of dopamine function in decision making and highlight the dissociable roles of dopamine receptor systems in the learning about outcomes that underpins value-based decision making. Moreover, genotypic influences on (interacting) prefrontal and striatal dopamine activity are associated with changes in choice behavior that might be relevant to understanding exploratory behaviors and vulnerability to addictive disorders. Manipulations of serotonin in laboratory tests of decision making in human participants have provided less consistent results, but the information gathered to date indicates a role for serotonin in learning about bad decision outcomes, non-normative aspects of risk-seeking behavior, and social choices involving affiliation and notions of fairness. Finally, I suggest that the role played by serotonin in the regulation of cognitive biases, and representation of context in learning, point toward a role in the cortically mediated cognitive appraisal of reinforcers when selecting between actions, potentially accounting for its influence upon the processing salient aversive outcomes and social choice. PMID:20881944

Rogers, Robert D

2011-01-01

20

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

PubMed Central

Neurophysiological experiments in primates, alongside neuropsychological and functional magnetic resonance investigations in humans, have significantly enhanced our understanding of the neural architecture of decision making. In this review, I consider the more limited database of experiments that have investigated how dopamine and serotonin activity influences the choices of human adults. These include those experiments that have involved the administration of drugs to healthy controls, experiments that have tested genotypic influences upon dopamine and serotonin function, and, finally, some of those experiments that have examined the effects of drugs on the decision making of clinical samples. Pharmacological experiments in humans are few in number and face considerable methodological challenges in terms of drug specificity, uncertainties about pre- vs post-synaptic modes of action, and interactions with baseline cognitive performance. However, the available data are broadly consistent with current computational models of dopamine function in decision making and highlight the dissociable roles of dopamine receptor systems in the learning about outcomes that underpins value-based decision making. Moreover, genotypic influences on (interacting) prefrontal and striatal dopamine activity are associated with changes in choice behavior that might be relevant to understanding exploratory behaviors and vulnerability to addictive disorders. Manipulations of serotonin in laboratory tests of decision making in human participants have provided less consistent results, but the information gathered to date indicates a role for serotonin in learning about bad decision outcomes, non-normative aspects of risk-seeking behavior, and social choices involving affiliation and notions of fairness. Finally, I suggest that the role played by serotonin in the regulation of cognitive biases, and representation of context in learning, point toward a role in the cortically mediated cognitive appraisal of reinforcers when selecting between actions, potentially accounting for its influence upon the processing salient aversive outcomes and social choice. PMID:20881944

Rogers, Robert D

2011-01-01

21

Serotonin, noradrenaline, dopamine metabolites in transcendental meditation-technique  

Microsoft Academic Search

Summary The highly significant increase of 5-HIAA (5-hydroxyindole-3-acetic acid) in Transcendental Meditation technique suggests systemic serotonin as “rest and fulfillment hormone” of deactivation-relaxation.

M. Bujatti; P. Biederer

1976-01-01

22

Methylenedioxymethamphetamine-induced inhibition of neuronal firing in the nucleus accumbens is mediated by both serotonin and dopamine  

Microsoft Academic Search

Methylenedioxymethamphetamine (MDMA) is a mood-altering, legally-restricted drug that has been reported to inhibit glutamate-evoked firing of cells in the nucleus accumbens. This study used extracellular recording combined with microiontophoresis to examine whether the inhibitory effect of MDMA on neuronal firing in the nucleus accumbens is mediated by serotonin and\\/or dopamine. Serotonin and serotonin agonists with relative selectivity for the receptor

T Obradovic; K. M Imel; S. R White

1996-01-01

23

Methamphetamine-induced hyperthermia and lethal toxicity: Role of the dopamine and serotonin transporters  

Microsoft Academic Search

We examined the hyperthermic and lethal toxic effects of methamphetamine in dopamine transporter (DAT) and\\/or serotonin transporter (SERT) knockout (KO) mice. Methamphetamine (45 mg\\/kg) caused significant hyperthermia even in the mice with a single DAT gene copy and no SERT copies (DAT+\\/? SERT?\\/? mice). Mice with no DAT copies and a single SERT gene copy (DAT?\\/? SERT+\\/? mice) showed significant but

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

2007-01-01

24

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

ERIC Educational Resources Information Center

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

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

2008-01-01

25

Involvement of dopamine D 2 receptors in apomorphine-induced facilitation of forebrain serotonin output  

Microsoft Academic Search

The effect of systemic administration of the nonselective dopamine receptor agonist apomorphine on efflux of serotonin (5-hydroxytryptamine, 5-HT) in striatum and hippocampus of freely moving rats was examined using in vivo microdialysis. 5-HT efflux was increased by a moderate dose of apomorphine sufficient for a postsynaptic dopaminergic effect (0.5 mg\\/kg, s.c.), but not by a lower dose (0.1 mg\\/kg, s.c.),

Anna Mendlin; Francisco J Mart??n; Barry L Jacobs

1998-01-01

26

In VivoEvidence for the Involvement of Dopamine-D 2Receptors in Striatum and Anterior Cingulate Gyrus in Major Depression  

Microsoft Academic Search

The dopaminergic system is a candidate neurotransmitter system thought to be involved in the pathogenesis of depression. This study addresses the issue whether the antidepressant efficacy of serotonin reuptake inhibition is related to changes in the cerebral dopaminergic system. Cerebral dopamine-D2receptors were characterized in 13 patients with major depression using the dopamine-D2receptor antagonist iodobenzamide and single photon emission tomography. Dopamine

R. Larisch; A. Klimke; H. Vosberg; S. Löffler; W. Gaebel; H.-W. Müller-Gärtner

1997-01-01

27

Effects of dopamine and serotonin antagonist injections into the striatopallidal complex of asymptomatic MPTP-treated monkeys.  

PubMed

The cardinal symptoms of Parkinson's disease (PD), akinesia, rigidity and tremor, are only observed when the striatal level of dopamine (DA) is decreased by 60-80%. It is likely that compensatory mechanisms during the early phase of DA depletion delay the appearance of motor symptoms. In a previous study, we proposed a new PD monkey model with progressive MPTP intoxication. Monkeys developed all of the motor symptoms and then fully recovered despite a large DA cell loss in the substantia nigra (SN). Compensatory mechanisms certainly help to offset the dysfunction induced by the DA lesion, facilitating motor recovery in this model. Neurotransmitter measurements in the striatal sensorimotor and associative/limbic territories of these monkeys subsequently revealed that DA and serotonin (5-HT) could play a role in recovery mechanisms. To try to determine the involvement of these neurotransmitters in compensatory mechanisms, we performed local injections of DA and 5-HT antagonists (cis-flupenthixol and mianserin, respectively) into these two striatal territories and into the external segment of the globus pallidus (GPe). Injections were performed on monkeys that were in an asymptomatic state after motor recovery. Most parkinsonian motor symptoms reappeared in animals with DA antagonist injections either in sensorimotor, associative/limbic striatal territories or in the GPe. In contrast to the effects with DA antagonist, there were mild parkinsonian effects with 5-HT antagonist, especially after injections in sensorimotor territories of the striatum and the GPe. These results support a possible, but slight, involvement of 5-HT in compensatory mechanisms and highlight the possible participation of 5-HT in some behavioural disorders. Furthermore, these results support the notion that the residual DA in the different striatal territories and the GPe could be involved in important mechanisms of compensation in PD. PMID:22728661

Neumane, Sara; Mounayar, Stéphanie; Jan, Caroline; Epinat, Justine; Ballanger, Bénédicte; Costes, Nicolas; Féger, Jean; Thobois, Stéphane; François, Chantal; Sgambato-Faure, Véronique; Tremblay, Léon

2012-10-01

28

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

PubMed

Among the non-motor phenomena of Parkinson's disease (PD) are depressive symptoms, with a prevalence of 40-70%. The reason for this high prevalence is not yet clear. The basal ganglia receives dopamine (DA) inputs from the substantia nigra pars compacta (SNpc), which is known to be impaired in PD patients. The neurotransmitter deficiency hypothesis of PD considers that low serotonin (5-hydroxytryptamine [5-HT]) activity in the brain in PD patients is a risk factor for depression. We investigated whether DA depletion promoted by the neurotoxin 6-hydroxydopamine (6-OHDA) is able to induce depressive-like behavior and neurotransmitter alterations that are similar to those observed in PD. To test this hypothesis, we performed intranigral injections of 6-OHDA in male Wistar rats and conducted motor behavior, depressive-like behavior, histological, and neurochemical tests. After the motor recovery period, 6-OHDA was able to produce anhedonia and behavioral despair 7, 14, and 21 days after neurotoxin infusion. These altered behavioral responses were accompanied by reductions of striatal DA. Additionally, decreases in hippocampal 5-HT content were detected in the 6-OHDA group. Notably, correlations were found between 5-HT and DA levels and swimming, immobility, and sucrose preference. Our results indicate that 6-OHDA produced depressive-like behavior accompanied by striatal DA and hippocampal 5-HT reductions. Moreover, DA and 5-HT levels were strongly correlated with "emotional" impairments, suggesting the important participation of these neurotransmitters in anhedonia and behavioral despair after 6-OHDA-induced nigral lesions. PMID:24183944

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

2014-02-01

29

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

SciTech Connect

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

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

1985-05-01

30

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

PubMed Central

Object In a companion study, the authors describe the development of a new instrument named the Wireless Instantaneous Neurotransmitter Concentration System (WINCS), which couples digital telemetry with fast-scan cyclic voltammetry (FSCV) to measure extracellular concentrations of dopamine. In the present study, the authors describe the extended capability of the WINCS to use fixed potential amperometry (FPA) to measure extracellular concentrations of dopamine, as well as glutamate and adenosine. Compared with other electrochemical techniques such as FSCV or high-speed chronoamperometry, FPA offers superior temporal resolution and, in combination with enzyme-linked biosensors, the potential to monitor nonelectroactive analytes in real time. Methods The WINCS design incorporated a transimpedance amplifier with associated analog circuitry for FPA; a microprocessor; a Bluetooth transceiver; and a single, battery-powered, multilayer, printed circuit board. The WINCS was tested with 3 distinct recording electrodes: 1) a carbon-fiber microelectrode (CFM) to measure dopamine; 2) a glutamate oxidase enzyme-linked electrode to measure glutamate; and 3) a multiple enzyme-linked electrode (adenosine deaminase, nucleoside phosphorylase, and xanthine oxidase) to measure adenosine. Proof-of-principle analyses included noise assessments and in vitro and in vivo measurements that were compared with similar analyses by using a commercial hardwired electrochemical system (EA161 Picostat, eDAQ; Pty Ltd). In urethane-anesthetized rats, dopamine release was monitored in the striatum following deep brain stimulation (DBS) of ascending dopaminergic fibers in the medial forebrain bundle (MFB). In separate rat experiments, DBS-evoked adenosine release was monitored in the ventrolateral thalamus. To test the WINCS in an operating room setting resembling human neurosurgery, cortical glutamate release in response to motor cortex stimulation (MCS) was monitored using a large-mammal animal model, the pig. Results The WINCS, which is designed in compliance with FDA-recognized consensus standards for medical electrical device safety, successfully measured dopamine, glutamate, and adenosine, both in vitro and in vivo. The WINCS detected striatal dopamine release at the implanted CFM during DBS of the MFB. The DBS-evoked adenosine release in the rat thalamus and MCS-evoked glutamate release in the pig cortex were also successfully measured. Overall, in vitro and in vivo testing demonstrated signals comparable to a commercial hardwired electrochemical system for FPA. Conclusions By incorporating FPA, the chemical repertoire of WINCS-measurable neurotransmitters is expanded to include glutamate and other nonelectroactive species for which the evolving field of enzyme-linked biosensors exists. Because many neurotransmitters are not electrochemically active, FPA in combination with enzyme-linked microelectrodes represents a powerful intraoperative tool for rapid and selective neurochemical sampling in important anatomical targets during functional neurosurgery. PMID:19425899

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

2009-01-01

31

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

SciTech Connect

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

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

1987-03-09

32

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

PubMed

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

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

2012-05-25

33

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

PubMed Central

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

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

2012-01-01

34

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

SciTech Connect

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

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

1986-04-01

35

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

PubMed Central

A molecularly imprinted polymer (MIP) with dual dopamine/serotonin-like binding sites (DS-MIP) was synthesized for use as a receptor model of study the drug-interaction of biological mixed receptors at a molecular level. The polymer material was produced using methacrylic acid (MAA) and acrylamide (ACM) as functional monomers, N,N?-methylene bisacrylamide (MBAA) as cross-linker, methanol/water mixture (4:1, v/v) as porogen and a mixture of dopamine (D) and serotonin (S) as templates. The prepared DS-MIP exhibited the greatest rebinding of the template(s) in aqueous methanol solution with decreased recognition in acetonitrile, water and methanol solvent. The binding affinity and binding capacity of DS-MIP with S were found to be higher than those of DS-MIP with D. The selectivity profiles of DS-MIP suggest that the D binding site of DS-MIP has sufficient integrity to discriminate between species of non-optimal functional group orientation, whilst the S binding site of DS-MIP is less selective toward species having structural features and functional group orientations different from S. The ligand binding activities of a series of ergot derivatives (ergocryptine, ergocornine, ergocristine, ergonovine, agroclavine, pergolide and terguride) have been studied with the DS-MIP using a competitive ligand binding assay protocol. The binding affinities of DS-MIP were demonstrated in the micro- or submicro-molar range for a series of ergot derivatives, whereas the binding affinities were considerably greater to natural receptors derived from the rat hypothalamus. The DS-MIP afforded the same pattern of differentiation as the natural receptors, i.e. affinity for the clavines > lysergic acid derivatives > ergopeptines. The results suggest that the discrimination for the ergot derivatives by the dopamine and serotonin sites of DS-MIP is due to the structural features and functional orientation of the phenylethylamine and indolylethylamine entities at the binding sites, and the fidelity of the dopamine and serotonin imprinted cavities. PMID:19330079

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

2008-01-01

36

Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator.  

PubMed

Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity (Ki < 1 nM) to human serotonin 1A (h5-HT1A)-, h5-HT2A-, long form of human D2 (hD2L)-, h?1B-, and h?2C-adrenergic receptors. It displayed partial agonism at h5-HT1A and hD2 receptors in cloned receptor systems and potent antagonism of h5-HT2A receptors and h?1B/2C-adrenoceptors. Brexpiprazole also had affinity (Ki < 5 nM) for hD3-, h5-HT2B-, h5-HT7-, h?1A-, and h?1D-adrenergic receptors, moderate affinity for hH1 (Ki = 19 nM), and low affinity for hM1 receptors (Ki > 1000 nM). Brexpiprazole potently bound to rat 5-HT2A and D2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT2A antagonism. Furthermore, in vivo D2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D2 partial agonist activity. In particular, based on a lower intrinsic activity at D2 receptors and higher binding affinities for 5-HT1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D2 receptor agonist- and antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders. PMID:24947465

Maeda, Kenji; Sugino, Haruhiko; Akazawa, Hitomi; Amada, Naoki; Shimada, Jun; Futamura, Takashi; Yamashita, Hiroshi; Ito, Nobuaki; McQuade, Robert D; Mørk, Arne; Pehrson, Alan L; Hentzer, Morten; Nielsen, Vibeke; Bundgaard, Christoffer; Arnt, Jørn; Stensbøl, Tine Bryan; Kikuchi, Tetsuro

2014-09-01

37

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

SciTech Connect

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

Smith, G.S.; Dewey, S.L.; Logan, J. [Brookhaven National Lab., Upton, NY (United States)] [and others

1994-05-01

38

A possible new role for fish retinal serotonin-N-acetyltransferase-1 (AANAT1): Dopamine metabolism.  

PubMed

Serotonin-N-acetyltransferase (arylalkylamine-N-acetyltransferase, AANAT) is the key enzyme in the generation of melatonin rhythms in the pineal gland and retinal photoreceptors. Rhythmic AANAT activity drives rhythmic melatonin production in these tissues. Two AANATs, AANAT1 and AANAT2, are present in teleost fish species. Different spatial expression patterns, enzyme kinetics and substrate preferences suggest that they may have different functions. Enzyme activity assays revealed that recombinant seabream and zebrafish AANAT1s, but not AANAT2s, acetylate dopamine with kinetic characteristics that are similar to those for tryptamine acetylation. High performance liquid chromatography analysis of seabream retinal extracts indicated the presence of N-acetyldopamine. Time-of-day analysis of retinal AANAT activity and concentration of melatonin, dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and N-acetyldopamine revealed a daily pattern of retinal melatonin and N-acetyldopamine production that are correlated with retinal AANAT1 activity. In situ hybridization analysis of seabream retinal sections indicated that tyrosine hydroxylase is expressed in the inner nuclear layer (INL) and that AANAT1 is expressed in the outer nuclear layer (ONL) and INL. Together, these observations point to the possibility that dopamine is acetylated by retinal AANAT1 in the INL. Such novel activity of AANAT1 may reflect an important function in the circadian physiology of the retina. PMID:16427617

Zilberman-Peled, Bina; Ron, Benny; Gross, Aviva; Finberg, John P M; Gothilf, Yoav

2006-02-16

39

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

PubMed Central

Prenatal viral infection has been associated with neurodevelopmental disorders such as schizophrenia and autism. It has previously been demonstrated that viral infection causes deleterious effects on brain structure and function in mouse offspring following late first trimester (E9) and middle-late second trimester (E18) administration of influenza virus. Neurochemical analysis following infection on E18 using this model has revealed significantly altered levels of serotonin, 5-hydroxyindoleacetic acid, and taurine, but not dopamine. In order to monitor these different patterns of monoamine expression in exposed offspring in more detail and to see if there are changes in the dopamine system at another time point, pregnant C57BL6J mice were infected with a sublethal dose of human influenza virus or sham-infected using vehicle solution on E16. Male offspring of the infected mice were collected at P0, P14, and P56, their brains removed and cerebellum dissected and flash frozen. Dopamine and serotonin levels were then measured using HPLC-ED technique. When compared to controls, there was a significant decrease in serotonin levels in the cerebella of offspring of virally exposed mice at P14. No differences in levels of dopamine were observed in exposed and control mice, although there was a significant decrease in dopamine at P14 and P56 when compared to P0. The present study shows that the serotonergic system is disrupted following prenatal viral infection, potentially modelling disruptions that occur in patients with schizophrenia and autism. PMID:18693086

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

2009-01-01

40

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

PubMed

A fast and simple isocratic high-performance liquid chromatography method for the determination of 3,4-dihydroxyphenylacetic acid (DOPAC), norepinephrine (NE), dopamine (DA), and serotonin (5-HT) in homogenate samples of mouse striatum employing the direct fluorescence of the neurotransmitters is described. The method has been optimized and validated. The analytes were separated in 15min on a reversed-phase column (C18) with acetate buffer (pH 4.0, 12mM)-methanol (86:14, v/v) as mobile phase; the flow rate was 1ml/min. The fluorescence measurements were carried out at 320nm with excitation at 279nm. The calibration curve for DA was linear up to about 2.5?g/ml, with a coefficient of determination (r(2)) of 0.9995 with a lower limit of quantification of 0.031?g/ml. Since the procedure does not involve sample pre-purification or derivatisation, the recovery ranged from 97% to 102% and relative standard deviation (RSD) was better than 2.9%, the use of the internal standard is not mandatory, further simplifying the method. Similar performance was obtained for the other analytes. As a result, thanks to its simplicity, rapidity and adequate working range, the method can be used for the determination of 3,4-dihydroxyphenylacetic acid, dopamine, norepinephrine and serotonin in animal tissues. An experimental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson-like disease has been used to demonstrate the method is fit-for-purpose. PMID:24971521

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

2014-09-01

41

Effect of Green Tea Catechins Intake on Brain Pattern of Certain Neurotransmitters in Stz Diabetic Rats  

Microsoft Academic Search

3 Abstract: Present work aimed to illustrate the changes in neurotransmitters secretion mainly noradrenaline, serotonin and dopamine as re levant to ox idative stress that induced i n STZ r ats. This was followed by intake of green tea extract (Catechin) in a dose level 50mg\\/kg body weight daily for 10 weeks. Collected data showed a significant decrease in blood

Mohamed M. Elseweidy; Atef E. Abd El-Bak; Ahmed Abdullah

2009-01-01

42

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

PubMed Central

Many animals, including humans, select alternate forms of motion (gaits) to move efficiently in different environments. However, it is unclear whether primitive animals, such as nematodes, also use this strategy. We used a multifaceted approach to study how the nematode Caenorhabditis elegans freely moves into and out of water. We demonstrate that C. elegans uses biogenic amines to switch between distinct crawling and swimming gaits. Dopamine is necessary and sufficient to initiate and maintain crawling after swimming. Serotonin is necessary and sufficient to transition from crawling to swimming and to inhibit a set of crawl-specific behaviors. Further study of locomotory switching in C. elegans and its dependence on biogenic amines may provide insight into how gait transitions are performed in other animals. PMID:21969584

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

2011-01-01

43

Saliva secretion and ionic composition of saliva in the cockroach Periplaneta americana after serotonin and dopamine stimulation, and effects of ouabain and bumetamide  

Microsoft Academic Search

Isolated salivary glands of Periplaneta americana were used to measure secretion rates and, by quantitative capillary electrophoresis, Na+, K+, and Cl? concentrations in saliva collected during dopamine (1 ?M) and serotonin (1 ?M) stimulation in the absence and presence of ouabain (100 ?M) or bumetanide (10 ?M). Dopamine stimulated secretion of a NaCl-rich hyposmotic saliva containing (mM): Na+ 95 ±

K. Rietdorf; I. Lang; B. Walz

2003-01-01

44

Effects of Age on Dopamine and Serotonin Receptors Measured by Positron Tomography in the Living Human Brain  

Microsoft Academic Search

D2 dopamine and S2 serotonin receptors were imaged and measured in healthy human subjects by positron emission tomography after intravenous injection of 11C-labeled 3-N-methylspiperone. Levels of receptor in the caudate nucleus, putamen, and frontal cerebral cortex declined over the age span studied (19 to 73 years). The decline in D2 receptor in males was different from that in females.

Dean F. Wong; Henry N. Wagner; Robert F. Dannals; Jonathan M. Links; J. James Frost; Hayden T. Ravert; Alan A. Wilson; Arthur E. Rosenbaum; Albert Gjedde; Kenneth H. Douglass; John D. Petronis; Marshal F. Folstein; J. K. Thomas Toung; H. Donald Burns; Michael J. Kuhar

1984-01-01

45

Aging and Diurnal Rhythms of Pineal Serotonin, 5-Hydroxyindoleacetic Acid, Norepinephrine, Dopamine and Serum Melatonin in the Male Rat  

Microsoft Academic Search

Pineal serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), norepinephrine (NE) and dopamine (DA) were measured by high-pressure liquid chromatography with electrochemical detection and serum melatonin was measured by radioimmunoassay in rats aged 3 weeks, 8 weeks and 18 months. They were killed either at mid-light or mid-dark of a 12 h light:12 h dark cycle. Diurnal rhythms were observed for 5-HT and

Fai Tang; Maria Hadjiconstantinou; Shiu Fun Pang

1985-01-01

46

Immunohistochemical mapping of histamine, dopamine, and serotonin in the central nervous system of the copepod Calanus finmarchicus (Crustacea; Maxillopoda; Copepoda).  

PubMed

Calanoid copepods constitute an important group of marine planktonic crustaceans that often dominate the metazoan biomass of the world's oceans. In proportion to their ecological importance, little is known about their nervous systems. We have used immunohistochemical techniques in a common North Atlantic calanoid to localize re-identifiable neurons that putatively contain the biogenic amines histamine, dopamine, and serotonin. We have found low numbers of such cells and cell groups (approximately 37 histamine pairs, 22 dopamine pairs, and 12 serotonin pairs) compared with those in previously described crustaceans. These cells are concentrated in the anterior part of the central nervous system, the majority for each amine being located in the three neuromeres that constitute the brain (protocerebrum, deutocerebrum, and tritocerebrum). Extensive histamine labeling occurs in several small compact protocerebral neuropils, three pairs of larger, more posterior, paired, dense neuropils, and one paired diffuse tritocerebral neuropil. The most concentrated neuropil showing dopamine labeling lies in the putative deutocerebrum, associated with heavily labeled commissural connections between the two sides of the brain. The most prominent serotonin neuropil is present in the anterior medial part of the brain. Tracts of immunoreactive fibers of all three amines are prominent in the cephalic region of the nervous system, but some projections into the most posterior thoracic regions have also been noted. PMID:20532915

Hartline, Daniel K; Christie, Andrew E

2010-07-01

47

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

PubMed

Depression is a frequently encountered non-motor feature of Parkinson's disease (PD) and it can have a significant impact on patient's quality of life. Considering the differential pathophysiology of depression in PD, it prompts the idea that a degenerated nigrostriatal system plays a role in depressive-like behaviors, whilst animal models of PD are employed. Therefore, we addressed the question of whether dopamine (DA) depletion, promoted by the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), lipopolysaccharide (LPS) and rotenone are able to induce depressive-like behaviors and neurotransmitters alterations similarly that encountered in PD. To test this rationale, we performed intranigral injections of each neurotoxin, followed by motor behavior, depressive-like behaviors, histological and neurochemical tests. After the motor recovery period, MPTP, 6-OHDA and rotenone were able to produce anhedonia and behavioral despair. These altered behavioral responses were accompanied by reductions of striatal DA, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) restricted to the 6-OHDA group. Additionally, decreases on the hippocampal serotonin (5-HT) content were detected for the MPTP, 6-OHDA and rotenone groups. Notably, strong correlations were detected among the groups when 5-HT and DA were correlated with swimming (r=+0.97; P=0.001) and immobility (r=-0.90; P=0.012), respectively. Our data indicate that MPTP, 6-OHDA and rotenone, but not LPS were able to produce depressive-like behaviors accompanied primarily by hippocampal 5-HT reductions. Moreover, DA and 5-HT strongly correlated with "emotional" impairments suggesting an important participation of these neurotransmitters in anhedonia and behavioral despair after nigral lesions promoted by the neurotoxins. PMID:20547199

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

2010-08-16

48

Structure-activity relationships for serotonin transporter and dopamine receptor selectivity.  

PubMed

Antipsychotic medications have a diverse pharmacology with affinity for serotonergic, dopaminergic, adrenergic, histaminergic and cholinergic receptors. Their clinical use now also includes the treatment of mood disorders, thought to be mediated by serotonergic receptor activity. The aim of our study was to characterise the molecular properties of antipsychotic agents, and to develop a model that would indicate molecular specificity for the dopamine (D(2)) receptor and the serotonin (5-HT) transporter. Back-propagation artificial neural networks (ANNs) were trained on a dataset of 47 ligands categorically assigned antidepressant or antipsychotic utility. The structure of each compound was encoded with 63 calculated molecular descriptors. ANN parameters including hidden neurons and input descriptors were optimised based on sensitivity analyses, with optimum models containing between four and 14 descriptors. Predicted binding preferences were in excellent agreement with clinical antipsychotic or antidepressant utility. Validated models were further tested by use of an external prediction set of five drugs with unknown mechanism of action. The SAR models developed revealed the importance of simple molecular characteristics for differential binding to the D(2) receptor and the 5-HT transporter. These included molecular size and shape, solubility parameters, hydrogen donating potential, electrostatic parameters, stereochemistry and presence of nitrogen. The developed models and techniques employed are expected to be useful in the rational design of future therapeutic agents. PMID:19442217

Agatonovic-Kustrin, Snezana; Davies, Paul; Turner, Joseph V

2009-05-01

49

Effect of co-administration of a serotonin-noradrenaline reuptake inhibitor and a dopamine agonist on extracellular monoamine concentrations in rats.  

PubMed

Recent studies have shown that dopamine agonists are useful for the treatment of not only Parkinson's disease, but also major depressive disorders. However, while these dopamine agonists provide a new treatment strategy for major depressive disorders, such as treatment-resistant cases, the antidepressant effect of dopamine agonists has yet to be investigated. To examine the mechanism of the antidepressive effect of dopamine agonists, we investigated the acute effect of the dopamine receptor agonist, cabergoline, and the serotonin-noradrenaline reuptake inhibitor, milnacipran, on extracellular noradrenaline, dopamine and serotonin concentrations in the rat medial prefrontal cortex. There was a greater increase in extracellular noradrenaline concentrations when acute milnacipran (30 mg/kg intraperitoneally) was administered after acute high-dose cabergoline (1 and 2 mg/kg subcutaneously) than when acute milnacipran was administered following acute vehicle or low-dose cabergoline (0.25 mg/kg subcutaneously). There were no significant differences noted in the dopamine or serotonin concentrations. These results suggest that the addition of cabergoline has the potential to strengthen the antidepressant effects of milnacipran and that the mechanism of action of the antidepressive effect of dopamine agonists might be due to enhancement of induced increases of extracellular noradrenaline. PMID:18336812

Kitaichi, Yuji; Inoue, Takeshi; Izumi, Takeshi; Nakagawa, Shin; Tanaka, Teruaki; Masui, Takuya; Koyama, Tsukasa

2008-04-28

50

Cloning of the cocaine-sensitive bovine dopamine transporter  

SciTech Connect

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

Usdin, T.B.; Chen, C.; Brownstein, M.J.; Hoffman, B.J. (National Inst. of Mental Health, Bethesda, MD (United States)); Mezey, E. (Semmelweis Univ., Budapest (Hungary))

1991-12-15

51

Acute effects of brexpiprazole on serotonin, dopamine, and norepinephrine systems: an in vivo electrophysiologic characterization.  

PubMed

Brexpiprazole, a compound sharing structural molecular characteristics with aripiprazole, is currently under investigation for the treatment of schizophrenia and depression. Using electrophysiologic techniques, the present study assessed the in vivo action of brexpiprazole on serotonin (5-HT) receptor subtypes 5-HT1A, 5-HT1B, and 5-HT2A; dopamine (DA) D2 autoreceptors, and ?1- and ?2-adrenergic receptors. In addition, the effects on 5-HT1A autoreceptors in the dorsal raphe nucleus (DRN) and D2 autoreceptors in the ventral tegmental area (VTA) were compared with those of aripiprazole, an agent in wide clinical use. In the DRN, brexpiprazole completely inhibited the firing of 5-HT neurons via 5-HT1A agonism and was more potent than aripiprazole (ED50 = 230 and 700 ?g/kg, respectively). In the locus coeruleus, brexpiprazole reversed the inhibitory effect of the preferential 5-HT2A receptor agonist DOI (2,5-dimethoxy-4-iodoamphetamine) on norepinephrine neuronal firing (ED50 = 110 ?g/kg), demonstrating 5-HT2A antagonistic action. Brexpiprazole reversed the inhibitory effect of the DA agonist apomorphine on VTA DA neurons (ED50 = 61 ?g/kg), whereas it was ineffective when administered alone, indicating partial agonistic action on D2 receptors. Compared with aripiprazole, which significantly inhibited the firing activity of VTA DA neurons, brexpiprazole displayed less efficacy at D2 receptors. In the hippocampus, brexpiprazole acted as a full agonist at 5-HT1A receptors on pyramidal neurons. Furthermore, it increased 5-HT release by terminal ?2-adrenergic heteroceptor but not 5-HT1B autoreceptor antagonism. In the lateral geniculate nucleus, brexpiprazole displayed ?1B-adrenoceptor antagonistic action. Taken together, these results provide insight into the in vivo action of brexpiprazole on monoamine targets relevant in the treatment of depression and schizophrenia. PMID:25225185

Oosterhof, Chris A; El Mansari, Mostafa; Blier, Pierre

2014-12-01

52

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

PubMed

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

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

2014-09-01

53

Antipsychotic-induced extrapyramidal symptoms in patients with schizophrenia: associations with dopamine and serotonin receptor and transporter polymorphisms  

Microsoft Academic Search

Background  Little is known about the influence of polymorphisms of the dopamine and serotonin system on the risk for extrapyramidal symptoms\\u000a (EPS) during treatment with antipsychotic drugs.\\u000a \\u000a \\u000a \\u000a Methods  Of 119 subjects with schizophrenia treated with antipsychotics, 63 had current or previous EPS (acute dystonia, parkinsonism,\\u000a tardive dyskinesia), and 56 had no such symptoms. All subjects were genotyped for a total of eight

Cüneyt Güzey; Maria Gabriella Scordo; Edoardo Spina; Veslemøy Malm Landsem; Olav Spigset

2007-01-01

54

Quantitative evaluation of serotonin release and clearance in Drosophila  

PubMed Central

Serotonin signaling plays a key role in the regulation of development, mood and behavior. Drosophila is well suited for the study of the basic mechanisms of serotonergic signaling, but the small size of its nervous system has previously precluded the direct measurements of neurotransmitters. This study demonstrates the first real-time measurements of changes in extracellular monoamine concentrations in a single larval Drosophila ventral nerve cord. Channelrhodopsin2-mediated, neuronal type-specific stimulation is used to elicit endogenous serotonin release, which is detected using fast-scan cyclic voltammetry at an implanted microelectrode. Release is decreased when serotonin synthesis or packaging are pharmacologically inhibited, confirming that the detected substance is serotonin. Similar to tetanus-evoked serotonin release in mammals, evoked serotonin concentrations are 280 – 640 nM in the fly, depending on the stimulation length. Extracellular serotonin signaling is prolonged after administering cocaine or fluoxetine, showing that transport regulates the clearance of serotonin from the extracellular space. When ChR2 is targeted to dopaminergic neurons, dopamine release is measured demonstrating that this method is broadly applicable to other neurotransmitter systems. This study shows that the dynamics of serotonin release and reuptake in Drosophila are analogous to those in mammals, making this simple organism more useful for the study of the basic physiological mechanisms of serotonergic signaling. PMID:19428541

Borue, Xenia; Cooper, Stephanie; Hirsh, Jay; Condron, Barry; Venton, B. Jill

2009-01-01

55

Serotonin involvement in the metamorphosis of the hydroid Eudendrium racemosum.  

PubMed

Hydroid planulae metamorphose in response to an inducing external stimulus, usually a bacterial cue. There is evidence that neurotransmitters participate in the signal transduction pathway of hydroid metamorphosis. Eudendrium racemosum is a colonial hydroid common in the Mediterranean Sea. It lacks the medusa stage and the planulae develop on female colonies during the fertile season. In this work, serotonin (5-HT) was localized in some planula ectodermal cells. Co-localization of serotonin and beta-tubulin suggested that 5-HT was present in sensory nervous cells and in different ectodermal cells. To investigate the role of neurotransmitters in metamorphosis, E. racemosum planulae were treated with serotonin and dopamine and with agonists and antagonists of the corresponding receptors. Serotonin and a serotonin receptor agonist induced metamorphosis, while a 5-HT receptor antagonist inhibited it. Dopamine and all dopaminergic drugs used did not show any significant effect on the onset of metamorphosis. Results from this work showed that 5-HT could stimulate metamorphosis in E. racemosum planulae in the presence of a natural inducer. A mechanism by which this neurotransmitter could act in this phase is proposed. PMID:17554682

Zega, Giuliana; Pennati, Roberta; Fanzago, Arianna; De Bernardi, Fiorenza

2007-01-01

56

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

SciTech Connect

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

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

1985-05-01

57

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

PubMed Central

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

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

2014-01-01

58

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

PubMed

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

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

2015-04-01

59

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

PubMed

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

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

2014-02-01

60

Comparative effect of lurasidone and blonanserin on cortical glutamate, dopamine, and acetylcholine efflux: role of relative serotonin (5-HT)2A and DA D2 antagonism and 5-HT1A partial agonism.  

PubMed

Atypical antipsychotic drugs (AAPDs) have been suggested to be more effective in improving cognitive impairment in schizophrenia than typical APDs, a conclusion supported by differences in receptor affinities and neurotransmitter efflux in the cortex and the hippocampus. More potent serotonin (5-HT)2A than dopamine (DA) D2 receptors antagonism, and direct or indirect 5-HT1A agonism, characterize almost all AAPDs. Blonanserin, an AAPD, has slightly greater affinity for D2 than 5-HT2A receptors. Using microdialysis and ultra performance liquid chromatography-mass spectrometry/mass spectrometry, we compared the abilities of the typical APD, haloperidol, three AAPDs, blonanserin, lurasidone, and olanzapine, and a selective 5-HT1A partial agonist, tandospirone, and all, except haloperidol, were found to ameliorate the cognitive deficits produced by the N-methyl-d-aspartate antagonist, phencyclidine, altering the efflux of neurotransmitters and metabolites in the rat cortex and nucleus accumbens. Blonanserin, lurasidone, olanzapine, and tandospirone, but not haloperidol, increased the efflux of cortical DA and its metabolites, homovanillic acid and 3,4-dihydroxyphenylacetic acid. Olanzapine and lurasidone increased the efflux of acetylcholine; lurasidone increased glutamate as well. None of the compounds significantly altered the efflux of 5-HT or its metabolite, 5-hydroxyindole acetic acid, or GABA, serine, and glycine. The ability to increase cortical DA efflux was the only shared effect of the compounds which ameliorates the deficit in cognition in rodents following phencyclidine. PMID:24164459

Huang, Mei; Panos, John J; Kwon, Sunoh; Oyamada, Yoshihiro; Rajagopal, Lakshmi; Meltzer, Herbert Y

2014-03-01

61

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

PubMed

Recent studies have reported that rats raised in an enriched condition (EC) have decreased dopamine transporter (DAT) function and expression in medial prefrontal cortex (mPFC), as well as increased d-amphetamine-induced glutamate release in nucleus accumbens compared to rats raised in an isolated condition (IC). In these previous studies, DAT function and expression were evaluated using mPFC pooled from four rats for each condition to obtain kinetic parameters due to sparse DAT expression in mPFC. In contrast, accumbal glutamate release was determined using individual rats. The current study extends the previous work and reports on the optimization of DAT and serotonin transporter (SERT) functional assays, as well as cell surface expression assays using both mPFC and orbitofrontal cortex (OFC) from individual EC or IC rats. In addition, the effect of d-amphetamine on glutamate release in mPFC and OFC of EC and IC rats was determined using in vivo microdialysis. Results show that environmental enrichment decreased maximal transport velocity (Vmax) for [(3)H]dopamine uptake in mPFC, but increased Vmax for [(3)H]dopamine uptake in OFC. Corresponding changes in DAT cell surface expression were not found. In contrast, Vmax for [(3)H]serotonin uptake and cellular localization of SERT in mPFC and OFC were not different between EC and IC rats. Further, acute d-amphetamine (2mg/kg, s.c.) increased extracellular glutamate concentrations in mPFC of EC rats only and in OFC of IC rats only. Overall, these results suggest that enrichment produces long-lasting alterations in mPFC and OFC DAT function via a trafficking-independent mechanism, as well as differential glutamate release in mPFC and OFC. Rearing-induced modulation of DAT function and glutamate release in prefrontal cortical subregions may contribute to the known protective effects of enrichment on drug abuse vulnerability. PMID:25536304

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

2015-03-01

62

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

PubMed Central

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

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

2014-01-01

63

SLC6 neurotransmitter transporters: structure, function, and regulation.  

PubMed

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 monoamine neurotransmitters serotonin (5-hydroxytryptamine), dopamine, and norepinephrine, and the amino acid neurotransmitters GABA and glycine. The SLC6 NTTs are widely expressed in the mammalian brain and play an essential role in regulating neurotransmitter signaling and homeostasis by mediating uptake of released neurotransmitters from the extracellular space into neurons and glial cells. The transporters are targets for a wide range of therapeutic drugs used in treatment of psychiatric diseases, including major depression, anxiety disorders, attention deficit hyperactivity disorder and epilepsy. 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 of these proteins has advanced rapidly. Furthermore, intensive efforts have been directed toward understanding the molecular and cellular mechanisms involved in regulation of the activity of this important class of transporters, leading to new methodological developments and important insights. This review provides an update of these advances and their implications for the current understanding of the SLC6 NTTs. PMID:21752877

Kristensen, Anders S; Andersen, Jacob; Jørgensen, Trine N; Sørensen, Lena; Eriksen, Jacob; Loland, Claus J; Strømgaard, Kristian; Gether, Ulrik

2011-09-01

64

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

PubMed Central

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

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

2014-01-01

65

Serotonin-2C antagonism augments the effect of citalopram on serotonin and dopamine levels in the ventral tegmental area and nucleus accumbens.  

PubMed

Many patients with major depression do not respond to selective serotonin reuptake inhibitors (SSRIs). Lack of response could be due to inhibition of dopamine (DA) release by serotonin (5-HT) through 5-HT2C receptors. Combining an SSRI with a 5-HT2C antagonist may result in improved efficacy by causing simultaneous increases of 5-HT and DA. In order to test this augmentation strategy, male Wistar rats were treated (s.c.) with an acute dose of the SSRI citalopram (Cit, 5?mg/kg), the 5-HT2C antagonist SB 242084 (SB, 2?mg/kg), or Cit?+?SB, and the effect on 5-HT and DA release in the nucleus accumbens (NAcc) was assessed by microdialysis. In a separate experiment, animals were treated with vehicle, Cit (20?mg/kg/d), SB (2?mg/kg/d) or Cit?+?SB for a period of 2 days (s.c.), and the impact on the release of 5-HT and DA in the ventral tegmental area (VTA) and NAcc was studied. On the day of microdialysis, 5-HT2C receptor sensitivity was assessed with an SB challenge. Acutely administered Cit?+?SB increased 5-HT release in the NAcc more than Cit alone. SB alone increased DA release in the NAcc (not in the VTA), but when administered together with Cit, this effect was abolished. A 2-day treatment with Cit or Cit?+?SB increased 5-HT release in both VTA and NAcc. Combining Cit with SB augmented the effect of Cit in the VTA. DA release in VTA and NAcc was only significantly increased after 2-days of treatment with Cit?+?SB. In conclusion, Cit?+?SB had synergistic effects on 5-HT and DA release after 2-days of treatment, probably related to a decreased tonic inhibition of DA release via 5-HT2C receptors. Regional differences occur and future studies should elucidate if this augmentation strategy is beneficial at the behavioral level. PMID:25542858

Visser, Anniek K D; Kleijn, Jelle; van Faassen, Martijn H J R; Dremencov, Eliyahu; Flik, Gunnar; Kema, Ido P; Den Boer, Johan A; van Waarde, Aren; Dierckx, Rudi A J O; Bosker, Fokko J

2015-02-01

66

Increased Serotonin and Dopamine Transporter Binding in Psychotropic Medication-Naõ ¨ve Patients with Generalized Social Anxiety Disorder Shown by 123Ib(4-Iodophenyl)Tropane SPECT  

Microsoft Academic Search

There is circumstantial evidence for the involvement of seroto- nergic and dopaminergic systems in the pathophysiology of so- cial anxiety disorder. In the present study, using SPECT imaging we examined the 123I-b-(4-iodophenyl)-tropane binding potential for the serotonin and dopamine transporters in patients with a generalized social anxiety disorder and in age- and sex-matched healthy controls. Methods: Twelve psychotropic medication- naõ¨ve

Nic J. van der Wee; Frederieke van Veen; Henk Stevens; Irene M. van Vliet; Peter P. van Rijk; Herman G. Westenberg

67

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

ERIC Educational Resources Information Center

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

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

2011-01-01

68

A possible new role for fish retinal serotonin- N-acetyltransferase-1 (AANAT1): Dopamine metabolism  

Microsoft Academic Search

Serotonin-N-acetyltransferase (arylalkylamine-N-acetyltransferase, AANAT) is the key enzyme in the generation of melatonin rhythms in the pineal gland and retinal photoreceptors. Rhythmic AANAT activity drives rhythmic melatonin production in these tissues. Two AANATs, AANAT1 and AANAT2, are present in teleost fish species. Different spatial expression patterns, enzyme kinetics and substrate preferences suggest that they may have different functions. Enzyme activity assays

Bina Zilberman-Peled; Benny Ron; Aviva Gross; John P. M. Finberg; Yoav Gothilf

2006-01-01

69

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

PubMed

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

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

2014-01-01

70

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

PubMed Central

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

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

2013-01-01

71

Binding of beta-carbolines and related agents at serotonin (5-HT(2) and 5-HT(1A)), dopamine (D(2)) and benzodiazepine receptors.  

PubMed

A large series of beta-carbolines was examined for their ability to bind at [3H]agonist-labeled 5-HT(2A) serotonin receptors. Selected beta-carbolines were also examined at 5-HT(2C) serotonin receptors, 5-HT(1A) serotonin receptors, dopamine D(2) receptors, and benzodiazepine receptors. Indolealkylamines and phenylisopropylamines were also evaluated in some of these binding assays. The beta-carbolines were found to bind with modest affinity at 5-HT(2A) receptors, and affinity was highly dependent upon the presence of ring substituents and ring saturation. The beta-carbolines displayed little to no affinity for 5-HT(1A) serotonin receptors, dopamine D(2) receptors and, with the exception of beta-CCM, for benzodiazepine receptors. Examples of beta-carbolines, indolealkylamines (i.e. N,N-dimethyltryptamine analogs), and phenylisopropylamines have been previously shown to produce common stimulus effects in animals trained to discriminate the phenylisopropylamine hallucinogen DOM (i.e. 1-(2, 5-dimethoxy-4-methylphenyl)-2-aminopropane) from vehicle. Although the only common receptor population that might account for this action is 5-HT(2A), on the basis of a lack of enhanced affinity for agonist-labeled 5-HT(2A) receptors, as well as on their lack of agonist action in the PI hydrolysis assay, it is difficult to conclude that the beta-carbolines behave in a manner consistent with that of other classical hallucinogens. PMID:10940539

Glennon, R A; Dukat, M; Grella, B; Hong, S; Costantino, L; Teitler, M; Smith, C; Egan, C; Davis, K; Mattson, M V

2000-08-01

72

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

PubMed Central

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

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

2014-01-01

73

Uremic anorexia: a consequence of persistently high brain serotonin levels? The tryptophan/serotonin disorder hypothesis.  

PubMed

Anorexia is a frequent part of uremic syndrome, contributing to malnutrition in dialysis patients. Many factors have been suggested as responsible for uremic anorexia. In this paper we formulate a new hypothesis to explain the appetite disorders in dialysis patients: "the tryptophan/serotonin disorder hypothesis." We review current knowledge of normal hunger-satiety cycle control and the disorders described in uremic patients. There are four phases in food intake regulation: (1) the gastric phase, during which food induces satiety through gastric distention and satiety peptide release; (2) the post absorptive phase, during which circulating compounds, including glucose and amino acids, cause satiety by hepatic receptors via the vagus nerve; (3) the hepatic phase, during which adenosine triphosphate (ATP) concentration is the main stimulus inducing hunger or satiety, with cytokines inhibiting ATP production; and (4) the central phase, during which appetite is regulated through peripheral (circulating plasma substances and neurotransmitters) and brain stimuli. Brain serotonin is the final target for peripheral mechanisms controlling appetite. High brain serotonin levels and a lower serotonin/dopamine ratio cause anorexia. Plasma and brain amino acid concentrations are recognized factors involved in neurotransmitter synthesis and appetite control. Tryptophan is the substrate of serotonin synthesis. High plasma levels of anorectics such as tryptophan (plasma and brain), cholecystokinin, tumor necrosis factor alpha, interleukin-1, and leptin, and deficiencies of nitric oxide and neuropeptide Y have been described in uremia; all increase intracerebral serotonin. We suggest that brain serotonin hyperproduction due to a uremic-dependent excess of tryptophan may be the final common pathway involved in the genesis of uremic anorexia. Various methods of ameliorating anorexia by decreasing the central effects of serotonin are proposed. PMID:11216590

Aguilera, A; Selgas, R; Codoceo, R; Bajo, A

2000-01-01

74

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

PubMed

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

Burke, Mary V; Nocjar, Christine; Sonneborn, Alex J; McCreary, Andrew C; Pehek, Elizabeth A

2014-11-01

75

Neurotransmitter-Specific Synaptosomes in Rat Corpus Striatum: Morphological Variations*  

PubMed Central

This communication describes ultrastructural variations among synaptosomal fractions isolated from the corpus striatum of the rat by incomplete equilibrium sedimentation in sucrose density gradients, and attempts to relate the variations to neurotransmitter-specific synaptosomes. The concentration of synaptosomes in each fraction of the density gradient was found to be correlated with the concentration of potassium, a marker for cytoplasm occluded within synaptosomes. Monoamine oxidase activity was found to be correlated with the incidence of free mitochondria in the gradients. Synaptosomes from denser gradient fractions showed a markedly increased frequency of adherent postsynaptic elements and intraterminal mitochondria. These denser gradient fractions were rich in synaptosomes containing norepinephrine, dopamine, serotonin, and acetylcholine, while synaptosomes in lighter portions of the gradients were rich in ?-aminobutyric acid and other amino acids. These data suggest that significant morphological variations may exist among different neurotransmitter-specific nerve terminals in the brain. Images PMID:4395685

Gfeller, Eduard; Kuhar, Michael J.; Snyder, Solomon H.

1971-01-01

76

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

SciTech Connect

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

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

1985-05-01

77

Serotonin2C receptors modulate dopamine transmission in the nucleus accumbens independently of dopamine release: behavioral, neurochemical and molecular studies with cocaine.  

PubMed

In keeping with its ability to control the mesoaccumbens dopamine (DA) pathway, the serotonin2C receptor (5-HT2C R) plays a key role in mediating the behavioral and neurochemical effects of drugs of abuse. Studies assessing the influence of 5-HT2C R agonists on cocaine-induced responses have suggested that 5-HT2C Rs can modulate mesoaccumbens DA pathway activity independently of accumbal DA release, thereby controlling DA transmission in the nucleus accumbens (NAc). In the present study, we assessed this hypothesis by studying the influence of the 5-HT2C R agonist Ro 60-0175 on cocaine-induced behavioral, neurochemical and molecular responses. The i.p. administration of 1?mg/kg Ro 60-0175 inhibited hyperlocomotion induced by cocaine (15?mg/kg, i.p.), had no effect on cocaine-induced DA outflow in the shell, and increased it in the core subregion of the NAc. Furthermore, Ro 60-0175 inhibited the late-onset locomotion induced by the subcutaneous administration of the DA-D2 R agonist quinpirole (0.5?mg/kg), as well as cocaine-induced increase in c-Fos immunoreactivity in NAc subregions. Finally, Ro 60-0175 inhibited cocaine-induced phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32?kDa (DARPP-32) at threonine residues in the NAc core, this effect being reversed by the selective 5-HT2C R antagonist SB 242084 (0.5?mg/kg, i.p.). Altogether, these findings demonstrate that 5-HT2C Rs are capable of modulating mesoaccumbens DA pathway activity at post-synaptic level by specifically controlling DA signaling in the NAc core subregion. In keeping with the tight relationship between locomotor activity and NAc DA function, this interaction could participate in the inhibitory control of cocaine-induced locomotor activity. PMID:24661380

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

2015-05-01

78

Long-term administration of the dopamine D3/2 receptor agonist pramipexole increases dopamine and serotonin neurotransmission in the male rat forebrain  

PubMed Central

Background Long-term administration of the dopamine (DA) D2-like (D3/2) receptor agonist pramipexole (PPX) has been previously found to desensitize D2 autoreceptors, thereby allowing a normalization of the firing of DA neurons and serotonin (5-HT)1A autoreceptors, permitting an enhancement of the spontaneous firing of 5-HT neurons. We hypothesized that PPX would increase overall DA and 5-HT neurotransmission in the forebrain as a result of these changes at the presynaptic level. Methods Osmotic minipumps were implanted subcutaneously in male Sprague-Dawley rats, delivering PPX at a dose of 1 mg/kg/d for 14 days. The in vivo electrophysiologic microiontophoretic experiments were carried out in anesthetized rats. Results The sensitivity of postsynaptic D2 receptors in the prefrontal cortex (PFC) remained unaltered following PPX administration, as indicated by the unchanged responsiveness to the microiontophoretic application of DA. Their tonic activation was, however, significantly increased by 104% compared with the control level. The sensitivity of postsynaptic 5-HT1A receptors was not altered, as indicated by the unchanged responsiveness to the microiontophoretic application of 5-HT. Similar to other antidepressant treatments, long-term PPX administration enhanced the tonic activation of 5-HT1A receptors on CA3 pyramidal neurons by 142% compared with the control level. Limitations The assessment of DA and 5-HT neuronal tone was restricted to the PFC and the hippocampus, respectively. Conclusion Chronic PPX administration led to a net enhancement in DA and 5-HT neurotransmission, as indicated by the increased tonic activation of postsynaptic D2 and 5-HT1A receptors in forebrain structures. PMID:22023785

Chernoloz, Olga; El Mansari, Mostafa; Blier, Pierre

2012-01-01

79

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

PubMed

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. PMID:25437353

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

2015-01-21

80

Direct control of the gonadotroph in a teleost, Poecilia latipinna. II. Neurohormones and neurotransmitters.  

PubMed

Pituitaries from male and female mollies were incubated with varying amounts of mammalian LH-RH, arginine vasotocin, dopamine, or serotonin for 18 hr. Ultrastructural differences between control and experimentally treated glands were used to define the direct effects of these neurohormones and neurotransmitters on the gonadotrophic cells of the adenohypophysis. The effects varied in intensity according to the sex and reproductive state of the donor animal. LH-RH stimulated gonadotrophin secretion by the gonadotrophs, as did vasotocin, although to a much lesser extent and with noticeable differences between the sexes. Dopamine inhibited secretion by basally active gonadotrophs and probably from active cells also, although to a lesser extent. Serotonin mildly stimulated secretion at all stages in both sexes. The results of this study indicate the possible involvement of neurohypophysial octapeptides and of monoamines in the direct control of the gonadotroph of Poecilia latipinna. PMID:2877917

Groves, D J; Batten, T F

1986-05-01

81

Serotonin neuron loss and nonmotor symptoms continue in Parkinson's patients treated with dopamine grafts.  

PubMed

Cell therapy studies in patients with Parkinson's disease (PD) have been confined to intrastriatal transplantation of dopamine-rich fetal mesencephalic tissue in efforts to improve motor performance. Although some PD patients receiving the dopamine-rich grafts showed improvements in motor symptoms due to replacement of dopaminergic neurons, they still suffered from nonmotor symptoms including depression, fatigue, visual hallucinations, and sleep problems. Using functional imaging and clinical evaluation of motor and nonmotor symptoms in three PD patients transplanted with intrastriatal fetal grafts 13 to 16 years previously, we assessed whether reestablishment of dopaminergic neuronal networks is sufficient to improve a broad range of symptoms. At 13 to 16 years after transplantation, dopaminergic innervation was restored to normal levels in basal ganglia and preserved in a number of extrabasal ganglia areas. These changes were associated with long-lasting relief of motor symptoms. Then, we assessed the integrity of their serotonergic and norepinephrine neuronal systems using [¹¹C]DASB {[¹¹C]3-amino-4-(2-dimethylaminomethylphenylthio) benzonitrile} positron emission tomography (PET) and ¹?F-dopa PET, respectively. ¹?F-dopa uptake in the locus coeruleus was within the normal range. In contrast, [¹¹C]DASB uptake in the raphe nuclei and regions receiving serotonergic projections was markedly reduced. These results indicate ongoing degeneration of serotonergic raphe nuclei and their projections to regions involved in the regulation of sleep, arousal, feeding, satiety, mood, and emotion. Our findings indicate that future cell-based therapies using fetal tissue or stem cells in PD patients may require additional grafts of serotonergic neurons to relieve nonmotor symptoms by restoring serotonergic neurotransmission in specific cerebral targets. PMID:22491951

Politis, Marios; Wu, Kit; Loane, Clare; Quinn, Niall P; Brooks, David J; Oertel, Wolfgang H; Björklund, Anders; Lindvall, Olle; Piccini, Paola

2012-04-01

82

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

PubMed

Seasonal affective disorder (SAD) is a subtype of major depressive or bipolar disorders associated with the shortened photoperiod in winter. This depressive disorder is integrally tied to the seasonal regulation of the brain's serotonergic system. Recently, we found that C57BL/6J mice subjected to a forced-swim test exhibited immobility, a photoperiod-dependent depression-associated behavior, and suppression of brain serotonin levels. However, mice are nocturnal animals, and it is unclear whether the brain serotonergic system responds similarly to photoperiod in nocturnal and diurnal species. This study compared the responses of brain serotonergic and dopaminergic systems to photoperiod in diurnal chipmunks and nocturnal C57BL/6J mice. In both species, serotonin levels in the dorsal raphe nuclei were higher under long-day conditions than short-day conditions, suggesting a similarity in the photoperiod responses of the serotonergic systems. However, photoperiod affected dopamine levels in various brain regions differently in the two species. Some chipmunk brain regions exhibited stronger photoperiod-induced changes in dopamine levels than those of C57BL/6J mice, and the direction of the changes in the hypothalamus was opposite. In conclusion, photoperiod may regulate the brain serotonergic system through similar mechanisms, regardless of whether the animals are diurnal or nocturnal, but photoperiod-dependent regulation of brain dopamine is species-specific. PMID:25797183

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

2015-04-23

83

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

PubMed

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 ?-sitosterol. We also exposed fish to two doses of the endogenous estrogen 17?-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 ?-sitosterol decreased norepinephrine and dopamine in the forebrain and hindbrain, respectively. Our results suggest that sources of environmental phytoestrogens, such as runoff or effluent from agricultural fields, wood pulp mills, and sewage treatment plants, have the potential to modulate neurotransmitter activity in free-living fishes in a way that could interfere with normal behavioral processes. PMID:20012186

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

2010-12-01

84

Gold nanoparticles modified GC electrodes: electrochemical behaviour dependence of different neurotransmitters and molecules of biological interest on the particles size and shape  

Microsoft Academic Search

Gold colloidal nanoparticles (AuNps), synthesized by gold chloride hydrate (HAuCl4) chemical reduction were used to realize a modified glassy carbon electrode (GCE). Different shapes and sizes were observed,\\u000a varying the molar ratio of HAuCl4 and polyvinylpyrrolidone (PVP). The electrochemical behaviour of different neurotransmitters and molecules of biological\\u000a interest (dopamine, caffeic acid, catechol, uric acid, epinephrine and serotonin) were investigated by

D. Caschera; F. Federici; D. Zane; F. Focanti; A. Curulli; G. Padeletti

2009-01-01

85

Behavioral, Hormonal, and Neurotransmitter Reactions to Stress in Adult Rats with a History of High IL-1? Content in the Early Postnatal Ontogeny.  

PubMed

Behavioral, hormonal, and neurotransmitter reactions to foot shock were studied in adult rats treated with IL-1? during week 3 of life. After stress, these animals differed from controls treated with saline by high levels of dopamine, serotonin, and 5-hydroxy-indolacetic acid in the hypothalamus. In contrast to controls, they developed a significant stress-induced increase of blood corticosterone level and exhibited lesser motor and exploratory activities in the open field test. PMID:25778643

Zubareva, O E; Schwartz, A P; Khnychenko, L K; Ishchenko, A M; Simbirtsev, A S; Klimenko, V M

2015-03-01

86

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

PubMed

In view of the effective traditional Chinese medicine (TCM) in the treatment of clinical depression, the mechanism is not clear, this study attempts to research the cause of depression in a complex situation to lay the foundation for the next step of TCM curative effect evaluation. Based on the brain wave of 120 depression patients and 40 ordinary person, the change regulation of acetylcholine, dopamine, norepinephrine, depression neurotransmitters and excited neurotransmitters in the whole and various encephalic regions' multi-neurotransmitters of depression patients-serotonin are analysed by search of encephalo-telex (SET) system, which lays the foundation for the diagnosis of depression. The result showed that: contrased with the normal person group, the mean value of the six neurotransmitters in depression patients group are: (1) in the whole encephalic region of depression patients group the dopamine fall (P < 0.05), and in the double centralregions, right temporal region and right parietal region distinct fall (P < 0.01); (2) in the right temporal region of depression patients group the serotonin rise (P < 0.05); (3) in the right central region, left parietal region of depression patients group the acetylcholine fall (P < 0.05), left rear temporal region fall obviously (P < 0.01). The correlation research between antagonizing pairs of neurotransmitters and neurotransmitters: (1) the three antagonizing pairs of neurotransmitters-serotonin and dopamine, acetylcholine and norepinephrine, depression neurotransmitters and excited neurotransmitters, in ordinary person group and depression patients group are characterizeed by middle or strong negative correlation. Serotonin and dopamine, which are characterized by weak negative correlation in the right rear temporal region of ordinary person group, are characterized by strong negative correlation in the other encephalic regions and the whole encephalic (ordinary person group except the right rear temporal region: the range of [r] is [0.82, 0.92], P < 0.01)/(depression patients group:the range of [r] is [0.88, 0.94], P < 0.01); acetylcholine and norepinephrine, in the whole and various encephalic region are characterized by middle negative correlation(ordinary person group:the range of [r] is [0.39, 0.76], P < 0.01 or P < 0.05)/(depression patients group: the range of [Ir] is [0.56, 0.64], P < 0.01); depression neurotransmitters and excited neurotransmitters are characterized by middle strong negative correlation (ordinary person group: the range of [r] is [0.57, 0.80], P < 0.01)/(depression patients group: the range of [r] is [0.68, 0.78], P < 0.01). (2) The two neurotransmitters which are not antagonizing pairs of neurotransmitters, serotonin and excited neurotransmitters, or acetylcholine and depression neurotra-nsmitters, or dopamine and depression neurotransmitters in the various encephalic regions are characterized by weak negative correlation. Serotonin and excited neurotransmitters are characterizeed by weak negative correlation (ordinary person group: in the right central region, left parietal region, double front temporal regions, right rear temporal region, the range of [r] is [0.25, 0.50], P < 0.01 or P < 0.05)/(depression patients group: in the whole encephalic regions, double parietal regions, double occipital regions, right front temporal region, left central region, left frontal region, the range of [r] is [0.18, 0.37], P < 0.01 or P < 0.05); acetylcholine and depression, neurotransmitters are characterized by weak negative correlation (ordinary person group: in the double frontal regions, left parietal region, left front temporal region, right rear temporal region, the range of [r] is [0.31, 0.46], P < 0.01 or P < 0.05)/(depression patients group: in double rear temporal regions, right front temporal region, double occipital regions, left central region, the range of [r] is [0.20, 0.32] , P < 0.01 or P < 0.05); do-pamine and depression neurotransmitters are characterized by weak middle negative co

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

2014-04-01

87

The effects of serotonin, dopamine, octopamine and tyramine on behavior of workers of the ant Formica polyctena during dyadic aggression tests.  

PubMed

We investigated the effect of injections of four biogenic amines (serotonin, dopamine, octopamine and tyramine) on behavior patterns displayed by workers of the red wood ant Formica polyctena during dyadic confrontations with four types of opponents: a nestmate, an alien conspecific, an allospecific ant (Formica fusca), and a potential prey, a nymph of the house cricket (Acheta domesticus). Significant effects of biogenic amine administration were observed almost exclusively in the case of confrontations with allospecific opponents. Serotonin treatment exerted stimulatory effects on behavior patterns involving physical aggression (biting accompanied by gaster flexing, dragging and formic acid spraying), but these effects were relatively weak and/or documented by indirect evidence. Dopamine administration exerted a stimulatory effect on open-mandible threats directed by F. polyctena to F. fusca and to cricket nymphs, and on biting behavior directed to cricket nymphs. Surprisingly, octopamine treatment did not exert significant effects on aggressive behavior of the tested ants. Tyramine administration exerted a suppressing effect on threatening behavior directed to F. fusca, but led to shortening of the latencies to the first open-mandible threat during the tests with cricket nymphs. Biogenic amine administration also influenced non-aggressive behavior of the tested ants. Our findings confirmed the role of serotonin and dopamine in the mediation of ant aggressive behavior and documented for the first time significant effects of tyramine treatment on ant aggressive behavior. We also demonstrated that not only specific patterns of ant aggressive behavior, but also behavioral effects of biogenic amine treatments are as a rule strongly context-dependent. PMID:24457641

Szczuka, Anna; Korczy?ska, Julita; Wnuk, Andrzej; Symonowicz, Beata; Gonzalez Szwacka, Anna; Mazurkiewicz, Pawe?; Kostowski, Wojciech; Godzi?ska, Ewa Joanna

2013-01-01

88

Molecular modeling and docking study on dopamine D2-like and serotonin 5-HT2A receptors.  

PubMed

Psychiatric disorders, such as schizophrenia, bipolar disorder and major depression, are paid more and more attention by human due to their upward tendency in modern society. D2-like and 5-HT2A receptors have been proposed as targets of antipsychotic drugs. Atypical antipsychotic drugs have been deemed to improve the treatment of positive, negative and extrapyramidal symptoms. Unfortunately, no experimental structures for these receptors are available except D3 receptor (D3R). Therefore, it is necessary to construct structures of D2-like and 5-HT2A receptors to investigate the interaction between these receptors and their antagonists. Accordingly, homology models of dopamine D2, D3, D4 and serotonin 5-HT2A receptors have been built on the high-resolution crystal structure of the ?2-adrenergic receptor, and refined by molecular dynamics simulations. The backbone root-mean-square deviation (RMSD) of D3R model relative to crystal structure is 1.3?, which proves the reliability of homology modeling. Docking studies reveal that the binding modes of four homology models and their antagonists are consistent with experimental site-directed mutagenesis data. The calculated pKi values agree well with the experimental pKi ones. Antagonists with linear structures such as butyrophenones and benzisoxazolyl piperidines are easily docked into D2-like and 5-HT2A receptors. Polycyclic aromatic compounds have weaker affinity with four receptors. Homology models of D2-like and 5-HT2A receptors will be helpful for predicting the affinity of novel ligands, and could be used as three-dimensional (3D) templates for antipsychotic virtual screening and further drug discovery. PMID:25728902

Duan, Xinli; Zhang, Min; Zhang, Xin; Wang, Fang; Lei, Ming

2015-04-01

89

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

PubMed Central

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

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

2009-01-01

90

Dissociating effects of cocaine and d -amphetamine on dopamine and serotonin in the perirhinal, entorhinal, and prefrontal cortex of freely moving rats  

Microsoft Academic Search

Rationale  Neuroimaging studies with humans showed widespread activation of the cortex in response to psychostimulant drugs. However,\\u000a the neurochemical nature of these brain activities is not characterized.\\u000a \\u000a \\u000a \\u000a Objective  The aim of the present study was to investigate the effects of cocaine and d-amphetamine on dopamine (DA) and serotonin (5-HT) in cortical areas of the hippocampal network in comparison to the prefrontal\\u000a cortex

M. Pum; R. J. Carey; J. P. Huston; C. P. Müller

2007-01-01

91

The Effects of LPM570065, a Novel Triple Reuptake Inhibitor, on Extracellular Serotonin, Dopamine and Norepinephrine Levels in Rats  

PubMed Central

Triple reuptake inhibitors (TRIs) are currently being developed as a new class of promising antidepressants that block serotonin (5-HT), dopamine (DA) and norepinephrine (NE) transporters, thereby increasing extracellular monoamine concentrations. The purpose of this study was to investigate the effects of LPM570065, a novel TRI and a desvenlafaxine prodrug, on extracellular 5-HT, DA and NE levels in the rat striatum after acute and chronic administration relative to desvenlafaxine, using High Performance Liquid Chromatography (HPLC) and microdialysis. Acute administration was performed by providing rodents with oral solutions (0.06 mmol·kg?1 p.o.), oral suspensions (0.06 mmol·kg?1 p.o.) and intravenous solutions (0.04 mmol·kg?1 i.v.) of LPM570065 and desvenlafaxine. Oral suspensions (0.06 mmol·kg?1·day?1) of the two drugs were also administered for a 14-day chronic period. HPLC analysis revealed that LPM570065 rapidly penetrated the rat striatum, converted into desvenlafaxine and exhibited larger total exposure compared with the administration of desvenlafaxine. Microdialysis revealed that acute and chronic administration of oral suspension of LPM570065 increased the 5-HT, DA and NE levels more than the relative administration of desvenlafaxine. Unlike desvenlafaxine, acute administration of an intravenous LPM570065 solution did not induce the undesirable 90% decrease in extracellular 5-HT levels. In contrast to the fully dose-dependent elevation of 5-HT induced by desvenlafaxine, the acute administration of LPM570065 showed a capped increase in extracellular 5-HT levels when combined with WAY-100635. Additionally, forced swim test demonstrated that acute and chronic administration of LPM570065 reduced the immobility time more than the relative administration of desvenlafaxine. These data suggest that LPM570065 may have greater efficacy and/or a more rapid onset of antidepressant action than desvenlafaxine and also counterbalance the harmful effects of desvenlafaxine on 5-HT neurotransmission related to 5-HT1A autoreceptors. Thus, this new class of drugs, TRIs has the potential to provide a new therapeutic mechanism for treating depression. PMID:24614602

Zhang, Renyu; Li, Xiang; Shi, Yanan; Shao, Yufeng; Sun, Kaoxiang; Wang, Aiping; Sun, Fengying; Liu, Wanhui; Wang, Di; Jin, Jingji; Li, Youxin

2014-01-01

92

Evidence for a gene–gene interaction in predicting children's behavior problems: Association of serotonin transporter short and dopamine receptor D4 long genotypes with internalizing and externalizing behaviors in typically developing 7-year-olds  

Microsoft Academic Search

Recent work on the molecular genetics of complex traits in typical and atypical human development has focused primarilyon associations of single genes with behavior. Disparate literature suggests that the presence of one or two copies of the short allele of the serotonin transporter (5-HTT) gene and the long allele (7-repeat allele) version of the dopamine receptor D4 (DRD4) gene predicts

Louis A. Schmidt; Nathan A. Fox; DEAN H. HAMERc

2007-01-01

93

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

PubMed Central

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

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

2013-01-01

94

Involvement of dopamine (DA)\\/serotonin (5HT)\\/sigma (?) receptor modulation in mediating the antidepressant action of ropinirole hydrochloride, a D 2\\/D 3 dopamine receptor agonist  

Microsoft Academic Search

Multiple lines of investigation have explored the role of dopaminergic systems in mental depression. Chronic treatment with antidepressant drugs has been reported to alter dopaminergic neurotransmission, most notably a sensitization of behavioural responses to agonists acting at D2\\/D3 dopamine receptors within the nucleus accumbens. Recent clinical evidences have shown that ropinirole, a D2\\/D3 dopamine receptor agonist, augments the action of

Ashish Dhir; S. K. Kulkarni

2007-01-01

95

Multisite Intracerebral Microdialysis to Study the Mechanism of L-DOPA Induced Dopamine and Serotonin Release in the Parkinsonian Brain  

PubMed Central

L-DOPA is currently one of the best medications for Parkinson’s disease. It was assumed for several years that its benefits and side effects were related to the enhancement of dopamine release in the dopamine-depleted striatum. The use of intracerebral microdialysis combined with a pharmacological approach has led to the discovery that serotonergic neurons are responsible for dopamine release induced by L-DOPA. The subsequent use of multisite microdialysis has further revealed that L-DOPA-stimulated dopamine release is widespread and related to the serotonergic innervation. The present Review emphasizes the functional impact of extrastriatal release of dopamine induced by L-DOPA in both the therapeutic and side effects of L-DOPA. PMID:23541043

2013-01-01

96

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

PubMed

Monoamine neurotransmitter deficiency has been implicated in the etiology of neuropsychiatric symptoms associated with chronic hyperphenylalaninemia in phenylketonuria (PKU). Two proposed explanations for neurotransmitter deficiency in PKU include first, that chronically elevated blood L-phenylalanine (Phe) inhibits the transport of L-tyrosine (Tyr) and L-tryptophan (Trp), the substrates for dopamine and serotonin synthesis respectively, into brain. In the second hypothesis, elevated Phe competitively inhibits brain tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities, the rate limiting steps in dopamine and serotonin synthesis. Dietary supplementation with large neutral amino acids (LNAA) including Tyr and Trp has been recommended for individuals with chronically elevated blood Phe in an attempt to restore amino acid and monoamine homeostasis in brain. As a potential alternative treatment approach, we demonstrate that pharmacologic inhibition of Tyr degradation through oral administration of nitisinone (NTBC) yielded sustained increases in blood and brain Tyr, decreased blood and brain Phe, and consequently increased dopamine synthesis in a murine model of PKU. Our results suggest that Phe-mediated inhibition of TH activity is the likely mechanism of impaired dopamine synthesis in PKU. Pharmacologic inhibition of Tyr degradation may be a promising adjunct therapy for CNS monoamine neurotransmitter deficiency in hyperphenylalaninemic individuals with PKU. PMID:24487571

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

2014-09-01

97

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

PubMed Central

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

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

2009-01-01

98

Extremely Low Frequency Magnetic Field Modulates the Level of Neurotransmitters  

PubMed Central

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

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

2015-01-01

99

Extremely low frequency magnetic field modulates the level of neurotransmitters.  

PubMed

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

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

2015-01-01

100

LeuT-Desipramine Structure Reveals How Antidepressants Block Neurotransmitter Reuptake  

SciTech Connect

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.

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

2007-01-01

101

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

PubMed Central

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

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

2014-01-01

102

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

PubMed Central

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

Buznikov, Gennady A.; Nikitina, Lyudmila A.; Seidler, Frederic J.; Slotkin, Theodore A.; Bezuglov, Vladimir V.; Miloševi?, Ivan; Lazarevi?, Lidija; Roga?, Ljubica; Ruzdiji?, Sabera; Raki?, Ljubiša M.

2008-01-01

103

Amyloid precursor protein 96-110 and beta-amyloid 1-42 elicit developmental anomalies in sea urchin embryos and larvae that are alleviated by neurotransmitter analogs for acetylcholine, serotonin and cannabinoids.  

PubMed

Amyloid precursor protein (APP) is overexpressed in the developing brain and portions of its extracellular domain, especially amino acid residues 96-110, play an important role in neurite outgrowth and neural cell differentiation. In the current study, we evaluated the developmental abnormalities caused by administration of exogenous APP(96-110) in sea urchin embryos and larvae, which, like the developing mammalian brain, utilize acetylcholine and other neurotransmitters as morphogens; effects were compared to those of beta-amyloid 1-42 (Abeta42), the neurotoxic APP fragment contained within neurodegenerative plaques in Alzheimer's Disease. Although both peptides elicited dysmorphogenesis, Abeta42 was far more potent; in addition, whereas Abeta42 produced abnormalities at developmental stages ranging from early cleavage divisions to the late pluteus, APP(96-110) effects were restricted to the intermediate, mid-blastula stage. For both agents, anomalies were prevented or reduced by addition of lipid-permeable analogs of acetylcholine, serotonin or cannabinoids; physostigmine, a carbamate-derived cholinesterase inhibitor, was also effective. In contrast, agents that act on NMDA receptors (memantine) or alpha-adrenergic receptors (nicergoline), and that are therapeutic in Alzheimer's Disease, were themselves embryotoxic, as was tacrine, a cholinesterase inhibitor from a different chemical class than physostigmine. Protection was also provided by agents acting downstream from receptor-mediated events: increasing cyclic AMP with caffeine or isobutylmethylxanthine, or administering the antioxidant, a-tocopherol, were all partially effective. Our findings reinforce a role for APP in development and point to specific interactions with neurotransmitter systems that act as morphogens in developing sea urchins as well as in the mammalian brain. PMID:18565728

Buznikov, Gennady A; Nikitina, Lyudmila A; Seidler, Frederic J; Slotkin, Theodore A; Bezuglov, Vladimir V; Milosevi?, Ivan; Lazarevi?, Lidija; Rogac, Ljubica; Ruzdiji?, Sabera; Raki?, Ljubisa M

2008-01-01

104

Carbon nanopipette electrodes for dopamine detection in Drosophila.  

PubMed

Small, robust, sensitive electrodes are desired for in vivo neurotransmitter measurements. Carbon nanopipettes have been previously manufactured and used for single-cell drug delivery and electrophysiological measurements. Here, a modified fabrication procedure was developed to produce batches of solid carbon nanopipette electrodes (CNPEs) with ?250 nm diameter tips, and controllable lengths of exposed carbon, ranging from 5 to 175 ?m. The electrochemical properties of CNPEs were characterized with fast-scan cyclic voltammetry (FSCV) for the first time. CNPEs were used to detect the electroactive neurotransmitters dopamine, serotonin, and octopamine. CNPEs were significantly more sensitive for serotonin detection than traditional carbon-fiber microelectrodes (CFMEs). Similar to CFMEs, CNPEs have a linear response for dopamine concentrations ranging from 0.1 to 10 ?M and a limit of detection of 25 ± 5 nM. Recordings with CNPEs were stable for over 3 h when the applied triangle waveform was scanned between -0.4 and +1.3 V vs Ag/AgCl/Cl(-) at 400 V/s. CNPEs were used to detect endogenous dopamine release in Drosophila larvae using optogenetics, which verified the utility of CNPEs for in vivo neuroscience studies. CNPEs are advantageous because they are 1 order of magnitude smaller in diameter than typical CFMEs and have a sharp, tunable geometry that facilitates penetration and implantation for localized measurements in distinct regions of small organisms, such as the Drosophila brain. PMID:25711512

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

2015-04-01

105

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

PubMed Central

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

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

2013-01-01

106

Serotonin Receptors in Hippocampus  

PubMed Central

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

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

2012-01-01

107

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

PubMed

Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by alterations of nigrostriatal dopaminergic neurotransmission. Compared to the wealth of data on the impairment of the dopamine system, relatively limited evidence is available concerning the role of major non-dopaminergic neurotransmitter systems in PD. Therefore, we comprehensively investigated the density and distribution of neurotransmitter receptors for glutamate, GABA, acetylcholine, adrenaline, serotonin, dopamine and adenosine in brains of homozygous aphakia mice being characterized by mutations affecting the Pitx3 gene. This genetic model exhibits crucial hallmarks of PD on the neuropathological, symptomatic and pharmacological level. Quantitative receptor autoradiography was used to characterize 19 different receptor binding sites in eleven brain regions in order to understand receptor changes on a systemic level. We demonstrated striking differential changes of neurotransmitter receptor densities for numerous receptor types and brain regions, respectively. Most prominent, a strong up-regulation of GABA receptors and associated benzodiazepine binding sites in different brain regions and concomitant down-regulations of striatal nicotinic acetylcholine and serotonergic receptor densities were found. Furthermore, the densities of glutamatergic kainate, muscarinic acetylcholine, adrenergic ?1 and dopaminergic D2/D3 receptors were differentially altered. These results present novel insights into the expression of neurotransmitter receptors in Pitx3(ak) mice supporting findings on PD pathology in patients and indicating on the possible underlying mechanisms. The data suggest Pitx3(ak) mice as an appropriate new model to investigate the role of neurotransmitter receptors in PD. Our study highlights the relevance of non-dopaminergic systems in PD and for the understanding of its molecular pathology. PMID:25451278

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

2015-01-29

108

Developmental Exposure to Fluoxetine Modulates the Serotonin System in Hypothalamus  

PubMed Central

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

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

2013-01-01

109

Wireless Instantaneous Neurotransmitter Concentration Sensing System (WINCS) for intraoperative neurochemical monitoring.  

PubMed

The Wireless Instantaneous Neurotransmitter Concentration Sensing System (WINCS) measures extracellular neurotransmitter concentration in vivo and displays the data graphically in nearly real time. WINCS implements two electroanalytical methods, fast-scan cyclic voltammetry (FSCV) and fixed-potential amperometry (FPA), to measure neurotransmitter concentrations at an electrochemical sensor, typically a carbon-fiber microelectrode. WINCS comprises a battery-powered patient module and a custom software application (WINCSware) running on a nearby personal computer. The patient module impresses upon the electrochemical sensor either a constant potential (for FPA) or a time-varying waveform (for FSCV). A transimpedance amplifier converts the resulting current to a signal that is digitized and transmitted to the base station via a Bluetooth radio link. WINCSware controls the operational parameters for FPA or FSCV, and records the transmitted data stream. Filtered data is displayed in various formats, including a background-subtracted plot of sequential FSCV scans - a representation that enables users to distinguish the signatures of various analytes with considerable specificity. Dopamine, glutamate, adenosine and serotonin were selected as analytes for test trials. Proof-of-principle tests included in vitro flow-injection measurements and in vivo measurements in rat and pig. Further testing demonstrated basic functionality in a 3-Tesla MRI unit. WINCS was designed in compliance with consensus standards for medical electrical device safety, and it is anticipated that its capability for real-time intraoperative monitoring of neurotransmitter release at an implanted sensor will prove useful for advancing functional neurosurgery. PMID:19963865

Kimble, Christopher J; Johnson, David M; Winter, Bruce A; Whitlock, Sidney V; Kressin, Kenneth R; Horne, April E; Robinson, Justin C; Bledsoe, Jonathan M; Tye, Susannah J; Chang, Su-Youne; Agnesi, Filippo; Griessenauer, Christoph J; Covey, Daniel; Shon, Young-Min; Bennet, Kevin E; Garris, Paul A; Lee, Kendall H

2009-01-01

110

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

PubMed

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

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

2015-06-01

111

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

PubMed

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

Pehek, E A; Hernan, A E

2015-04-01

112

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

PubMed Central

Monoamine releasers constitute one class of candidate medications for treatment of cocaine abuse, and concurrent cocaine-versus-food choice procedures are potentially valuable as experimental tools to evaluate the efficacy and safety of candidate medications. This study assessed choice between cocaine and food by rhesus monkeys during treatment with five monoamine releasers that varied in selectivity to promote release of dopamine and norepinephrine (DA/NE) vs. serotonin (5HT) [m-fluoroamphetamine, (+)-phenmetrazine, (+)-methamphetamine, napthylisopropylamine and (±)-fenfluramine]. Rhesus monkeys (n=8) responded under a concurrent-choice schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and cocaine injections (0 – 0.1 mg/kg/inj, fixed-ratio 10 schedule). Cocaine choice dose-effect curves were determined daily during continuous seven-day treatment with saline or each test compound dose. During saline treatment, cocaine maintained a dose-dependent increase in cocaine choice, and the highest cocaine doses (0.032 – 0.1 mg/kg/inj) maintained almost exclusive cocaine choice. Efficacy of monoamine releasers to decrease cocaine choice corresponded to their pharmacological selectivity to release DA/NE vs. 5HT. None of the releasers reduced cocaine choice or promoted reallocation of responding to food choice to the same extent as substituting saline for cocaine. These results extend the range of conditions across which DA/NE-selective releasers have been shown to reduce cocaine self-administration. PMID:22015808

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

2011-01-01

113

Dopamine transporters govern diurnal variation in extracellular dopamine tone  

PubMed Central

The majority of neurotransmitter systems shows variations in state-dependent cell firing rates that are mechanistically linked to variations in extracellular levels, or tone, of their respective neurotransmitter. Diurnal variation in dopamine tone has also been demonstrated within the striatum, but this neurotransmitter is unique, in that variation in dopamine tone is likely not related to dopamine cell firing; this is largely because of the observation that midbrain dopamine neurons do not display diurnal fluctuations in firing rates. Therefore, we conducted a systematic investigation of possible mechanisms for the variation in extracellular dopamine tone. Using microdialysis and fast-scan cyclic voltammetry in rats, as well as wild-type and dopamine transporter (DAT) knock-out mice, we demonstrate that dopamine uptake through the DAT and the magnitude of subsecond dopamine release is inversely related to the magnitude of extracellular dopamine tone. We investigated dopamine metabolism, uptake, release, D2 autoreceptor sensitivity, and tyrosine hydroxylase expression and activity as mechanisms for this variation. Using this approach, we have pinpointed the DAT as a critical governor of diurnal variation in extracellular dopamine tone and, as a consequence, influencing the magnitude of electrically stimulated dopamine release. Understanding diurnal variation in dopamine tone is critical for understanding and treating the multitude of psychiatric disorders that originate from perturbations of the dopamine system. PMID:24979798

Ferris, Mark J.; España, Rodrigo A.; Locke, Jason L.; Konstantopoulos, Joanne K.; Rose, Jamie H.; Chen, Rong; Jones, Sara R.

2014-01-01

114

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

SciTech Connect

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

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

1986-03-05

115

GABA Neurotransmitter  

NSDL National Science Digital Library

GABA occurs in 30-40% of all synapses-only glutamate is more widely distributed. Neurons in every region of the brain use GABA to fine-tune neurotransmission. Increasing GABA at the neuronal synapse inhibits the generation of the action potential of the neuron, thereby making it less likely to excite nearby neurons. A single neuron may have thousands of other neurons synapsing onto it. Some of these release activating (or depolarizing) neurotransmitters; others release inhibitory (or hyperpolarizing) neurotransmitters. GABA is the primary inhibitory neurotransmitter, which means it decreases the neuron's action potential. When the action potential drops below a certain level, known as the threshold potential, the neuron will not generate action potentials and thus not excite nearby neurons. The nucleus of a neuron is located in the cell body. Extending out from the cell body are dendrites and axons. Dendrites conduct impulses toward the cell body, Axons conducting impulses away from the cell body. A recording electrode has been attached to a voltmeter to record the charge across the cell membrane, the thin layer that controls movement in and out of the neuron. The resting potential in excitable neurons is usually around -65 to -70 millivolts (mV), which can be seen on the voltmeter. Excitatory synapses reduce the membrane potential: The synapses labeled A, B, and C are excitatory (e.g. glutamate ACH). These synapses release activating neurotransmitters, which reduce the resting potential of the neuron. If the voltage reaches the threshold potential, typically around -50 mv, an action potential is generated, which will travel down the axon, where it will communicate with a nearby cell. The strength of the stimuli that produce an action potential is important only insomuch as it reaches threshold potential. The resultant action potential is always the same, whether it was created by relatively strong or relatively weak stimuli. action potential is a constant. Decreasing the action potential: GABA is the primary inhibitory neurotransmitter, which means it decreases the neuron�s action potential. When the action potential drops below the threshold potential, the neuron will not excite nearby neurons. Exitatory PostSynaptic Potential (EPSP): The Exitatory PostSynaptic Potential (EPSP) of a single excitatory synapse is not sufficient to reach the threshold of the neuron. Rather, when a number of EPSPs are created in quick succession, their charges sum together. It is the combined sum of these EPSPs that creates an action potential Activation of inhibitory synapses such as GABA, on the other hand, makes resting potential more negative. This hyperpolarization is called an inhibitory postsynaptic potential (IPSP). Activation of inhibitory synapses (D and E) makes the resting potential of the neuron more negative. The resulting IPSP may also prevent what would otherwise have been effective EPSPs from triggering an action potential. It is the total summation of the EPSPs and IPSPs that determines whether a neuron�s charge is sufficient to cross the potential threshold.

2009-04-14

116

[Neurotransmitter disorders in children--special reference to Segawa disease].  

PubMed

Aminergic neurotransmitter disorders occurring in childhood include metabolic disorders of pteridine and tyrosine hydroxylase (TH). Pteridine metabolic disorders cause a deficiency of serotonin (5-HT) and dopamine (DA) and TH disorder causes a deficiency of noradrenaline (NA) and DA in the terminals of each aminergic neuron. The activities of TH or DA in the terminals are marked in early childhood, and then they show an exponential age-dependent decrement and achieve stationary or minimal levels in the twenties. As observed in Segawa disease, TH or DA activities in these disorders follow this age-related decrease with levels around 20% of normal, and patients develop symptoms age-dependently, with onset in childhood, progression by the late teens, and a stationary period after the twenties, but this does not cause morphological changes. These phenomena may occur with other neurotransmitters. So replacement therapies are effective irrespective of the clinical course. However, early-onset cases in infancy or early childhood showing a marked decrement of 5-HT or NA activities show postural hypotonia and failed locomotion. These cause failure in atonia restriction in the REM stage and induce dysfunction of the pedunculopontine nucleus, and, consequently induce dysfunction or failure in the development of DA neurons in the sutbstantia nigra and ventrotegmental area. These relate to failure in the development of higher cortical functions. Thus, assessing of ages at onset and activities of antigravity muscles and locomotion in infancy is cardinal for the treatment the neurotransmitter disorders occurring in infancy and early childhood. PARK2 with deficiency of DA in the substantia nigra leads to dystonia in the teens and Parkinson disease after 20 years, although these respond to 1-Dopa favorably but induce D2 receptor upregulation and intractable dyskinesia. A decrease of DA in the perikaryon leads to symptoms after 10 years and causes dysfunction of the target structures. PMID:21941841

Segawa, Masaya

2011-09-01

117

Why are neurotransmitters neurotoxic? An evolutionary perspective  

PubMed Central

In the CNS, minor changes in the concentration of neurotransmitters such as glutamate or dopamine can lead to neurodegenerative diseases. We present an evolutionary perspective on the function of neurotransmitter toxicity in the CNS. We hypothesize that neurotransmitters are selected because of their toxicity, which serves as a test of neuron quality and facilitates the selection of neuronal pathways. This perspective may offer additional explanations for the reduction of neurotransmitter concentration in the CNS with age, and suggest an additional role for the blood-brain barrier. It may also suggest a connection between the specific toxicity of the neurotransmitters released in a specific region of the CNS, and elucidate their role as chemicals that are optimal for testing the quality of cells in that region. PMID:25580225

Harris, Keith D.; Weiss, Meital; Zahavi, Amotz

2014-01-01

118

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

PubMed Central

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

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

2013-01-01

119

Dopamine D4 receptor (D4DR) and serotonin transporter promoter (5-HTTLPR) polymorphisms in the determination of temperament in 2-month-old infants.  

PubMed

We and others have previously shown that the dopamine D4 exon III repeat (D4DR) and the serotonin-transporter promoter region (5-HTTLPR) polymorphisms are not only associated with adult personality traits1-7 but also with temperament in 2-week-old neonates.8 We now report the results of a second study of these infants and their temperament at 2 months using Rothbart's Infant Behavior Questionnaire (IBQ).9 There were significant negative correlations between neonatal orientation and motor organization as measured by the Neonatal Behavioral Assessment Scale (NBAS)10 at 2 weeks and negative emotionality, especially distress in daily situations, at 2 months of age. There were significant main effects for negative emotionality and distress when the infants were grouped by the D4DR and the 5-HTTLPR polymorphisms. Infants with long D4DR alleles had significantly lower scores on Negative Emotionality (F[1, 72] = 8.50, P = 0.005) and Distress to Limitations (F[1,72] = 4.93, P = 0.03) than infants with short D4DR alleles. In contrast, infants with the short homozygous (s/s) 5-HTTLPR genotype had higher scores on Negative Emotionality (F[1,72] = 3.88, P = 0.053) and Distress to Limitations (F[1,72] = 4.94, P = 0.029) than infants with the I/s or I/I genotypes. The strongest effects occurred in those infants with the s/s 5-HTTLPR polymorphism who also were lacking long D4DR alleles which in some studies has been linked to adult novelty seeking.1,6 These infants showed most negative emotionality and most distress to daily situations, temperament traits that are perhaps the underpinning of adult neuroticism. PMID:10483054

Auerbach, J; Geller, V; Lezer, S; Shinwell, E; Belmaker, R H; Levine, J; Ebstein, R

1999-07-01

120

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

PubMed

The serotonin(2C) receptor (5-HT(2C)R) is known to control dopamine (DA) neuron function by modulating DA neuronal firing and DA exocytosis at terminals. Recent studies assessing the influence of 5-HT(2C)Rs on cocaine-induced neurochemical and behavioral responses have shown that 5-HT2CRs can also modulate mesoaccumbens DA pathway activity at post-synaptic level, by controlling DA transmission in the nucleus accumbens (NAc), independently of DA release itself. A similar mechanism has been proposed to occur at the level of the nigrostriatal DA system. Here, using in vivo microdialysis in freely moving rats and molecular approaches, we assessed this hypothesis by studying the influence of the 5-HT(2C)R agonist Ro 60-0175 on cocaine-induced responses in the striatum. The intraperitoneal (i.p.) administration of 1 mg/kg Ro 60-0175 had no effect on the increase in striatal DA outflow induced by cocaine (15 mg/kg, i.p.). Conversely, Ro 60-0175 inhibited cocaine-induced Fos immunoreactivity and phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine 75 residue in the striatum. Finally, the suppressant effect of Ro 60-0175 on cocaine-induced DARPP-32 phosphorylation was reversed by the selective 5-HT(2C)R antagonist SB 242084 (0.5 mg/kg, i.p.). In keeping with the key role of DARPP-32 in DA neurotransmission, our results demonstrate that 5-HT(2C)Rs are capable of modulating nigrostriatal DA pathway activity at post-synaptic level, by specifically controlling DA signaling in the striatum. PMID:25446572

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

2015-02-01

121

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

PubMed

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

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

2013-02-28

122

High-sensitive liquid chromatographic method for determination of neuronal release of serotonin, noradrenaline and dopamine monitored by microdialysis in the rat prefrontal cortex.  

PubMed

A high-sensitive liquid chromatographic method based on precolumn derivatization and fluorescence detection allowing simultaneous determination of serotonin (5-HT), noradrenaline (NA) and dopamine (DA) in brain microdialysis samples is described. 5-HT, NA and DA were derivatized with benzylamine and 1,2-diphenylethylenediamine in the presence of potassium hexacyanoferrate(III) and glycine, which yielded to highly fluorescent and stable benzoxazoles. The derivatized samples were separated on a microbore column (150 mm x 1.0mm i.d., packed with C18 silica, 5 microm) within 60 min. The mobile phase consisted of acetonitrile-Briton-Robinson buffer (pH 7.2) (32:68, v/v) containing 5 mM Na2EDTA and 5 mM octanesulfonic acid sodium salt. The detection limits (signal-to-noise ratio of 3) for 5-HT, NA and DA were 76, 42 and 95 amol/10 microl injected on-column, respectively. Microdialysis samples were collected at 10-min intervals from the probes implanted in the prefrontal cortex of awake rats. The basal levels of 5-HT, NA and DA were 7.3 +/- 0.7, 5.3 +/- 0.31 and 8.1 +/- 0.47 fmol/5 microl (mean +/- S.E.M., n = 5). Following 90-min perfusion with tetrodotoxin (1 microM) or calcium-free Ringer solution, the DA and NA levels were reduced to about 15 and 20%, respectively and the 5-HT levels to 45 and 60% of the basal levels, respectively. Reserpine, 12h after a dose of 5mg/kg i.p., reduced the extracellular 5-HT, NA and DA concentrations to about 34, 39 and 32% of the basal levels, respectively. In conclusion, the preset microdialysis/analytical method enables simultaneous monitoring of basal and pharmacologically reduced neuronal release of 5-HT, NA and DA in the rat brain. PMID:15589346

Yoshitake, Takashi; Yoshitake, Shimako; Fujino, Kaoru; Nohta, Hitoshi; Yamaguchi, Masatoshi; Kehr, Jan

2004-12-30

123

Inhibition of synaptosomal neurotransmitter uptake by hallucinogens.  

PubMed

The effect of 13 hallucinogens on the uptake of serotonin and norepinephrine into hippocampal synaptosomes and of serotonin and dopamine into caudate synaptosomes was found to be inhibitory, except for lysergic acid diethylamide and 2-bromolysergic acid diethylamide, which were inactive. The indolealkylamines were generally more potent than the phenylethylamines. The reported inhibition of uptake of serotonin by 5-methoxy-N,N-dimethyltryptamine and lysergic acid diethylamide into whole brain synaptosomes was not reproducible at concentrations 10(2) to 10(4) times higher than those stated in the literature. PMID:6131933

Whipple, M R; Reinecke, M G; Gage, F H

1983-04-01

124

Classical Neurotransmitters and their Significance within the Nervous System.  

ERIC Educational Resources Information Center

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

Veca, A.; Dreisbach, J. H.

1988-01-01

125

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

PubMed

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

Mithila, M V; Khanum, Farhath

2014-09-01

126

Increased accumbal dopamine during daily alcohol consumption and subsequent aggressive behavior in rats  

Microsoft Academic Search

Background  Alcohol drinking may lead to increased aggression in certain individuals, and both fighting and drinking increase levels of\\u000a dopamine and serotonin in mesocorticolimbic structures. Assessing the dynamic changes in these neurotransmitters during the\\u000a course of drinking and fighting has remained challenging.\\u000a \\u000a \\u000a \\u000a Objective  The objective of the study was to learn about ongoing monoaminergic activity in the nucleus accumbens of rats that

Annemoon M. M. van Erp; Klaus A. Miczek

2007-01-01

127

Neurotransmitters - Duration: 20 seconds.  

NASA Video Gallery

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

128

Positron Emission Tomography (PET) and Graphical Kinetic Data Analysis of the Dopamine Neurotransmitter System: An Exercise for an Undergraduate Laboratory Course.  

PubMed

Neuroimaging techniques, including positron emission tomography (PET), are widely used in clinical settings and in basic neuroscience research. Education in these methods and their applications may be incorporated into curricula to keep pace with this expanding field. Here, we have developed pedagogical materials on the fundamental principles of PET that incorporate a hands-on laboratory activity to view and analyze human brain scans. In this activity, students will use authentic PET brain scans generated from original research at Brookhaven National Laboratory (Volkow et al., 2009) to explore the neurobiological effects of a drug on the dopamine system. We provide lecture and assignment materials (including a 50-minute PowerPoint presentation introducing PET concepts), written background information for students and instructors, and explicit instructions for a 4-hour, computer-based laboratory to interested educators. Also, we discuss our experience implementing this exercise as part of an advanced undergraduate laboratory course at Stony Brook University in 2010 and 2011. Observing the living human brain is intriguing, and this laboratory is designed to illustrate how PET neuroimaging techniques are used to directly probe biological processes occurring in the living brain. Laboratory course modules on imaging techniques such as PET can pique the interest of students potentially interested in neuroscience careers, by exposing them to current research methods. This activity provides practical experience analyzing PET data using a graphical analysis method known as the Logan plot, and applies core neuropharmacology concepts. We hope that this manuscript inspires college instructors to incorporate education in PET neuroimaging into their courses. PMID:24693258

Mirrione, Martine M; Ruth, Nora; Alexoff, David; Logan, Jean; Fowler, Joanna; Kernan, Maurice

2014-01-01

129

Positron Emission Tomography (PET) and Graphical Kinetic Data Analysis of the Dopamine Neurotransmitter System: An Exercise for an Undergraduate Laboratory Course  

PubMed Central

Neuroimaging techniques, including positron emission tomography (PET), are widely used in clinical settings and in basic neuroscience research. Education in these methods and their applications may be incorporated into curricula to keep pace with this expanding field. Here, we have developed pedagogical materials on the fundamental principles of PET that incorporate a hands-on laboratory activity to view and analyze human brain scans. In this activity, students will use authentic PET brain scans generated from original research at Brookhaven National Laboratory (Volkow et al., 2009) to explore the neurobiological effects of a drug on the dopamine system. We provide lecture and assignment materials (including a 50-minute PowerPoint presentation introducing PET concepts), written background information for students and instructors, and explicit instructions for a 4-hour, computer-based laboratory to interested educators. Also, we discuss our experience implementing this exercise as part of an advanced undergraduate laboratory course at Stony Brook University in 2010 and 2011. Observing the living human brain is intriguing, and this laboratory is designed to illustrate how PET neuroimaging techniques are used to directly probe biological processes occurring in the living brain. Laboratory course modules on imaging techniques such as PET can pique the interest of students potentially interested in neuroscience careers, by exposing them to current research methods. This activity provides practical experience analyzing PET data using a graphical analysis method known as the Logan plot, and applies core neuropharmacology concepts. We hope that this manuscript inspires college instructors to incorporate education in PET neuroimaging into their courses. PMID:24693258

Mirrione, Martine M.; Ruth, Nora; Alexoff, David; Logan, Jean; Fowler, Joanna; Kernan, Maurice

2014-01-01

130

Receptors and Other Signaling Proteins Required for Serotonin Control of Locomotion in Caenorhabditis elegans  

E-print Network

A better understanding of the molecular mechanisms of signaling by the neurotransmitter serotonin is required to assess the hypothesis that defects in serotonin signaling underlie depression in humans. Caenorhabditis elegans ...

Gustafson, Megan A.

131

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

SciTech Connect

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

Mulholland, G.K.; Zheng, Q.H.; Zhou, F.C. [Indiana Univ. Medical Center, Indianapolis, IN (United States)] [and others

1996-05-01

132

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

PubMed

d-Amphetamine selectively promotes release of both dopamine (DA) and norepinephrine (NE) versus serotonin (5HT), and chronic d-amphetamine treatment decreases cocaine-taking behavior in rats, nonhuman primates, and humans. However, abuse liability limits the clinical utility of amphetamine maintenance for treating cocaine abuse. One strategy to improve safety and efficacy of monoamine releasers as candidate anticocaine medications has been to develop dual DA/5HT releasers like 1-napthyl-2-aminopropane (PAL-287), but the pharmacology of this class of compounds has not been extensively examined. In particular, PAL-287 has similar potencies to release DA, 5HT, and NE, and the role of manipulating NE release potency on abuse-related or anticocaine effects of dual DA/5HT releasers is not known. To address this issue, the present study compared effects of four novel DA/5HT releasers that varied >800-fold in their selectivities to release DA/5HT versus NE: [1-(5-chloro-1H-indol-3-yl)propan-2-amine (PAL-542), 1-(5-fluoro-1H-indol-3-yl)propan-2-amine (PAL-544), 1-(1H-indol-5-yl)propan-2-amine (PAL-571), and (R)-1-(1H-indol-1-yl)propain-2-amine (PAL-569). Abuse-related effects of all four compounds were evaluated in assays of intracranial self-stimulation (ICSS) in rats and cocaine discrimination in rats and monkeys, and none of the compounds reliably facilitated ICSS or substituted for cocaine. Anticocaine effects of the compound with highest selectivity to release DA/5HT versus NE (PAL-542) were tested in an assay of cocaine versus food choice in rhesus monkeys, and PAL-542 failed to reduce cocaine choice. These results suggests that potency to release NE has minimal influence on abuse liability of dual DA/5HT releasers, and reducing relative potency to release NE versus DA/5HT does not improve anticocaine efficacy. PMID:24796848

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

2014-06-01

133

Analysis of serum levels of cytokines, chemokines, growth factors, and monoamine neurotransmitters in patients with tick-borne encephalitis: Identification of novel inflammatory markers with implications for pathogenesis.  

PubMed

Tick-borne encephalitis (TBE) is a leading human neuroinfection in Europe and northeastern Asia. However, the pathophysiology of TBE is not understood completely. This study sought to determine the specific serum mediators that are associated with acute TBE. The levels of 30 cytokines, chemokines, and growth factors were measured in serum samples from 87 patients with clinically and serologically confirmed acute TBE and from 32 control subjects using the Cytokine Human Magnetic 30-Plex Panel for the Luminex platform. Serum levels of the monoamine neurotransmitters serotonin, dopamine, and noradrenaline were measured via enzyme-linked immunosorbent assay. TBE virus infection elicited increased levels of the pro-inflammatory cytokines interleukin (IL)-6, IL-8, and IL-12. TBE patients had higher IL-12:IL-4 and IL-12:IL-10 ratios than control patients, reflecting the global pro-inflammatory cytokine balance. Serum levels of the monoamine neurotransmitters serotonin, dopamine, and noradrenaline were significantly lower in TBE patients than in the control group. Most interestingly, increased levels of hepatocyte growth factor and vascular endothelial growth factor were observed in TBE patients; these proteins may be novel and mechanistically important inflammatory biomarkers of TBE. J. Med. Virol. 87:885-892, 2015. © 2015 Wiley Periodicals, Inc. PMID:25675945

Palus, Martin; Formanová, Petra; Salát, Ji?í; Žampachová, Eva; Elsterová, Jana; R?žek, Daniel

2015-05-01

134

Polymelamine modified edge plane pyrolytic graphite sensor for the electrochemical assay of serotonin.  

PubMed

A sensitive and novel electrochemical method has been developed for the determination of an important neurotransmitter, serotonin, using a polymelamine modified edge plane pyrolytic graphite sensor (EPPGS). Melamine was used for the modification of sensor by electropolymerizing it at the surface of EPPGS in acidic medium to form a layer of conducting polymer. Field emission scanning electron microscopy (FE-SEM) and electrochemical impedance spectroscopy (EIS) were used for the characterization of the surface of polymer modified sensor. The electrochemical measurements were carried out using square wave voltammetry and cyclic voltammetry. The polymelamine modified sensor exhibited excellent electrocatalytic activity towards the electrochemical oxidation of serotonin, exhibiting a larger peak current and shift of peak potential to less positive potentials as compared to the unmodified sensor. The dynamic range for the serotonin determination was found between 1-100 µm and 0.1-100 µm with detection limit of 492 nM and 30 nM for unmodified and polymer modified sensors, respectively. The determination of serotonin in human blood serum and urine has been carried out. The common metabolites such as ascorbic acid, dopamine, xanthine and hypoxanthine do not interfere in the determination up to 10-fold concentration, revealing good selectivity of the proposed sensor. PMID:24468336

Gupta, Pankaj; Goyal, Rajendra N

2014-03-01

135

Structure-activity relationship studies of novel 4-[2-[bis(4-fluorophenyl)methoxy]ethyl]-1-(3-phenylpropyl)piperidine analogs: synthesis and biological evaluation at the dopamine and serotonin transporter sites.  

PubMed

Several analogs of the potent dopamine (DA) transporter ligand 4-[2-[bis(4-fluorophenyl)-methoxy]ethyl]-1-(3-phenylpropyl)piperidine, 1b, were made and biologically evaluated for their binding at the DA and serotonin (5HT) transporters in rat striatal membranes. Different alkyl chain lengths and substitutions were introduced in these molecules to generate an optimum activity and selectivity for the DA transporter. In general, unsubstituted and fluoro-substituted compounds were the most active and selective for the DA transporter. The compound 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine, 9a, showed high potency and was the most selective for the DA transporter (5HT/DA = 49) in this series of compounds. Some of these novel analogs were found to be more selective in binding at the DA transporter than the original GBR 12909 molecule, 1-[2-]bis(4-fluorophenyl)methoxy]ethyl]-4-(3- phenylpropyl)piperidine. PMID:8576918

Dutta, A K; Xu, C; Reith, M E

1996-02-01

136

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

PubMed

Olfaction plays an important role in emotions in our daily life. Pleasant odors are known to evoke positive emotions, inducing relaxation and calmness. The beneficial effects of vanillin on depressive model rats were investigated using a combination of behavioral assessments and neurotransmitter measurements. Before and after chronic stress condition (or olfactory bulbectomy), and at the end of vanillin or fluoxetine treatment, body weight, immobility time on the forced swimming test and sucrose consumption in the sucrose consumption test were measured. Changes in these assessments revealed the characteristic phenotypes of depression in rats. Neurotransmitters were measured using ultrahigh-performance liquid chromatography. Our results indicated that vanillin could alleviate depressive symptoms in the rat model of chronic depression via the olfactory pathway. Preliminary analysis of the monoamine neurotransmitters revealed that vanillin elevated both serotonin and dopamine levels in brain tissue. These results provide important mechanistic insights into the protective effect of vanillin against chronic depressive disorder via olfactory pathway. This suggests that vanillin may be a potential pharmacological agent for the treatment of major depressive disorder. PMID:25595338

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

2015-02-28

137

Abnormalities of neurotransmitter and neuropeptide systems in human neuroepithelioma cells infected by three Toxoplasma strains  

PubMed Central

Since Toxoplasma gondii can establish a persistent infection in the central nervous system in humans, we studied its effects on a host's neurotransmitter and neuropeptide systems (NNS). Using microarray technology we have screened the expression of genes coding for NNS in human neuroepithelioma cells in response to representative strains of Toxoplasma to identify potential target genes. Transcripts that displayed expression levels distinct from uninfected controls were examined by RT-PCR and Western blot. Our results indicate the presence of disturbed NNS upon Toxoplasma infection and the extent of this disturbance varies considerably among the three strains. In cells infected by type I strain, three neurotransmitter systems (dopamine, glutamate and serotonin) and two neuropeptides (PROK2 and TAC1) displayed abnormalities relative to controls. Type III infection led to the change of a critical enzyme, TDO2, in the kynurenine pathway. No significant effects of type II infection were found in the NNS. These data may have implications for understanding the pathogenesis and heterogeneity of neurologic disturbances in toxoplasmosis. PMID:23821371

Xiao, Jianchun; Li, Ye; Jones-Brando, Lorraine; Yolken, Robert H.

2014-01-01

138

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

PubMed Central

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 L-tryptophan (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 NAc and open-field behaviors and (c) ketanserin inhibits 5-HT release in NAc and open-field behaviors produced by caffeine, but, surprisingly, acts to increase DA release in NAc. Importantly, the latter effect may be a possible adverse effect of the moderate dose of caffeine in hypertensive patients. Thus, an antihypertensive medication is shown here to play a role in inhibiting brain reward possibly via antihypertensive mechanisms at DA and 5-HT receptor subtypes within DA motor neurons. An explanatory note for the results obtained, is the role likely played by the G Protein Receptor Complex (GPRC) family of proteins. Empirical evidence shows that GPRC dimers, heteromers and heterotrimers may cause cross-talk between distinct signalling cascade pathways in the actions of cocaine and caffeine. Ligand-directed functional selectivity, particularly for ketanserin, in addition to GPRCs, may also cause differential responses. The results promise new therapeutic strategies for drug addiction, brain reward and cardiovascular medicine.

Broderick, Patricia A.; Ho, Helen; Wat, Karyn; Murthy, Vivek

2008-01-01

139

Hepatic fibrogenesis requires sympathetic neurotransmitters  

PubMed Central

Background and aims: Hepatic stellate cells (HSC) are activated by liver injury to become proliferative fibrogenic myofibroblasts. This process may be regulated by the sympathetic nervous system (SNS) but the mechanisms involved are unclear. Methods: We studied cultured HSC and intact mice with liver injury to test the hypothesis that HSC respond to and produce SNS neurotransmitters to promote fibrogenesis. Results: HSC expressed adrenoceptors, catecholamine biosynthetic enzymes, released norepinephrine (NE), and were growth inhibited by ?- and ?-adrenoceptor antagonists. HSC from dopamine ?-hydroxylase deficient (Dbh?/?) mice, which cannot make NE, grew poorly in culture and were rescued by NE. Inhibitor studies demonstrated that this effect was mediated via G protein coupled adrenoceptors, mitogen activated kinases, and phosphatidylinositol 3-kinase. Injury related fibrogenic responses were inhibited in Dbh?/? mice, as evidenced by reduced hepatic accumulation of ?-smooth muscle actin+ve HSC and decreased induction of transforming growth factor ?1 (TGF-?1) and collagen. Treatment with isoprenaline rescued HSC activation. HSC were also reduced in leptin deficient ob/ob mice which have reduced NE levels and are resistant to hepatic fibrosis. Treating ob/ob mice with NE induced HSC proliferation, upregulated hepatic TGF-?1 and collagen, and increased liver fibrosis. Conclusions: HSC are hepatic neuroglia that produce and respond to SNS neurotransmitters to promote hepatic fibrosis. PMID:14960531

Oben, J A; Roskams, T; Yang, S; Lin, H; Sinelli, N; Torbenson, M; Smedh, U; Moran, T H; Li, Z; Huang, J; Thomas, S A; Diehl, A M

2004-01-01

140

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

PubMed

Ichthyophis kohtaoensis, a member of the limbless Gymnophiona, has a specialized subterranean burrowing mode of life and a predominantly olfactory-guided orientation. The only visually guided behavior seems to be negative phototaxis. As these animals possess extremely small eyes (only 540 microm in diameter in adults), functional investigations of single retinal cells by electrophysiological methods have so far failed. Therefore, the content and distribution of retinal transmitters have been investigated as indications of a functioning sense organ in an animal that is supposed to be blind. Previous immunohistochemical investigation of the retinal transmitter system revealed immunoreactivity for gamma-aminobutyric acid (GABA), serotonin, dopamine and tyrosine hydroxylase, the rate-limiting enzyme in the catecholamine synthetic pathway. The present studies have been performed in order to determine a possible colocalization of serotonin and GABA in retinal neurons of the caecilian retina. Therefore retinal cryostat sections of various developmental stages have been investigated by the indirect fluorescence method. In single-label preparations, serotonin is localized to cells in the inner nuclear layer and the ganglion cell layer. GABA immunocytochemistry labels a variety of cell types in the inner nuclear layer as well as cell bodies in the ganglion cell layer. In double-label preparations, some of the serotonergic cells are found to express GABA immunoreactivity and some GABAergic neurons also label for serotonin immunocytochemistry. Thus, despite the fact that caecilians mainly rely on olfaction and are believed to have a reduced visual system, their retina exhibits a surprisingly "normal" distribution of neurotransmitters and neuromodulators, also typical of other anamniotes with a well-developed visual system, including the partial colocalization of serotonin and GABA at all developmental stages of I. kohtaoensis. These results indicate that a functional system that is under no strong selective pressure obviously has a long evolutionary persistence irrespective of its need for use. PMID:9462859

Dünker, N

1998-01-01

141

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

PubMed

Monoamine transporters have been implicated in dopamine or serotonin release in response to abused drugs such as methamphetamine or ecstasy (MDMA). In addition, monoamine transporters show substrate-induced inward currents that may modulate excitability and Ca(2+) mobilization, which could also contribute to neurotransmitter release. How monoamine transporters modulate Ca(2+) permeability is currently unknown. We investigate the functional interaction between the human serotonin transporter (hSERT) and voltage-gated Ca(2+) channels (CaV). We introduce an excitable expression system consisting of cultured muscle cells genetically engineered to express hSERT. Both 5HT and S(+)MDMA depolarize these cells and activate the excitation-contraction (EC)-coupling mechanism. However, hSERT substrates fail to activate EC-coupling in CaV1.1-null muscle cells, thus implicating Ca(2+) channels. CaV1.3 and CaV2.2 channels are natively expressed in neurons. When these channels are co-expressed with hSERT in HEK293T cells, only cells expressing the lower-threshold L-type CaV1.3 channel show Ca(2+) transients evoked by 5HT or S(+)MDMA. In addition, the electrical coupling between hSERT and CaV1.3 takes place at physiological 5HT concentrations. The electrical coupling between monoamine neurotransmitter transporters and Ca(2+) channels such as CaV1.3 is a novel mechanism by which endogenous substrates (neurotransmitters) or exogenous substrates (like ecstasy) could modulate Ca(2+)-driven signals in excitable cells. PMID:24854234

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

2014-07-01

142

Further structural optimization of cis-(6-benzhydryl-piperidin-3-yl)-benzylamine and 1,4-diazabicyclo[3.3.1]nonane derivatives by introducing an exocyclic hydroxyl group: Interaction with dopamine, serotonin and norepinephrine transporters  

PubMed Central

Our earlier effort to develop constrained analogues of flexible piperidine analogs for monoamine transporters led to the development of a series of 3,6-disubstituted piperidine derivatives, and a series of 4,8-disubstituted 1,4-diazabicyclo[3.3.1]nonane derivatives. In further structure-activity relationship (SAR) studies on these constrained derivatives, several novel analogues were developed where an exocyclic hydroxyl group was introduced on the N-alkyl-aryl side chain. All synthesized derivatives were tested for their affinities for the dopamine transporter (DAT), serotonin (5-HT) transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in inhibiting the uptake of [3H]DA, [3H]5-HT, and [3H]NE, respectively. Compounds were also tested for their binding potency at the DAT by their ability to inhibit binding of [3H]WIN 35,428. The results indicated that position of the hydroxyl group on the N-alkyl side chain is important along with the length of the side chain. In general, hydroxyl derivatives derived from more constrained bicyclic diamines exhibited greater selectivity for interaction with DAT compared to the corresponding 3,6-disubstituted diamines. In the current series of molecules, compound 11b with N-propyl side chain with the hydroxyl group attached in the benzylic position was the most potent and selective for DAT (Ki = 8.63 nM; SERT/DAT = 172 and NET/DAT = 48.4). PMID:18249549

Mishra, Manoj; Kolhatkar, Rohit; Zhen, Juan; Parrington, Ingrid; Reith, Maarten E. A.; Dutta, Aloke K.

2008-01-01

143

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

SciTech Connect

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

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

1988-01-01

144

THE ROLE OF NEUROTRANSMITTERS IN ALCOHOL DEPENDENCE: ANIMAL RESEARCH  

Microsoft Academic Search

Abstract — Animal studies have demonstrated,that alcohol changes neurotransrrutter concentrations in the brain. These changes in levels of dopamine, serotonin, ^aminobutync acid (GABA), endogenous opioid peptides, and noradrcnaline are associated with activation of reward centres in the brain. It is this property of alcohol that is believed to be responsible for the reinforcing effect of alcohol consumption in rats. One

Philippe De Witte

145

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

PubMed

Antidepressants that enter receiving waters through final treated wastewater effluent have exhibited relatively low acute toxicity in traditional fish tests at currently measured concentrations. However, the psychotropic mode of action of these compounds warrants examination of the behavioral effects these chemicals may have on aquatic organisms. Previous research has demonstrated that exposure to the antidepressant fluoxetine causes decreased brain serotonin levels in fish and results in a decreased ability to capture prey. Another antidepressant, venlafaxine, has been found at low ?g/L concentrations in final treated wastewater effluent. The objective of this study was to quantify the effects of venlafaxine on fish predation behavior and determine if this effect was correlated with changes in brain neurotransmitter concentrations. The predator prey bioassay used hybrid striped bass (Morone saxatilis x Morone chrysops) as the predator and fathead minnows (Pimephales promelas) as prey. Bass were exposed to venlafaxine (0-500 ?g/L) for a period of 6 days and then allowed to recover for 6 days. During both exposure and recovery, bass were fed four minnows every third day. The time to capture the minnows was quantified and compared among treatments to determine if there was an effect on predation behavior. Brain tissue was analyzed for serotonin, norepinephrine, and dopamine, to determine the relationship between exposure concentration, brain monoamine levels, and predation behavior. Results indicated that venlafaxine exposures increased time to capture prey 1 and 2 by day 6 for the 250 and 500 ?g/L treatments. Time to capture prey 3 was increased for all venlafaxine treatments by day 6. Venlafaxine caused a statistically significant decrease in brain serotonin concentrations that initially decreased in a dose dependent manner before reaching a steady state by the end of exposures for all treatments. No significant, dose-dependent changes in dopamine or norepinephrine were seen. Brain serotonin alone did not adequately explain behavioral results. Serotonin response in other tissues as well as peripheral effects may have accounted for additional behavioral responses after brain serotonin reached a depressed steady state. PMID:24679646

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

2014-06-01

146

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

PubMed

Antidepressants that enter receiving waters through final treated wastewater effluent have exhibited relatively low acute toxicity in traditional fish tests at currently measured concentrations. However, the psychotropic mode of action of these compounds warrants examination of the behavioral effects these chemicals may have on aquatic organisms. Previous research has demonstrated that exposure to the antidepressant fluoxetine causes decreased brain serotonin levels in fish and results in a decreased ability to capture prey. Another antidepressant, venlafaxine, has been found at low ?g/L concentrations in final treated wastewater effluent. The objective of this study was to quantify the effects of venlafaxine on fish predation behavior and determine if this effect was correlated with changes in brain neurotransmitter concentrations. The predator prey bioassay used hybrid striped bass (Morone saxatilis x Morone chrysops) as the predator and fathead minnows (Pimephales promelas) as prey. Bass were exposed to venlafaxine (0-500 ?g/L) for a period of 6 days and then allowed to recover for 6 days. During both exposure and recovery, bass were fed four minnows every third day. The time to capture the minnows was quantified and compared among treatments to determine if there was an effect on predation behavior. Brain tissue was analyzed for serotonin, norepinephrine, and dopamine, to determine the relationship between exposure concentration, brain monoamine levels, and predation behavior. Results indicated that venlafaxine exposures increased time to capture prey 1 and 2 by day 6 for the 250 and 500 ?g/L treatments. Time to capture prey 3 was increased for all venlafaxine treatments by day 6. Venlafaxine caused a statistically significant decrease in brain serotonin concentrations that initially decreased in a dose dependent manner before reaching a steady state by the end of exposures for all treatments. No significant, dose-dependent changes in dopamine or norepinephrine were seen. Brain serotonin alone did not adequately explain behavioral results. Serotonin response in other tissues as well as peripheral effects may have accounted for additional behavioral responses after brain serotonin reached a depressed steady state. PMID:24486880

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

2014-03-01

147

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

PubMed

Understanding the impact of pesticides in amphibians is of growing concern to assess the causes of their decline. Among pesticides, endosulfan belongs to one of the potential sources of danger because of its wide use and known effects, particularly neurotoxic, on a variety of organisms. However, the effect of endosulfan was not yet evaluated on amphibians at levels encompassing simultaneously brain neurotransmitters and behavioural endpoints. In this context, tadpoles of the African clawed frog Xenopus laevis were submitted to four treatments during 27 d: one control, one ethanol control, and two low environmental concentrations of endosulfan (0.1 and 1 ?g L(-1)). Endosulfan induced a significant increase of brain serotonin level at both concentrations and a significant increase of brain dopamine and GABA levels at the lower exposure but acetylcholinesterase activity was not modified by the treatment. The gene coding for the GABA transporter 1 was up-regulated in endosulfan contaminated tadpoles while the expression of other genes coding for the neurotransmitter receptors or for the enzymes involved in their metabolic pathways was not significantly modified by endosulfan exposure. Endosulfan also affected foraging, and locomotion in links with the results of the physiological assays, but no effects were seen on growth. These results show that low environmental concentrations of endosulfan can induce adverse responses in X. laevis tadpoles. At a broader perspective, this suggests that more research using and linking multiple markers should be used to understand the complex mode of action of pollutants. PMID:25192837

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

2015-02-01

148

RNA Editing of Neurotransmitter Receptors in the Mammalian Brain  

NSDL National Science Digital Library

RNA editing refers to various posttranscriptional mechanisms that alter the nucleotide sequence of RNA. In the mammalian brain, RNA editing results in significant changes in the functional properties of receptors for the important neurotransmitters glutamate and serotonin. These changes result from site-specific deamination of single adenosines in the pre-messenger RNA encoding these receptors. Here, we review what is known about the mechanisms underlying this editing, the consequences of RNA editing for glutamate and serotonin receptor function, and recent studies on transgenic mice and human post-mortem tissue that have begun to elucidate the role of RNA editing in the intact mammalian brain.

Claudia Schmauss (Columbia University College of Physicians and Surgeons and New York State Psychiatric Institute; Department of Psychiatry REV)

2002-05-21

149

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

PubMed

In the present study we found that repeated co-treatment with fluoxetine and amantadine for 14 days (but not for 7 days) enhanced the hyperactivity induced by amphetamine or quinpirole (a dopamine D(2/3) agonist), compared to treatment with either drug alone. Whereas repeated co-treatment with fluoxetine and amantadine for 7 days more potently inhibited the behavioral syndrome evoked by the 5-hydroxytryptamine (5-HT)(1A) receptor agonist (+/-)-8-hydroxy-2(di-n-propylamino)-tetralin hydrobromide (8-OH-DPAT), it did not change the action of the 5-HT(2) receptor agonist (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (/+/-/-DOI). The obtained results support the hypothesis that repeated co-treatment with fluoxetine and amantadine may evoke more effective antidepressant activity than treatment with fluoxetine alone. Moreover, our results suggest that 5-HT(1A) receptors are useful targets for the development of more rapidly acting and more effective medication. PMID:19904017

Rogóz, Zofia; Skuza, Grazyna

2009-01-01

150

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

PubMed Central

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

Barth, Claudia; Villringer, Arno; Sacher, Julia

2015-01-01

151

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

PubMed Central

Object Emerging evidence supports the hypothesis that modulation of specific central neuronal systems contributes to the clinical efficacy of deep brain stimulation (DBS) and motor cortex stimulation (MCS). Real-time monitoring of the neurochemical output of targeted regions may therefore advance functional neurosurgery by, among other goals, providing a strategy for investigation of mechanisms, identification of new candidate neurotransmitters, and chemically guided placement of the stimulating electrode. The authors report the development of a device called the Wireless Instantaneous Neurotransmitter Concentration System (WINCS) for intraoperative neurochemical monitoring during functional neurosurgery. This device supports fast-scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM) for real-time, spatially and chemically resolved neurotransmitter measurements in the brain. Methods The FSCV study consisted of a triangle wave scanned between ?0.4 and 1 V at a rate of 300 V/second and applied at 10 Hz. All voltages were compared with an Ag/AgCl reference electrode. The CFM was constructed by aspirating a single carbon fiber (r = 2.5 ?m) into a glass capillary and pulling the capillary to a microscopic tip by using a pipette puller. The exposed carbon fiber (that is, the sensing region) extended beyond the glass insulation by ~ 100 ?m. The neurotransmitter dopamine was selected as the analyte for most trials. Proof-of-principle tests included in vitro flow injection and noise analysis, and in vivo measurements in urethane-anesthetized rats by monitoring dopamine release in the striatum following high-frequency electrical stimulation of the medial forebrain bundle. Direct comparisons were made to a conventional hardwired system. Results The WINCS, designed in compliance with FDA-recognized consensus standards for medical electrical device safety, consisted of 4 modules: 1) front-end analog circuit for FSCV (that is, current-to-voltage transducer); 2) Bluetooth transceiver; 3) microprocessor; and 4) direct-current battery. A Windows-XP laptop computer running custom software and equipped with a Universal Serial Bus–connected Bluetooth transceiver served as the base station. Computer software directed wireless data acquisition at 100 kilosamples/second and remote control of FSCV operation and adjustable waveform parameters. The WINCS provided reliable, high-fidelity measurements of dopamine and other neurochemicals such as serotonin, norepinephrine, and ascorbic acid by using FSCV at CFM and by flow injection analysis. In rats, the WINCS detected subsecond striatal dopamine release at the implanted sensor during high-frequency stimulation of ascending dopaminergic fibers. Overall, in vitro and in vivo testing demonstrated comparable signals to a conventional hardwired electrochemical system for FSCV. Importantly, the WINCS reduced susceptibility to electromagnetic noise typically found in an operating room setting. Conclusions Taken together, these results demonstrate that the WINCS is well suited for intraoperative neurochemical monitoring. It is anticipated that neurotransmitter measurements at an implanted chemical sensor will prove useful for advancing functional neurosurgery. PMID:19425890

Bledsoe, Jonathan M.; Kimble, Christopher J.; Covey, Daniel P.; Blaha, Charles D.; Agnesi, Filippo; Mohseni, Pedram; Whitlock, Sidney; Johnson, David M.; Horne, April; Bennet, Kevin E.; Lee, Kendall H.; Garris, Paul A.

2009-01-01

152

The antimalarial drug quinine interferes with serotonin biosynthesis and action  

PubMed Central

The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor of the neurotransmitter serotonin (5-HT), here we test the hypothesis that quinine disrupts serotonin function. Quinine inhibited serotonin-induced proliferation of yeast as well as human (SHSY5Y) cells. One possible cause of this effect is through inhibition of 5-HT receptor activation by quinine, as we observed here. Furthermore, cells exhibited marked decreases in serotonin production during incubation with quinine. By assaying activity and kinetics of the rate-limiting enzyme for serotonin biosynthesis, tryptophan hydroxylase (TPH2), we showed that quinine competitively inhibits TPH2 in the presence of the substrate tryptophan. The study shows that quinine disrupts both serotonin biosynthesis and function, giving important new insight to the action of quinine on mammalian cells. PMID:24402577

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

2014-01-01

153

Chromosome 11: gene for dopamine receptors, Matt RidleySite: DNA Interactive (www.dnai.org)  

NSDL National Science Digital Library

Interviewee: Matt Ridley DNAi Location:Genome>tour>genome spots>Dopamine receptor Location: chromosome 11 gene name: D4DR (dopamine receptor) This gene on chromosome 11 appears to influence personality. The protein produced from this gene is a receptor for the neurotransmitter dopamine. Dopamine pathways control many aspects of the brain, including blood flow. If this gene contains many repeated sequences the person is less responsive to dopamine and more likely to seek external "thrills" in their lives.

2008-10-06

154

Genes Affecting Sensitivity to Serotonin in Caenorhabditis Elegans  

PubMed Central

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

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

1996-01-01

155

Neurotransmitters of cephalopods  

Microsoft Academic Search

ACh, dopamine, noradrenaline, 5-HT, I_-glutamate, and GABA are widely distributed in cephalopods and probably all function as neurotransrnitters; octopamine also occurs and at one site is known to act as a neuromodulator. 2. Several peptides are also present, as well as nitric oxide synthase. 3. in the brain and sense organs cholinergic, aminergic, serotonergic and glutamatergic systems seem to be

J. B. Messenger

1996-01-01

156

Synergistic dopamine increase in the rat prefrontal cortex with the combination of quetiapine and fluvoxamine  

Microsoft Academic Search

Rationale The combination of atypical antipsychotic drugs in addition to serotonin reuptake inhibitors has recently proven to be beneficial in a number of neuropsychiatric disorders, such as major depression, schizophrenia, and obsessive–compulsive disorder. Objectives To investigate the effects of an atypical antipsychotic drug in combination with a serotonin reuptake inhibitor on extracellular serotonin [5-HT] ex, and dopamine levels [DA] ex

Damiaan Denys; André A. Klompmakers; Herman G. M. Westenberg

2004-01-01

157

Determination of serotonin, noradrenaline, dopamine and their metabolites in rat brain extracts and microdialysis samples by column liquid chromatography with fluorescence detection following derivatization with benzylamine and 1,2-diphenylethylenediamine.  

PubMed

A highly selective and sensitive column liquid chromatographic method for fluorescence determination of serotonin (5-HT), dopamine (DA), noradrenaline (NA) and their related metabolites 5-hydroxyindole-3-acetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC) following derivatization with benzylamine and 1,2-diphenylethylenediamine (DPE) is described. The monoamines and the metabolites (20 microl samples) were derivatized in a two-step reaction, initiated with 20 microl of 0.3M benzylamine in 0.3M 3-cyclohexylaminopropanesulfonic acid (CAPS) buffer (pH 10.0), (for 5-HT, 5-HIAA, 2 min, 24 degrees C) and followed by 20 microl of 0.1M DPE in 0.3M glycine buffer (pH 10.0), (for DA, NA, DOPAC, 20 min, 50 degrees C). Both reagents contained 0.02 M potassium hexacyanoferrate(III) and 50% (v/v) methanol. The resulting highly fluorescent and stable benzoxazole derivatives were isocratically separated on a reversed-phase column (150 mm x 1.5 mm i.d., packed with C18 silica, 5 microm) within 45 min. Using fluorescence detection at ex. and em. wavelengths of 345 and 480 nm, respectively, the detection limit (signal-to-noise ratio of 3) for 5-HT, DA, NA, 5-HIAA, L-DOPA and DOPAC ranged between 0.08 and 5.65 fmol per 20-microl injection (12-847.5 pM in standard solution). The concentrations of monoamines (expressed in microg/g wet weight, mean +/- S.E.M., n=5) in tissue extracts from the rat striatum were: 0.45+/-0.05 (5-HT), 4.27+/-0.08 (DA), 0.27+/-0.04 (NA), 0.55+/-0.06 (5-HIAA), 1.26+/-0.16 (L-DOPA) and 1.62+/-0.11 (DOPAC). Microdialysis samples were collected in 20 min intervals from the probes implanted in the striatum of awake rats. The basal monoamine levels (in fmol/20 microl, mean +/- S.E.M., n=5) in the dialysates were: 4.0+/-0.7 (5-HT), 78.4+/-9.1 (DA), 6.4+/-0.8 (NA), 785.5+/-64.5 (5-HIAA) and 5504.5+/-136.5 (DOPAC). It is concluded that the new fluorescence derivatization protocol provides an excellent means for simultaneous determination of all three monoamines both in the complex samples (e.g. brain homogenates) and also at trace levels, such as those found in the microdialysis samples. PMID:15203027

Yoshitake, Takashi; Kehr, Jan; Yoshitake, Shimako; Fujino, Kaoru; Nohta, Hitoshi; Yamaguchi, Masatoshi

2004-08-01

158

Relationship between serotonin and mast cells: inhibitory effect of anti-serotonin.  

PubMed

Serotonin (5-HT) is an important neurotransmitter that acts in both central and peripheral nervous system, and has an impact on cell proliferation, migration and apoptosis. 5HT exerts its effects via several receptors. Treatment with anti-5-HT receptors diminish the severity of contact allergy in experimental animals, an effect mediated by mast cells; while an agonist reduces the stress level and relieves pruritus in patients with atopic dermatitis. Mast cells are important for both innate and adaptive immunity and they are activated by cross-linking of FceRI molecules, which are involved in the binding of multivalent antigens to the attached IgE molecules, resulting in a variety of responses including the immediate release of potent inflammatory mediators. Serotonin is present in murine mucosal mast cells and some authors reported that human mast cells may also contain serotonin, especially in subjects with mastocytosis. Here we report the interrelationship between mast cells, serotonin and its receptor inhibitor. PMID:25316126

Kritas, S K; Saggini, A; Cerulli, G; Caraffa, A; Antinolfi, P; Pantalone, A; Rosati, M; Tei, M; Speziali, A; Saggini, R; Conti, P

2014-01-01

159

Hallucinogens, Serotonin and Obsessive-Compulsive Disorder  

Microsoft Academic Search

The serotonin (5-HT) neurotransmitter system has been implicated in the pathophysiology of several neuropsychiatric disorders, especially obsessive-compulsive disorder (OCD). Blockade of 5-HT reuptake appears to be an important initial neurobiological event in the therapeutic mechanism of action of antiobsessional drugs. However, for reasons that continue to be poorly understood, clinical improvement following initiation of treatment with 5-HT reuptake inhibitors can

Pedro L. Delgado; Francisco A. Moreno

1998-01-01

160

Serotonin enhances solitariness in phase transition of the migratory locust  

PubMed Central

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

Guo, Xiaojiao; Ma, Zongyuan; Kang, Le

2013-01-01

161

Cochlear Damage Affects Neurotransmitter Chemistry in the Central Auditory System  

PubMed Central

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, intense 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 and/or magnitude 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. PMID:25477858

Lee, Augustine C.; Godfrey, Donald A.

2014-01-01

162

Imaging Dopamine Receptors in the Human Brain by Positron Tomography  

Microsoft Academic Search

Neurotransmitter receptors may be involved in a number of neuropsychiatric disease states. The ligand 3-N-[11C]methylspiperone, which preferentially binds to dopamine receptors in vivo, was used to image the receptors by positron emission tomography scanning in baboons and in humans. This technique holds promise for noninvasive clinical studies of dopamine receptors in humans.

Henry N. Wagner; H. Donald Burns; Robert F. Dannals; Dean F. Wong; Bengt Langstrom; Timothy Duelfer; J. James Frost; Hayden T. Ravert; Jonathan M. Links; Shelley B. Rosenbloom; Scott E. Lukas; Alfred V. Kramer; Michael J. Kuhar

1983-01-01

163

Imaging dopamine receptors in the human brain by position tomography  

SciTech Connect

Neurotransmitter receptors may be involved in a number of neuropsychiatric disease states. The ligand 3-N-(/sup 11/C)methylspiperone, which preferentially binds to dopamine receptors in vivo, was used to image the receptors by positron emission tomography scanning in baboons and in humans. This technique holds promise for noninvasive clinical studies of dopamine receptors in humans.

Wagner, H.N. Jr.; Burns, H.D.; Dannals, R.F.; Wong, D.F.; Langstrom, B.; Duelfer, T.; Frost, J.J.; Ravert, H.T.; Links, J.M.; Rosenbloom, S.B.

1983-01-01

164

Serotonin Transporter and Receptor Expression in Osteocytic MLO-Y4 Cells  

PubMed Central

Neurotransmitter regulation of bone metabolism has been a subject of increasing interest and investigation. We reported previously that osteoblastic cells express a functional serotonin (5-HT) signal transduction system, with mechanisms for responding to and regulating uptake of 5-HT. The clonal murine osteocytic cell line, MLO-Y4, demonstrates expression of the serotonin transporter (5-HTT), and the 5-HT1A, and 5-HT2A receptors by real-time RT-PCR and immunoblot analysis. Immunohistochemistry using antibodies for the 5-HTT, and the 5-HT1A and 5-HT2A receptors reveals expression of all three proteins in both osteoblasts and osteocytes in rat tibia. 5-HTT binding sites were demonstrated in the MLO-Y4 cells with nanomolar affinity for the stable cocaine analog [125I]RTI-55. Imipramine and fluoxetine, antagonists with specificity for 5-HTT, show the highest potency to antagonize [125I]RTI-55 binding in the MLO-Y4 cells. GBR-12935, a relatively selective dopamine transporter antagonist, had a much lower potency, as did desipramine, a selective norepinephrine transporter antagonist. The maximal [3H]5-HT uptake rate in MLO-Y4 cells was 2.85 pmol/15 min/well, with a Km value of 290 nM. Imipramine and fluoxetine inhibited specific [3H]5-HT uptake with IC50 values in the nanomolar range. 5-HT rapidly stimulated PGE2 release from MLO-Y4 cells; the EC50 for 5-HT was 0.1 ?M, with a 3-fold increase seen at 60 min. The rate limiting enzyme for serotonin synthesis, tryptophan hydroxylase, is expressed in MLO-Y4 cells as well as osteoblastic MC3T3-E1 cells. Thus, osteocytes, as well as osteoblasts, are capable of 5-HT synthesis, and express functional receptor and transporter components of the 5-HT signal transduction system. PMID:16884969

BLIZIOTES, M.; ESHLEMAN, A.; BURT-PICHAT, B.; ZHANG, X.-W.; HASHIMOTO, J.; WIREN, K.; CHENU, C.

2006-01-01

165

Receptors and Other Signaling Proteins Required for Serotonin Control of Locomotion in Caenorhabditis elegans  

PubMed Central

A better understanding of the molecular mechanisms of signaling by the neurotransmitter serotonin is required to assess the hypothesis that defects in serotonin signaling underlie depression in humans. Caenorhabditis elegans uses serotonin as a neurotransmitter to regulate locomotion, providing a genetic system to analyze serotonin signaling. From large-scale genetic screens we identified 36 mutants of C. elegans in which serotonin fails to have its normal effect of slowing locomotion, and we molecularly identified eight genes affected by 19 of the mutations. Two of the genes encode the serotonin-gated ion channel MOD-1 and the G-protein-coupled serotonin receptor SER-4. mod-1 is expressed in the neurons and muscles that directly control locomotion, while ser-4 is expressed in an almost entirely non-overlapping set of sensory and interneurons. The cells expressing the two receptors are largely not direct postsynaptic targets of serotonergic neurons. We analyzed animals lacking or overexpressing the receptors in various combinations using several assays for serotonin response. We found that the two receptors act in parallel to affect locomotion. Our results show that serotonin functions as an extrasynaptic signal that independently activates multiple receptors at a distance from its release sites and identify at least six additional proteins that appear to act with serotonin receptors to mediate serotonin response. PMID:23023001

Gürel, Güliz; Gustafson, Megan A.; Pepper, Judy S.; Horvitz, H. Robert; Koelle, Michael R.

2012-01-01

166

Quantitative pharmacologic MRI: Mapping the cerebral blood volume response to cocaine in dopamine transporter knockout mice  

E-print Network

Quantitative pharmacologic MRI: Mapping the cerebral blood volume response to cocaine in dopamine employed CBV-weighted phMRI to compare cocaine-modulated neuronal activity in dopamine transporter (DAT) knockout (KO) and wild-type mice. Cocaine acts to block the dopamine, norepinephrine, and serotonin

Reber, Paul J.

167

Dopamine transporter (DAT1) VNTR polymorphism in 12 Indian populations  

Microsoft Academic Search

The dopamine transporter (DAT1) is a membrane spanning protein that binds the neurotransmitter dopamine and performs re-uptake\\u000a of dopamine from the synapse into a neuron. The gene encoding DAT1 consists of 15 exons spanning 60 kb on chromosome 5p15.32.\\u000a Several studies have investigated the possible associations between variants in DAT1 gene and psychiatric disorders. The present\\u000a study aimed to determine the

L. V. K. S. Bhaskar; Kumarasamy Thangaraj; Connie J. Mulligan; Samiksha Wasnik; Amrita Nandan; Varun Kumar Sharma; Vishwas Sharma; Alla Govardhana Reddy; Lalji Singh; Vadlamudi Raghavendra Rao

2009-01-01

168

Serotonin synthesis, release and reuptake in terminals: a mathematical model  

Microsoft Academic Search

BACKGROUND: Serotonin is a neurotransmitter that has been linked to a wide variety of behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders. Full understanding of serotonergic systems in the central nervous system involves genomics, neurochemistry, electrophysiology, and behavior. Though associations have been found between functions at these different levels,

Janet Best; H. Frederik Nijhout; Michael Reed

2010-01-01

169

ORIGINAL PAPER Octopamine and serotonin have opposite effects on antipredator  

E-print Network

, neurotransmitters such as serotonin (5-HT) and octopamine (OA) have such broad behavioral effects they are commonlyb) in honeybees; posture and locomotion in crayfish (Tierney et al. 2004); and courtship behavior by wasps and birds), but may also be parasitized by wasps and flies (Foelix 1996). A common antipredator T

Jones, Thomas C.

170

Effects of Postnatal Serotonin Agonism on Fear Response and Memory  

Technology Transfer Automated Retrieval System (TEKTRAN)

The neurotransmitter serotonin (5-HT) also acts as a neurogenic compound in the developing brain. Early administration of a 5-HT agonist could alter the development of the serotonergic circuitry, altering behaviors mediated by 5-HT signaling, such as memory, fear and aggression. White leghorn chicks...

171

Role of Serotonin via 5-HT2B Receptors in the Reinforcing Effects of MDMA in Mice  

PubMed Central

The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) reverses dopamine and serotonin transporters to produce efflux of dopamine and serotonin, respectively, in regions of the brain that have been implicated in reward. However, the role of serotonin/dopamine interactions in the behavioral effects of MDMA remains unclear. We previously showed that MDMA-induced locomotion, serotonin and dopamine release are 5-HT2B receptor-dependent. The aim of the present study was to determine the contribution of serotonin and 5-HT2B receptors to the reinforcing properties of MDMA. We show here that 5-HT2B?/? mice do not exhibit behavioral sensitization or conditioned place preference following MDMA (10 mg/kg) injections. In addition, MDMA-induced reinstatement of conditioned place preference after extinction and locomotor sensitization development are each abolished by a 5-HT2B receptor antagonist (RS127445) in wild type mice. Accordingly, MDMA-induced dopamine D1 receptor-dependent phosphorylation of extracellular regulated kinase in nucleus accumbens is abolished in mice lacking functional 5-HT2B receptors. Nevertheless, high doses (30 mg/kg) of MDMA induce dopamine-dependent but serotonin and 5-HT2B receptor-independent behavioral effects. These results underpin the importance of 5-HT2B receptors in the reinforcing properties of MDMA and illustrate the importance of dose-dependent effects of MDMA on serotonin/dopamine interactions. PMID:19956756

Doly, Stéphane; Bertran-Gonzalez, Jesus; Callebert, Jacques; Bruneau, Alexandra; Banas, Sophie Marie; Belmer, Arnauld; Boutourlinsky, Katia; Hervé, Denis; Launay, Jean-Marie; Maroteaux, Luc

2009-01-01

172

Androgens coordinate neurotransmitter-related gene expression in male whiptail lizards  

PubMed Central

Sex steroid hormones coordinate neurotransmitter systems in the male brain to facilitate sexual behavior. Although neurotransmitter release in the male brain has been well documented, little is known about how androgens orchestrate changes in gene expression of neurotransmitter receptors. We used male whiptail lizards (Cnemidophorus inornatus) to investigate how androgens alter neurotransmitter-related gene expression in brain regions involved in social decision-making. We focused on three neurotransmitter systems involved in male-typical sexual behavior, including the NMDA glutamate receptor, nitric oxide, and dopamine receptors. Here we show that in androgen-treated males, there are coordinated changes in neurotransmitter-related gene expression. In androgen-implanted castrates compared to blank-implanted castrates (control group), we found associated increases in neuronal nitric oxide synthase (nNOS) gene expression in the nucleus accumbens, preoptic area and ventromedial hypothalamus, a decrease of NR1 gene expression (obligate subunit of NMDA receptors) in the medial amygdaloid area and nucleus accumbens, and a decrease in D1 and D2 dopamine receptor gene expression in the nucleus accumbens. Our results support and expand the current model of androgen-mediated gene expression changes of neurotransmitter-related systems that facilitate sexual behavior in males. This also suggests that the proposed evolutionarily ancient reward system that reinforces sexual behavior in amniote vertebrates extends to reptiles. PMID:22862958

O’Connell, Lauren A.; Mitchell, Maggie M.; Hofmann, Hans A.; Crews, David

2012-01-01

173

Head-to-Head Comparisons of Carbon Fiber Microelectrode Coatings for Sensitive and Selective Neurotransmitter Detection by Voltammetry  

PubMed Central

Voltammetry is widely used to investigate neurotransmission and other biological processes but is limited by poor chemical selectivity and fouling of commonly used carbon fiber microelectrodes (CFMs). We performed direct comparisons of three key coating materials purported to impart selectivity and fouling resistance to electrodes: Nafion, base-hydrolyzed cellulose acetate (BCA), and fibronectin. We systematically evaluated the impact on a range of electrode parameters. Fouling due to exposure to brain tissue was investigated using an approach that minimizes the use of animals while enabling evaluation of statistically significant populations of electrodes. We find that BCA is relatively fouling resistant. Moreover, detection at BCA-coated CFMs can be tuned by altering hydrolysis times to minimize the impact on sensitivity losses while maintaining fouling resistance. Fibronectin coating is associated with moderate losses in sensitivity after coating and fouling. Nafion imparts increased sensitivity for dopamine and norepinephrine but not serotonin, as well as the anticipated selectivity for cationic neurotransmitters over anionic metabolites. However, while Nafion has been suggested to resist fouling, both dip-coating and electro-deposition of Nafion are associated with substantial fouling, similar to levels observed at bare electrodes after exposure to brain tissue. Direct comparisons of these coatings identified unique electroanalytical properties of each that can be used to guide selection tailored to the goals and environment of specific studies. PMID:21770471

Singh, Yogesh S.; Sawarynski, Lauren E.; Dabiri, Pasha D.; Choi, Wonwoo R.; Andrews, Anne M.

2011-01-01

174

Using a collection of MUPP1 domains to investigate the similarities of neurotransmitter transporters C-terminal PDZ motifs.  

PubMed

A ubiquitous feature of neurotransmitter transporters is the presence of short C-terminal PDZ binding motifs acting as important trafficking elements. Depending on their very C-terminal sequences, PDZ binding motifs are usually divided into at least three groups; however this classification has recently been questioned. To introduce a 3D aspect into transporter's PDZ motif similarities, we compared their interactions with the natural collection of all 13 PDZ domains of the largest PDZ binding protein MUPP1. The GABA, glycine and serotonin transporters showed unique binding preferences scattered over one or several MUPP1 domains. On the contrary, the dopamine and norepinephrine transporter PDZ motifs did not show any significant affinity to MUPP1 domains. Interestingly, despite their terminal sequence diversity all three GABA transporter PDZ motifs interacted with MUPP1 domain 7. These results indicate that similarities in binding schemes of individual transporter groups might exist. Results also suggest the existence of variable PDZ binding modes, allowing several transporters to interact with identical PDZ domains and potentially share interaction partners in vivo. PMID:25305483

Baliova, Martina; Juhasova, Anna; Jursky, Frantisek

2014-11-01

175

Serotonin-immunoreactive neurons and endogenous serotonin in the opisthosomal ventral nerve cord of the horseshoe crab, Limulus polyphemus.  

PubMed

It has been suggested that serotonin serves as a neurotransmitter in the horseshoe crab, Limulus polyphemus. While some studies of identified groups of central neurons have been conducted, little is known concerning the neuronal organization in Limulus central ganglia. This study was undertaken to determine the localization of serotoninergic neurons in the opisthosomal ventral nerve cord of Limulus and to construct a basis for further comparative biochemical and pharmacological studies of the specific function of these neurons. Endogenous serotonin was detected in the ventral nerve cord (chain of abdominal ganglia) by high-performance liquid chromatography and electrochemical detection (HPLC-EC). Endogenous serotonin was quantified in the 9th through 13th ganglia, anterior (hemal) nerves, posterior (branchial) nerves, and connectives. The serotonin content in the abdominal ganglia was significantly reduced when the ganglia were incubated for 24 hours in Leibovitz's (L-15) medium containing reserpine or 5,7-dihydroxytryptamine (5,7-DHT), neurotoxins that block the uptake of serotonin into storage vesicles. The distribution of serotonin-immunoreactive neurons in the ventral nerve cord was determined by indirect immunocytochemistry. Treatment of the chain of ganglia with an anti-serotonin antiserum followed by treatment with a fluorescent-labeled antiserum raised against the primary antibody demonstrated specific staining in each ganglion, the ganglionic roots, and connectives. Clusters of serotonin-immunoreactive neurons were observed anteriolaterally and posteriorly in each ganglion. Processes from dense fiber bundles extended from these clusters of neurons to the central region of each ganglion. These results demonstrate that serotonin-immunoreactive neurons are present in the opisthosomal ventral nerve cord of the horseshoe crab and that serotonin may function as a neurotransmitter. PMID:7814671

Washington, B; Higgins, D E; McAdory, B; Newkirk, R F

1994-09-01

176

Voltammetric and mathematical evidence for dual transport mediation of serotonin clearance in vivo.  

PubMed

The neurotransmitter serotonin underlies many of the brain's functions. Understanding serotonin neurochemistry is important for improving treatments for neuropsychiatric disorders such as depression. Antidepressants commonly target serotonin clearance via serotonin transporters and have variable clinical effects. Adjunctive therapies, targeting other systems including serotonin autoreceptors, also vary clinically and carry adverse consequences. Fast scan cyclic voltammetry is particularly well suited for studying antidepressant effects on serotonin clearance and autoreceptors by providing real-time chemical information on serotonin kinetics in vivo. However, the complex nature of in vivo serotonin responses makes it difficult to interpret experimental data with established kinetic models. Here, we electrically stimulated the mouse medial forebrain bundle to provoke and detect terminal serotonin in the substantia nigra reticulata. In response to medial forebrain bundle stimulation we found three dynamically distinct serotonin signals. To interpret these signals we developed a computational model that supports two independent serotonin reuptake mechanisms (high affinity, low efficiency reuptake mechanism, and low affinity, high efficiency reuptake system) and bolsters an important inhibitory role for the serotonin autoreceptors. Our data and analysis, afforded by the powerful combination of voltammetric and theoretical methods, gives new understanding of the chemical heterogeneity of serotonin dynamics in the brain. This diverse serotonergic matrix likely contributes to clinical variability of antidepressants. PMID:24702305

Wood, Kevin M; Zeqja, Anisa; Nijhout, H Frederik; Reed, Michael C; Best, Janet; Hashemi, Parastoo

2014-08-01

177

Glycogen Synthase Kinase-3 is an Intermediate Modulator of Serotonin Neurotransmission  

PubMed Central

Serotonin is a neurotransmitter with broad functions in brain development, neuronal activity, and behaviors; and serotonin is the prominent drug target in several major neuropsychiatric diseases. The multiple actions of serotonin are mediated by diverse serotonin receptor subtypes and associated signaling pathways. However, the key signaling components that mediate specific function of serotonin neurotransmission have not been fully identified. This review will provide evidence from biochemical, pharmacological, and animal behavioral studies showing that serotonin regulates the activation states of brain glycogen synthase kinase-3 (GSK3) via type 1 and type 2 serotonin receptors. In return, GSK3 directly interacts with serotonin receptors in a highly selective manner, with a prominent effect on modulating serotonin 1B receptor activity. Therefore, GSK3 acts as an intermediate modulator in the serotonin neurotransmission system, and balanced GSK3 activity is essential for serotonin-regulated brain function and behaviors. Particularly important, several classes of serotonin-modulating drugs, such as antidepressants and atypical antipsychotics, regulate GSK3 by inhibiting its activity in brain, which reinforces the importance of GSK3 as a potential therapeutic target in neuropsychiatric diseases associated with abnormal serotonin function. PMID:22028682

Polter, Abigail M.; Li, Xiaohua

2011-01-01

178

Unconventional neurotransmitters, neurodegeneration and neuroprotection.  

PubMed

Neurotransmitters are also involved in functions other than conventional signal transfer between nerve cells, such as development, plasticity, neurodegeneration, and neuroprotection. For example, there is a considerable amount of data indicating developmental roles for the glutamatergic, cholinergic, dopaminergic, GABA-ergic, and ATP/adenosine systems. In this review, we discuss the existing literature on these 'new' functions of neurotransmitters in relation to some unconventional neurotransmitters, such as the endocannabinoids and nitric oxide. Data indicating both transcriptional and post-transcriptional modulation of endocannabinoid and nitrinergic systems after neural lesions are discussed in relation to the non-conventional roles of these neurotransmitters. Knowledge of the roles of neurotransmitters in brain functions other than information transfer is critical for a more complete understanding of the functional organization of the brain and to provide more opportunities for the development of therapeutical tools aimed at minimizing neuronal death. PMID:19219299

Leonelli, M; Torrão, A S; Britto, L R G

2009-01-01

179

Serotonin-immunoreactive sensory neurons in the antenna of the cockroach Periplaneta americana.  

PubMed

The antennae of insects contain a vast array of sensory neurons that process olfactory, gustatory, mechanosensory, hygrosensory, and thermosensory information. Except those with multimodal functions, most sensory neurons use acetylcholine as a neurotransmitter. Using immunohistochemistry combined with retrograde staining of antennal sensory neurons in the cockroach Periplaneta americana, we found serotonin-immunoreactive sensory neurons in the antenna. These were selectively distributed in chaetic and scolopidial sensilla and in the scape, the pedicel, and first 15 segments of the flagellum. In a chaetic sensillum, A single serotonin-immunoreactive sensory neuron cohabited with up to four serotonin-negative sensory neurons. Based on their morphological features, serotonin-immunopositive and -negative sensory neurons might process mechanosensory and contact chemosensory modalities, respectively. Scolopidial sensilla constitute the chordotonal and Johnston's organs within the pedicel and process antennal vibrations. Immunoelectron microscopy clearly revealed that serotonin-immunoreactivities selectively localize to a specific type of mechanosensory neuron, called type 1 sensory neuron. In a chordotonal scolopidial sensillum, a serotonin-immunoreactive type 1 neuron always paired with a serotonin-negative type 1 neuron. Conversely, serotonin-immunopositive and -negative type 1 neurons were randomly distributed in Johnston's organ. In the deutocerebrum, serotonin-immunoreactive sensory neuron axons formed three different sensory tracts and those from distinct types of sensilla terminated in distinct brain regions. Our findings indicate that a biogenic amine, serotonin, may act as a neurotransmitter in peripheral mechanosensory neurons. PMID:23852943

Watanabe, Hidehiro; Shimohigashi, Miki; Yokohari, Fumio

2014-02-01

180

Serotonin modulation of cortical neurons and networks  

PubMed Central

The serotonergic pathways originating in the dorsal and median raphe nuclei (DR and MnR, respectively) are critically involved in cortical function. Serotonin (5-HT), acting on postsynaptic and presynaptic receptors, is involved in cognition, mood, impulse control and motor functions by (1) modulating the activity of different neuronal types, and (2) varying the release of other neurotransmitters, such as glutamate, GABA, acetylcholine and dopamine. Also, 5-HT seems to play an important role in cortical development. Of all cortical regions, the frontal lobe is the area most enriched in serotonergic axons and 5-HT receptors. 5-HT and selective receptor agonists modulate the excitability of cortical neurons and their discharge rate through the activation of several receptor subtypes, of which the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT3 subtypes play a major role. Little is known, however, on the role of other excitatory receptors moderately expressed in cortical areas, such as 5-HT2C, 5-HT4, 5-HT6, and 5-HT7. In vitro and in vivo studies suggest that 5-HT1A and 5-HT2A receptors are key players and exert opposite effects on the activity of pyramidal neurons in the medial prefrontal cortex (mPFC). The activation of 5-HT1A receptors in mPFC hyperpolarizes pyramidal neurons whereas that of 5-HT2A receptors results in neuronal depolarization, reduction of the afterhyperpolarization and increase of excitatory postsynaptic currents (EPSCs) and of discharge rate. 5-HT can also stimulate excitatory (5-HT2A and 5-HT3) and inhibitory (5-HT1A) receptors in GABA interneurons to modulate synaptic GABA inputs onto pyramidal neurons. Likewise, the pharmacological manipulation of various 5-HT receptors alters oscillatory activity in PFC, suggesting that 5-HT is also involved in the control of cortical network activity. A better understanding of the actions of 5-HT in PFC may help to develop treatments for mood and cognitive disorders associated with an abnormal function of the frontal lobe. PMID:23626526

Celada, Pau; Puig, M. Victoria; Artigas, Francesc

2013-01-01

181

Neurotransmitters of the suprachiasmatic nuclei  

PubMed Central

There has been extensive research in the recent past looking into the molecular basis and mechanisms of the biological clock, situated in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. Neurotransmitters are a very important component of SCN function. Thorough knowledge of neurotransmitters is not only essential for the understanding of the clock but also for the successful manipulation of the clock with experimental chemicals and therapeutical drugs. This article reviews the current knowledge about neurotransmitters in the SCN, including neurotransmitters that have been identified only recently. An attempt was made to describe the neurotransmitters and hormonal/diffusible signals of the SCN efference, which are necessary for the master clock to exert its overt function. The expression of robust circadian rhythms depends on the integrity of the biological clock and on the integration of thousands of individual cellular clocks found in the clock. Neurotransmitters are required at all levels, at the input, in the clock itself, and in its efferent output for the normal function of the clock. The relationship between neurotransmitter function and gene expression is also discussed because clock gene transcription forms the molecular basis of the clock and its working. PMID:16480518

Reghunandanan, Vallath; Reghunandanan, Rajalaxmy

2006-01-01

182

Harmane: An atypical neurotransmitter?  

PubMed

Harmane is an active component of clonidine displacing substance and a candidate endogenous ligand for imidazoline binding sites. The neurochemistry of tritiated harmane was investigated in the present study examining its uptake and release properties in the rat brain central nervous system (CNS) in vitro. At physiological temperature, [(3)H]harmane was shown to be taken up in rat brain cortex. Further investigations demonstrated that treatment with monoamine uptake blockers (citalopram, nomifensine and nisoxetine) did not alter [(3)H]harmane uptake implicating that the route of [(3)H]harmane transport was distinct from the monoamine uptake systems. Furthermore, imidazoline ligands (rilmenidine, efaroxan, 2-BFI and idazoxan) showed no prominent effect on [(3)H]harmane uptake suggesting the lack of involvement of imidazoline binding sites. Subsequent analyses showed that disruption of the Na(+) gradient using ouabain or choline chloride did not block [(3)H]harmane uptake suggesting a Na(+)-independent transport mechanism. Moreover, higher temperatures (50°C) failed to impede [(3)H]harmane uptake implying a non-physiological transporter. The failure of potassium to evoke the release of preloaded [(3)H]harmane from rat brain cortex indicates that the properties of this putative endogenous ligand for imidazoline binding sites do not resemble that of a conventional neurotransmitter. PMID:25625221

Abu Ghazaleh, Haya; Lalies, Maggie D; Nutt, David J; Hudson, Alan L

2015-03-17

183

Activation of hypothalamic insulin by serotonin is the primary event of the insulin-serotonin interaction involved in the control of feeding.  

PubMed

In previous experiments, we reported a close parallelism in the responses of both serotonin (5-HT) and insulin in the hypothalamic PVN-VMH region of freely-moving rats during feeding. Thus, hypothalamic 5-HT and insulin may participate, independently or in interaction, in the control of carbohydrate and fat ingestion. The precedence of the activation of one or the other substance remained to be investigated. In adult male Wistar rats, (a) dexfenfluramine was administered to the PVN-VMH region by reverse microdialysis (80 microM for 10 min) while local insulin was assessed; (b) insulin was locally infused (400 mU for 10 min) through the tip of the dialysis probe while 5-HT was measured. Dexfenfluramine immediately increased 5-HT release, and also extracellular insulin levels (+102%). This activation of insulin by serotonin is actually a central effect since neither insulinemia nor glycemia were affected. Conversely, insulin enhanced 5-HT release (+81%), but only 45 min after the beginning of its infusion. Noradrenaline, dopamine and metabolites were slightly or not at all modified by insulin. These data demonstrate that an interaction does exist between insulin and 5-HT in the VMH-PVN area. Because of the delay of 5-HT response to insulin, an activation of the serotonergic system would be the causal event acting immediately on insulin, and not the contrary. Whatever the exact mechanism of this interaction, it seems to be a link in a larger cascade of events involving numerous neurotransmitters and peptides leading to the regulation of feeding. PMID:10924676

Orosco, M; Rouch, C; Gerozissis, K

2000-07-28

184

Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter  

E-print Network

and specific behavioral abnormalities Rodney C. Samacoa , Caleigh Mandel-Brehma , Hsiao-Tuan Chaob, we analyzed the levels of the dopamine metabolite homovanillic acid (HVA) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in spinal fluid from women who both met the clinical criteria

185

The role of serotonin in adult hippocampal neurogenesis.  

PubMed

Serotonin is probably best known for its role in conveying a sense of contentedness and happiness. It is one of the most unique and pharmacologically complex monoamines in both the peripheral and central nervous system (CNS). Serotonin has become in focus of interest for the treatment of depression with multiple serotonin-mimetic and modulators of adult neurogenesis used clinically. Here we will take a broad view of serotonin from development to its physiological role as a neurotransmitter and its contribution to homeostasis of the adult rodent hippocampus. This chapter reflects the most significant findings on cellular and molecular mechanisms from neuroscientists in the field over the last two decades. We illustrate the action of serotonin by highlighting basic receptor targeting studies, and how receptors impact brain function. We give an overview of recent genetically modified mouse models that differ in serotonin availability and focus on the role of the monoamine in antidepressant response. We conclude with a synthesis of the most recent data surrounding the role of serotonin in activity and hippocampal neurogenesis. This synopsis sheds light on the mechanisms and potential therapeutic model by which serotonin plays a critical role in the maintenance of mood. PMID:25125239

Alenina, Natalia; Klempin, Friederike

2015-01-15

186

Neurotransmitter signaling in white matter.  

PubMed

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 signaling in WM, which largely exclude neuronal cell bodies, indicates it must have physiological functions other than neuron-to-neuron communication. A surprising aspect is the diversity of neurotransmitter signaling in WM, with evidence for glutamatergic, purinergic (ATP and adenosine), GABAergic, glycinergic, adrenergic, cholinergic, dopaminergic and serotonergic signaling, acting via a wide range of ionotropic and metabotropic receptors. Both axons and glia are potential sources of neurotransmitters and may express the respective receptors. The physiological functions of neurotransmitter signaling in WM are subject to debate, but glutamate and ATP-mediated signaling have been shown to evoke Ca(2+) signals in glia and modulate axonal conduction. Experimental findings support a model of neurotransmitters being released from axons during action potential propagation acting on glial receptors to regulate the homeostatic functions of astrocytes and myelination by oligodendrocytes. Astrocytes also release neurotransmitters, which act on axonal receptors to strengthen action potential propagation, maintaining signaling along potentially long axon tracts. The co-existence of multiple neurotransmitters in WM tracts suggests they may have diverse functions that are important for information processing. Furthermore, the neurotransmitter signaling phenomena described in WM most likely apply to myelinated axons of the cerebral cortex and GM areas, where they are doubtless important for higher cognitive function. PMID:24753049

Butt, Arthur M; Fern, Robert F; Matute, Carlos

2014-11-01

187

Neurotransmitter transporters: structure meets function  

PubMed Central

Summary At synapses, sodium-coupled transporters remove released neurotransmitters, thereby recycling them and maintaining a low extracellular concentration of the neurotransmitter. The molecular mechanism underlying sodium-coupled neurotransmitter uptake is not completely understood. Several structures of homologues of human neurotransmitter transporters have been solved with X-ray crystallography. These crystal structures have spurred a plethora of computational and experimental work to elucidate the molecular mechanism underlying sodium-coupled transport. Here, we compare the structures of GltPh, a glutamate transporter homologue, and LeuT, a homologue of neurotransmitter transporters for the biogenic amines and inhibitory molecules GABA and glycine. We relate these structures to data obtained from experiments and computational simulations, to draw conclusions about the mechanism of uptake by sodium-coupled neurotransmitter transporters. We here propose how sodium and substrate binding is coupled and how binding of sodium and substrate opens and closes the gates in these transporters, thereby leading to an efficient coupled transport. PMID:23664361

Focke, Paul; Wang, Xiaoyu; Larsson, H. Peter

2013-01-01

188

From Galactorrhea to Osteopenia: Rethinking Serotonin–Prolactin Interactions  

Microsoft Academic Search

The widespread use of the selective serotonin reuptake inhibitors (SSRIs) has been accompanied by numerous reports describing a potential association with hyperprolactinemia. Antipsychotics are commonly known to elevate serum prolactin (PRL) through blockade of dopamine receptors in the pituitary. However, there is little awareness of the mechanisms by which SSRIs stimulate PRL release. Hyperprolactinemia may result in overt symptoms such

Ana B F Emiliano; Julie L Fudge; ABF Emiliano

2004-01-01

189

Serotonin and Serotonin Transporter Gene Variant in Rotating Shift Workers  

PubMed Central

Study Objectives: Because serotonin (5-HT) is a neurotransmitter associated with circadian rhythm regulation, we explored a possible relation among 5-HT, serotonin metabolite, 5-hydroxyindolacetic acid (5-HIAA), and the functional polymorphism of the serotonin transporter gene (SLC6A4) promoter with rotating shift work. Design and Participants: 683 men were included in this study: 437 day workers were compared with 246 rotating shift workers. Results: Platelet 5-HT content differed significantly (P = 0.002) between day workers (41.28±1.99 pg/mg) and rotating shift workers (37.91±4.16 pg/mg); 5-HIAA content was also significantly (P = 0.00004) higher in day workers (11.40±0.82 pg/mg) than in rotating shift workers (9.33±1.02 pg/mg). We looked for further differences in SLC6A4 promoter (5-HTTLPR, 44 bp insertion: long (L)/deletion: short (S) alleles). We found a significant (P = 0.016) difference in genotype distribution between day workers LL: 126 (28.8%), LS: 202 (46.2%), and SS: 109 (24.9%), and rotating shift workers LL: 47 (19.1%), LS: 124 (50.4%), and SS: 75 (30.5%). When we divided the subjects between workers with less and more than 60 month rotating shift-work exposure, the difference in SLC6A4 genotypes frequency was only significant in the group with ?60 months (P = 0.011). In addition, there was a significantly lower content of platelet 5-HIM in S allele carriers in comparison with the other genotypes (SS: 9.2±1.0 pg/mg vs. SL/LL: 11.0±0.8 pg/mg, P <0.02). Conclusions: Platelet 5-HT and 5-HIM contents were significantly lower in rotating shift workers than day workers, and there was a significant association between the S variant of SLC6A4 promoter and shift work. These findings may be important for targeting effective therapeutic strategies to ameliorate the associated comorbidities and behavioral problems in rotating shift workers. Citation: Sookoian S; Gemma C; Gianotti TF; Burgueño A; Alvarez A; Gonzalez CD; Pirola CJ. Serotonin and serotonin transporter gene variant in rotating shift workers. SLEEP 2007;30(8):1049-1053. PMID:17702275

Sookoian, Silvia; Gemma, Carolina; Gianotti, Tomas Fernández; Burgueño, Adriana; Alvarez, Azucena; González, Claudio Daniel; Pirola, Carlos Jose

2007-01-01

190

Mimicking subsecond neurotransmitter dynamics with femtosecond laser stimulated nanosystems  

NASA Astrophysics Data System (ADS)

Existing nanoscale chemical delivery systems target diseased cells over long, sustained periods of time, typically through one-time, destructive triggering. Future directions lie in the development of fast and robust techniques capable of reproducing the pulsatile chemical activity of living organisms, thereby allowing us to mimic biofunctionality. Here, we demonstrate that by applying programmed femtosecond laser pulses to robust, nanoscale liposome structures containing dopamine, we achieve sub-second, controlled release of dopamine - a key neurotransmitter of the central nervous system - thereby replicating its release profile in the brain. The fast delivery system provides a powerful new interface with neural circuits, and to the larger range of biological functions that operate on this short timescale.

Nakano, Takashi; Chin, Catherine; Myint, David Mo Aung; Tan, Eng Wui; Hale, Peter John; Krishna M., Bala Murali; Reynolds, John N. J.; Wickens, Jeff; Dani, Keshav M.

2014-06-01

191

The Cytoplasmic Permeation Pathway of Neurotransmitter Transporters†  

PubMed Central

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 substrate diffusion to the cytoplasm. From the difference between the model and the crystal structures, a simple “rocking bundle” mechanism was proposed, in which a 4-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. PMID:21774491

Rudnick, Gary

2011-01-01

192

Pyrethroid insecticides evoke neurotransmitter release from rabbit striatal slices  

SciTech Connect

The effects of the synthetic pyrethroid insecticide fenvalerate ((R,S)-alpha-cyano-3-phenoxybenzyl(R,S)-2-(4-chlorophenyl)-3- methylbutyrate) on neurotransmitter release in rabbit brain slices were investigated. Fenvalerate evoked a calcium-dependent release of (/sup 3/H)dopamine and (/sup 3/H)acetylcholine from rabbit striatal slices that was concentration-dependent and specific for the toxic stereoisomer of the insecticide. The release of (/sup 3/H)dopamine and (/sup 3/H)acetylcholine by fenvalerate was modulated by D2 dopamine receptor activation and antagonized completely by the sodium channel blocker, tetrodotoxin. These findings are consistent with an action of fenvalerate on the voltage-dependent sodium channels of the presynaptic membrane resulting in membrane depolarization, and the release of dopamine and acetylcholine by a calcium-dependent exocytotic process. In contrast to results obtained in striatal slices, fenvalerate did not elicit the release of (/sup 3/H)norepinephrine or (/sup 3/H)acetylcholine from rabbit hippocampal slices indicative of regional differences in sensitivity to type II pyrethroid actions.

Eells, J.T.; Dubocovich, M.L.

1988-08-01

193

A Preliminary Study of Gene Polymorphisms Involved in the Neurotransmitters Metabolism of a Homogeneous Spanish Autistic Group  

ERIC Educational Resources Information Center

Twin studies have shown a strong genetic component for autism. Neurotransmitters, such as serotonin and catecholamines, have been suggested to play a role in the disease since they have an essential function in synaptogenesis and brain development. In this preliminary study, polymorphism of genes implicated in the serotonergic and dopaminergic…

Calahorro, Fernando; Alejandre, Encarna; Anaya, Nuria; Guijarro, Teresa; Sanz, Yolanza; Romero, Auxiliadora; Tienda, Pilar; Burgos, Rafael; Gay, Eudoxia; Sanchez, Vicente; Ruiz-Rubio, Manuel

2009-01-01

194

Brain neurotransmitters in aging and dementia: similar changes across diagnostic dementia groups.  

PubMed

Reductions of the levels of transmitter substances and of the activities of enzymes involved in their synthesis have been demonstrated in the aging brain. The sensitivity to the aging process varies for different transmitters and brain regions. Dopamine neurons are more age-sensitive than most other neurons investigated. The metabolism of monoaminergic neurotransmitters is enhanced in the aging brain, as evidenced by increased metabolite/neurotransmitter ratios, perhaps to compensate for the loss of transmitter. In various types of dementia, including Alzheimer's disease (AD) and senile dementia of Alzheimer type (SDAT), several neurotransmitter indices are reduced, as compared to age-matched controls. Moreover, a decrease in neurotransmitter metabolites suggests that compensatory mechanisms are insufficient. No correlation could be found between the neurotransmitter changes and the histological changes characteristic of AD (senile plaques and neurofibrillary tangles). Neither could any relationship between multiple infarctions and neurotransmitter indices be detected. Recently observed changes in the lipid composition of the white matter, indicating demyelinization, in the brains of patients with AD/SDAT, emphasize the multifactorial aspects of dementia. Taken together, the data underline the difficulties in drawing clear demarcation lines between normal and pathological aging and between different subgroups of dementia. Despite the obvious difficulties, future therapeutic efforts should aim at substitution for the neurotransmitter deficiencies. Preventive measures have to await the clarification of the mechanisms underlying neural degeneration. Studies of the toxicity of oxygen and of autoxidation products are among the areas of research that may help to shed light on this problem. PMID:2888709

Carlsson, A

1987-01-01

195

Automated mass spectrometric analysis of urinary and plasma serotonin.  

PubMed

Serotonin emerges as crucial neurotransmitter and hormone in a growing number of different physiologic processes. Besides extensive serotonin production previously noted in patients with metastatic carcinoid tumors, serotonin now is implicated in liver cell regeneration and bone formation. The aim was to develop a rapid, sensitive, and highly selective automated on-line solid-phase extraction method coupled to high-performance liquid chromatography-tandem mass spectrometry (XLC-MS/MS) to quantify low serotonin concentrations in matrices such as platelet-poor plasma and urine. Fifty microliters plasma or 2.5 microL urine equivalent were pre-purified by automated on-line solid-phase extraction, using weak cation exchange. Chromatography of serotonin and its deuterated internal standard was performed with hydrophilic interaction chromatography. Mass spectrometric detection was operated in multiple reaction monitoring mode using a quadrupole tandem mass spectrometer with positive electrospray ionization. Serotonin concentrations were determined in platelet-poor plasma of metastatic carcinoid patients (n = 23) and healthy controls (n = 22). Urinary reference intervals were set by analyzing 24-h urine collections of 120 healthy subjects. Total run-time was 6 min. Intra- and inter-assay analytical variation were <10%. Linearity in the 0-7300 micromol/L calibration range was excellent (R(2) > 0.99). Quantification limits were 30 and 0.9 nmol/L in urine and plasma, respectively. Platelet-poor serotonin concentrations in metastatic carcinoid patients were significantly higher than in controls. The urinary reference interval was 10-78 micromol/mol creatinine. Serotonin analysis with sensitive and specific XLC-MS/MS overcomes limitations of conventional HPLC. This enables accurate quantification of serotonin for both routine diagnostic procedures and research in serotonin-related disorders. PMID:20140664

de Jong, Wilhelmina H A; Wilkens, Marianne H L I; de Vries, Elisabeth G E; Kema, Ido P

2010-04-01

196

Effect of Serotonin Inhibition on Glucocorticoid and Mineralocorticoid Expression in Various Brain Structures  

Microsoft Academic Search

Many studies have shown the existence of functional interactions between central neurotransmitter systems and the hypothalamo-pituitary adrenal axis. Mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) are regulated by multiple factors including glucocorticoids themselves. Neurotransmitters such as serotonin (5-hydroxytryptamine: 5-HT) can regulate brain corticosteroid receptors in a complex way. The present study examined the short-term (48 h) effects of parachlorophenylalanine (PCPA),

Alexandra Semont; Marie-Pierre Fache; L’Houcine Ouafik; Micheline Hery; Maxime Faudon; Francis Hery

1999-01-01

197

Neurobehavioral toxic effects of perinatal oral exposure to aluminum on the developmental motor reflexes, learning, memory and brain neurotransmitters of mice offspring.  

PubMed

Aluminum (Al) is a known neurotoxicant and circumstantial evidence has linked this metal with several neurodegenerative disorders like Alzheimer's disease, but no causal relationship has yet been proved. Al-induced behavioral alterations as well as cognitive deficits and rodent brain neurotransmitter level, are well known in adults but the exact mechanism in the offspring of perinatally Al exposed dams is not yet understood properly and needs more attention. In the present study, the perinatal oral exposure of the dams to 300 and 600mg/kg/day Al (aluminum chloride) resulted in significant and deleterious effects in the offspring inflicting a dose-dependent reduction in postnatal body weight gain, delays in opening of the eyes and appearance of body hair fuzz, and deficits in the sensory motor reflexes of the mice pups during weaning period (from the day of birth to postnatal day 21). During adolescent ages of the male offspring, a significant and dose-dependent deficit was also observed in their locomotor activity at postnatal day 22 (PD 22), learning capability (at PD 25), and cognitive behavior (at PD 30-36). Furthermore, a significant and dose-dependent disturbance in the levels of neurotransmitters like dopamine (DA) and serotonin (5-HT) was also observed in the forebrain region of the offspring at PD 7, PD 14, PD 21, PD 30, and PD 36. Thus, perinatal Al exposure, particularly during pregnancy and lactation period, can affect the in utero developing fetus and postnatal developing sucklings, raising the concerns that during a critical perinatal period of brain development, Al exposure has potential and long lasting neurotoxic hazards and might modify the properties of the dopaminergic system and thus can change the threshold of that system or other related systems at later ages. A reduced use of Al during pregnancy is of crucial importance in preventing Al-induced delayed neurotoxicity in the offspring. PMID:22115621

Abu-Taweel, Gasem M; Ajarem, Jamaan S; Ahmad, Mohammad

2012-03-01

198

Comparative Developmental Neurotoxicity of Organophosphates In Vivo: Transcriptional Responses of Pathways for Brain Cell Development, Cell Signaling, Cytotoxicity and Neurotransmitter Systems  

PubMed Central

Organophosphates affect mammalian brain development through a variety of mechanisms beyond their shared property of cholinesterase inhibition. We used microarrays to characterize similarities and differences in transcriptional responses to chlorpyrifos and diazinon, assessing defined gene groupings for the pathways known to be associated with the mechanisms and/or outcomes of chlorpyrifos-induced developmental neurotoxicity. We exposed neonatal rats to daily doses of chlorpyrifos (1 mg/kg) or diazinon (1 or 2 mg/kg) on postnatal days 1-4 and evaluated gene expression profiles in brainstem and forebrain on day 5; these doses produce little or no cholinesterase inhibition. We evaluated pathways for general neural cell development, cell signaling, cytotoxicity and neurotransmitter systems, and identified significant differences for >60% of 252 genes. Chlorpyrifos elicited major transcriptional changes in genes involved in neural cell growth, development of glia and myelin, transcriptional factors involved in neural cell differentiation, cAMP-related cell signaling, apoptosis, oxidative stress, excitotoxicity, and development of neurotransmitter synthesis, storage and receptors for acetylcholine, serotonin, norepinephrine and dopamine. Diazinon had similar effects on many of the same processes but also showed major differences from chlorpyrifos. Our results buttress the idea that different organophosphates target multiple pathways involved in neural cell development but also that they deviate in key aspects that may contribute to disparate neurodevelopmental outcomes. Equally important, these pathways are compromised at exposures that are unrelated to biologically significant cholinesterase inhibition and its associated signs of systemic toxicity. The approach used here demonstrates how planned comparisons with microarrays can be used to screen for developmental neurotoxicity. PMID:17452286

Slotkin, Theodore A.; Seidler, Frederic J.

2007-01-01

199

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

PubMed

Orthotopic liver transplant (OLT) significantly improves patient outcomes in maple syrup urine disease (MSUD; OMIM: 248600), yet organ shortages point to the need for alternative therapies. Hepatocyte transplantation has shown both clinical and preclinical efficacy as an intervention for metabolic liver diseases, yet the availability of suitable livers for hepatocyte isolation is also limited. Conversely, human amnion epithelial cells (hAEC) may have utility as a hepatocyte substitute, and they share many of the characteristics of pluripotent embryonic stem cells while lacking their safety and ethical concerns. We reported that like hepatocytes, transplantation of hAEC significantly improved survival and lifespan, normalized body weight, and significantly improved branched-chain amino acid (BCAA) levels in sera and brain in a transgenic murine model of intermediate maple syrup urine disease (imsud). In the current report, we detail the neural and peripheral metabolic improvements associated with hAEC transplant in imsud mice, including amino acids associated with bioenergetics, the urea cycle, as well as the neurotransmitter systems for serotonin, dopamine, and gamma-aminobutyric acid (GABA). This stem cell therapy results in significant global correction of the metabolic profile that characterizes the disease, both in the periphery and the central nervous system, the target organ for toxicity in iMSUD. The significant correction of the disease phenotype, coupled with the theoretical benefits of hAEC, particularly their lack of immunogenicity and tumorigenicity, suggests that human amnion epithelial cells deserve serious consideration for clinical application to treat metabolic liver diseases. PMID:23566440

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

2013-06-01

200

Further structural exploration of trisubstituted asymmetric pyran derivatives (2S,4R,5R)-2-benzhydryl-5-benzylamino-tetrahydropyran-4-ol and their corresponding disubstituted (3S,6S) pyran derivatives: a proposed pharmacophore model for high-affinity interaction with the dopamine, serotonin, and norepinephrine transporters.  

PubMed

In our previous report, we described a novel series of asymmetric pyran derivatives (2S,4R,5R)-2-benzhydryl-5-benzylamino-tetrahydropyran-4-ol and their enantiomers as blockers of monoamine transporters in the brain. In this report, we describe the further exploration of this series of molecules by incorporating functional groups in the molecular template, which should promote the formation of H bonds with the transporters. In addition, a new synthetic scheme for the asymmetric synthesis of disubstituted cis-(6-benzhydryl-tetrahydro-pyran-3-yl)-benzylamine analogues and their biological characterization is reported. All synthesized derivatives were tested for their affinities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in inhibiting the uptake of [(3)H]DA, [(3)H]5-HT, and [(3)H]NE, respectively. The compounds were also tested for their binding potency at the DAT by their ability to inhibit binding of [(3)H]WIN 35, 428. The results indicated that the presence of functional groups, such as -OH, -NH(2), and the bioisosteric 5-substituted indole moiety in both di and trisubstituted compounds, significantly increased their potencies for the SERT and NET, especially for the NET. Among the trisubstituted compounds, (-)-4b exhibited the highest potency for the NET and the SERT (K(i) of 2.13 and 15.3 nM, respectively) and was a serotonin norepinephrine reuptake inhibitor (SNRI). Compound (-)-4a exhibited the highest selectivity for the NET. Among the disubstituted compounds, a number of compounds, such as (-)-9a, (+)-9b, (-)-9b, and (+)-9d, exhibited significant low-nanomolar potencies for the SERT and the NET. Interestingly, compound (-)-9d exhibited appreciable potencies at all three transporters. On the basis of our present and past findings, we propose a qualitative model for the interaction of these compounds with monoamine transporters, which will be refined further in the future. PMID:16821783

Zhang, Shijun; Fernandez, Fernando; Hazeldine, Stuart; Deschamps, Jeffrey; Zhen, Juan; Reith, Maarten E A; Dutta, Aloke K

2006-07-13

201

Circadian neurotransmitter activity resets the endogenous annual cycle in a migratory sparrow  

Microsoft Academic Search

Daily injections of neurotransmitter?affecting drugs induced spring migratory and reproductive conditions in white?throated sparrows, Zonotrichia albicollis, during the fall. Injections of DOPA (catecholamine precursor) 12 h after 5?HTP (serotonin precursor) was most stimulatory for development of spring conditions. Summer and fall conditions followed during subsequent months in a manner similar to the natural sequence. Changes in the temporal relations of

Larry J. Miller; Albert H. Meier

1983-01-01

202

A conserved salt bridge between transmembrane segments 1 and 10 constitutes an extracellular gate in the dopamine transporter.  

PubMed

Neurotransmitter transporters play an important role in termination of synaptic transmission by mediating reuptake of neurotransmitter, but the molecular processes behind translocation are still unclear. The crystal structures of the bacterial homologue, LeuT, provided valuable insight into the structural and dynamic requirements for substrate transport. These structures support the existence of gating domains controlling access to a central binding site. On the extracellular side, access is controlled by the "thin gate" formed by an interaction between Arg-30 and Asp-404. In the human dopamine transporter (DAT), the corresponding residues are Arg-85 and Asp-476. Here, we present results supporting the existence of a similar interaction in DAT. The DAT R85D mutant has a complete loss of function, but the additional insertion of an arginine in opposite position (R85D/D476R), causing a charge reversal, results in a rescue of binding sites for the cocaine analogue [(3)H]CFT. Also, the coordination of Zn(2+) between introduced histidines (R85H/D476H) caused a ? 2.5-fold increase in [(3)H]CFT binding (Bmax). Importantly, Zn(2+) also inhibited [(3)H]dopamine transport in R85H/D476H, suggesting that a dynamic interaction is required for the transport process. Furthermore, cysteine-reactive chemistry shows that mutation of the gating residues causes a higher proportion of transporters to reside in the outward facing conformation. Finally, we show that charge reversal of the corresponding residues (R104E/E493R) in the serotonin transporter also rescues [(3)H](S)-citalopram binding, suggesting a conserved feature. Taken together, these data suggest that the extracellular thin gate is present in monoamine transporters and that a dynamic interaction is required for substrate transport. PMID:25339174

Pedersen, Anders V; Andreassen, Thorvald F; Loland, Claus J

2014-12-12

203

Effect of novel atypical antipsychotic, blonanserin, on extracellular neurotransmitter level in rat prefrontal cortex.  

PubMed

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 ?(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 ?(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. PMID:21147094

Ohoyama, Keiko; Yamamura, Satoshi; Hamaguchi, Tatsuya; Nakagawa, Masanori; Motomura, Eishi; Shiroyama, Takashi; Tanii, Hisashi; Okada, Motohiro

2011-02-25

204

The D1 dopamine receptor agonist SKF-38393 stimulates the release of glutamate in the hippocampus  

Microsoft Academic Search

The present study was undertaken to better assess the role of dopamine on exocytosis. Since direct activation of adenylate cyclase (e.g., with forskolin) enhances neurotransmitter release it was of interest to see whether the activation of D1-type dopamine receptors, which are positively coupled to adenylate cyclase, could also modulate the molecular machinery underlying the fusion of synaptic vesicles and the

A. Bouron; H. Reuter

1999-01-01

205

Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease  

Microsoft Academic Search

Parkinson's disease is a widespread condition caused by the loss of midbrain neurons that synthesize the neurotransmitter dopamine. Cells derived from the fetal midbrain can modify the course of the disease, but they are an inadequate source of dopamine-synthesizing neurons because their ability to generate these neurons is unstable. In contrast, embryonic stem (ES) cells proliferate extensively and can generate

Jong-Hoon Kim; Jonathan M. Auerbach; José A. Rodríguez-Gómez; Iván Velasco; Denise Gavin; Nadya Lumelsky; Sang-Hun Lee; John Nguyen; Rosario Sánchez-Pernaute; Krys Bankiewicz; Ron McKay

2002-01-01

206

Dopamine-beta hydroxylase polymorphism and cocaine addiction  

Microsoft Academic Search

Cocaine addiction involves a number of medical, psychological and social problems. Understanding the genetic aetiology of this disorder will be essential for design of effective treatments. Dopamine-beta hydroxylase (DbH) catalyzes the conversion of dopamine to norepinephrine and could, therefore, have an influence on both cocaine action and the basal sensitivity of neurotransmitter systems to cocaine. Recently, the -1021C>T polymorphism have

Camila Guindalini; Ronaldo Laranjeira; David Collier; Guilherme Messas; Homero Vallada; Gerome Breen

2008-01-01

207

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

PubMed

Closely related species can exhibit different behaviours despite homologous neural substrates. The nudibranch molluscs Tritonia diomedea and Melibe leonina swim differently, yet their nervous systems contain homologous serotonergic neurons. In Tritonia, the dorsal swim interneurons (DSIs) are members of the swim central pattern generator (CPG) and their neurotransmitter serotonin is both necessary and sufficient to elicit a swim motor pattern. Here it is shown that the DSI homologues in Melibe, the cerebral serotonergic posterior-A neurons (CeSP-As), are extrinsic to the swim CPG, and that neither the CeSP-As nor their neurotransmitter serotonin is necessary for swim motor pattern initiation, which occurred when the CeSP-As were inactive. Furthermore, the serotonin antagonist methysergide blocked the effects of both the serotonin and CeSP-As but did not prevent the production of a swim motor pattern. However, the CeSP-As and serotonin could influence the Melibe swim circuit; depolarization of a cerebral serotonergic posterior-A was sufficient to initiate a swim motor pattern and hyperpolarization of a CeSP-A temporarily halted an ongoing swim motor pattern. Serotonin itself was sufficient to initiate a swim motor pattern or make an ongoing swim motor pattern more regular. Thus, evolution of species-specific behaviour involved alterations in the functions of identified homologous neurons and their neurotransmitter. PMID:18782747

Newcomb, James M; Katz, Paul S

2009-01-01

208

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

PubMed Central

Closely related species can exhibit different behaviours despite homologous neural substrates. The nudibranch molluscs Tritonia diomedea and Melibe leonina swim differently, yet their nervous systems contain homologous serotonergic neurons. In Tritonia, the dorsal swim interneurons (DSIs) are members of the swim central pattern generator (CPG) and their neurotransmitter serotonin is both necessary and sufficient to elicit a swim motor pattern. Here it is shown that the DSI homologues in Melibe, the cerebral serotonergic posterior-A neurons (CeSP-As), are extrinsic to the swim CPG, and that neither the CeSP-As nor their neurotransmitter serotonin is necessary for swim motor pattern initiation, which occurred when the CeSP-As were inactive. Furthermore, the serotonin antagonist methysergide blocked the effects of both the serotonin and CeSP-As but did not prevent the production of a swim motor pattern. However, the CeSP-As and serotonin could influence the Melibe swim circuit; depolarization of a cerebral serotonergic posterior-A was sufficient to initiate a swim motor pattern and hyperpolarization of a CeSP-A temporarily halted an ongoing swim motor pattern. Serotonin itself was sufficient to initiate a swim motor pattern or make an ongoing swim motor pattern more regular. Thus, evolution of species-specific behaviour involved alterations in the functions of identified homologous neurons and their neurotransmitter. PMID:18782747

Newcomb, James M; Katz, Paul S

2008-01-01

209

Serotonin, dopamine, noradrenaline and their metabolites: levels in the brain of the house cricket (Acheta domesticus L.) during a 24-hour period and after administration of quipazine--a 5-HT2 receptor agonist.  

PubMed

1. The levels of 5-HT, DA, NA and DA metabolites (NADA, DOPAC) measured by HPLC (with electrochemical detection) in the brain of the house cricket did not change over a 24-hr period. The level of 5-HIAA, a 5-HT metabolite, was below the limit of detection. 2. The 5-HT and DOPAC levels decreased and NADA increased after quipazine injection but DA and NA levels did not change after it. 3. [3H]Ketanserin was used to identify serotonin receptors bound to sites in the house cricket brain with a KD of 5 nM and a concentration of Bmax 180 fmol/mg protein. PMID:1687530

Pyza, E; Go?embiowska, K; Antkiewicz-Michaluk, L

1991-01-01

210

Molecular cloning of the mouse dopamine transporter and pharmacological comparison with the human homologue  

Microsoft Academic Search

Drug abuse is a serious problem in the United States and in the world. Cocaine and amphetamines, widely used drugs of abuse, bind to dopamine (DA), serotonin, and norepinephrine transporters with high affinity and block their functions. It is believed that the dopamine transporter plays a key role in the mechanism of cocaine addiction. Because a good portion of our

Xiaohong Wu; Howard H. Gu

1999-01-01

211

PET evaluation of the dopamine system of the human brain  

SciTech Connect

Dopamine plays a pivotal role in the regulation and control of movement, motivation and cognition. It also is closely linked to reward, reinforcement and addiction. Abnormalities in brain dopamine are associated with many neurological and psychiatric disorders including Parkinson`s disease, schizophrenia and substance abuse. This close association between dopamine and neurological and psychiatric diseases and with substance abuse make it an important topic in research in the neurosciences and an important molecular target in drug development. PET enables the direct measurement of components of the dopamine system in the living human brain. It relies on radiotracers which label dopamine receptors, dopamine transporters, precursors of dopamine or compounds which have specificity for the enzymes which degrade dopamine. Additionally, by using tracers that provide information on regional brain metabolism or blood flow as well as neurochemically specific pharmacological interventions, PET can be used to assess the functional consequences of change in brain dopamine activity. PET dopamine measurements have been used to investigate the normal human brain and its involvement in psychiatric and neurological diseases. It has also been used in psychopharmacological research to investigate dopamine drugs used in the treatment of Parkinson`s disease and of schizophrenia as well as to investigate the effects of drugs of abuse on the dopamine system. Since various functional and neurochemical parameters can be studied in the same subject, PET enables investigation of the functional integrity of the dopamine system in the human brain and investigation of the interactions of dopamine with other neurotransmitters. This paper summarizes the different tracers and experimental strategies developed to evaluate the various elements of the dopamine system in the human brain with PET and their applications to clinical research. 254 refs., 7 figs., 3 tabs.

Volkow, N.D.; Fowler, J.S.; Gatley, S. [Brookhaven National Laboratory, Upton, NY (United States)]|[SUNY-Stony Brook, NY (United States)] [and others

1996-07-01

212

New Arylpiperazinylalkyl Derivatives of 8-Alkoxy-purine-2,6-dione and Dihydro[1,3]oxazolo[2,3-f]purinedione Targeting the Serotonin 5-HT1A /5-HT2A /5-HT7 and Dopamine D2 Receptors.  

PubMed

To obtain potential antidepressants and/or antipsychotics, a series of new long-chain arylpiperazine derivatives of 8-alkoxy-purine-2,6-dione (10-24) and dihydro[1,3]oxazolo[2,3-f]purinedione (30-34) were synthesized and their serotonin (5-HT1A , 5-HT2A , 5-HT6 , 5-HT7 ) and dopamine (D2 ) receptor affinities were determined. The study allowed the identification of some potent 5-HT1A /5-HT7 /D2 ligands with moderate affinity for 5-HT2A sites. The binding mode of representative compounds from both chemical classes (11 and 31) in the site of 5-HT1A receptor was analyzed in computational studies. In functional in vitro studies, the selected compounds 15 and 16 showed antagonistic properties for the evaluated receptors. 8-Methoxy-7-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-1,3-dimethyl-purine-2,6-dione (15) showed a lack of activity in terms and under the conditions of the forced swim, four plate and amphetamine-induced hyperactivity tests in mice, probably as a result of its high first pass effect in the liver. PMID:25773907

Ch?o?-Rzepa, Gra?yna; Zagórska, Agnieszka; Bucki, Adam; Ko?aczkowski, Marcin; Paw?owski, Maciej; Sata?a, Grzegorz; Bojarski, Andrzej J; Partyka, Anna; Weso?owska, Anna; P?kala, El?bieta; S?oczy?ska, Karolina

2015-04-01

213

Monoamine neurotransmitters and fibroblast growth factor-2 in the brains of rats with post-stroke depression.  

PubMed

The aim of the present study was to investigate the changes in the levels of serotonin (5-HT), dopamine (DA), norepinephrine (NE) and fibroblast growth factor-2 (FGF-2) in the brains of rats with post-stroke depression (PSD). A rat model of stroke was established by middle cerebral artery occlusion and the rats were randomly divided into two groups: Control and modification groups. The rats in the modification group had PSD, while the rats in the control group had experienced a stroke only. The PSD model was established by applying chronic mild stress to the individually housed rats. High-performance liquid chromatography was used to detect the levels of 5-HT, DA and NE, while western blotting was used to detect the FGF-2 protein expression levels in the frontal lobe and hippocampus. Quantitative polymerase chain reaction was also used to determine the mRNA expression levels of FGF-2 in the frontal lobes of the two groups. The levels of 5-HT, DA and NE in the frontal lobe and hippocampus of the rats in the PSD group were significantly lower than the levels observed in the rats in the stroke group (P<0.01). In addition, protein expression levels of FGF-2 in the frontal lobe of the rats in the PSD group were significantly lower when compared with the control group rats (P<0.01), however, the protein expression levels of FGF-2 in the hippocampus did not exhibit a statistically significant difference (P>0.05). The mRNA expression levels of FGF-2 in the frontal lobe of the rats in the modification group were significantly lower than the levels in the control group rats (P<0.01). Therefore, reduced levels of monoamine neurotransmitters and FGF-2 expression in the brains of rats with PSD are associated with the incidence of PSD. PMID:24944615

Ji, Xiao-Wei; Wu, Chun-Ling; Wang, Xing-Chen; Liu, Jie; Bi, Jian-Zhong; Wang, Dian-Yun

2014-07-01

214

Effects of novel monoamine oxidases and cholinesterases targeting compounds on brain neurotransmitters and behavior in rat model of vascular dementia.  

PubMed

Neurodegenerative disorders are associated with different neurochemical and morphological alterations in the brain leading to cognitive and behavioural impairments. New therapeutic strategies comprise multifunctional drugs. The aim of the presented studies is to evaluate in vivo the novel compounds - ASS188 and ASS234 - which combine the benzylpiperidine moiety of the acetylcholinesteras (AChE) inhibitor donepezil and the indolyl propargylamino moiety of the monoaminooxidase (MAO) inhibitor, N-[(5-benzyloxy-1- methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine, with respect to their influence on cerebral amine neurotransmitters systems and neuroprotective activity. The presumed therapeutic potential of these compounds has been evaluated following their administration to rats with experimental vascular dementia. A rat model of the permanent bilateral occlusion of the common carotid arteries (BCCAO) and the holeboard memory test were employed for this purpose. Wistar rats were used, either intact or 1 day after BCCAO. ASS188 (1 mg/kg) and ASS234 (5 mg/kg) were given s.c. for 5 consecutive days. Working and reference memory in rats was evaluated by holeboard tests before- and 7 and 12 days after BCCAO. The activities of MAOs, AChE and histamine N-methyltransferase (HMT), as well as cerebral amines concentrations were assayed. A significant inhibition of brain MAO A (>95%) and weaker MAO B (ca 60%) and HMT (<30%) and reduced AChE activities were recorded with a pronounced (2 - 10 fold) increase in the cerebral concentrations of serotonin, dopamine, and noradrenaline and smaller rises (up to 30%) of histamine. The BCCAO rats treated with ASS188 or ASS234 tended to perform holeboard tests better than the BCCAO untreated group, indicating a beneficial effect of the administered therapeutics. PMID:23701539

Stasiak, Anna; Mussur, Miros?aw; Unzeta, Mercedes; Samadi, Abdelouahid; Marco-Contelles, José L; Fogel, W Agnieszka

2014-01-01

215

Serotonin and Mental Disorders: A Concise Review on Molecular Neuroimaging Evidence  

PubMed Central

Serotonin is one of the most important neurotransmitters influencing mental health and, thus, is a potential target for pharmaco-logical treatments. Functional neuroimaging techniques, such as positron-emission tomography (PET) and single photon emission computed tomography (SPECT), could provide persuasive evidence for the association between mental disorders and serotonin. In this concise review, we focus on evidence of the links between serotonin and major depressive disorders, as well as other mood disorders, anxiety disorders, schizophrenia, addiction, attention deficit hyperactivity disorder (ADHD), and autism. PMID:25598822

Lin, Shih-Hsien; Yang, Yen Kuang

2014-01-01

216

Monitoring serotonin signaling on a subsecond time scale  

PubMed Central

Serotonin modulates a variety of processes throughout the brain, but it is perhaps best known for its involvement in the etiology and treatment of depressive disorders. Microdialysis studies have provided a clear picture of how ambient serotonin levels fluctuate with regard to behavioral states and pharmacological manipulation, and anatomical and electrophysiological studies describe the location and activity of serotonin and its targets. However, few techniques combine the temporal resolution, spatial precision, and chemical selectivity to directly evaluate serotonin release and uptake. Fast-scan cyclic voltammetry (FSCV) is an electrochemical method that can detect minute changes in neurotransmitter concentration on the same temporal and spatial dimensions as extrasynaptic neurotransmission. Subsecond measurements both in vivo and in brain slice preparations enable us to tease apart the processes of release and uptake. These studies have particularly highlighted the significance of regulatory mechanisms to proper functioning of the serotonin system. This article will review the findings of FSCV investigations of serotonergic neurotransmission and discuss this technique's potential in future studies of the serotonin system. PMID:23760548

Dankoski, Elyse C.; Wightman, R. Mark

2013-01-01

217

Monitoring serotonin signaling on a subsecond time scale.  

PubMed

Serotonin modulates a variety of processes throughout the brain, but it is perhaps best known for its involvement in the etiology and treatment of depressive disorders. Microdialysis studies have provided a clear picture of how ambient serotonin levels fluctuate with regard to behavioral states and pharmacological manipulation, and anatomical and electrophysiological studies describe the location and activity of serotonin and its targets. However, few techniques combine the temporal resolution, spatial precision, and chemical selectivity to directly evaluate serotonin release and uptake. Fast-scan cyclic voltammetry (FSCV) is an electrochemical method that can detect minute changes in neurotransmitter concentration on the same temporal and spatial dimensions as extrasynaptic neurotransmission. Subsecond measurements both in vivo and in brain slice preparations enable us to tease apart the processes of release and uptake. These studies have particularly highlighted the significance of regulatory mechanisms to proper functioning of the serotonin system. This article will review the findings of FSCV investigations of serotonergic neurotransmission and discuss this technique's potential in future studies of the serotonin system. PMID:23760548

Dankoski, Elyse C; Wightman, R Mark

2013-01-01

218

The identification of a selective dopamine D2 partial agonist, D3 antagonist displaying high levels of brain exposure.  

PubMed

The identification of a highly selective D(2) partial agonist, D(3) antagonist tool molecule which demonstrates high levels of brain exposure and selectivity against an extensive range of dopamine, serotonin, adrenergic, histamine, and muscarinic receptors is described. PMID:20153647

Holmes, Ian P; Blunt, Richard J; Lorthioir, Olivier E; Blowers, Stephen M; Gribble, Andy; Payne, Andrew H; Stansfield, Ian G; Wood, Martyn; Woollard, Patrick M; Reavill, Charlie; Howes, Claire M; Micheli, Fabrizio; Di Fabio, Romano; Donati, Daniele; Terreni, Silvia; Hamprecht, Dieter; Arista, Luca; Worby, Angela; Watson, Steve P

2010-03-15

219

Increased expression of the dopamine transporter leads to loss of dopamine neurons, oxidative stress and l-DOPA reversible motor deficits.  

PubMed

The dopamine transporter is a key protein responsible for regulating dopamine homeostasis. Its function is to transport dopamine from the extracellular space into the presynaptic neuron. Studies have suggested that accumulation of dopamine in the cytosol can trigger oxidative stress and neurotoxicity. Previously, ectopic expression of the dopamine transporter was shown to cause damage in non-dopaminergic neurons due to their inability to handle cytosolic dopamine. However, it is unknown whether increasing dopamine transporter activity will be detrimental to dopamine neurons that are inherently capable of storing and degrading dopamine. To address this issue, we characterized transgenic mice that over-express the dopamine transporter selectively in dopamine neurons. We report that dopamine transporter over-expressing (DAT-tg) mice display spontaneous loss of midbrain dopamine neurons that is accompanied by increases in oxidative stress markers, 5-S-cysteinyl-dopamine and 5-S-cysteinyl-DOPAC. In addition, metabolite-to-dopamine ratios are increased and VMAT2 protein expression is decreased in the striatum of these animals. Furthermore, DAT-tg mice also show fine motor deficits on challenging beam traversal that are reversed with l-DOPA treatment. Collectively, our findings demonstrate that even in neurons that routinely handle dopamine, increased uptake of this neurotransmitter through the dopamine transporter results in oxidative damage, neuronal loss and l-DOPA reversible motor deficits. In addition, DAT over-expressing animals are highly sensitive to MPTP-induced neurotoxicity. The effects of increased dopamine uptake in these transgenic mice could shed light on the unique vulnerability of dopamine neurons in Parkinson's disease. PMID:25447236

Masoud, S T; Vecchio, L M; Bergeron, Y; Hossain, M M; Nguyen, L T; Bermejo, M K; Kile, B; Sotnikova, T D; Siesser, W B; Gainetdinov, R R; Wightman, R M; Caron, M G; Richardson, J R; Miller, G W; Ramsey, A J; Cyr, M; Salahpour, A

2015-02-01

220

The effect of brominated flame retardants on neurotransmitter uptake into rat brain synaptosomes and vesicles  

Microsoft Academic Search

The environmental levels of brominated flame retardants (BFRs) are increasing, but little is known about their toxic effects. In this paper, we show that some of the most important BFRs in commercial use today, have a neurotoxicological potential. Hexabromocyclododecane (HBCD) and tetrabromobisphenol-A (TBBPA) inhibit plasma membrane uptake of the neurotransmitters dopamine, glutamate and ?-amino-n-butyric acid (GABA) at a concentration level

Espen Mariussen; Frode Fonnum

2003-01-01

221

Dopamine receptor activation increases HIV entry into primary human macrophages.  

PubMed

Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers. PMID:25268786

Gaskill, Peter J; Yano, Hideaki H; Kalpana, Ganjam V; Javitch, Jonathan A; Berman, Joan W

2014-01-01

222

Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages  

PubMed Central

Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers. PMID:25268786

Gaskill, Peter J.; Yano, Hideaki H.; Kalpana, Ganjam V.; Javitch, Jonathan A.; Berman, Joan W.

2014-01-01

223

Increased dopamine tone during meditation-induced change of consciousness  

Microsoft Academic Search

This is the first in vivo demonstration of an association between endogenous neurotransmitter release and conscious experience. Using 11C-raclopride PET we demonstrated increased endogenous dopamine release in the ventral striatum during Yoga Nidra meditation. Yoga Nidra is characterized by a depressed level of desire for action, associated with decreased blood flow in prefrontal, cerebellar and subcortical regions, structures thought to

Troels W Kjaer; Camilla Bertelsen; Paola Piccini; David Brooks; Jørgen Alving; Hans C Lou

2002-01-01

224

Piribedil Could Modify Dopamine Turnover in Cochleas Under Noise Stimulation  

Microsoft Academic Search

Dopamine (DA) is one of the putative neurotransmitters of the lateral efferent olivocochlear fibers. The cochlear DA content after noise exposure was analyzed using high-performance liquid chromatography coupled with electrochemical detection. Animals were exposed for 1 h to white noise at 70, 90 or 110 dB SPL or were kept in conditions of silence. Half of the animals were pretreated

M. A. Vicente-Torres; P. Gil-Loyzaga; P. Fernández; A. Arce; A. Esquifino

1993-01-01

225

Serotonin decreases aggression via 5HT 1A receptors in the fighting fish Betta splendens  

Microsoft Academic Search

The role of the monoamine neurotransmitter serotonin (5-HT) in the modulation of conspecific aggression in the fighting fish (Betta splendens) was investigated using pharmacological manipulations. We used a fish's response to its mirror image as our index of aggressive behavior. We also investigated the effects of some manipulations on monoamine levels in the B. splendens brain. Acute treatment with 5-HT

Ethan D. Clotfelter; Erin P. O'Hare; Meredith M. McNitt; Russ E. Carpenter; Cliff H. Summers

2007-01-01

226

Larvae of small white butterfly, Pieris rapae, express a novel serotonin receptor  

Technology Transfer Automated Retrieval System (TEKTRAN)

The biogenic amine serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter in vertebrates and invertebrates. It acts in regulation and modulation of many physiological and behavioral processes through G protein-coupled receptors. Insects express five 5-HT receptor subtypes that share high simila...

227

Effects of Early Serotonin Programming on Fear Response, Memory and Aggression  

Technology Transfer Automated Retrieval System (TEKTRAN)

The neurotransmitter serotonin (5-HT) also acts as a neurogenic compound in the developing brain. Early administration of a 5-HT agonist could alter development of serotonergic circuitry, altering behaviors mediated by 5-HT signaling, including memory, fear and aggression. The present study was desi...

228

Serotonin as a Modulator of Glutamate- and GABA-Mediated Neurotransmission: Implications in Physiological Functions and in Pathology  

PubMed Central

The neurotransmitter serotonin (5-HT), widely distributed in the central nervous system (CNS), is involved in a large variety of physiological functions. In several brain regions 5-HT is diffusely released by volume transmission and behaves as a neuromodulator rather than as a “classical” neurotransmitter. In some cases 5-HT is co-localized in the same nerve terminal with other neurotransmitters and reciprocal interactions take place. This review will focus on the modulatory action of 5-HT on the effects of glutamate and ?-amino-butyric acid (GABA), which are the principal neurotransmitters mediating respectively excitatory and inhibitory signals in the CNS. Examples of interaction at pre-and/or post-synaptic levels will be illustrated, as well as the receptors involved and their mechanisms of action. Finally, the physiological meaning of neuromodulatory effects of 5-HT will be briefly discussed with respect to pathologies deriving from malfunctioning of serotonin system. PMID:18615128

Ciranna, L

2006-01-01

229

Chemical stimulants of leaf-trenching by cabbage loopers: natural products, neurotransmitters, insecticides, and drugs.  

PubMed

Larvae of the cabbage looper, Trichoplusia ni (Lepidoptera: Noctuidae), often transect leaves with a narrow trench before eating the distal section. The trench reduces larval exposure to exudates, such as latex, during feeding. Plant species that do not emit exudate, such as Plantago lanceolata, are not trenched. However, if exudate is applied to a looper's mouth during feeding on P. lanceolata, the larva will often stop and cut a trench. Dissolved chemicals can be similarly applied and tested for effectiveness at triggering trenching. With this assay, I have documented that lactucin from lettuce latex (Lactuca sativa), myristicin from parsley oil (Petroselinum crispum), and lobeline from cardinal flower (Lobelia cardinalis) elicit trenching. These compounds are the first trenching stimulants reported. Several other constituents of lettuce and parsley, including some phenylpropanoids, monoterpenes, and furanocoumarins had little or no activity. Cucurbitacin E glycoside found in cucurbits, another plant family trenched by cabbage loopers, also was inactive. Lactucin, myristicin, and lobeline all affect the nervous system of mammals, with lobeline acting specifically as an antagonist of nicotinic acetylcholine receptors. To determine if cabbage loopers respond selectively to compounds active at acetylcholine synapses, I tested several neurotransmitters, insecticides, and drugs with known neurological activity, many of which triggered trenching. Active compounds included dopamine, serotonin, the insecticide imidacloprid, and various drugs such as ipratropium, apomorphine, buspirone, and metoclopramide. These results document that noxious plant chemicals trigger trenching, that loopers respond to different trenching stimulants in different plants, that diverse neuroactive chemicals elicit the behavior, and that feeding deterrents are not all trenching stimulants. The trenching assay offers a novel approach for identifying defensive plant compounds with potential uses in agriculture or medicine. Cabbage loopers in the lab and field routinely trench and feed on plants in the Asteraceae and Apiaceae. However, first and third instar larvae enclosed on Lobelia cardinalis (Campanulaceae) failed to develop, even though the third instar larvae attempted to trench. Trenching ability does not guarantee effective feeding on plants with canal-borne exudates. Cabbage loopers must not only recognize and respond to trenching stimulants, they must also tolerate exudates during the trenching procedure to disable canalicular defenses. PMID:14584674

Dussourd, David E

2003-09-01

230

BASAL GANGLIA PATHOLOGY IN SCHIZOPHRENIA: DOPAMINE CONNECTIONS and ANOMALIES  

PubMed Central

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

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

2010-01-01

231

Biosensors for Brain Trauma and Dual Laser Doppler Flowmetry: Enoxaparin Simultaneously Reduces Stroke-Induced Dopamine and Blood Flow while Enhancing Serotonin and Blood Flow in Motor Neurons of Brain, In Vivo  

PubMed Central

Neuromolecular Imaging (NMI) based on adsorptive electrochemistry, combined with Dual Laser Doppler Flowmetry (LDF) is presented herein to investigate the brain neurochemistry affected by enoxaparin (Lovenox®), an antiplatelet/antithrombotic medication for stroke victims. NMI with miniature biosensors enables neurotransmitter and neuropeptide (NT) imaging; each NT is imaged with a response time in milliseconds. A semiderivative electronic reduction circuit images several NT’s selectively and separately within a response time of minutes. Spatial resolution of NMI biosensors is in the range of nanomicrons and electrochemically-induced current ranges are in pico- and nano-amperes. Simultaneously with NMI, the LDF technology presented herein operates on line by illuminating the living brain, in this example, in dorso-striatal neuroanatomic substrates via a laser sensor with low power laser light containing optical fiber light guides. NMI biotechnology with BRODERICK PROBE® biosensors has a distinct advantage over conventional electrochemical methodologies both in novelty of biosensor formulations and on-line imaging capabilities in the biosensor field. NMI with unique biocompatible biosensors precisely images NT in the body, blood and brain of animals and humans using characteristic experimentally derived half-wave potentials driven by oxidative electron transfer. Enoxaparin is a first line clinical treatment prescribed to halt the progression of acute ischemic stroke (AIS). In the present studies, BRODERICK PROBE® laurate biosensors and LDF laser sensors are placed in dorsal striatum (DStr) dopaminergic motor neurons in basal ganglia of brain in living animals; basal ganglia influence movement disorders such as those correlated with AIS. The purpose of these studies is to understand what is happening in brain neurochemistry and cerebral blood perfusion after causal AIS by middle cerebral artery occlusion in vivo as well as to understand consequent enoxaparin and reperfusion effects actually while enoxaparin is inhibiting blood clots to alleviate AIS symptomatology. This research is directly correlated with the medical and clinical needs of stroke victims. The data are clinically relevant, not only to movement dysfunction but also to the depressive mood that stroke patients often endure. These are the first studies to image brain neurotransmitters while any stroke medications, such as anti-platelet/anti-thrombotic and/or anti-glycoprotein are working in organ systems to alleviate the debilitating consequences of brain trauma and stroke/brain attacks. PMID:22346571

Broderick, Patricia A.; Kolodny, Edwin H.

2011-01-01

232

How Addictive Drugs Disrupt Presynaptic Dopamine Neurotransmission  

PubMed Central

The fundamental principle that unites addictive drugs appears to be that each enhances synaptic dopamine by means that dissociate it from normal behavioral control, so that they act to reinforce their own acquisition. This occurs via the modulation of synaptic mechanisms involved in learning, including enhanced excitation or disinhibition of dopamine neuron activity, blockade of dopamine reuptake, and altering the state of the presynaptic terminal to enhance evoked over basal transmission. Amphetamines offer an exception to such modulation in that they combine multiple effects to produce non-exocytic stimulation-independent release of neurotransmitter via reverse transport independent from normal presynaptic function. Questions on the molecular actions of addictive drugs, prominently including the actions of alcohol and solvents, remain unresolved, but their ability to co-opt normal presynaptic functions helps to explain why treatment for addiction has been challenging. PMID:21338876

Sulzer, David

2011-01-01

233

Ectopic Expression of the Serotonin 1c Receptor and the Triggering of Malignant Transformation  

NASA Astrophysics Data System (ADS)

Neurotransmitter receptors are usually restricted to neuronal cells, but the signaling pathways activated by these receptors are widely distributed in both neural and non-neural cells. The functional consequences of activating a brain-specific neurotransmitter receptor, the serotonin 5HTlc receptor, in the unnatural environment of a fibroblast were examined. Introduction of functional 5HTlc receptors into NIH 3T3 cells results, at high frequency, in the generation of transformed foci. Moreover, the generation and maintenance of transformed foci requires continued activation of the serotonin receptor. In addition, the injection of cells derived from transformed foci into nude mice results in the generation of tumors. The serotonin 5HTlc receptor therefore functions as a protooncogene when expressed in NIH 3T3 fibroblasts.

Julius, David; Livelli, Thomas J.; Jessell, Thomas M.; Axel, Richard

1989-06-01

234

The serotonin aldehyde, 5-HIAL, oligomerizes alpha-synuclein.  

PubMed

In Parkinson's disease (PD) alpha-synuclein oligomers are thought to be pathogenic, and 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate aldehyde intermediate in neuronal dopamine metabolism, potently oligomerizes alpha-synuclein. PD involves alpha-synuclein deposition in brainstem raphe nuclei; however, whether 5-hydroxyindoleacetaldehyde (5-HIAL), the aldehyde of serotonin, oligomerizes alpha-synuclein has been unknown. In this study we tested whether 5-HIAL oligomerizes alpha-synuclein in vitro and in PC12 cells conditionally over-expressing alpha-synuclein. Alpha-synuclein oligomers were quantified by western blotting after incubation of alpha-synuclein with serotonin and monoamine oxidase-A (MAO-A) to generate 5-HIAL or dopamine to generate DOPAL. Oligomerization of alpha-synuclein in PC12 cells over-expressing the protein was compared between vehicle-treated cells and cells incubated with levodopa to generate DOPAL or 5-hydroxytryptophan to generate 5-HIAL. Monoamine aldehyde mediation of the oligomerization was assessed using the MAO inhibitor, pargyline. Dopamine and serotonin incubated with MAO-A both strongly oligomerized alpha-synuclein (more than 10 times control); pargyline blocked the oligomerization. In synuclein overexpressing PC12 cells, levodopa and 5-hydroxytryptophan elicited pargyline-sensitive alpha-synuclein oligomerization. 5-HIAL oligomerizes alpha-synuclein both in vitro and in synuclein-overexpressing PC12 cells, in a manner similar to DOPAL. The findings may help explain loss of serotonergic neurons in PD. PMID:25637699

Jinsmaa, Yunden; Cooney, Adele; Sullivan, Patricia; Sharabi, Yehonatan; Goldstein, David S

2015-03-17

235

Mifepristone modulates serotonin transporter function  

PubMed Central

Regulating serotonin expression can be used to treat psychotic depression. Mifepristone, a glucocorticoid receptor antagonist, is an effective candidate for psychotic depression treatment. However, the underlying mechanism related to serotonin transporter expression is poorly understood. In this study, we cloned the human brain serotonin transporter into Xenopus oocytes, to establish an in vitro expression system. Two-electrode voltage clamp recordings were used to detect serotonin transporter activity. Our results show that mifepristone attenuates serotonin transporter activity by directly inhibiting the serotonin transporter, and suggests that the serotonin transporter is a pharmacological target of mifepristone for the treatment of psychotic depression. PMID:25206868

Li, Chaokun; Shan, Linlin; Li, Xinjuan; Wei, Linyu; Li, Dongliang

2014-01-01

236

Neurotransmitter mechanisms in gabapentin antinociception.  

PubMed

The present study was done to investigate the neurotransmitter mechanisms involved in gabapentin antinociception in healthy albino rats. The formalin test was used to asses antinociception. Gabapentin (10-120 mg/kg s.c.) decreased the pain score in the formalin test. In order to study the putative neurotransmitter mechanisms involved in gabapentin action, the effect of gabapentin (30 mg/kg s.c.) alone and in rats pretreated with different receptor blockers, e.g. bicuculine, saclofen, naloxone, mecamylamine, atropine, DL-p-chlorophenylalanine methyl ester hydrochloride, glibenclamide, theophylline, and L-arginine was assessed. Gabapentin decreased the pain score, and the ED(50) of gabapentin was 36.8 +/- 8.2 (30.2-43.1) mg/kg s.c. Pretreatment with different receptor blockers did not modify gabapentin (30 mg/kg s.c.) antinociception except for L-arginine which increased the pain score from 1.68 +/- 0.29 (gabapentin) to 2.29 +/- 0.41. Results suggest the involvement of L-arginine nitric oxide pathways in gabapentin antinociception. PMID:12119449

Dixit, R K; Bhargava, V K

2002-08-01

237

Zn 2+ Modulation of Neurotransmitter Transporters  

Microsoft Academic Search

Neurotransmitter transporters located at the presynaptic or glial cell membrane are responsible for the stringent and rapid\\u000a clearance of the transmitter from the synapse, and hence they terminate signaling and control the duration of synaptic inputs\\u000a in the brain. Two distinct families of neurotransmitter transporters have been identified based on sequence homology: (1)\\u000a the neurotransmitter sodium symporter family (NSS), which

K. Nørgaard-Nielsen; U. Gether

238

Prefrontal and striatal dopamine metabolism during enhanced rebound hyperphagia induced by space restriction—a rat model of binge eating  

Microsoft Academic Search

Background: Several lines of evidence indicate that abnormalities in brain dopamine and serotonin metabolism may play an important role in bulimia nervosa. However, the regional neurochemical mechanism of the binge eating is poorly understood. Our purpose was to elucidate brain neurochemical mechanisms of binge eating using a rat model.Methods: The dopamine release and metabolism in the prefrontal cortex (PFC) and

Koki Inoue; Nobuo Kiriike; Masakage Okuno; Yasutoshi Fujisaki; Masanori Kurioka; Shinichi Iwasaki; Sakae Yamagami

1998-01-01

239

The Dopamine D2 Receptor Gene, Perceived Parental Support, and Adolescent Loneliness: Longitudinal Evidence for Gene-Environment Interactions  

ERIC Educational Resources Information Center

Background: Loneliness is a common problem in adolescence. Earlier research focused on genes within the serotonin and oxytocin systems, but no studies have examined the role of dopamine-related genes in loneliness. In the present study, we focused on the dopamine D2 receptor gene (DRD2). Methods: Associations among the DRD2, sex, parental support,…

van Roekel, Eeske; Goossens, Luc; Scholte, Ron H. J.; Engels, Rutger C. M. E.; Verhagen, Maaike

2011-01-01

240

Serotonin Deficiency Exacerbates Acetaminophen-Induced Liver Toxicity In Mice  

PubMed Central

Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-induced hepatotoxicity, as well as the role of 5-HT in the liver's response to APAP toxicity. We induced APAP hepatotoxicity in mice either sufficient of serotonin (wild-type mice and TPH1-/- plus 5- Hydroxytryptophan (5-HTP)) or lacking peripheral serotonin (Tph1-/- and wild-type mice plus p-chlorophenylalanine (PCPA)).Mice with sufficient 5-HT exposed to acetaminophen have a significantly lower mortality rate and a better outcome compared with mice deficient of 5-HT. This difference is at least partially attributable to a decreased level of inflammation, oxidative stress and endoplasmic reticulum (ER) stress, Glutathione (GSH) depletion, peroxynitrite formation, hepatocyte apoptosis, elevated hepatocyte proliferation, activation of 5-HT2B receptor, less activated c-Jun NH2-terminal kinase (JNK) and hypoxia-inducible factor (HIF)-1? in the mice sufficient of 5-HT versus mice deficient of 5-HT. We thus propose a physiological function of serotonin that serotonin could ameliorate APAP-induced liver injury mainly through inhibiting hepatocyte apoptosis ER stress and promoting liver regeneration. PMID:25631548

Zhang, Jingyao; Song, Sidong; Pang, Qing; Zhang, Ruiyao; Zhou, Lei; Liu, Sushun; Meng, Fandi; Wu, Qifei; Liu, Chang

2015-01-01

241

Serotonin deficiency exacerbates acetaminophen-induced liver toxicity in mice.  

PubMed

Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-induced hepatotoxicity, as well as the role of 5-HT in the liver's response to APAP toxicity. We induced APAP hepatotoxicity in mice either sufficient of serotonin (wild-type mice and TPH1-/- plus 5- Hydroxytryptophan (5-HTP)) or lacking peripheral serotonin (Tph1-/- and wild-type mice plus p-chlorophenylalanine (PCPA)). Mice with sufficient 5-HT exposed to acetaminophen have a significantly lower mortality rate and a better outcome compared with mice deficient of 5-HT. This difference is at least partially attributable to a decreased level of inflammation, oxidative stress and endoplasmic reticulum (ER) stress, Glutathione (GSH) depletion, peroxynitrite formation, hepatocyte apoptosis, elevated hepatocyte proliferation, activation of 5-HT2B receptor, less activated c-Jun NH?-terminal kinase (JNK) and hypoxia-inducible factor (HIF)-1? in the mice sufficient of 5-HT versus mice deficient of 5-HT. We thus propose a physiological function of serotonin that serotonin could ameliorate APAP-induced liver injury mainly through inhibiting hepatocyte apoptosis ER stress and promoting liver regeneration. PMID:25631548

Zhang, Jingyao; Song, Sidong; Pang, Qing; Zhang, Ruiyao; Zhou, Lei; Liu, Sushun; Meng, Fandi; Wu, Qifei; Liu, Chang

2015-01-01

242

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

PubMed Central

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

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

2014-01-01

243

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

PubMed

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

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

2015-05-01

244

Reduced presynaptic dopamine receptor density after chronic antidepressant treatment in rats.  

PubMed

Chronic administration of desipramine and nomifensine to rats reduced the number of presynaptic dopamine receptors as labeled by 3H-dopamine in rat striatal tissues, with no change in receptor affinity. This change can only be brought about by continuous daily treatment with antidepressants for a duration of at least 21 days or longer. All antidepressants did not displace 3H-spiperone or 3H-dopamine at low concentrations in vitro, suggesting that the agents may not act on the dopamine receptors directly. A possible interaction between neurotransmitters in the central nervous system for the overall therapeutic effect of antidepressant drugs was proposed. PMID:6957896

Lee, T; Tang, S W

1982-08-01

245

The serotonin transporter gene (5-HTT) variant and psychiatric disorders: review of current literature.  

PubMed

Both serotonin and the serotonin transporter, which transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons, play an important role in the pathophysiology of several psychiatric disorders. Mutations associated with the serotonin transporter gene may result in changes in serotonin transporter function. The serotonin transporter gene promoter variant, consisting of a long (L) and a short (S) variant, is one of the major factors which contribute to the etiology of many psychiatric disorders. In this regard, many studies have been published on association of this variant with various psychiatric disorders. This repeat length variant in the promoter region of this gene has been shown to affect the rate of serotonin uptake and may play a role in post-traumatic stress disorder and depression-susceptibility in people experiencing emotional trauma. Associations between a functional variant in the serotonin transporter anxiety-related personality traits were found, as well as the risk of developing depression, alcoholism or suicidal behavior. Understanding of possible associations of these variants and psychiatric disorders would bring progress in principles and treatment of many disorders. PMID:20150867

Kuzelova, Hana; Ptacek, Radek; Macek, Milan

2010-01-01

246

Combined serotonin (5-HT)1A agonism, 5-HT2A and dopamine D2 receptor antagonism reproduces atypical antipsychotic drug effects on phencyclidine-impaired novel object recognition in rats.  

PubMed

Subchronic administration of an N-methyl-d-aspartate receptor (NMDAR) antagonist, e.g. phencyclidine (PCP), produces prolonged impairment of novel object recognition (NOR), suggesting they constitute a hypoglutamate-based model of cognitive impairment in schizophrenia (CIS). Acute administration of atypical, e.g. lurasidone, but not typical antipsychotic drugs (APDs), e.g. haloperidol, are able to restore NOR following PCP (acute reversal model). Furthermore, atypical APDs, when co-administered with PCP, have been shown to prevent development of NOR deficits (prevention model). Most atypical, but not typical APDs, are more potent 5-HT2A receptor inverse agonists than dopamine (DA) D2 antagonists, and have been shown to enhance cortical and hippocampal efflux and to be direct or indirect 5-HT1A agonists in vivo. To further clarify the importance of these actions to the restoration of NOR by atypical APDs, sub-effective or non-effective doses of combinations of the 5-HT1A partial agonist (tandospirone), the 5-HT2A inverse agonist (pimavanserin), or the D2 antagonist (haloperidol), as well as the combination of all three agents, were studied in the acute reversal and prevention PCP models of CIS. Only the combination of all three agents restored NOR and prevented the development of PCP-induced deficit. Thus, this triple combination of 5-HT1A agonism, 5-HT2A antagonism/inverse agonism, and D2 antagonism is able to mimic the ability of atypical APDs to prevent or ameliorate the PCP-induced NOR deficit, possibly by stimulating signaling cascades from D1 and 5-HT1A receptor stimulation, modulated by D2 and 5-HT2A receptor antagonism. PMID:25448429

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

2015-05-15

247

Neurotransmitter Receptors in Fetal Tissue Transplants: Expression and Functional Significance  

PubMed Central

Numerous studies have examined receptor expression in neural transplants and their possible role in transplant-induced functional recovery from lesion-induced deficits. Herein we attempt to summarize the results of these studies, especially those from studies involving striatal transplants. Autoradiographic studies indicate that dopamine D1 and D2, muscarinic, cholinergic, 5-HT2, opiate ?, ? adrenergic and cholecystokinin (CCK) receptors are present in striatal transplants. Many of these receptors are present regardless of the transplant location and surrounding environment. This suggests that the expression of these receptors is determined by intrinsic properties of transplanted tissue, and is independent of transplant location and environment. Some transplant receptors, such as dopamine D1 and D2 and muscarinic receptors in striatal transplants, or 5-HT2 receptors in cortical transplants, display a patchy distribution which is dissimilar to that in the corresponding adult host tissue. This manuscript discusses this “abnormal” receptor distribution and possible explanations. Electrophysiological studies have indicated that some of the transplant receptors respond to physiological and pharmacological stimulation, suggesting that they are functional. However, the association of receptor expression with behavioral recovery is uncertain. The expression of neurotransmitter receptors in neural transplants may not be essential for the functional recovery associated with trophic mechanisms. However, neurotrammitter receptors may play an important role when functional recovery requires neur0anatomical integration between the host brain and the transplanted tissue. PMID:8018753

Lu, Sunny Y.; Norman, Andrew B.

1993-01-01

248

Signaling Pathways Take Aim at Neurotransmitter Transporters  

NSDL National Science Digital Library

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

Michael B. Robinson (University of Pennsylvania; Departments of Pediatrics and Pharmacology, Children's Hospital of Philadelphia REV)

2003-11-04

249

Getting his act together: roles of glutamate, nitric oxide, and dopamine in the medial preoptic area.  

PubMed

Gonadal hormones have primarily slow, genomically mediated effects, but copulation requires rapid interactions with a partner. A major way in which hormones facilitate male sexual behavior is by increasing production of neurotransmitter receptors or of enzymes that regulate neurotransmitter synthesis or release. Dopamine is an important facilitative neurotransmitter, and the medial preoptic area (MPOA) is a critical integrative site for male sexual behavior. MPOA dopamine is released before and during mating and facilitates copulation, genital reflexes, and sexual motivation. Gonadal hormones regulate dopamine release in the MPOA of male rats in part by increasing nitric oxide synthase (NOS) in the MPOA; the resultant increase in production of nitric oxide (NO) increases both basal and female-stimulated dopamine release. Glutamate also increases dopamine release via increased production of NO. At least some of the glutamatergic inputs to the MPOA are from the medial amygdala (MeA) and bed nucleus of the stria terminalis (BNST), which mediate the female-stimulated increase in dopamine, which in turn enhances copulatory ability. Extracellular glutamate in the MPOA increases during copulation, especially during ejaculation, and increased glutamate facilitates copulation and genital reflexes. Previous sexual experience also facilitates copulation and confers resistance to impairment by various lesions, drugs, and stress. Experience enhances processing of sexual stimuli, and its effects require activation of glutamate NMDA receptors and NOS in the MPOA. Neuronal NOS is increased in the MPOA of experienced males. Therefore, glutamate, NO, and dopamine interact in the MPOA to facilitate mating and to enhance future sexual responsiveness. PMID:16963001

Hull, Elaine M; Dominguez, Juan M

2006-12-18

250

Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects: dopamine transporter occupancy as measured by PET.  

PubMed

Tesofensine (TE) is a novel triple monoamine re-uptake inhibitor inducing a potent inhibition of the re-uptake process in the synaptic cleft of the neurotransmitters dopamine, norepinephrine, and serotonin. In recent preclinical and clinical evaluations TE showed a robust anti-obesity effect, but the specific mechanism of this triple monoamine re-uptake inhibitor still needs to be further elucidated. This positron emission tomography (PET) study, using [¹¹C]?CIT-FE, aimed to assess the degree of the dopamine transporter (DAT) occupancy, at constant TE plasma levels, following different oral, multiple doses of TE during totally 8-12 days. In addition, the relationships between DAT occupancy and TE plasma concentrations, or doses, were investigated to enable assessment of DAT occupancies in subsequent clinical trials. The results demonstrated that TE induced a dose-dependent blockade of DAT following multiple doses of 0.125-1 mg TE at anticipated steady-state conditions. The mean striatal DAT occupancy varied dose-dependently between 18% and 77%. A sigmoid E(max) model well described the relationship between striatal DAT occupancy and TE plasma concentrations or doses. It was estimated that the maximum achievable DAT occupancy was about 80% and that half of this effect was accomplished by approximately 0.25 mg TE and a plasma drug concentration of 4 ng/ml. The results indicated an important mechanism of action of TE on DAT. Further, these results suggest that the previously reported dose-dependent weight loss, in TE treated subjects, was in part mediated by an up-regulation of dopaminergic pathways due to enhanced amounts of synaptic dopamine after blockade of DAT. PMID:24239329

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

2014-02-01

251

Fast Phasic Release Properties of Dopamine Studied with a Channel Biosensor  

PubMed Central

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

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

2014-01-01

252

Presence and Function of Dopamine Transporter (DAT) in Stallion Sperm: Dopamine Modulates Sperm Motility and Acrosomal Integrity  

PubMed Central

Dopamine is a catecholamine with multiple physiological functions, playing a key role in nervous system; however its participation in reproductive processes and sperm physiology is controversial. High dopamine concentrations have been reported in different portions of the feminine and masculine reproductive tract, although the role fulfilled by this catecholamine in reproductive physiology is as yet unknown. We have previously shown that dopamine type 2 receptor is functional in boar sperm, suggesting that dopamine acts as a physiological modulator of sperm viability, capacitation and motility. In the present study, using immunodetection methods, we revealed the presence of several proteins important for the dopamine uptake and signalling in mammalian sperm, specifically monoamine transporters as dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters in equine sperm. We also demonstrated for the first time in equine sperm a functional dopamine transporter using 4-[4-(Dimethylamino)styryl]-N-methylpyridinium iodide (ASP+), as substrate. In addition, we also showed that dopamine (1 mM) treatment in vitro, does not affect sperm viability but decreases total and progressive sperm motility. This effect is reversed by blocking the dopamine transporter with the selective inhibitor vanoxerine (GBR12909) and non-selective inhibitors of dopamine reuptake such as nomifensine and bupropion. The effect of dopamine in sperm physiology was evaluated and we demonstrated that acrosome integrity and thyrosine phosphorylation in equine sperm is significantly reduced at high concentrations of this catecholamine. In summary, our results revealed the presence of monoamine transporter DAT, NET and SERT in equine sperm, and that the dopamine uptake by DAT can regulate sperm function, specifically acrosomal integrity and sperm motility. PMID:25402186

Covarrubias, Alejandra A.; Rodríguez-Gil, Joan Enric; Ramírez-Reveco, Alfredo; Concha, Ilona I.

2014-01-01

253

Effects of dietary amino acids, carbohydrates, and choline on neurotransmitter synthesis  

NASA Technical Reports Server (NTRS)

The ability of a meal to increase or decrease brain neurotransmitter synthesis has been studied. It is concluded that brain serotonin synthesis is directly controlled by the proportions of carbohydrate to protein in meals and snacks that increase or decrease brain tryptophan levels, thereby changing the substrate saturation of tryptophan hydroxylase and the rate of serotonin synthesis. The ability of serotoninergic neurons to have their output coupled to dietary macronutrients enables them to function as sensors of peripheral metabolism, and to subserve an important role in the control of appetite. The robust and selective responses of catecholaminergic and cholinergic neurons to supplemental tyrosine and choline suggest that these compounds may become useful as a new type of drug for treating deseases or conditions in which adequate quantities of the transmitter would otherwise be unavailable.

Wurtman, Richard J.

1988-01-01

254

Acute pancreatitis affects the metabolism of catecholamine neurotransmitters in rats.  

PubMed

Abnormalities of mental status represent a severe complication and an important cause of death in acute pancreatitis (AP), which is characterized by a pattern of neurological signs and symptoms. As some of the symptoms of AP are also affected by catecholamine neurotransmitters, they cannot be ruled out of the pathophysiology of AP; however, little research has been performed exploring this hypothesis. Our study aimed to elucidate whether AP affects the metabolism of catecholamine neurotransmitters in rats. A total of 300 male SD rats were randomly divided into five groups: control, 6H, 24H, 48H and 72H experimental groups. AP was induced in rats by an injection of a sodium taurocholate solution via a cannulated bile-pancreatic duct. In the striatum, hippocampus and cerebellum, catecholamine neurotransmitters were tested using high performance liquid chromatography equipped with a electrochemical detector, and the activities and protein concentration levels of monoamine oxidase A (MAO-A) and tyrosine hydroxylase (TH) were also evaluated using ELISA and Western blotting analyses. In the hippocampus, the dopamine (DA) concentrations increased in the 48-h and 72-h groups. The 3,4-dihydroxyphenylacetic acid (DOPAC) concentration of the 72-h group also increased. The MAO-A and TH activity of the 6-h and 24-h groups decreased, respectively. The TH activities of the 48-h groups also decreased. The MAO-A and TH protein concentration of the 6-h and 24-h groups decreased. In the corpus striatum, the homovanillic acid concentration of the 72-h group and norepinephrine concentrations of the 24-h and 48-h groups increased, respectively. The MAO-A and TH activities of the 6-h and 24-h groups decreased. The MAO-A and TH protein concentrations of the 6-h and 24-h groups decreased. In the prefrontal cortex (left prefrontal lobe), the DA and DOPAC concentrations of the 48-h group increased. The MAO-A and TH activities of the 6-h, 24-h and 48-h groups decreased. The MAO-A and TH protein concentrations of the 6-h and 24-h groups also decreased. The other catecholamine concentration and enzyme activities fluctuated, but there was no statistically significant difference compared with the control group. Catecholamine neurotransmitter metabolic systems are widely affected in AP, and these fluctuations may play an important role in determining the symptomatology of AP. PMID:24657461

Jiang, H; Li, F; Liu, S; Sun, H; Cui, Y; Wu, Y

2014-05-30

255

Immunohistological localization of serotonin in the CNS and feeding system of the stable fly stomoxys calcitrans L. (Diptera: muscidae)  

Technology Transfer Automated Retrieval System (TEKTRAN)

Serotonin, or 5-hydroxytryptamine (5-HT), plays critical roles as a neurotransmitter and neuromodulator that control or modulate many behaviors in insects, such as feeding. Neurons immunoreactive (IR)to 5-HT were detected in the central nervous system (CNS) of the larval and adult stages of the stab...

256

Neurotransmitters, temperament and social functioning.  

PubMed

Dimensional models can be usefully employed to describe both normal and disordered personality. Studies in molecular genetics, receptor binding, peripheral monoamines and pharmacological challenges have investigated the neurochemical basis of personality. Substantial evidence now exists to support a psychobiological model but the specificity of Cloninger's theory has not always been confirmed. Clinical studies have shown both temperament and character dimensions to improve with pharmacological treatment especially in treatment responders. Some personality changes are found to be independent of clinical effects and even to occur in normal subjects. Models of personality can help in predicting treatment outcome but individual dimensions may not be useful. It is hypothesised that social adaptation is related to the character dimensions and different sources of evidence link these to serotonergic actions. However, recent clinical studies have shown a specific effect of noradrenaline on self-perception and social motivation. Drugs with specific actions on different neurotransmitters may exert a distinctive pattern of effects on personality and social behaviour. PMID:11532380

Bond, A J

2001-08-01

257

Rationality and emotionality: serotonin transporter genotype influences reasoning bias  

PubMed Central

Reasoning often occurs under emotionally charged, opinion-laden circumstances. The belief-bias effect indexes the extent to which reasoning is based upon beliefs rather than logical structure. We examined whether emotional content increases this effect, particularly for adults genetically predisposed to be more emotionally reactive. SS/SLG carriers of the serotonin transporter genotype (5-HTTLPR) were less accurate selectively for evaluating emotional relational reasoning problems with belief-logic conflict relative to LALA carriers. Trait anxiety was positively associated with emotional belief-bias, and the 5-HTTLPR genotype significantly accounted for the variance in this association. Thus, deductive reasoning, a higher cognitive ability, is sensitive to differences in emotionality rooted in serotonin neurotransmitter function. PMID:22275169

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

2013-01-01

258

Antidepressant Binding Site in a Bacterial Homologue of Neurotransmitter Transporters  

SciTech Connect

Sodium-coupled transporters are ubiquitous pumps that harness pre-existing sodium gradients to catalyse the thermodynamically unfavourable uptake of essential nutrients, neurotransmitters and inorganic ions across the lipid bilayer. Dysfunction of these integral membrane proteins has been implicated in glucose/galactose malabsorption, congenital hypothyroidism, Bartter's syndrome, epilepsy, depression, autism and obsessive-compulsive disorder. Sodium-coupled transporters are blocked by a number of therapeutically important compounds, including diuretics, anticonvulsants and antidepressants, many of which have also become indispensable tools in biochemical experiments designed to probe antagonist binding sites and to elucidate transport mechanisms. Steady-state kinetic data have revealed that both competitive and noncompetitive modes of inhibition exist. Antagonist dissociation experiments on the serotonin transporter (SERT) have also unveiled the existence of a low-affinity allosteric site that slows the dissociation of inhibitors from a separate high-affinity site. Despite these strides, atomic-level insights into inhibitor action have remained elusive. Here we screen a panel of molecules for their ability to inhibit LeuT, a prokaryotic homologue of mammalian neurotransmitter sodium symporters, and show that the tricyclic antidepressant (TCA) clomipramine noncompetitively inhibits substrate uptake. Cocrystal structures show that clomipramine, along with two other TCAs, binds in an extracellular-facing vestibule about 11 {angstrom} above the substrate and two sodium ions, apparently stabilizing the extracellular gate in a closed conformation. Off-rate assays establish that clomipramine reduces the rate at which leucine dissociates from LeuT and reinforce our contention that this TCA inhibits LeuT by slowing substrate release. Our results represent a molecular view into noncompetitive inhibition of a sodium-coupled transporter and define principles for the rational design of new inhibitors.

Singh,S.; Yamashita, A.; Gouaux, E.

2007-01-01

259

Neurotransmitter GABA activates muscle but not ?7 nicotinic receptors.  

PubMed

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 (?Y190 and ?G153) affect GABA activation similarly as ACh activation, whereas a mutation at the complementary face (?G57) shows a selective effect for GABA. Studies with subunit-lacking receptors show that GABA can activate muscle nAChRs through the ?/? 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 ?7 or the chimeric ?7-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. PMID:25492812

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

2015-01-01

260

Serotonin and Social Norms  

PubMed Central

How do people sustain resources for the benefit of individuals and communities and avoid the tragedy of the commons, in which shared resources become exhausted? In the present study, we examined the role of serotonin activity and social norms in the management of depletable resources. Healthy adults, alongside social partners, completed a multiplayer resource-dilemma game in which they repeatedly harvested from a partially replenishable monetary resource. Dietary tryptophan depletion, leading to reduced serotonin activity, was associated with aggressive harvesting strategies and disrupted use of the social norms given by distributions of other players’ harvests. Tryptophan-depleted participants more frequently exhausted the resource completely and also accumulated fewer rewards than participants who were not tryptophan depleted. Our findings show that rank-based social comparisons are crucial to the management of depletable resources, and that serotonin mediates responses to social norms. PMID:24815611

Bilderbeck, Amy C.; Brown, Gordon D. A.; Read, Judi; Woolrich, Mark; Cowen, Phillip J.; Behrens, Tim E. J.

2014-01-01

261

Effects of endogenous dopamine on measures of [18F]N-methylspiroperidol binding in the basal ganglia: Comparison of simulations and experimental results from PET studies in baboons  

Microsoft Academic Search

The effect of endogenous dopamine on PET measures of radioligand binding is important to the measurement of receptor density (or availability) and neurotransmitter interactions in vivo. We recently reported that pretreatment with amphetamine, a drug which stimulates dopamine release, significantly reduced NMS binding in the baboon brain as determined by the product Ak3 derived from the graphical analysis method for

Jean Logan; Stephen L. Dewey; Alfred P. Wolf; Joanna S. Fowler; Jonathan D. Brodie; Burton Angrist; Nora D. Volkow; S. John Gatley

1991-01-01

262

Serotonin Could Play a Large Role in Bone Loss  

NSDL National Science Digital Library

Press release - Scientists have long known that calcium leaches from the bones both during lactation and in certain types of cancer. The driver behind these phenomena is a molecule called parathyroid hormone related protein (PTHrP), which is secreted by the mammary glands. The signal that regulates the secretion of PTHrP, and where this other unknown molecule exerts its influence, has remained a mystery. Now, in a new study using cells and tissues from mice, cows, and people, a team of researchers at the University of Cincinnati have identified this mystery molecule as serotonin, a neurotransmitter most often recognized for its role in happiness and well-being. The scientists also identified the specific receptor that serotonin acts on in mammary tissue. Understanding these two findings more deeply could lead to better ways to combat bone loss, potentially by using drugs that affect serotonin signaling. The study is entitled Â?Mammary Gland Serotonin Regulates Parathyroid Hormone-Related Protein and Other Bone-Related SignalsÂ?. It appears in the Articles in PresS section of the American Journal of Physiology Â? Endocrinology and Metabolism, published by the American Physiological Society (APS).

APS Communications Office (American Physiological Society Communications Office)

2012-02-21

263

Waterborne lead affects circadian variations of brain neurotransmitters in fathead minnows  

SciTech Connect

Lead is a potent neurotoxin affecting brain levels of a number of vertebrate neurotransmitters. Reports on these effects are, however, not consistent either among or within species. For example, with lead-intoxicated rats there are reports of decreased acetylcholine (ACh) release and decreased ACh brain levels as well as reports of increased levels or no change in levels. Also, with rats there are reports of increased levels, decreased levels, or no change in brain catecholamines, with lead producing similar changes in both norephinephrine (NE) and dopamine (DA) in some cases and differences in response between the two in others. Although most early reports dealt with whole brain levels, reports on neurotransmitter levels in specific brain regions can be equally conflicting. Similar sorts of discrepancies exist among studies with fishes. Much of the variation among studies on lead effects on neurotransmitters is, no doubt, due to differences among the studies in variables such as: species, age, dosage and duration, route of administration. However, lead can apparently affect circadian locomotor rhythms of both rats and fishes. Therefore, another possible cause for the variation among studies is that there is an interaction among dosage, sampling time and endogenous rhythms. A lead-produced phase shift or disruption in endogenous neurotransmitter rhythms could in turn elicit a host of varying results and interpretations depending on the circadian time of sampling. We elected to examine this possibility in the fathead minnow, Pimephales promelas, a freshwater species widely used for toxicity studies. 15 refs., 3 figs.

Spieler, R.E. [Nova Southeastern Univ., Dania, FL (United States); Russo, A.C. [California State Univ., Long Beach, CA (United States); Weber, D.N. [Univ. of Wisconsin, Milwaukee, WI (United States)

1995-09-01

264

l-dopa-induced dopamine synthesis and oxidative stress in serotonergic cells  

PubMed Central

l-dopa is a precursor for dopamine synthesis and a mainstay treatment for Parkinson's disease. However, l-dopa therapy is not without side effects that may be attributed to non-dopaminergic mechanisms. Synthesized dopamine can be neurotoxic through its enzymatic degradation by monoamine oxidase (MAO) to form the reactive byproduct, hydrogen peroxide and hydroxyl radicals or through auto-oxidation to form highly reactive quinones that can bind proteins and render them non-functional. Since l-dopa could be decarboxylated by aromatic amino acid decarboxylase (AADC) present within both dopamine and serotonin neurons, it was hypothesized that serotonin neurons convert l-dopa into dopamine to generate excessive reactive oxygen species and quinoproteins that ultimately lead to serotonin neuron death. To examine the effects of l-dopa on serotonin neurons, the RN46A-B14 cell line was used. These immortalized serotonergic cell cultures were terminally differentiated and then incubated with varying concentrations of l-dopa. Results show that RN46A-B14 cells contain AADC and can synthesize dopamine after incubation with l-dopa. Furthermore, l-dopa dose-dependently increased intracellular reactive oxygen species (ROS) and cell death. Dopamine, ROS production and cell death were attenuated by co-incubation with the AADC inhibitor, NSD-1015. The MAO inhibitor, pargyline, also attenuated cell death and ROS after l-dopa treatment. Lastly, quinoprotein formation was enhanced significantly by incubation with l-dopa. Taken together, these data illustrate that serotonergic cells can produce dopamine and that the accumulation of dopamine after l-dopa and its subsequent degradation can lead to ROS production and death of RN46A-B14 serotonergic cells. PMID:23196068

Stansley, Branden J.; Yamamoto, Bryan K.

2013-01-01

265

Role of Dopamine Transporter in Methamphetamine-Induced Neurotoxicity: Evidence from Mice Lacking the Transporter  

Microsoft Academic Search

The role of the dopamine transporter (DAT) in mediating the neurotoxic effects of methamphetamine (METH) was tested in mice lacking DAT. Dopamine (DA) and serotonin (5-HT) content, glial fibrillary acidic protein (GFAP) expression, and free radical formation were assessed as markers of METH neurotoxicity in the striatum and\\/or hippocampus of wild-type, heterozygote, and homozygote (DAT 2\\/2) mice. Four injections of

Fabio Fumagalli; Raul R. Gainetdinov; Kenneth J. Valenzano; Marc G. Caron

1998-01-01

266

The neurotropic parasite Toxoplasma gondii increases dopamine metabolism.  

PubMed

The highly prevalent parasite Toxoplasma gondii manipulates its host's behavior. In infected rodents, the behavioral changes increase the likelihood that the parasite will be transmitted back to its definitive cat host, an essential step in completion of the parasite's life cycle. The mechanism(s) responsible for behavioral changes in the host is unknown but two lines of published evidence suggest that the parasite alters neurotransmitter signal transduction: the disruption of the parasite-induced behavioral changes with medications used to treat psychiatric disease (specifically dopamine antagonists) and identification of a tyrosine hydroxylase encoded in the parasite genome. In this study, infection of mammalian dopaminergic cells with T. gondii enhanced the levels of K+-induced release of dopamine several-fold, with a direct correlation between the number of infected cells and the quantity of dopamine released. Immunostaining brain sections of infected mice with dopamine antibody showed intense staining of encysted parasites. Based on these analyses, T. gondii orchestrates a significant increase in dopamine metabolism in neural cells. Tyrosine hydroxylase, the rate-limiting enzyme for dopamine synthesis, was also found in intracellular tissue cysts in brain tissue with antibodies specific for the parasite-encoded tyrosine hydroxylase. These observations provide a mechanism for parasite-induced behavioral changes. The observed effects on dopamine metabolism could also be relevant in interpreting reports of psychobehavioral changes in toxoplasmosis-infected humans. PMID:21957440

Prandovszky, Emese; Gaskell, Elizabeth; Martin, Heather; Dubey, J P; Webster, Joanne P; McConkey, Glenn A

2011-01-01

267

Discovery of Novel Selective Serotonin Reuptake Inhibitors Through Development of a Protein-Based Pharmacophore  

PubMed Central

The serotonin transporter (SERT), a member of the neurotransmitter sodium symporter (NSS) family, is responsible for the reuptake of serotonin from the synaptic cleft to maintain neurotransmitter homeostasis. SERT is established as an important target in the treatment of anxiety and depression. Because a high-resolution crystal structure is not available, a computational model of SERT was built based upon the x-ray coordinates of the leucine transporter LeuT, a bacterial NSS homolog. The model was used to develop the first SERT structure-based pharmacophore. Virtual screening (VS) of a small molecule structural library using the generated SERT computational model yielded candidate ligands of diverse scaffolds. Pharmacological analysis of the VS hits identified two SERT-selective compounds, potential lead compounds for further SERT-related medication development. PMID:21834587

Manepalli, Sankar; Geffert, Laura M.; Surratt, Christopher K.

2011-01-01

268

Genetic variation of serotonin receptor function affects prepulse inhibition of the startle  

Microsoft Academic Search

Prepulse inhibition (PPI) is the attenuation of the startle response towards an instantaneous and intense stimulus when preceded\\u000a by a weaker non-startling stimulus. Deficits in this sensorimotor gating process have been associated with the pathophysiology\\u000a of schizophrenia and other psychiatric disorders. Among the neurotransmitters involved in PPI modulation, serotonin (5-HT)\\u000a has so far received comparably little attention. While a recent

David Bräuer; Alexander Strobel; Tilman Hensch; Kersten Diers; Klaus-Peter Lesch; Burkhard Brocke

2009-01-01

269

Serotonin stimulates secretion of exosomes from microglia cells.  

PubMed

Microglia are resident immune cells in the brain and exert important functions in the regulation of inflammatory processes during infection or cellular damage. Upon activation, microglia undergo complex morphological and functional transitions, including increased motility, phagocytosis and cytokine secretion. Recent findings indicate that exosomes, small vesicles that derive from fusion of multivesicular bodies with the plasma membrane, are involved in secretion of certain cytokines. The presence of specific receptors on the surface of microglia suggests communication with neurons by neurotransmitters. Here, we demonstrate expression of serotonin receptors, including 5-HT2a,b and 5-HT4 in microglial cells and their functional involvement in the modulation of exosome release by serotonin. Our data demonstrate the involvement of cAMP and Ca(2+) dependent signaling pathways in the regulation of exosome secretion. Co-culture of microglia with embryonic stem cell-derived serotonergic neurons further demonstrated functional signaling between neurons and microglia. Together, these data provide evidence for neurotransmitter-dependent signaling pathways in microglial cells that regulate exosome release. GLIA 2015;63:626-634. PMID:25451814

Glebov, Konstantin; Löchner, Marie; Jabs, Ronald; Lau, Thorsten; Merkel, Olaf; Schloss, Patrick; Steinhäuser, Christian; Walter, Jochen

2015-04-01

270

In Vivo Calibration of Microdialysis Using Infusion of Stable-Isotope Labeled Neurotransmitters  

PubMed Central

In vivo calibration of microdialysis probes is required for interpreting measured concentrations. The most popular method of in vivo calibration is no-net-flux (NNF), which requires infusing several concentrations of neurotransmitters to determine in vivo recoveries (extraction fraction or Ed) and extracellular concentrations. A new method for in vivo calibration of microdialysis of neurotransmitters using glutamate (GLU) and dopamine (DA) as model analytes is reported. 13C6-DA and 13C5-GLU were perfused through microdialysis probes as internal calibrators. Using liquid chromatography with mass spectrometry, it was possible to distinguish the 13C-forms from the endogenous forms of each neurotransmitter. Ed was directly calculated by measuring the loss of the 13C-forms during infusion. The measured endogenous 12C forms of the neurotransmitters could be corrected for Ed to give calibrated extracellular concentrations in vivo. Retrodialysis of stable-isotope-labeled (SIL) neurotransmitters gave Ed and extracellular concentrations of 13C5-GLU and 13C6-DA that matched no-net-flux measurements; however, the values were obtained in a fraction of time because no added measurements were required to obtain the calibration. Ed was reduced during uptake inhibition for GLU and DA when measured by SIL retrodialysis. Because Ed is directly measured at each microdialysis fraction, it was possible to monitor changes in Ed under transient conditions created by systemic injection of uptake inhibitors. The results show that DA and GLU concentrations are underestimated by as much as 50% if not corrected for Ed during uptake inhibition. SIL retrodialysis provides equivalent information to NNF at much reduced time and animal use. PMID:23374073

2013-01-01

271

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

ERIC Educational Resources Information Center

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

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

2012-01-01

272

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

ERIC Educational Resources Information Center

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

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

2010-01-01

273

Effects of ethanol on striatal dopamine overflow and clearance: An in vivo electrochemical study  

Microsoft Academic Search

Previous studies have shown that the neurotransmitter dopamine (DA) is implicated in the reinforcing effects of ethanol and other abused drugs. Ethanol also alters DA overflow and uptake in vivo. Further studies of the role of DA in the behavioral and neurochemical effects of ethanol may help explain the pharmacological mechanisms by which these effects are produced. In these studies

Yun Wang; Michael R. Palmer; Elizabeth J. Cline; Greg A. Gerhardt

1997-01-01

274

Dopamine toxicity in neuroblastoma cells: role of glutathione depletion by l-BSO and apoptosis  

Microsoft Academic Search

Dopamine (DA), while an essential neurotransmitter, is also a known neurotoxin that potentially plays an etiologic role in several neurodegenerative diseases. DA metabolism and oxidation readily produce reactive oxygen species (ROS) and DA can also be oxidized to a reactive quinone via spontaneous, enzyme-catalyzed or metal-enhanced reactions. A number of these reactions are cytotoxic, yet the precise mechanisms by which

Alan H Stokes; Denise Y Lewis; Lawrence H Lash; W. Gray Jerome; Ken W Grant; Michael Aschner; Kent E Vrana

2000-01-01

275

GTP cyclohydrolase I feedback regulatory protein is expressed in serotonin neurons and regulates tetrahydrobiopterin biosynthesis.  

PubMed

Tetrahydrobiopterin, the coenzyme required for hydroxylation of phenylalanine, tyrosine, and tryptophan, regulates its own synthesis through feedback inhibition of GTP cyclohydrolase I (GTPCH) mediated by a regulatory subunit, the GTP cyclohydrolase feedback regulatory protein (GFRP). In the liver, L-phenylalanine specifically stimulates tetrahydrobiopterin synthesis by displacing tetrahydrobiopterin from the GTPCH-GFRP complex. To explore the role of this regulatory system in rat brain, we examined the localization of GFRP mRNA using double-label in situ hybridization. GFRP mRNA expression was abundant in serotonin neurons of the dorsal raphe nucleus but was undetectable in dopamine neurons of the midbrain or norepinephrine neurons of the locus coeruleus. Simultaneous nuclease protection assays for GFRP and GTPCH mRNAs showed that GFRP mRNA is most abundant within the brainstem and that the ratio of GFRP to GTPCH mRNA is much higher than in the ventral midbrain. Two species of GFRP mRNA differing by approximately 20 nucleotides in length were detected in brainstem but not in other tissues, with the longer, more abundant form being common to other brain regions. It is interesting that the pineal and adrenal glands did not contain detectable levels of GFRP mRNA, although GTPCH mRNA was abundant in both. Primary neuronal cultures were used to examine the role of GFRP-mediated regulation of GTPCH on tetrahydrobiopterin synthesis within brainstem serotonin neurons and midbrain dopamine neurons. L-Phenylalanine increased tetrahydrobiopterin levels in serotonin neurons to a maximum of twofold in a concentration-dependent manner, whereas D-phenylalanine and L-tryptophan were without effect. In contrast, tetrahydrobiopterin levels within cultured dopamine neurons were not altered by L-phenylalanine. The time course of this effect was very rapid, with a maximal response observed within 60 min. Inhibitors of tetrahydrobiopterin biosynthesis prevented the L-phenylalanine-induced increase in tetrahydrobiopterin levels. 7,8-Dihydroneopterin, a reduced pteridine capable of inhibiting GTPCH in a GFRP-dependent manner, decreased tetrahydrobiopterin levels in cultures of both serotonin and dopamine neurons. This inhibition was reversed by L-phenylalanine in serotonin but not in dopamine neurons. Our data suggest that GTPCH activity within serotonin neurons is under a tonic inhibitory tone mediated by GFRP and that tetrahydrobiopterin levels are maintained by the balance of intracellular concentrations of tetrahydrobiopterin and L-phenylalanine. In contrast, although tetrahydrobiopterin biosynthesis within dopamine neurons is also feedback-regulated, L-phenylalanine plays no role, and therefore tetrahydrobiopterin may have a direct effect on GTPCH activity. PMID:9930739

Kapatos, G; Hirayama, K; Shimoji, M; Milstien, S

1999-02-01

276

Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin  

PubMed Central

Serotonin is a major neurotransmitter in the central nervous system (CNS). Dysregulation of serotonin transmission in the CNS is reported to be related to different psychiatric disorders in humans including depression, impulsive aggression and anxiety disorders. The most frequently prescribed antidepressants and anxiolytics target the serotonergic system. However, these drugs are not effective in 20–30% of cases. The causes of this failure as well as the molecular mechanisms involved in the origin of psychological disorders are poorly understood. Biosynthesis of serotonin in the CNS is initiated by tryptophan hydroxylase 2 (TPH2). In this study, we used Tph2-deficient (Tph2?/?) mice to evaluate the impact of serotonin depletion in the brain on mouse behavior. Tph2?/? mice exhibited increased depression-like behavior in the forced swim test but not in the tail suspension test. In addition, they showed decreased anxiety-like behavior in three different paradigms: elevated plus maze, marble burying and novelty-suppressed feeding tests. These phenotypes were accompanied by strong aggressiveness observed in the resident–intruder paradigm. Despite carrying only one copy of the gene, heterozygous Tph2+/? mice showed only 10% reduction in brain serotonin, which was not sufficient to modulate behavior in the tested paradigms. Our findings provide unequivocal evidence on the pivotal role of central serotonin in anxiety and aggression. PMID:22832966

Mosienko, V; Bert, B; Beis, D; Matthes, S; Fink, H; Bader, M; Alenina, N

2012-01-01

277

Hypothalamic dopamine and serotonin in the regulation of food intake  

Microsoft Academic Search

Because daily food intake is the product of the size of a meal and the frequency of meals ingested, the characteristic of meal size to meal number during a 24-h light–dark cycle constitutes an identifiable pattern specific to normal states and obesity and that occurs during early cancer anorexia. An understanding of simultaneous changes in meal size and meal number

Michael M Meguid; Serguei O Fetissov; Madhu Varma; Tomoi Sato; Lihua Zhang; Alessandro Laviano; Filippo Rossi-Fanelli

2000-01-01

278

Modeling Dopamine and Serotonin Systems in a Visual Recognition Network  

E-print Network

would like to thank Majtoba Solgi for his aid in providing the facial images used for both testing. The development consists of three stages: prenatal, birth, and development. During the prenatal stage, the agent

279

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

ERIC Educational Resources Information Center

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

Qi, Zhenghan; Gold, Paul E.

2009-01-01

280

Synthesis on accumulation of putative neurotransmitters by cultured neural crest cells  

SciTech Connect

The events mediating the differentiation of embryonic neural crest cells into several types of neurons are incompletely understood. In order to probe one aspect of this differentiation, we have examined the capacity of cultured quail trunk neural crest cells to synthesize, from radioactive precursors, and store several putative neurotransmitter compounds. These neural crest cultures develop the capacity to synthesize and accumulate acetylcholine and the catecholamines norepinephrine and dopamine. In contrast, detectable but relatively little synthesis and accumulation of 5-hydroxytryptamine gamma-aminobutyric acid, or octopamine from the appropriate radiolabeled precursors were observed. The capacity for synthesis and accumulation of radiolabeled acetylcholine and catecholamines is very low or absent at 2 days in vitro. Between 3 and 7 days in vitro, there is a marked rise in both catecholamine and acetylcholine accumulation in the cultures. These findings suggest that, under the particular conditions used in these experiments, the development of neurotransmitter biosynthesis in trunk neural crest cells ijs restricted and resembles, at least partially, the pattern observed in vivo. The development of this capacity to synthesize and store radiolabeled acetylcholine and catecholamines from the appropriate radioactive precursors coincides closely with the development of the activities of the synthetic enzymes choline acetyltransferase and dopamine beta-hydroxylase reported by others.

Maxwell, G.D.; Sietz, P.D.; Rafford, C.E.

1982-07-01

281

Neurotransmitter receptor heteromers and their integrative role in ‘local modules’: The striatal spine module  

PubMed Central

‘Local module’ is a fundamental functional unit of the central nervous system that can be defined as the minimal portion of one or more neurons and-or one or more glial cells that operates as an independent integrative unit. This review focuses on the importance of neurotransmitter receptor heteromers for the operation of local modules. To illustrate this, we use the striatal spine module (SSM), comprised of the dendritic spine of the medium spiny neuron (MSN), its glutamatergic and dopaminergic terminals and astroglial processes. The SSM is found in the striatum, and although aspects such as neurotransmitters and receptors will be specific to the SSM, some general principles should apply to any local module in the brain. The analysis of some of the receptor heteromers in the SSM shows that receptor heteromerization is associated with particular elaborated functions in this local module. Adenosine A2A receptor-dopamine D2 receptor-glutamate metabotropic mGlu5 receptor heteromers are located adjacent to the glutamatergic synapse of the dendritic spine of the enkephalin MSN, and their cross-talk within the receptor heteromers helps to modulate postsynaptic plastic changes at the glutamatergic synapse. A1 receptor-A2A receptor heteromers are found in the glutamatergic terminals and the molecular cross-talk between the two receptors in the heteromer helps to modulate glutamate release. Finally, dopamine D2 receptor-non-?7 nicotinic acetylcholine receptor heteromers, which are located in dopaminergic terminals, introduce the new concept of autoreceptor heteromer. PMID:17408563

Ferré, Sergi; Agnati, Luigi F.; Ciruela, Francisco; Lluis, Carme; Woods, Amina S.; Fuxe, Kjell; Franco, Rafael

2007-01-01

282

Dopamine D3 and 5-HT1B receptor dysregulation as a result of psychostimulant intake and forced abstinence: Implications for medications development  

PubMed Central

Addiction to psychostimulants, including cocaine and amphetamine, is associated with dysregulation of dopamine and serotonin (5-HT) neurotransmitter systems. Neuroadaptations in these systems vary depending on the stage of the drug taking-abstinence-relapse cycle. Consequently, the effects of potential treatments that target these systems may vary depending on whether they are given during abstinence or relapse. In this review, we discuss evidence that dopamine D3 receptors (D3Rs) and 5-HT1B receptors (5-HT1BRs) are dysregulated in response to both chronic psychostimulant use and subsequent abstinence. We then review findings from preclinical self-administration models which support targeting D3Rs and 5-HT1BRs as potential medications for psychostimulant dependence. Potential side effects of the treatments are discussed and attention is given to studies reporting positive treatment outcomes that depend on: 1) whether testing occurs during abstinence versus relapse, 2) whether escalation of drug self-administration has occurred, 3) whether the treatments are given repeatedly, and 4) whether social factors influence treatment outcomes. We conclude that D3/D2 agonists may decrease psychostimulant intake; however, side effects of D3/D2R full agonists may limit their therapeutic potential, whereas D3/D2R partial agonists likely have fewer undesirable side effects. D3-selective antagonists may not reduce psychostimulant intake during relapse, but nonetheless, may decrease motivation for seeking psychostimulants with relatively few side-effects. 5-HT1BR agonists provide a striking example of treatment outcomes that are dependent on the stage of the addiction cycle. Specifically, these agonists initially increase cocaine’s reinforcing effects during maintenance of self-administration, but after a period of abstinence they reduce psychostimulant seeking and the resumption of self-administration. In conclusion, we suggest that factors contributing to dysregulation of monoamine systems, including drug history, abstinence, and social context, should be considered when evaluating potential treatments to better model treatment effects in humans. PMID:23973315

Neisewander, Janet L.; Cheung, Timothy H. C.; Pentkowski, Nathan S.

2014-01-01

283

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

PubMed

Serotonin is a neuromodulator that is involved extensively in behavioral, affective, and cognitive functions in the brain. Previous recording studies of the midbrain dorsal raphe nucleus (DRN) revealed that the activation of putative serotonin neurons correlates with the levels of behavioral arousal [1], rhythmic motor outputs [2], salient sensory stimuli [3-6], reward, and conditioned cues [5-8]. The classic theory on serotonin states that it opposes dopamine and inhibits behaviors when aversive events are predicted [9-14]. However, the therapeutic effects of serotonin signal-enhancing medications have been difficult to reconcile with this theory [15, 16]. In contrast, a more recent theory states that serotonin facilitates long-term optimal behaviors and suppresses impulsive behaviors [17-21]. To test these theories, we developed optogenetic mice that selectively express channelrhodopsin in serotonin neurons and tested how the activation of serotonergic neurons in the DRN affects animal behavior during a delayed reward task. The activation of serotonin neurons reduced the premature cessation of waiting for conditioned cues and food rewards. In reward omission trials, serotonin neuron stimulation prolonged the time animals spent waiting. This effect was observed specifically when the animal was engaged in deciding whether to keep waiting and was not due to motor inhibition. Control experiments showed that the prolonged waiting times observed with optogenetic stimulation were not due to behavioral inhibition or the reinforcing effects of serotonergic activation. These results show, for the first time, that the timed activation of serotonin neurons during waiting promotes animals' patience to wait for a delayed reward. PMID:25155504

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

2014-09-01

284

Association study of serotonin 2A receptor ( 5HT2A) gene with schizophrenia and suicidal behavior using systematic meta-analysis  

Microsoft Academic Search

Serotonin 2A receptor (5-HT2A) gene was implicated to be associated with both schizophrenia and suicidal behavior due to its role of key neurotransmitter in many physiologic processes. Association studies were reported in different populations, however, a great number of subsequent studies have produced contrary results, possibly reflecting inadequate statistical power. With the cumulative data in recent years in both European

Dawei Li; Yun Duan; Lin He

2006-01-01

285

Presynaptic inhibition of elicited neurotransmitter release  

Microsoft Academic Search

Activation of presynaptic receptors for a variety of neurotransmitters and neuromodulators inhibits transmitter release at many synapses. Such presynaptic inhibition might serve as a means of adjusting synaptic strength or preventing excessive transmitter release, or both. Previous evidence showed that presynaptic modulators inhibit Ca2+ channels and activate K+ channels at neuronal somata. These modulators also inhibit spontaneous transmitter release by

Ling-Gang Wu; Peter Saggau

1997-01-01

286

Detection and Quantification of Neurotransmitters in Dialysates  

PubMed Central

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

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

2010-01-01

287

Lipid raft microdomains and neurotransmitter signalling  

Microsoft Academic Search

Lipid rafts are specialized structures on the plasma membrane that have an altered lipid composition as well as links to the cytoskeleton. It has been proposed that these structures are membrane domains in which neurotransmitter signalling might occur through a clustering of receptors and components of receptor-activated signalling cascades. The localization of these proteins in lipid rafts, which is affected

John A. Allen; Robyn A. Halverson-Tamboli; Mark M. Rasenick

2006-01-01

288

RESPONSES OF NEUROTRANSMITTER SYSTEMS TO TOXICANT EXPOSURE  

EPA Science Inventory

As technology has become more refined and available in recent years, a major focus for neurotoxicologists has been the evaluation of toxicant effects on neuronal function. This interest will probably increase as the number of new chemical messengers (i.e., neurotransmitters and n...

289

Potential Strategies for Ameliorating Early Cancer Anorexia  

Microsoft Academic Search

Background.Normally the lateral hypothalamic area (LHA) and the ventromedial nucleus (VMN) interact to regulate food intake (FI), the product of meal number (MN) and meal size (MZ), by changes in neurotransmitters, mainly dopamine and serotonin. Change in LHA dopamine influences meal size; while in VMN, decreasing dopamine and increasing serotonin levels influence meal number. Whether this situation exists in early

M. Varma; G. F. Torelli; M. M. Meguid; J-K Chai; V. Blaha; A. Laviano; H-J Kim

1999-01-01

290

Imaging neurotransmitter uptake and depletion in astrocytes  

SciTech Connect

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

Tan, W. [Ames Laboratory-USDOE and Department of Chemistry, Iowa State University, Ames, Iowa 50011 (United States)] [Ames Laboratory-USDOE and Department of Chemistry, Iowa State University, Ames, Iowa 50011 (United States); [Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200 (United States); Haydon, P.G. [Department of Zoology and Genetics, Laboratory of Cellular Signaling, Iowa State University, Ames, Iowa 50011 (United States)] [Department of Zoology and Genetics, Laboratory of Cellular Signaling, Iowa State University, Ames, Iowa 50011 (United States); Yeung, E.S. [Ames Laboratory-USDOE and Department of Chemistry, Iowa State University, Ames, Iowa 50011 (United States)] [Ames Laboratory-USDOE and Department of Chemistry, Iowa State University, Ames, Iowa 50011 (United States)

1997-08-01

291

Serotonin System Implication in l-DOPA-Induced Dyskinesia: From Animal Models to Clinical Investigations  

PubMed Central

In the recent years, the serotonin system has emerged as a key player in the induction of l-DOPA-induced dyskinesia (LID) in animal models of Parkinson’s disease. In fact, serotonin neurons possess the enzymatic machinery able to convert exogenous l-DOPA to dopamine (DA), and mediate its vesicular storage and release. However, serotonin neurons lack a feedback control mechanism able to regulate synaptic DA levels. While in a situation of partial DA depletion spared DA terminals can buffer DA released from serotonin neurons, the progression of DA neuron degeneration impairs this protective mechanism, causing swings in synaptic DA levels and pulsatile stimulation of post-synaptic DA receptors. In line with this view, removal of serotonin neurons by selective toxin, or pharmacological silencing of their activity, produced complete suppression of LID in animal models of Parkinson’s disease. In this article, we will revise the experimental evidence pointing to the important role of serotonin neurons in dyskinesia, and we will discuss the clinical implications. PMID:24904522

Carta, Manolo; Tronci, Elisabetta

2014-01-01

292

Intranasal exposure to manganese disrupts neurotransmitter release from glutamatergic synapses in the central nervous system in vivo  

PubMed Central

Chronic exposure to aerosolized manganese induces a neurological disorder that includes extrapyramidal motor symptoms and cognitive impairment. Inhaled manganese can bypass the blood-brain barrier and reach the central nervous system by transport down the olfactory nerve to the brain’s olfactory bulb. However, the mechanism by which Mn disrupts neural function remains unclear. Here we used optical imaging techniques to visualize exocytosis in olfactory nerve terminals in vivo in the mouse olfactory bulb. Acute Mn exposure via intranasal instillation of 2–200 ?g MnCl2 solution caused a dose-dependent reduction in odorant-evoked neurotransmitter release, with significant effects at as little as 2 ?g MnCl2 and a 90% reduction compared to vehicle controls with a 200 ?g exposure. This reduction was also observed in response to direct electrical stimulation of the olfactory nerve layer in the olfactory bulb, demonstrating that Mn’s action is occurring centrally, not peripherally. This is the first direct evidence that Mn intoxication can disrupt neurotransmitter release, and is consistent with previous work suggesting that chronic Mn exposure limits amphetamine-induced dopamine increases in the basal ganglia despite normal levels of dopamine synthesis (Guilarte et al., J Neurochem 2008). The commonality of Mn’s action between glutamatergic neurons in the olfactory bulb and dopaminergic neurons in the basal ganglia suggests that a disruption of neurotransmitter release may be a general consequence wherever Mn accumulates in the brain and could underlie its pleiotropic effects. PMID:22542936

Moberly, Andrew H.; Czarnecki, Lindsey A.; Pottackal, Joseph; Rubinstein, Tom; Turkel, Daniel J.; Kass, Marley D.; McGann, John P.

2012-01-01

293

Effects of their nutrient precursors on the synthesis and release of serotonin, the catecholamines, and acetylcholine - Implications for behavioral disorders  

NASA Technical Reports Server (NTRS)

Authentic foods affect brain serotonin synthesis by modifying brain tryptophan levels, carbohydrates increasing and proteins decreasing these levels. The carbohydrate-induced rise in brain serotonin tends to diminish the likelihood that one carbohydrate-rich, protein-poor meal or snack will be followed by another. This mechanism is apparently disturbed in carbohydrate-craving obesity, which may explain why this syndrome responds well to d-fenfluramine, a serotoninergic drug. Pure nutrients like tyrosine or choline can also affect the rates at which their neurotransmitter products, the catecholamines and acetylcholine, are synthesized in and released from nerve terminals, suggesting that these compounds may find uses as drugs.

Wurtman, Richard J.

1988-01-01

294

Serotonin and the bone assessment  

PubMed Central

Introduction: Lately, the in vitro and in vivo studies on serotonin metabolism have been pointing its influence in bone health. Also, there are no particular recommendations in performing the serum serotonin assessment in order to evaluate the skeletal status. Aim: We aimed to correlate the bone turnover markers and lumbar bone mineral density (BMD) with serotonin. Material and methods: There is a cross-sectional study in Caucasian postmenopausal women. They were not diagnosed with carcinoid syndrome, or bone anomalies, and received no treatment (including antiresorptives). The following bone formation markers were performed: serum alkaline phosphatase (AP), serum osteocalcin (OC), and the bone resorption marker: serum CrossLaps (CL). Serum serotonin (high-pressure liquid chromatography), as well as central DXA (GE Prodigy) were assessed. Results: 191 women of 57.1 years mean age were grouped according to DXA (WHO criteria). The linear regression analysis between serum serotonin and CL were not statistically significant (SS), between serotonin and OC was SS in the newly diagnosed osteoporosis group (N=40, r=0.4, p=0.03), between serotonin and AP SS was found in osteopenia group (N=88, r=0.24, p=0.03), with no changes when adjusting for age and BMI. The partial correlation between serotonin and BMD was not SS. Discussion: The study raises the question of serotonin as a bone metabolism marker seeing that the results were not consistent. The main limit of our study was that we did not analyze the possible use of antidepressants to these women. Overall, this was a pilot study in clinical practice where few reports have been published, but still necessary, because the use of serum serotonin in current skeletal evaluation is still unclear.

Carsote, M; Radoi, V; Geleriu, A; Mihai, A; Ferechide, D; Opris, D; Paun, D; Poiana, C

2014-01-01

295

5-Hydroxytryptamine (serotonin) in the gastrointestinal tract  

PubMed Central

Purpose of review Although the gut contains most of the body’s 5-hydroxytryptamine (5-HT), many of its most important functions have recently been discovered. This review summarizes and directs attention to this new burst of knowledge. Recent findings Enteroendocrine cells have classically been regarded as pressure sensors, which secrete 5-HT to initiate peristaltic reflexes; nevertheless, recent data obtained from studies of mice that selectively lack 5-HT either in enterochromaffin cells (deletion of tryptophan hydroxylase 1 knockout; TPH1KO) or neurons (TPH2KO) imply that neuronal 5-HT is more important for constitutive gastrointestinal transit than that of enteroendocrine cells. The enteric nervous system of TPH2KO mice, however, also lacks a full complement of neurons; therefore, it is not clear whether slow transit in TPH2KO animals is due to their neuronal deficiency or absence of serotonergic neurotransmission. Neuronal 5-HT promotes the growth/maintenance of the mucosa as well as neurogenesis. Enteroendocrine cell derived 5-HT is an essential component of the gastrointestinal inflammatory response; thus, deletion of the serotonin transporter increases, whereas TPH1KO decreases the severity of intestinal inflammation. Enteroendocrine cell derived 5-HT, moreover, is also a hormone, which inhibits osteoblast proliferation and promotes hepatic regeneration. Summary New studies show that enteric 5-HT is a polyfunctional signalling molecule, acting both in developing and mature animals as a neurotransmitter paracrine factor, endocrine hormone and growth factor. PMID:23222853

Gershon, Michael D.

2013-01-01

296

Effects of age of serotonin 5HT2 receptors in cocaine abusers and normal subjects  

Microsoft Academic Search

We measured the effect of age on serotonin 5-HT2 receptor availability and compared it with the effects on dopamine D2 receptors on 19 chronic cocaine abusers (35.2±9.8 years, range 18-54 years old) and 19 age matched normal controls using positron emission tomography (PET) and F-18 N-methylspiperone (NMS). 5-HT2 Receptor availability was measure din frontal (FR), occipital (OC), cingulate (CI) and

G. J. Wang; N. D. Volkow; J. Logan

1995-01-01

297

Isolated venlafaxine-induced serotonin syndrome  

Microsoft Academic Search

Serotonin syndrome is a potentially fatal complication of serotonergic drug therapy. Usually, serotonin syndrome occurs with the concomitant use of two serotonergic drugs; this case report describes a patient with a classic presentation of serotonin syndrome induced solely by a venlafaxine overdose. Emergency physicians need to be aware that the serotonin syndrome may occur not only with serotonergic drug combinations

Paul Kolecki

1997-01-01

298

Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): enhancing serotonin release by combining serotonin (5HT) transporter inhibition with actions at 5HT receptors (5HT1A, 5HT1B, 5HT1D, 5HT7 receptors).  

PubMed

Vortioxetine is an antidepressant that targets multiple pharmacologic modes of action at sites-or nodes-where serotonergic neurons connect to various brain circuits. These multimodal pharmacologic actions of vortioxetine lead to enhanced release of various neurotransmitters, including serotonin, at various nodes within neuronal networks. PMID:25831967

Stahl, Stephen M

2015-04-01

299

Microwave-induced post-exposure hyperthermia: Involvement of endogenous opioids and serotonin  

SciTech Connect

Acute exposure to pulsed microwaves (2450 MHz, 1 mW/ cm/sup 2/, SAR 0.6 W/kg, 2-..mu..s pulses, 500 pulses/s) induces a transient post-exposure hyperthermia in the rat. The hyperthermia was attenuated by treatment with either the narcotic antagonist naltrexone or one of the serotonin antagonists cinanserin, cyproheptadine, or metergoline. It was not affected, however, by treatment with the peripheral serotonin antagonist xylamidine nor the dopamine antagonist haloperidol. It thus appears that both endogenous opioids and central serotonin are involved. It is proposed that pulsed microwaves activate endogenous opioid systems, and that they in turn activate a serotonergic mechanism that induces the rise in body temperature.

Lai, H.; Chou, C.K.; Guy, A.W.; Horita, A.

1984-08-01

300

Physiologically Relevant Changes in Serotonin Resolved by Fast Microdialysis  

PubMed Central

Online microdialysis is a sampling and detection method that enables continuous interrogation of extracellular molecules in freely moving subjects under behaviorally relevant conditions. A majority of recent publications using brain microdialysis in rodents report sample collection times of 20–30 min. These long sampling times are due, in part, to limitations in the detection sensitivity of high performance liquid chromatography (HPLC). By optimizing separation and detection conditions, we decreased the retention time of serotonin to 2.5 min and the detection threshold to 0.8 fmol. Sampling times were consequently reduced from 20 to 3 min per sample for online detection of serotonin (and dopamine) in brain dialysates using a commercial HPLC system. We developed a strategy to collect and to analyze dialysate samples continuously from two animals in tandem using the same instrument. Improvements in temporal resolution enabled elucidation of rapid changes in extracellular serotonin levels associated with mild stress and circadian rhythms. These dynamics would be difficult or impossible to differentiate using conventional microdialysis sampling rates. PMID:23614776

2013-01-01

301

Single Cell Measurement of Dopamine Release with Simultaneous Voltage-clamp and Amperometry  

PubMed Central

After its release into the synaptic cleft, dopamine exerts its biological properties via its pre- and post-synaptic targets1. The dopamine signal is terminated by diffusion2-3, extracellular enzymes4, and membrane transporters5. The dopamine transporter, located in the peri-synaptic cleft of dopamine neurons clears the released amines through an inward dopamine flux (uptake). The dopamine transporter can also work in reverse direction to release amines from inside to outside in a process called outward transport or efflux of dopamine5. More than 20 years ago Sulzer et al. reported the dopamine transporter can operate in two modes of activity: forward (uptake) and reverse (efflux)5. The neurotransmitter released via efflux through the transporter can move a large amount of dopamine to the extracellular space, and has been shown to play a major regulatory role in extracellular dopamine homeostasis6. Here we describe how simultaneous patch clamp and amperometry recording can be used to measure released dopamine via the efflux mechanism with millisecond time resolution when the membrane potential is controlled. For this, whole-cell current and oxidative (amperometric) signals are measured simultaneously using an Axopatch 200B amplifier (Molecular Devices, with a low-pass Bessel filter set at 1,000 Hz for whole-cell current recording). For amperometry recording a carbon fiber electrode is connected to a second amplifier (Axopatch 200B) and is placed adjacent to the plasma membrane and held at +700 mV. The whole-cell and oxidative (amperometric) currents can be recorded and the current-voltage relationship can be generated using a voltage step protocol. Unlike the usual amperometric calibration, which requires conversion to concentration, the current is reported directly without considering the effective volume7. Thus, the resulting data represent a lower limit to dopamine efflux because some transmitter is lost to the bulk solution. PMID:23207721

Saha, Kaustuv; Swant, Jarod; Khoshbouei, Habibeh

2012-01-01

302

Interspecific comparisons of immunohistochemical localization of retinal neurotransmitters in four species of bats.  

PubMed

Four ecologically distinctive Neotropical bat species of the family Phyllostomidae were collected and their retinae surveyed immunohistochemically for the presence of neurotransmitter candidates: glucagon, somatostatin, vasoactive intestinal peptide, substance P (SP), methionine enkephalin, serotonin (5-HT) and two enzymes, glutamic acid decarboxylase (GAD) and tyrosine hydroxylase (TOH). In all four species immunoreactivity (IR) to GAD, TOH and SP was found. GAD-IR and SP-IR showed little interspecies variation whereas TOH-IR differed interspecifically in a pattern that matched the systematic relationships and the ecological characteristics of the bats. 5-HT-IR, which has not previously been reported from mammalian retinae, was found in fibers in the inner nuclear layer and in the outer and inner plexiform layers of Macrotus waterhousii, which is a relatively underived insectivorous phyllostomid bat, but was not found in the retinae from frugivorous or nectarivorous species. PMID:2444311

Studholme, K M; Yazulla, S; Phillips, C J

1987-01-01

303

Impact of delays and noise on dopamine signal transduction.  

PubMed

Dopamine is a critical neurotransmitter for the normal functioning of the central nervous system. Abnormal dopamine signal transmission in the brain has been implicated in diseases such as Parkinson's disease (PD) and schizophrenia, as well as in various types of drug addition. It is therefore important to understand the dopamine signaling dynamics in the presynaptic neuron of the striatum and the synaptic cleft, where dopamine synthesis, degradation, compartmentalization, release, reuptake, and numerous regulatory processes occur. The biochemical and biological processes governing this dynamics consist of interacting discrete and continuous components, operate at different time scales, and must function effectively in spite of intrinsic stochasticity and external perturbations. Not fitting into the realm of purely deterministic phenomena, the hybrid nature of the system requires special means of mathematical modeling, simulation and analysis. We show here how hybrid functional Petri-nets (HFPNs) and the software Cell Illustrator® facilitate computational analyses of systems that simultaneously contain deterministic, stochastic, and delay components. We evaluate the robustness of dopamine signaling in the presence of delays and noise and discuss implications for normal and abnormal states of the system. PMID:22430222

Wu, Jialiang; Qi, Zhen; Voit, Eberhard O

2010-01-01

304

Impact of delays and noise on dopamine signal transduction.  

PubMed

Dopamine is a critical neurotransmitter for the normal functioning of the central nervous system. Abnormal dopamine signal transmission in the brain has been implicated in diseases such as Parkinson's disease (PD) and schizophrenia, as well as in various types of drug addition. It is therefore important to understand the dopamine signaling dynamics in the presynaptic neuron of the striatum and the synaptic cleft, where dopamine synthesis, degradation, compartmentalization, release, reuptake, and numerous regulatory processes occur. The biochemical and biological processes governing this dynamics consist of interacting discrete and continuous components, operate at different time scales, and must function effectively in spite of intrinsic stochasticity and external perturbations. Not fitting into the realm of purely deterministic phenomena, the hybrid nature of the system requires special means of mathematical modeling, simulation and analysis. We show here how hybrid functional Petri-nets (HFPNs) and the software Cell Illustrator® facilitate computational analyses of systems that simultaneously contain deterministic, stochastic, and delay components. We evaluate the robustness of dopamine signaling in the presence of delays and noise and discuss implications for normal and abnormal states of the system. PMID:21685574

Wu, Jialiang; Qi, Zhen; Voit, Eberhard O

2011-01-01

305

Attenuated methamphetamine-induced locomotor sensitization in serotonin transporter knockout mice is restored by serotonin 1B receptor antagonist treatment.  

PubMed

Repeated administration of methamphetamine (METH) enhances acute locomotor responses to METH administered in the same context, a phenomenon termed as 'locomotor sensitization'. Although many of the acute effects of METH are mediated by its influences on the compartmentalization of dopamine, serotonin systems have also been suggested to influence the behavioral effects of METH in ways that are not fully understood. The present experiments examined serotonergic roles in METH-induced locomotor sensitization by assessing: (a) the effect of serotonin transporter (SERT; Slc6A4) knockout (KO) on METH-induced locomotor sensitization; (b) extracellular monoamine levels in METH-treated animals as determined by in-vivo microdialysis; and (c) effects of serotonin (5-HT) receptor antagonists on METH-induced behavioral sensitization, with focus on effects of the 5-HT1B receptor antagonist SB 216641 and a comparison with the 5-HT2 receptor antagonist ketanserin. Repeated METH administration failed to induce behavioral sensitization in homozygous SERT KO (SERT-/-) mice under conditions that produced substantial sensitization in wild-type or heterozygous SERT KO (SERT+/-) mice. The selective 5-HT1B antagonist receptor SB 216641 restored METH-induced locomotor sensitization in SERT-/- mice, whereas ketanserin was ineffective. METH-induced increases in extracellular 5-HT (5-HTex) levels were substantially reduced in SERT-/- mice, although SERT genotype had no effect on METH-induced increases in extracellular dopamine. These experiments demonstrate that 5-HT actions, including those at 5-HT1B receptors, contribute to METH-induced locomotor sensitization. Modulation of 5-HT1B receptors might aid therapeutic approaches to the sequelae of chronic METH use. PMID:25485646

Igari, Moe; Shen, Hao-Wei; Hagino, Yoko; Fukushima, Setsu; Kasahara, Yoshiyuki; Lesch, Klaus-Peter; Murphy, Dennis L; Hall, Frank Scott; Uhl, George R; Ikeda, Kazutaka; Yaegashi, Nobuo; Sora, Ichiro

2015-02-01

306

Conformational changes in dopamine transporter intracellular regions upon cocaine binding and dopamine translocation.  

PubMed

The dopamine transporter (DAT), a member of the neurotransmitter:sodium symporter family, mediates the reuptake of dopamine at the synaptic cleft. DAT is the primary target for psychostimulants such as cocaine and amphetamine. We previously demonstrated that cocaine binding and dopamine transport alter the accessibility of Cys342 in the third intracellular loop (IL3). To study the conformational changes associated with the functional mechanism of the transporter, we made cysteine substitution mutants, one at a time, from Phe332 to Ser351 in IL3 of the background DAT construct, X7C, in which 7 endogenous cysteines were mutated. The accessibility of the 20 engineered cysteines to polar charged sulfhydryl reagents was studied in the absence and presence of cocaine or dopamine. Of the 11 positions that reacted with methanethiosulfonate ethyl ammonium, as evidenced by inhibition of ligand binding, 5 were protected against this inhibition by cocaine and dopamine (S333C, S334C, N336C, M342C and T349C), indicating that reagent accessibility is affected by conformational changes associated with inhibitor and substrate binding. In some of the cysteine mutants, transport activity is disrupted, but can be rescued by the presence of zinc, most likely because the distribution between inward- and outward-facing conformations is restored by zinc binding. The experimental data were interpreted in the context of molecular models of DAT in both the inward- and outward-facing conformations. Differences in the solvent accessible surface area for individual IL3 residues calculated for these states correlate well with the experimental accessibility data, and suggest that protection by ligand binding results from the stabilization of the outward-facing configuration. Changes in the residue interaction networks observed from the molecular dynamics simulations also revealed the critical roles of several positions during the conformational transitions. We conclude that the IL3 region of DAT undergoes significant conformational changes in transitions necessary for both cocaine binding and substrate transport. PMID:24576496

Dehnes, Yvette; Shan, Jufang; Beuming, Thijs; Shi, Lei; Weinstein, Harel; Javitch, Jonathan A

2014-07-01

307

Dynamic neurotransmitter interactions measured with PET  

SciTech Connect

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 biologically distinct neurochemical systems that interact to produce a variety of behaviors and disorders. Neurotransmitters are neither static nor isolated in their distribution. In fact, it is through interactions with other neurochemically distinct systems that the central nervous system (CNS) performs its vital role in sustaining life. Exclusive quantitative capabilities intrinsic to PET make this technology a suitable experimental tool to measure not only the regional distribution of specific receptors and their subtypes, but also the dynamic properties of neuroreceptors and their inherent influence on related neurotransmitter pathways. The ability to investigate dynamic properties in a non-invasive and reproducible manner provides a powerful tool that can extend our current knowledge of these interactions. Coupled with innovative paradigms including pharmacologic manipulations, physiologic models and reconstruction theories, knowledge derived from PET studies can greatly advance our understanding of normal and abnormal brain function.

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

2001-04-02

308

18F-MCL-524, an 18F-Labeled Dopamine D2 and D3 Receptor Agonist Sensitive to Dopamine: A Preliminary PET Study.  

PubMed

PET has been used to examine changes in neurotransmitter concentrations in the living brain. Pioneering PET studies on the dopamine system have used D2 and D3 receptor (D2/D3) antagonists such as (11)C-raclopride. However, more recently developed agonist radioligands have shown enhanced sensitivity to endogenous dopamine. A limitation of available agonist radioligands is that they incorporate the short-lived radioisotope (11)C. In the current study, we developed the (18)F-labeled D2/D3 receptor agonist (R)-(-)-2-(18)F-fluoroethoxy-N-n-propylnorapomorphine ((18)F-MCL-524). PMID:24790219

Finnema, Sjoerd J; Stepanov, Vladimir; Nakao, Ryuji; Sromek, Anna W; Zhang, Tangzhi; Neumeyer, John L; George, Susan R; Seeman, Philip; Stabin, Michael G; Jonsson, Cathrine; Farde, Lars; Halldin, Christer

2014-05-01

309

Dopamine modulates the kinetics of ion channels gated by excitatory amino acids in retinal horizontal cells.  

PubMed Central

Upon exposure to dopamine, cultured teleost retinal horizontal cells become more responsive to the putative photoreceptor neurotransmitter L-glutamate and to its analog kainate. We have recorded unitary and whole-cell currents to determine the mechanism by which dopamine enhances ion channels activated by these agents. In single-channel recordings from cell-attached patches with agonist in the patch pipette, the frequency of 5- to 10-pS unitary events, but not their amplitude, increased by as much as 150% after application of dopamine to the rest of the cell. The duration of channel openings also increased somewhat, by 20-30%. In whole-cell experiments, agonists with and without dopamine were applied to voltage-clamped horizontal cells by slow superfusion. Analysis of whole-cell current variance as a function of mean current indicated that dopamine increased the probability of channel opening for a give agonist concentration without changing the amount of current passed by an individual channel. For kainate, noise analysis additionally demonstrated that dopamine did not alter the number of functional channels. Dopamine also increased a slow spectral component of whole-cell currents elicited by kainate or glutamate, suggesting a change in the open-time kinetics of the channels. This effect was more pronounced for currents induced by glutamate than for those induced by kainate. We conclude that dopamine potentiates the activity of horizontal cell glutamate receptors by altering the kinetics of the ion channel to favor the open state. PMID:1689053

Knapp, A G; Schmidt, K F; Dowling, J E

1990-01-01

310

The effects of scopolamine and the nootropic drug phenotropil on rat brain neurotransmitter receptors during testing of the conditioned passive avoidance task  

Microsoft Academic Search

We studied the effects of administration of the new nootropic drug phenotropil (N-carbamoylmethyl-4-phenyl-2-pyrrolidone) at a dose of 100 mg\\/kg on the quantitative characteristics of dopamine (DA), serotonin\\u000a (5-HT), glutamate (NMDA), GABA-A (BDZ), and acetylcholine (nACh) receptors in rats using the conditioned passive avoidance\\u000a task (PAT) under normal conditions and during scopolamine-induced amnesia ex vivo. We found that the cholinolytic drug

Yu. Yu. Firstova; D. A. Abaimov; I. G. Kapitsa; T. A. Voronina; G. I. Kovalev

2011-01-01

311

Parallel Recording of Neurotransmitters Release from Chromaffin Cells Using a 10 × 10 CMOS IC Potentiostat Array with On-Chip Working Electrodes  

PubMed Central

Neurotransmitter release is modulated by many drugs and molecular manipulations. We present an active CMOS-based electrochemical biosensor array with high throughput capability (100 electrodes) for on-chip amperometric measurement of neurotransmitter release. The high-throughput of the biosensor array will accelerate the data collection needed to determine statistical significance of changes produced under varying conditions, from several weeks to a few hours. The biosensor is designed and fabricated using a combination of CMOS integrated circuit (IC) technology and a photolithography process to incorporate platinum working electrodes on-chip. We demonstrate the operation of an electrode array with integrated high-gain potentiostats and output time-division multiplexing with minimum dead time for readout. The on-chip working electrodes are patterned by conformal deposition of Pt and lift-off photolithography. The conformal deposition method protects the underlying electronic circuits from contact with the electrolyte that covers the electrode array during measurement. The biosensor was validated by simultaneous measurement of amperometric currents from 100 electrodes in response to dopamine injection, which revealed the time course of dopamine diffusion along the surface of the biosensor array. The biosensor simultaneously recorded neurotransmitter release successfully from multiple individual living chromaffin cells. The biosensor was capable of resolving small and fast amperometric spikes reporting release from individual vesicle secretions. We anticipate that this device will accelerate the characterization of the modulation of neurotransmitter secretion from neuronal and endocrine cells by pharmacological and molecular manipulations of the cells. PMID:23084756

Kim, Brian Namghi; Herbst, Adam D.; Kim, Sung June; Minch, Bradley A.; Lindau, Manfred

2012-01-01

312

Serotonin signaling in C. elegans  

E-print Network

Wild-type animals that have been acutely food deprived slow their locomotory rate upon encountering bacteria more than do well-fed animals. This behavior, called the enhanced slowing response, is partly serotonin (5-HT) ...

Gustafson, Megan Alyse

2007-01-01

313

Increased dopamine tone during meditation-induced change of consciousness.  

PubMed

This is the first in vivo demonstration of an association between endogenous neurotransmitter release and conscious experience. Using 11C-raclopride PET we demonstrated increased endogenous dopamine release in the ventral striatum during Yoga Nidra meditation. Yoga Nidra is characterized by a depressed level of desire for action, associated with decreased blood flow in prefrontal, cerebellar and subcortical regions, structures thought to be organized in open loops subserving executive control. In the striatum, dopamine modulates excitatory glutamatergic synapses of the projections from the frontal cortex to striatal neurons, which in turn project back to the frontal cortex via the pallidum and ventral thalamus. The present study was designed to investigate whether endogenous dopamine release increases during loss of executive control in meditation. Participants underwent two 11C-raclopride PET scans: one while attending to speech with eyes closed, and one during active meditation. The tracer competes with endogenous dopamine for access to dopamine D2 receptors predominantly found in the basal ganglia. During meditation, 11C-raclopride binding in ventral striatum decreased by 7.9%. This corresponds to a 65% increase in endogenous dopamine release. The reduced raclopride binding correlated significantly with a concomitant increase in EEG theta activity, a characteristic feature of meditation. All participants reported a decreased desire for action during meditation, along with heightened sensory imagery. The level of gratification and the depth of relaxation did not differ between the attention and meditation conditions. Here we show increased striatal dopamine release during meditation associated with the experience of reduced readiness for action. It is suggested that being in the conscious state of meditation causes a suppression of cortico-striatal glutamatergic transmission. To our knowledge this is the first time in vivo evidence has been provided for regulation of conscious states at a synaptic level. PMID:11958969

Kjaer, Troels W; Bertelsen, Camilla; Piccini, Paola; Brooks, David; Alving, Jørgen; Lou, Hans C

2002-04-01

314

Effects of serotonin-norepinephrine reuptake inhibitors on locomotion and prefrontal monoamine release in spontaneously hypertensive rats.  

PubMed

Catecholamine neurotransmission in the prefrontal cortex plays a key role in the therapeutic actions of drugs for attention-deficit/hyperactivity disorder (ADHD). Recent clinical studies show that several serotonin-norepinephrine reuptake inhibitors have potential for treating ADHD. In this study, we examined the effects of acute treatment with serotonin-norepinephrine reuptake inhibitors on locomotion and the extracellular levels of monoamines in the prefrontal cortex in spontaneously hypertensive rats (SHR), an animal model of ADHD. Adolescent male SHR exhibited greater horizontal locomotion in an open-field test than male WKY control rats. Psychostimulant methylphenidate (0.3 and 1 mg/kg), the selective norepinephrine reuptake inhibitor atomoxetine (1 and 3 mg/kg), and serotonin-norepinephrine reuptake inhibitors duloxetine (10 mg/kg), venlafaxine (10 and 30 mg/kg) and milnacipran (30 mg/kg) reduced the horizontal activity in SHR, but did not affect in WKY rats. The selective norepinephrine reuptake inhibitor reboxetine (10 mg/kg) and the tricyclic antidepressant desipramine (10 and 30 mg/kg) also reduced the horizontal activity in SHR, whereas the selective serotonin reuptake inhibitor citalopram (30 mg/kg) did not. Microdialysis studies showed that atomoxetine, methylphenidate, duloxetine, venlafaxine, milnacipran, and reboxetine increased the extracellular levels of norepinephrine and dopamine in the prefrontal cortex in SHR. Citalopram did not affect norepinephrine and dopamine levels in the prefrontal cortex, although it increased the serotonin levels. Neither duloxetine nor venlafaxine increased the dopamine levels in the striatum. These findings suggest that serotonin-norepinephrine reuptake inhibitors, similar to methylphenidate and atomoxetine, have potential for ameliorating motor abnormality in the SHR model. PMID:23376565

Umehara, Masato; Ago, Yukio; Fujita, Kazumi; Hiramatsu, Naoki; Takuma, Kazuhiro; Matsuda, Toshio

2013-02-28

315

Regulation of systemic energy homeostasis by serotonin in adipose tissues.  

PubMed

Central serotonin (5-HT) is an anorexigenic neurotransmitter in the brain. However, accumulating evidence suggests peripheral 5-HT may affect organismal energy homeostasis. Here we show 5-HT regulates white and brown adipose tissue function. Pharmacological inhibition of 5-HT synthesis leads to inhibition of lipogenesis in epididymal white adipose tissue (WAT), induction of browning in inguinal WAT and activation of adaptive thermogenesis in brown adipose tissue (BAT). Mice with inducible Tph1 KO in adipose tissues exhibit a similar phenotype as mice in which 5-HT synthesis is inhibited pharmacologically, suggesting 5-HT has localized effects on adipose tissues. In addition, Htr3a KO mice exhibit increased energy expenditure and reduced weight gain when fed a high-fat diet. Treatment with an Htr2a antagonist reduces lipid accumulation in 3T3-L1 adipocytes. These data suggest important roles for adipocyte-derived 5-HT in controlling energy homeostasis. PMID:25864946

Oh, Chang-Myung; Namkung, Jun; Go, Younghoon; Shong, Ko Eun; Kim, Kyuho; Kim, Hyeongseok; Park, Bo-Yoon; Lee, Ho Won; Jeon, Yong Hyun; Song, Junghan; Shong, Minho; Yadav, Vijay K; Karsenty, Gerard; Kajimura, Shingo; Lee, In-Kyu; Park, Sangkyu; Kim, Hail

2015-01-01

316

Pharmacogenetics of nicotine addiction: role of dopamine.  

PubMed

The neurotransmitter dopamine (DA) plays a central role in addictive disorders, including nicotine addiction. Specific DA-related gene variants have been studied to identify responsiveness to treatment for nicotine addiction. Genetic variants in DRD2, DRD4, ANKK1, DAT1, COMT and DBH genes show some promise in informing personalized prescribing of smoking cessation pharmacotherapies. However, many trials studying these variants had small samples, used retrospective design or were composed of mainly self-identified Caucasian individuals. Furthermore, many of these studies lacked a comprehensive measurement of nicotine metabolism rate, did not assess the roles of sex or the menstrual cycle, and did not investigate the role of rare variants and/or epigenetic factors. Future work should be conducted addressing these limitations to more effectively utilize DA genetic information to unlock the potential of smoking cessation pharmacogenetics. PMID:24444411

Herman, Aryeh I; DeVito, Elise E; Jensen, Kevin P; Sofuoglu, Mehmet

2014-02-01

317

Two dimensional array of ZnSe-ferritin for dopamine detection  

NASA Astrophysics Data System (ADS)

Less toxic zinc selenide (ZnSe) quantum dots were synthesized in the cavity of the apoferritin from horse spleen (HsAFr), and the two-dimensional ZnSe-ferritin nanodots were prepared on modified silicon surface. For utilizing the array as a biosensor, the photoluminescence (PL) spectrum change was investigated by accompanying its conjugation reaction with a neurotransmitter dopamine. When the array was conjugated with dopamine, a significant quenching of the fluorescence occurred and the PL intensity was a linear function of the dopamine concentration in the range of 0-0.6 µM. Accordingly, the ZnSe-ferritin nanodot arrays can be employed as a useful sensing media for tiny concentration of dopamine.

Choi, Eun Ah; Park, Sang Joon

2014-01-01

318

[Effect of intranasal administration of dopamine on anxiety and locomotor activity of two lines of mice].  

PubMed

Intranasal administration of dopamine (0.3; 3 and 30 microg/kg) on anxious behaviour of mice was studied using elevated plus-maze and open fields tests and the pinch-induced catalepsy on parallel bars test. Dopamine was introduced as nose drops or inhalation of nanoparticles of the compound solution in C57B1/6J and CBA/Lac mice with differences of dopaminergic function features. In our experiment, dopamine had anxiolytic and elevated motor activity effects in C57B1/6J, but not in the CBA/Lac mice. Nose drops were more effective than inhalation; perhaps, it was a more stressful manipulation. Apparently dopamine increased the number of CBA/Lac mice who demonstrated catalepsy and the reflex duration. Indeed, the neurotransmitter is active in different psycho-emotional phenomena. PMID:21961293

Kholodar', A V; Amikishieva, A V; Anisimov, M P

2011-07-01

319

Neurotransmitter receptors and voltage-dependent Ca2+ channels encoded by mRNA from the adult corpus callosum.  

PubMed Central

The presence of mRNAs encoding neurotransmitter receptors and voltage-gated channels in the adult human and bovine corpus callosum was investigated using Xenopus oocytes. Oocytes injected with mRNA extracted from the corpus callosum expressed functional receptors to glutamate, acetylcholine, and serotonin, and also voltage-operated Ca2+ channels, all with similar properties in the two species studied. Acetylcholine and serotonin elicited oscillatory Cl- currents due to activation of the inositol phosphate-Ca2+ receptor-channel coupling system. Glutamate and its analogs N-methyl-D-aspartate (NMDA), kainate, quisqualate, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) induced smooth currents. The non-NMDA responses showed a strong inward rectification at positive potentials and were potently blocked by 6,7-dinitroquinoxaline-2,3-dione, as observed for the AMPA/kainate glutamate receptors GLUR1 and GLUR3. Furthermore, in situ hybridization experiments showed that GLUR1 and GLUR3 mRNAs are present in corpus callosum cells that were labeled with antiserum to glial fibrillary acid protein and that, in primary cell cultures, had the morphology of type 2 astrocytes. These results indicate that glial cells in the adult corpus callosum possess mRNA encoding functional neurotransmitter receptors and Ca2+ channels. These molecules may provide a mechanism for glial-neuronal interactions. Images Fig. 1 Fig. 5 Fig. 6 Fig. 7 PMID:7682696

Matute, C; Miledi, R

1993-01-01

320

Creating Dynamic Images of Short-lived Dopamine Fluctuations with lp-ntPET: Dopamine Movies of Cigarette Smoking  

PubMed Central

We describe experimental and statistical steps for creating dopamine movies of the brain from dynamic PET data. The movies represent minute-to-minute fluctuations of dopamine induced by smoking a cigarette. The smoker is imaged during a natural smoking experience while other possible confounding effects (such as head motion, expectation, novelty, or aversion to smoking repeatedly) are minimized. We present the details of our unique analysis. Conventional methods for PET analysis estimate time-invariant kinetic model parameters which cannot capture short-term fluctuations in neurotransmitter release. Our analysis - yielding a dopamine movie - is based on our work with kinetic models and other decomposition techniques that allow for time-varying parameters 1-7. This aspect of the analysis – temporal-variation- is key to our work. Because our model is also linear in parameters, it is practical, computationally, to apply at the voxel level. The analysis technique is comprised of 5 main steps: pre-processing, modeling, statistical comparison, masking and visualization. Preprocessing is applied to the PET data with a unique ‘HYPR’ spatial filter 8 that reduces spatial noise but preserves critical temporal information. Modeling identifies the time-varying function that best describes the dopamine effect on 11C-raclopride uptake. The statistical step compares the fit of our (lp-ntPET) model 7 to a conventional model 9. Masking restricts treatment to those voxels best described by the new model. Visualization maps the dopamine function at each voxel to a color scale and produces a dopamine movie. Interim results and sample dopamine movies of cigarette smoking are presented. PMID:23963311

Morris, Evan D.; Kim, Su Jin; Sullivan, Jenna M.; Wang, Shuo; Normandin, Marc D.; Constantinescu, Cristian C.; Cosgrove, Kelly P.

2014-01-01

321

Antisera against small neurotransmitter-like molecules.  

PubMed

Antisera were produced against three types of small neurotransmitter-like molecules: indolealkylamines, catecholamines and amino acid derivatives such as GABA. The specificity of the antisera were evaluated using radioimmunological or immunoenzymatic competition tests between a radiolabelled ligand or conjugated hapten, and analog molecules from the same metabolic pathway. The antibody site was characterized by the ratios of cross-reactivity and the affinity constants. On the basis of these in vitro studies, each immune response was found to be specific for the target molecule. PMID:20492941

Geffard, M; Henrich-Rock, A M; Dulluc, J; Seguela, P

1985-01-01

322

Neurotransmitter CART as a New Therapeutic Candidate for Parkinson’s Disease  

PubMed Central

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. PMID:23543038

Mao, Peizhong; Meshul, Charles K.; Thuillier, Philippe; Reddy, P. Hemachandra

2013-01-01

323

Monoamine Neurotransmitters as Substrates for Novel Tick Sulfotransferases, Homology Modeling, Molecular Docking, and Enzyme Kinetics  

PubMed Central

Blacklegged ticks (Ixodes scapularis) transmit the causative agent of Lyme disease in the Northeastern and upper Midwestern US. Current research focuses on elucidating biochemical pathways which may be disrupted to prevent pathogen transmission, thereby preventing disease. A genome screening process reported transcripts coding for two putative sulfotransferases in salivary glands of adult Ixodes scapularis and in whole tick extracts of the nymphal and larval stages. Sulfotransferases are known to sulfonate phenolic and alcoholic receptor agonists such as 17?-estradiol, thereby inactivating the receptor ligands. We used bioinformatic approaches to predict substrates for these two sulfotransferases (designated Ixosc Sult 1 and Ixosc Sult 2), and tested the predictions with biochemical assays. Amino acid sequence analysis showed that Ixosc Sult 1 and 2 are members of the cytosolic sulfotransferase superfamily. Homology models of 3D-protein structure were prepared for each tick sulfotransferase based on sulfotransferase X-ray crystal structures. Visualization of the electrostatic surface of the ligand binding cavities showed regions of negative electrostatic charge. Molecular docking identified potential substrates including dopamine, R-octopamine and S-octopamine, which docked into Ixosc Sult 1 with favorable binding affinity and correct conformation for sulfonation. Dopamine, but not R- or S-octopamine, also docked into Ixosc Sult 2 in a catalytic binding mode. Other molecules including 17?-estradiol, pregnenolone and serotonin, did not dock in catalytically active position to either protein. The predictions were tested and confirmed using cytosolic fractions of extracts of whole ticks. Dopamine was found to be a good substrate (Km 0.1 – 0.4 ?M) for the native Ixodes scapularis sulfotransferases from larval and nymphal stages regardless of their fed/unfed status. Octopamine–sulfonation was only detected after feeding when gene expression data suggests that only Ixosc Sult 1 is present. These results agree with the docking predictions that octopamine is sulfonated only by Ixosc Sult 1, whereas dopamine is sulfonated by both Ixosc Sult 1 and Sult 2. Because dopamine is known to stimulate salivation in ticks through receptor stimulation, these results imply that the function/s of Ixosc Sult 1 or Sult 2 in the Ixodid tick may include inactivation of the salivation signal via sulfonation of dopamine and/or octopamine. PMID:21043483

Yalcin, Emine Bihter; Stangl, Hubert; Pichu, Sivakamasundari; Mather, Thomas N.; King, Roberta S.

2010-01-01

324

Surface-enhanced Raman spectroscopy detection of dopamine by DNA Targeting amplification assay in Parkisons's model.  

PubMed

Dopamine is a potent neuromodulator in the brain that influences a variety of motivated behaviors and is involved in several neurologic diseases. We evaluated a bio-barcode amplification assay for its ability to detect dopamine in a mouse model with and without prior administration of the neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Our approach uses a combination of DNA barcodes and bead-based immunoassays for detecting neurotransmitters with surface-enhanced Raman spectroscopy (SERS). This method relies on a gold nanoplate with adsorbed antibodies and gold nanoparticles that are encoded with DNA and antibodies that can sandwich the target protein captured by the nanoparticle-bound antibodies. C57BL/6 mice were infused intranasally with MPTP (25mg/kg/day) over 7 consecutive days. At 7 and 21 days after the last administration of MPTP, dopamine was found by western blot analysis to have decreased in the midbrain by 37.44% and 92.95%, respectively. Furthermore, the Raman intensity of dopamine in the midbrains of MPTP-treated mice decreased by 56.77% and 61.12% on days 7 and 21, respectively. Our results demonstrate that the concentration of dopamine in midbrain and striatum of MPTP-treated mice can be easily detected using the bio-barcode assay, which is a rapid, high-throughput screening tool for detecting neurotransmitters. PMID:25465795

An, Jeung Hee; Choi, Dong-Kug; Lee, Kwon-Jai; Choi, Jeong-Woo

2015-05-15

325

The D1 dopamine receptor agonist SKF-38393 stimulates the release of glutamate in the hippocampus.  

PubMed

The present study was undertaken to better assess the role of dopamine on exocytosis. Since direct activation of adenylate cyclase (e.g., with forskolin) enhances neurotransmitter release it was of interest to see whether the activation of D1-type dopamine receptors, which are positively coupled to adenylate cyclase, could also modulate the molecular machinery underlying the fusion of synaptic vesicles and the release of neurotransmitter. To answer this question we have looked at the effect of the D1-type dopamine receptor agonist SKF-38393 on the spontaneous release of glutamate from cultured rat hippocampal neurons. SKF-38393 enhanced the frequency but not the amplitude of tetrodotoxin-resistant excitatory postsynaptic currents which argues for a presynaptic locus of D1 action. This effect was blocked by the D1-dopaminergic receptor antagonist SCH-23390 and the protein kinase A inhibitors H-7 and Rp-cAMP whereas pertussis toxin failed to affect the dopaminergic response. In addition, carbachol and Ruthenium Red also stimulated exocytosis but did not occlude the SKF-38393-induced modulation. These results indicate that SKF-38393 presynaptically enhances the release of glutamate via a pertussis toxin-insensitive and protein kinase A-dependent mechanism, which most likely involves D1-type dopamine receptors. Our results underline the importance of protein kinase A as potent modulator of synaptic transmission and suggest that high concentrations of dopamine can greatly enhance the release of glutamate in the hippocampus. PMID:10625048

Bouron, A; Reuter, H

1999-01-01

326

Fluorescent dopamine tracer resolves individual dopaminergic synapses and their activity in the brain  

PubMed Central

We recently introduced fluorescent false neurotransmitters (FFNs) as optical tracers that enable the visualization of neurotransmitter release at individual presynaptic terminals. Here, we describe a pH-responsive FFN probe, FFN102, which as a polar dopamine transporter substrate selectively labels dopamine cell bodies and dendrites in ventral midbrain and dopaminergic synaptic terminals in dorsal striatum. FFN102 exhibits greater fluorescence emission in neutral than acidic environments, and thus affords a means to optically measure evoked release of synaptic vesicle content into the extracellular space. Simultaneously, FFN102 allows the measurement of individual synaptic terminal activity by following fluorescence loss upon stimulation. Thus, FFN102 enables not only the identification of dopamine cells and their processes in brain tissue, but also the optical measurement of functional parameters including dopamine transporter activity and dopamine release at the level of individual synapses. As such, the development of FFN102 demonstrates that, by bringing together organic chemistry and neuroscience, molecular entities can be generated that match the endogenous transmitters in selectivity and distribution, allowing for the study of both the microanatomy and functional plasticity of the normal and diseased nervous system. PMID:23277566

Rodriguez, Pamela C.; Pereira, Daniela B.; Borgkvist, Anders; Wong, Minerva Y.; Barnard, Candace; Sonders, Mark S.; Zhang, Hui; Sames, Dalibor; Sulzer, David

2013-01-01

327

Autoradiographic localization of /sup 3/H-paroxetine-labeled serotonin uptake sites in rat brain  

SciTech Connect

Paroxetine is a potent and selective inhibitor of serotonin uptake into neurons. Serotonin uptake sites have been identified, localized, and quantified in rat brain by autoradiography with 3H-paroxetine; 3H-paroxetine binding in slide-mounted sections of rat forebrain was of high affinity (KD = 10 pM) and the inhibition affinity constant (Ki) values of various drugs in competing 3H-paroxetine binding significantly correlated with their reported potencies in inhibiting synaptosomal serotonin uptake. Serotonin uptake sites labeled by 3H-paroxetine were highly concentrated in the dorsal and median raphe nuclei, central gray, superficial layer of the superior colliculus, lateral septal nucleus, paraventricular nucleus of the thalamus, and the islands of Calleja. High concentrations of 3H-paroxetine binding sites were found in brainstem areas containing dopamine (substantia nigra and ventral tegmental area) and norepinephrine (locus coeruleus) cell bodies. Moderate concentrations of 3H-paroxetine binding sites were present in laminae I and IV of the frontal parietal cortex, primary olfactory cortex, olfactory tubercle, regions of the basal ganglia, septum, amygdala, thalamus, hypothalamus, hippocampus, and some brainstem areas including the interpeduncular, trigeminal, and parabrachial nuclei. Lower densities of 3H-paroxetine binding sites were found in other regions of the neocortex and very low to nonsignificant levels of binding were present in white matter tracts and in the cerebellum. Lesioning of serotonin neurons with 3,4-methylenedioxyamphetamine caused large decreases in 3H-paroxetine binding. The autoradiographic distribution of 3H-paroxetine binding sites in rat brain corresponds extremely well to the distribution of serotonin terminals and cell bodies as well as with the pharmacological sites of action of serotonin.

De Souza, E.B.; Kuyatt, B.L.

1987-01-01

328

Neurotransmitter signaling in the pathophysiology of microglia  

PubMed Central

Microglial cells are the resident immune cells of the central nervous system. In the resting state, microglia are highly dynamic and control the environment by rapidly extending and retracting motile processes. Microglia are closely associated with astrocytes and neurons, particularly at the synapses, and more recent data indicate that neurotransmission plays a role in regulating the morphology and function of surveying/resting microglia, as they are endowed with receptors for most known neurotransmitters. In particular, microglia express receptors for ATP and glutamate, which regulate microglial motility. After local damage, the release of ATP induces microgliosis and activated microglial cells migrate to the site of injury, proliferate, and phagocytose cells, and cellular compartments. However, excessive activation of microglia could contribute to the progression of chronic neurodegenerative diseases, though the underlying mechanisms are still unclear. Microglia have the capacity to release a large number of substances that can be detrimental to the surrounding neurons, including glutamate, ATP, and reactive oxygen species. However, how altered neurotransmission following acute insults or chronic neurodegenerative conditions modulates microglial functions is still poorly understood. This review summarizes the relevant data regarding the role of neurotransmitter receptors in microglial physiology and pathology. PMID:23626522

Domercq, María; Vázquez-Villoldo, Nuria; Matute, Carlos

2013-01-01

329

A Role for Adenosine A1 Receptors in GABA and NMDA-Receptor Mediated Modulation of Dopamine Release: Studies Using Fast Cyclic Voltammetry  

PubMed Central

In the striatum many neurotransmitters including GABA, glutamate, acetylcholine, dopamine, nitric oxide and adenosine interact to regulate synaptic transmission. Dopamine release in the striatum is regulated by a number of pre- and post-synaptic receptors including adenosine. We have recently shown using isolated rat striatal slices, and the technique of fast cyclic voltammetry, that adenosine A1 receptor-mediated inhibition of dopamine release is modulated by dopamine D1 receptors. In the present study we have investigated the influence of NMDA and GABA receptor activation on the modulation of electrically stimulated dopamine release by adenosine. Application of the adenosine A1 receptor agonist, N6-cyclopentyladenosine (CPA), concentration-dependently inhibited dopamine release to a maxiumum of 50%. Perfusion of the glutamate receptor agonist, NMDA, in low magnesium, caused a rapid and concentration-dependent inhibition of dopamine release. Prior perfusion with the adenosine A1 receptor antagonist, DPCPX, significantly reduced the effect of 5 ?M and 10 ?M NMDA on dopamine release. The GABAA receptor agonist, isoguvacine, had a significant concentration-dependent inhibitory effect on dopamine release which was reversed by prior application of the GABAA receptor antagonist, picrotoxin, but not DPCPX. Finally inhibition of dopamine release by CPA (1?M) was significantly enhanced by prior perfusion with picrotoxin. These data demonstrate an important role for GABA, NMDA and adenosine in the modulation of dopamine release.

O?Connor, John J.; O?Neill, Carmel

2008-01-01

330

Serotonin receptor 3A controls interneuron migration into the neocortex  

PubMed Central

Neuronal excitability has been shown to control the migration and cortical integration of reelin-expressing cortical interneurons (INs) arising from the caudal ganglionic eminence (CGE), supporting the possibility that neurotransmitters could regulate this process. Here we show that the ionotropic serotonin receptor 3A (5-HT3AR) is specifically expressed in CGE-derived migrating interneurons and upregulated while they invade the developing cortex. Functional investigations using calcium imaging, electrophysiological recordings and migration assays indicate that CGE-derived INs increase their response to 5-HT3AR activation during the late phase of cortical plate invasion. Using genetic loss-of-function approaches and in vivo grafts, we further demonstrate that the 5-HT3AR is cell autonomously required for the migration and proper positioning of reelin-expressing CGE-derived INs in the neocortex. Our findings reveal a requirement for a serotonin receptor in controlling the migration and laminar positioning of a specific subtype of cortical IN. PMID:25409778

Murthy, Sahana; Niquille, Mathieu; Hurni, Nicolas; Limoni, Greta; Frazer, Sarah; Chameau, Pascal; van Hooft, Johannes A.; Vitalis, Tania; Dayer, Alexandre

2014-01-01

331

Interaction of anesthetics with neurotransmitter release machinery proteins  

PubMed Central

General anesthetics produce anesthesia by depressing central nervous system activity. Activation of inhibitory GABAA 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 Ca2+ 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. PMID:23136341

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

2013-01-01

332

Dopamine D(3) receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: role of hyperthermia.  

PubMed

Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia. PMID:24685638

Baladi, Michelle G; Newman, Amy H; Nielsen, Shannon M; Hanson, Glen R; Fleckenstein, Annette E

2014-06-01

333

A Mechanism for Intracellular Release of Na+ by Neurotransmitter: Sodium Symporters  

PubMed Central

Neurotransmitter:sodium symporters (NSS) terminate synaptic signal transmission by Na+-dependent reuptake of released neurotransmitters, with key conformational states reported for a bacterial homolog LeuT and an inhibitor-bound Drosophila dopamine transporter. However, a coherent mechanism of Na+-driven transport has not been described. Here, we present two crystal structures of MhsT, a NSS member from Bacillus halodurans, in occluded inward-facing states with bound Na+ ions and L-Trp that provide insight into the cytoplasmic release of Na+. The switch from outward- to inward-oriented states is centered on the partial unwinding of transmembrane helix 5, which is facilitated by a conserved GlyX9Pro motif that opens an intracellular pathway for water to access the Na2 site. Based on our structural and functional findings we propose a mechanism according to which solvation through the TM5 pathway facilitates Na+ release from Na2 and the transition to an inward-open state. PMID:25282149

Malinauskaite, Lina; Reinhard, Linda; Lyons, Joseph A.; Yano, Hideaki; Javitch, Jonathan A.

2015-01-01

334

A mechanism for intracellular release of Na+ by neurotransmitter/sodium symporters.  

PubMed

Neurotransmitter/sodium symporters (NSSs) terminate synaptic signal transmission by Na+-dependent reuptake of released neurotransmitters. Key conformational states have been reported for the bacterial homolog LeuT and an inhibitor-bound Drosophila dopamine transporter. However, a coherent mechanism of Na+-driven transport has not been described. Here, we present two crystal structures of MhsT, an NSS member from Bacillus halodurans, in occluded inward-facing states with bound Na+ ions and L-tryptophan, providing insight into the cytoplasmic release of Na+. The switch from outward- to inward-oriented states is centered on the partial unwinding of transmembrane helix 5, facilitated by a conserved GlyX9Pro motif that opens an intracellular pathway for water to access the Na2 site. We propose a mechanism, based on our structural and functional findings, in which solvation through the TM5 pathway facilitates Na+ release from Na2 and the transition to an inward-open state. PMID:25282149

Malinauskaite, Lina; Quick, Matthias; Reinhard, Linda; Lyons, Joseph A; Yano, Hideaki; Javitch, Jonathan A; Nissen, Poul

2014-11-01

335

Neuromodulatory Neurotransmitters Influence LTP-Like Plasticity in Human Cortex: A Pharmaco-TMS Study  

PubMed Central

Long-term potentiation (LTP) of synaptic efficacy is considered a fundamental mechanism of learning and memory. At the cellular level a large body of evidence demonstrated that the major neuromodulatory neurotransmitters dopamine (DA), norepinephrine (NE), and acetylcholine (ACh) influence LTP magnitude. Noninvasive brain stimulation protocols provide the opportunity to study LTP-like plasticity at the systems level of human cortex. Here we applied paired associative stimulation (PAS) to induce LTP-like plasticity in the primary motor cortex of eight healthy subjects. In a double-blind, randomized, placebo-controlled, crossover design, the acute effects of a single oral dose of the neuromodulatory drugs cabergoline (DA agonist), haloperidol (DA antagonist), methylphenidate (indirect NE agonist), prazosine (NE antagonist), tacrine (ACh agonist), and biperiden (ACh antagonist) on PAS-induced LTP-like plasticity were examined. The antagonists haloperidol, prazosine, and biperiden depressed significantly the PAS-induced LTP-like plasticity observed under placebo, whereas the agonists cabergoline, methylphenidate, and tacrine had no effect. Findings demonstrate that antagonists in major neuromodulatory neurotransmitter systems suppress LTP-like plasticity at the systems level of human cortex, in accord with evidence of their modulating action of LTP at the cellular level. This provides further supportive evidence for the known detrimental effects of these drugs on LTP-dependent mechanisms such as learning and memory. PMID:21544070

Korchounov, Alexei; Ziemann, Ulf

2011-01-01

336

Brain serotonin determines maternal behavior and offspring survival.  

PubMed

Maternal care is an indispensable component of offspring survival and development in all mammals and necessary for reproductive success. Although brain areas regulating maternal behaviors are innervated by serotonergic afferents, very little is known about the role of this neurotransmitter in these behaviors. To evaluate the contribution of serotonin to maternal care, we used mice with a null mutation in the gene for tryptophan hydroxylase-2 (TPH2), which results in a genetic depletion of brain serotonin, and tested them in a wide range of maternal behavior paradigms. We found that litters born to and reared by TPH2(-/-) mothers showed decreased survival, lower weaning weights and increased cannibalization. In addition, TPH2(-/-) mothers performed poorly in pup retrieval, huddling, nest construction and high-arched back nursing. Aggression in TPH2(-/-) dams was not triggered by lactation and was steadily high. Survival and weaning weight deficits of TPH2(-/-) pups were rescued by cross-fostering and in litters of mixed genotype (TPH2(-/-) and TPH2(-/+) ). However, the maternal behaviors of TPH2(-/-) dams did not improve when rearing either TPH2(+/+) pups or mixed-genotype litters. In addition, TPH2(-/-) pups significantly worsened the behavior of TPH2(+/+) dams with respect to cannibalism, weaning weight and latency to attack. Olfactory and auditory functions of TPH2(-/-) females or anxiety-like behaviors did not account for these maternal alterations as they were equal to their TPH2(+/+) counterparts. These findings illustrate a profound influence of brain serotonin on virtually all elements of maternal behavior and establish that TPH2(-/-) pups can engender maladaptive mothering in dams of both genotypes. PMID:25077934

Angoa-Pérez, M; Kane, M J; Sykes, C E; Perrine, S A; Church, M W; Kuhn, D M

2014-09-01

337

Pathological gambling induced by dopamine antagonists: a case report.  

PubMed

Pathological gambling is defined as inappropriate, persistent, and maladaptive gambling behaviour. It is a non-pharmacological addiction classified as an impulse control disorder. However, pathological gambling has been associated with dopamine agonist use. Here we report of a 28-year-old man with a first major depressive episode and a post-traumatic stress disorder who has been treated with a combination of the serotonine/noradrenaline reuptake inhibitor duloxetine and the tricyclic antidepressant maprotiline. The administration of antipsychotic flupentixole (up to 7 mg) turned this slight online poker gambler into an excessive gambler. Only after the discontinuation of the antidopaminergic agents and the switch to bupropion did this gambling behaviour stop which suggests a causal relationship between dopamine antagonists and pathological gambling. PMID:24356928

Grötsch, Philipp; Lange, Claudia; Wiesbeck, Gerhard A; Lang, Undine

2015-03-01

338

The Dopamine Imbalance Hypothesis of Fatigue in Multiple Sclerosis and Other Neurological Disorders  

PubMed Central

Fatigue is one of the most pervasive symptoms of multiple sclerosis (MS), and has engendered hundreds of investigations on the topic. While there is a growing literature using various methods to study fatigue, a unified theory of fatigue in MS is yet to emerge. In the current review, we synthesize findings from neuroimaging, pharmacological, neuropsychological, and immunological studies of fatigue in MS, which point to a specific hypothesis of fatigue in MS: the dopamine imbalance hypothesis. The communication between the striatum and prefrontal cortex is reliant on dopamine, a modulatory neurotransmitter. Neuroimaging findings suggest that fatigue results from the disruption of communication between these regions. Supporting the dopamine imbalance hypothesis, structural and functional neuroimaging studies show abnormalities in the frontal and striatal regions that are heavily innervated by dopamine neurons. Further, dopaminergic psychostimulant medication has been shown to alleviate fatigue in individuals with traumatic brain injury, chronic fatigue syndrome, and in cancer patients, also indicating that dopamine might play an important role in fatigue perception. This paper reviews the structural and functional neuroimaging evidence as well as pharmacological studies that suggest that dopamine plays a critical role in the phenomenon of fatigue. We conclude with how specific aspects of the dopamine imbalance hypothesis can be tested in future research.

Dobryakova, Ekaterina; Genova, Helen M.; DeLuca, John; Wylie, Glenn R.

2015-01-01

339

Midbrain dopamine neurons associated with reward processing innervate the neurogenic subventricular zone.  

PubMed

Coordinated regulation of the adult neurogenic subventricular zone (SVZ) is accomplished by a myriad of intrinsic and extrinsic factors. The neurotransmitter dopamine is one regulatory molecule implicated in SVZ function. Nigrostriatal and ventral tegmental area (VTA) midbrain dopamine neurons innervate regions adjacent to the SVZ, and dopamine synapses are found on SVZ cells. Cell division within the SVZ is decreased in humans with Parkinson's disease and in animal models of Parkinson's disease following exposure to toxins that selectively remove nigrostriatal neurons, suggesting that dopamine is critical for SVZ function and nigrostriatal neurons are the main suppliers of SVZ dopamine. However, when we examined the aphakia mouse, which is deficient in nigrostriatal neurons, we found no detrimental effect to SVZ proliferation or organization. Instead, dopamine innervation of the SVZ tracked to neurons at the ventrolateral boundary of the VTA. This same dopaminergic neuron population also innervated the SVZ of control mice. Characterization of these neurons revealed expression of proteins indicative of VTA neurons. Furthermore, exposure to the neurotoxin MPTP depleted neurons in the ventrolateral VTA and resulted in decreased SVZ proliferation. Together, these results reveal that dopamine signaling in the SVZ originates from a population of midbrain neurons more typically associated with motivational and reward processing. PMID:21917791

Lennington, Jessica B; Pope, Sara; Goodheart, Anna E; Drozdowicz, Linda; Daniels, Stephen B; Salamone, John D; Conover, Joanne C

2011-09-14

340

Determination of dopamine in pharmaceutical formulation using enhanced luminescence from europium complex  

NASA Astrophysics Data System (ADS)

Biologically important compound dopamine plays an important role in the central and peripheral nervous systems. Insufficient dopamine level due to the loss of dopamine producing cells may lead to disease called Schizophrenia and Parkinson's disease. Hence, a simple and fast detection of dopamine is necessary to study in the fields of neurophysiology and clinical medicine. An enhanced fluorimetric determination of dopamine in the presence of ascorbic acid is achieved using photoluminescence of europium complex, Eu(III)-dipicolinic acid. In order to obtain better responses, several operational parameters have been investigated. Under the optimum conditions, the method showed good stability and reproducibility. The application of this method for the determination of dopamine neurotransmitters was satisfactory. Linear response was found down to 3.0 × 10-7 M with limit of detection 1.0 × 10-8 M. The relative standard deviation was found to be 3.33% from 20 independent measurements for 1.0 × 10-5 M of dopamine.

Wabaidur, Saikh Mohammad; ALOthman, Zeid Abdullah; Naushad, Mu.

341

The dopamine imbalance hypothesis of fatigue in multiple sclerosis and other neurological disorders.  

PubMed

Fatigue is one of the most pervasive symptoms of multiple sclerosis (MS), and has engendered hundreds of investigations on the topic. While there is a growing literature using various methods to study fatigue, a unified theory of fatigue in MS is yet to emerge. In the current review, we synthesize findings from neuroimaging, pharmacological, neuropsychological, and immunological studies of fatigue in MS, which point to a specific hypothesis of fatigue in MS: the dopamine imbalance hypothesis. The communication between the striatum and prefrontal cortex is reliant on dopamine, a modulatory neurotransmitter. Neuroimaging findings suggest that fatigue results from the disruption of communication between these regions. Supporting the dopamine imbalance hypothesis, structural and functional neuroimaging studies show abnormalities in the frontal and striatal regions that are heavily innervated by dopamine neurons. Further, dopaminergic psychostimulant medication has been shown to alleviate fatigue in individuals with traumatic brain injury, chronic fatigue syndrome, and in cancer patients, also indicating that dopamine might play an important role in fatigue perception. This paper reviews the structural and functional neuroimaging evidence as well as pharmacological studies that suggest that dopamine plays a critical role in the phenomenon of fatigue. We conclude with how specific aspects of the dopamine imbalance hypothesis can be tested in future research. PMID:25814977

Dobryakova, Ekaterina; Genova, Helen M; DeLuca, John; Wylie, Glenn R

2015-01-01

342

Dopamine signaling in Caenorhabditis elegans-potential for parkinsonism research.  

PubMed

The nematode Caenorhabditis elegans is an attractive model system for the study of many biological processes. It possesses a simple nervous system with known anatomy and connectivity, is conveniently and cheaply cultured in the laboratory, and is amenable to many genetic manipulations that are impossible in mammalian systems. The recent completion of the C. elegans genome sequence provides a rich resource of genomic and bioinformatic data to researchers in diverse fields. This organism, however, has been underexploited in the studies of many basic processes related to nervous system function, neuropsychiatric disorders and neuromuscular function. Anatomical, biochemical, behavioral, pharmacological and genetic evidence accumulated to date strongly suggests that dopamine is used as a neurotransmitter by C. elegans, and that its effects are mediated through pathway(s) that share many features with those of mammals. DNA sequence analysis reveals genes highly homologous to those encoding mammalian dopamine receptors. Probably, C. elegans has dopamine receptors that transduce environmental cues into behaviors, and these receptors pharmacologically most closely resemble the D2 family. Here we present a review of the current state of research into the dopamine system of the worm, focussing on its potential for use in the study of biological processes related to parkinsonism. PMID:11331184

Wintle, R F.; Van Tol, H H.M.

2001-07-01

343

Serotonin and depression: pathophysiological mechanism or  

E-print Network

Serotonin and depression: pathophysiological mechanism or marketing myth? Philip J. Cowen serotonin (5-HT) function can lead to clinical depression has a long history but is still controversial a simplistic biological model of depression to market selective serotonin reuptake inhibitors (SSRIs

Alford, Simon

344

Serotonin decreases aggression via 5-HT1A receptors in the fighting fish Betta splendens.  

PubMed

The role of the monoamine neurotransmitter serotonin (5-HT) in the modulation of conspecific aggression in the fighting fish (Betta splendens) was investigated using pharmacological manipulations. We used a fish's response to its mirror image as our index of aggressive behavior. We also investigated the effects of some manipulations on monoamine levels in the B. splendens brain. Acute treatment with 5-HT and with the 5-HT1A receptor agonist 8-OH-DPAT both decreased aggressive behavior; however, treatment with the 5-HT1A receptor antagonist WAY-100635 did not increase aggression. Chronic treatment with the selective serotonin reuptake inhibitor fluoxetine caused no significant changes in aggressive behavior and a significant decline in 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations. Treatment with the serotonin synthesis inhibitor p-chlorophenylalanine resulted in no change in aggression, yet serotonergic activity decreased significantly. Finally, a diet supplemented with L-tryptophan (Trp), the precursor to 5-HT, showed no consistent effects on aggressive behavior or brain monoamine concentrations. These results suggest a complex role for serotonin in the expression of aggression in teleost fishes, and that B. splendens may be a useful model organism in pharmacological and toxicological studies. PMID:17553555

Clotfelter, Ethan D; O'Hare, Erin P; McNitt, Meredith M; Carpenter, Russ E; Summers, Cliff H

2007-01-01

345

Serotonin transporter gene polymorphism and psychiatric disorders: Is there a link?  

PubMed Central

Though still in infancy, the field of psychiatric genetics holds great potential to contribute to the development of new diagnostic and therapeutic options to treat these disorders. Among a large number of existing neurotransmitter systems, the serotonin system dysfunction has been implicated in many psychiatric disorders and therapeutic efficacy of many drugs is also thought to be based on modulation of serotonin. Serotonin transporter gene polymorphism is one of the most extensively studied polymorphisms in psychiatric behavioral genetics. In this article, we review the status of evidence for association between the serotonin gene polymorphism and some common mental disorders like affective disorders, post-traumatic stress disorder, obsessive-compulsive disorder, suicide, autism, and other anxiety and personality disorders. Going beyond traditional association studies, gene-environment interaction, currently gaining momentum, is also discussed in the review. While the existing information of psychiatric genetics is inadequate for putting into practice genetic testing in the diagnostic work-up of the psychiatric patient, if consistent in future research attempts, such results can be of great help to improve the clinical care of a vast majority of patients suffering from such disorders. PMID:22303036

Margoob, Mushtaq A.; Mushtaq, Dhuha

2011-01-01

346

How Do We Re-Engage the Pharmaceutical Industry in Research on Serotonin and Psychiatric Disorders?  

PubMed Central

The Serotonin Club celebrated its silver jubilee in 2012 with a meeting in Montpellier, France. During the past 25 years, great advances have been made in our understanding of the pharmacology of serotonin receptors and the roles of this neurotransmitter in psychiatric disorders. Most of these advances have involved effective collaborations between academic and industrial scientists. In recent years, however, this picture has changed, as many of the major pharmaceutical companies have pulled out of in-house psychopharmacology research into the major psychiatric disorders, despite an increasing worldwide burden of these disorders and a clear need for improved treatment, particularly in terms of improved efficacy. This Viewpoint investigates the reasons for the decline in industrial involvement and makes proposals as to how future academic research on serotonin function in the brain might reawaken industry interest in serotonin-based research. Briefly, academic preclinical scientists need to alter their experimental approach to research into the psychiatric disorders. This will require a move from a single-target approach to understanding the complex neuronal pathways the cause diverse functional and behavioral outputs, using novel technological advances and the development of animal models with enhanced translational values. It is hoped that such an approach will reveal novel drug targets and thus re-engage the pharmaceutical industry in research that will result in improved human health and social well-being. PMID:23336037

2013-01-01

347

Trans-synaptic (GABA-dopamine) modulation of cocaine induced dopamine release: A potential therapeutic strategy for cocaine abuse  

SciTech Connect

We recently developed a new experimental strategy for measuring interactions between functionally-linked neurotransmitter systems in the primate and human brain with PET. As part of this research, we demonstrated that increases in endogenous GABA concentrations significantly reduced striatal dopamine concentrations in the primate brain. We report here the application of the neurotransmitter interaction paradigm with PET and with microdialysis to the investigation of a novel therapeutic strategy for treating cocaine abuse based on the ability of GABA to inhibit cocaine induced increases in striatal dopamine. Using gamma-vinyl GABA (GVG, a suicide inhibitor of GABA transaminase), we performed a series of PET studies where animals received a baseline PET scan with labeled raclopride injection, animals received cocaine (2.0 mg/kg). Normally, a cocaine challenge significantly reduces the striatal binding of {sup 11}C-raclopride. However, in animals pretreated with GVG, {sup 11}C-raclopride binding was less affected by a cocaine challenge compared to control studies. Furthermore, microdialysis studies in freely moving rats demonstrate that GVG (300 mg/kg) significantly inhibited cocaine-induced increases in extracellular dopamine release. GVG also attenuated cocaine-induced increases in locomotor activity. However, at a dose of 100 mg/kg, GVG had no effect. Similar findings were obtained with alcohol. Alcohol pretreatment dose dependantly (1-4 g/kg) inhibited cocaine-induced increases in extracellular dopamine concentrations in freely moving rats. Taken together, these studies suggest that therapeutic strategies targeted at increasing central GABA concentrations may be beneficial for the treatment of cocaine abuse.

Dewey, S.L.; Straughter-Moore, R.; Chen, R. [Brookhaven National Laboratory, Upton, NY (United States)] [and others

1995-05-01

348

BDE99 (2,2',4,4',5-pentabromodiphenyl ether) suppresses differentiation into neurotransmitter phenotypes in PC12 cells.  

PubMed

Early-life exposures to brominated diphenyl ethers (BDEs) lead to neurobehavioral abnormalities later in life. Although these agents are thyroid disruptors, it is not clear whether this mechanism alone accounts for the adverse effects. We evaluated the impact of 2,2',4,4',5-pentabromodiphenyl ether (BDE99) on PC12 cells undergoing neurodifferentiation, contrasting the effects with chlorpyrifos, a known developmental neurotoxicant. BDE99 elicited decrements in the number of cells, evidenced by a reduction in DNA levels, to a lesser extent than did chlorpyrifos. This did not reflect cytotoxicity from oxidative stress, since cell enlargement, monitored by the total protein/DNA ratio, was not only unimpaired by BDE99, but was actually enhanced. Importantly, BDE99 impaired neurodifferentiation into both the dopamine and acetylcholine neurotransmitter phenotypes. The cholinergic phenotype was affected to a greater extent, so that neurotransmitter fate was diverted away from acetylcholine and toward dopamine. Chlorpyrifos produced the same imbalance, but through a different underlying mechanism, promoting dopaminergic development at the expense of cholinergic development. In our earlier work, we did not find these effects with BDE47, a BDE that has greater endocrine disrupting and cytotoxic effects than BDE99. Thus, our results point to interference with neurodifferentiation by specific BDE congeners, distinct from cytotoxic or endocrine mechanisms. PMID:23422510

Slotkin, Theodore A; Card, Jennifer; Infante, Alice; Seidler, Frederic J

2013-01-01

349

BDE99 (2,2?,4,4?,5-PENTABROMODIPHENYL ETHER) SUPPRESSES DIFFERENTIATION INTO NEUROTRANSMITTER PHENOTYPES IN PC12 CELLS  

PubMed Central

Early-life exposures to brominated diphenyl ethers (BDEs) lead to neurobehavioral abnormalities later in life. Although these agents are thyroid disruptors, it is not clear whether this mechanism alone accounts for the adverse effects. We evaluated the impact of 2,2?,4,4?,5-pentabromodiphenyl ether (BDE99) on PC12 cells undergoing neurodifferentiation, contrasting the effects with chlorpyrifos, a known developmental neurotoxicant. BDE99 elicited decrements in the number of cells, evidenced by a reduction in DNA levels, to a lesser extent than did chlorpyrifos. This did not reflect cytotoxicity from oxidative stress, since cell enlargement, monitored by the total protein/DNA ratio, was not only unimpaired by BDE99, but was actually enhanced. Importantly, BDE99 impaired neurodifferentiation into both the dopamine and acetylcholine neurotransmitter phenotypes. The cholinergic phenotype was affected to a greater extent, so that neurotransmitter fate was diverted away from acetylcholine and toward dopamine. Chlorpyrifos produced the same imbalance, but through a different underlying mechanism, promoting dopaminergic development at the expense of cholinergic development. In our earlier work, we did not find these effects with BDE47, a BDE that has greater endocrine disrupting and cytotoxic effects than BDE99. Thus, our results point to interference with neurodifferentiation by specific BDE congeners, distinct from cytotoxic or endocrine mechanisms. PMID:23422510

Slotkin, Theodore A.; Card, Jennifer; Infante, Alice; Seidler, Frederic J.

2013-01-01

350

Two Intracellular Pathways Mediate Metabotropic Glutamate Receptor-Induced Ca2 Mobilization in Dopamine Neurons  

Microsoft Academic Search

Activation of metabotropic glutamate receptors (mGluRs) causes membrane hyperpolarization in midbrain dopamine neurons. This hyperpolarization results from the opening of Ca 2-sensitive K channels, which is mediated by the release of Ca 2 from intracellular stores. Neurotransmitter-induced mobilization of Ca 2 is generally ascribed to the action of inositol 1,4,5-triphosphate (IP3 ) in neurons. Here we show that the mGluR-mediated

Hitoshi Morikawa; Kamran Khodakhah; John T. Williams

351

Vesicular and Plasma Membrane Transporters for Neurotransmitters  

PubMed Central

The regulated exocytosis that mediates chemical signaling at synapses requires mechanisms to coordinate the immediate response to stimulation with the recycling needed to sustain release. Two general classes of transporter contribute to release, one located on synaptic vesicles that loads them with transmitter, and a second at the plasma membrane that both terminates signaling and serves to recycle transmitter for subsequent rounds of release. Originally identified as the target of psychoactive drugs, these transport systems have important roles in transmitter release, but we are only beginning to understand their contribution to synaptic transmission, plasticity, behavior, and disease. Recent work has started to provide a structural basis for their activity, to characterize their trafficking and potential for regulation. The results indicate that far from the passive target of psychoactive drugs, neurotransmitter transporters undergo regulation that contributes to synaptic plasticity. PMID:22199021

Blakely, Randy D.; Edwards, Robert H.

2012-01-01

352

Dopamine genes and ADHD.  

PubMed

Family, twin, and adoption studies have documented a strong genetic basis for ADHD/HKD, but these studies do not identify specific genes linked to the disorder. Molecular genetic studies can identify allelic variations of specific genes that are functionally associated with ADHD/HKD, and dopamine genes have been the initial candidates based on the site of action of the stimulants drugs, which for a half century have provided the primary pharmacological treatment for ADHD/HKD. Two candidate dopamine genes have been investigated and reported to be associated with ADHD/HKD: the dopamine transporter (DAT1) gene [Cook et al., American Journal of Human Genetics 1995;56:993-998, Gill et al., Molecular Psychiatry 1997;2:311-313] and the dopamine receptor D4 (DRD4) gene [LaHoste et al., Molecular Psychiatry 1996;1:121-124: Smalley et al., 1998;3:427-430; Swanson et al., Molecular Psychiatry 1998;3:38-41]. Speculative hypotheses [Swanson and Castellanos, NIH Consensus Development Conference: Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder, November 1998. p. 37-42] have suggested that specific alleles of these dopamine genes may alter dopamine transmission in the neural networks implicated in ADHD/HKD (e.g. that the 10-repeat allele of the DAT1 gene may be associated with hyperactive re-uptake of dopamine or that the 7-repeat allele of the DRD4 gene may be associated with a subsensitive postsynaptic receptor). These and other variants of the dopamine hypothesis of ADHD will be discussed. PMID:10654656

Swanson, J M; Flodman, P; Kennedy, J; Spence, M A; Moyzis, R; Schuck, S; Murias, M; Moriarity, J; Barr, C; Smith, M; Posner, M

2000-01-01

353

Synthesis and Structure-Activity Studies of Benzyl Ester Meperidine and Normeperidine Derivatives as Selective Serotonin Transporter Ligands  

PubMed Central

A series of benzyl esters of meperidine and normeperidine were synthesized and evaluated for binding affinity at serotonin, dopamine and norepinephrine transporters. The 4-methoxybenzyl ester 8b and 4-nitrobenzyl ester 8c in the meperidine series and 4-methoxybenzyl ester 14a in the normeperidine series exhibited low nanomolar binding affinities at the SERT (Ki values < 2 nM) and high SERT selectivity (DAT/SERT >1500 and NET/SERT > 1500). PMID:20980153

Gu, Xiaobo; Izenwasser, Sari; Wade, Dean; Housman, Amy; Gulasey, Gerard; Rhoden, Jill B.; Savoie, Christopher D.; Mobley, David L.; Lomenzo, Stacey A.; Trudell, Mark L.

2013-01-01

354

CURRENT LITERATURE NEUROTRANSMITTER SUPPLY AND DEMAND IN EPILEPSY  

E-print Network

CURRENT LITERATURE NEUROTRANSMITTER SUPPLY AND DEMAND IN EPILEPSY Block of Glutamate Contributes to Neurotransmitter GABA Synthesis and Epilepsy Sepkuty JP, Cohen AS, Eccles C, Rafiq A, Behar K and thus could cause epilepsy in rats when inactivated. Reduced ex- pression of EAAC1 by antisense

Huguenard, John R.

355

Secondary Abnormalities of Neurotransmitters in Infants with Neurological Disorders  

ERIC Educational Resources Information Center

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…

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

356

NEUROTRANSMITTER TRANSPORTERS: THREE IMPORTANT GENE FAMILIES FOR NEURONAL FUNCTION  

Microsoft Academic Search

Summary Three distinct gene families encode transporter proteins that aid in temporal and spatial buffering of neurotransmitter and neurotransmitter metabolite concentrations and allow neurons to cycle and recycle transmitter molecules. Analyses of these gene families and their products are likely to enhance understanding of the molecular neurobiology of neuronal function and may elucidate contributors to the genetic etiologies of neurological

GEORGE R. UHL; PETER S. JOHNSON

1994-01-01

357

Serotonin release varies with brain tryptophan levels  

NASA Technical Reports Server (NTRS)

This study examines directly the effects on serotonin release of varying brain tryptophan levels within the physiologic range. It also addresses possible interactions between tryptophan availability and the frequency of membrane depolarization in controlling serotonin release. We demonstrate that reducing tryptophan levels in rat hypothalamic slices (by superfusing them with medium supplemented with 100 microM leucine) decreases tissue serotonin levels as well as both the spontaneous and the electrically-evoked serotonin release. Conversely, elevating tissue tryptophan levels (by superfusing slices with medium supplemented with 2 microM tryptophan) increases both the tissue serotonin levels and the serotonin release. Serotonin release was found to be affected independently by the tryptophan availability and the frequency of electrical field-stimulation (1-5 Hz), since increasing both variables produced nearly additive increases in release. These observations demonstrate for the first time that both precursor-dependent elevations and reductions in brain serotonin levels produce proportionate changes in serotonin release, and that the magnitude of the tryptophan effect is unrelated to neuronal firing frequency. The data support the hypothesis that serotonin release is proportionate to intracellular serotonin levels.

Schaechter, Judith D.; Wurtman, Richard J.

1990-01-01

358

Platelet-Derived Serotonin Mediates Liver Regeneration  

NASA Astrophysics Data System (ADS)

The liver can regenerate its volume after major tissue loss. In a mouse model of liver regeneration, thrombocytopenia, or impaired platelet activity resulted in the failure to initiate cellular proliferation in the liver. Platelets are major carriers of serotonin in the blood. In thrombocytopenic mice, a serotonin agonist reconstituted liver proliferation. The expression of 5-HT2A and 2B subtype serotonin receptors in the liver increased after hepatectomy. Antagonists of 5-HT2A and 2B receptors inhibited liver regeneration. Liver regeneration was also blunted in mice lacking tryptophan hydroxylase 1, which is the rate-limiting enzyme for the synthesis of peripheral serotonin. This failure of regeneration was rescued by reloading serotonin-free platelets with a serotonin precursor molecule. These results suggest that platelet-derived serotonin is involved in the initiation of liver regeneration.

Lesurtel, Mickael; Graf, Rolf; Aleil, Boris; Walther, Diego J.; Tian, Yinghua; Jochum, Wolfram; Gachet, Christian; Bader, Michael; Clavien, Pierre-Alain

2006-04-01

359

Linezolid-induced serotonin syndrome  

PubMed Central

A young drug abuser was admitted to our intensive care unit for organophosphorus poisoning. He required mechanical ventilation and was started empirically on linezolid for suspected nosocomial infection. The patient developed high-grade fever with altered sensorium and clonus. Serotonin syndrome was suspected and the patient was started on cyproheptadine. He recovered within 3?days of withdrawing linezolide and administering cyproheptadine. PMID:23513014

Gupta, Vishal; Karnik, Niteen D; Deshpande, Rushikesh; Patil, Meenakshi Amit

2013-01-01

360

Serotonin and Blood Pressure Regulation  

PubMed Central

5-Hydroxytryptamine (5-HT; serotonin) was discovered more than 60 years ago as a substance isolated from blood. The neural effects of 5-HT have been well investigated and understood, thanks in part to the pharmacological tools available to dissect the serotonergic system and the development of the frequently prescribed selective serotonin-reuptake inhibitors. By contrast, our understanding of the role of 5-HT in the control and modification of blood pressure pales in comparison. Here we focus on the role of 5-HT in systemic blood pressure control. This review provides an in-depth study of the function and pharmacology of 5-HT in those tissues that can modify blood pressure (blood, vasculature, heart, adrenal gland, kidney, brain), with a focus on the autonomic nervous system that includes mechanisms of action and pharmacology of 5-HT within each system. We compare the change in blood pressure produced in different species by short- and long-term administration of 5-HT or selective serotonin receptor agonists. To further our understanding of the mechanisms through which 5-HT modifies blood pressure, we also describe the blood pressure effects of commonly used drugs that modify the actions of 5-HT. The pharmacology and physiological actions of 5-HT in modifying blood pressure are important, given its involvement in circulatory shock, orthostatic hypotension, serotonin syndrome and hypertension. PMID:22407614

Morrison, Shaun F.; Davis, Robert Patrick; Barman, Susan M.

2012-01-01

361

Serotonin and Aggressiveness in Chickens  

Technology Transfer Automated Retrieval System (TEKTRAN)

Serotonin (5-HT) regulates aggressive behavior in animals. This study examined if 5-HT regulation of aggressiveness is gene-dependent. Chickens from two divergently selected lines KGB and MBB (Kind Gentle Birds and Mean Bad Birds displaying low and high aggressiveness, respectively) and DXL (Dekalb ...

362

Selective serotonin reuptake inhibitor exposure.  

PubMed

Many antidepressants inhibit serotonin or norepinephrine reuptake or both to achieve their clinical effect. The selective serotonin reuptake inhibitor class of antidepressants (SSRIs) includes citalopram, escitalopram (active enantiomer of citalopram), fluoxetine, fluvoxamine, paroxetine, and sertraline. The SSRIs are as effective as tricyclic antidepressants in treatment of major depression with less significant side effects. As a result, they have become the largest class of medications prescribed to humans for depression. They are also used to treat obsessive-compulsive disorder, panic disorders, alcoholism, obesity, migraines, and chronic pain. An SSRI (fluoxetine) has been approved for veterinary use in treatment of canine separation anxiety. SSRIs act specifically on synaptic serotonin concentrations by blocking its reuptake in the presynapse and increasing levels in the presynaptic membrane. Clinical signs of SSRI overdose result from excessive amounts of serotonin in the central nervous system. These signs include nausea, vomiting, mydriasis, hypersalivation, and hyperthermia. Clinical signs are dose dependent and higher dosages may result in the serotonin syndrome that manifests itself as ataxia, tremors, muscle rigidity, hyperthermia, diarrhea, and seizures. Current studies reveal no increase in appearance of any specific clinical signs of serotonin toxicity with regard to any SSRI medication. In people, citalopram has been reported to have an increased risk of electrocardiographic abnormalities. Diagnosis of SSRI poisoning is based on history, clinical signs, and response to therapy. No single clinical test is currently available to confirm SSRI toxicosis. The goals of treatment in this intoxication are to support the animal, prevent further absorption of the drug, support the central nervous system, control hyperthermia, and halt any seizure activity. The relative safety of the SSRIs in overdose despite the occurrence of serotonin syndrome makes them more desirable than other antidepressants. The prognosis in animals that receive treatment is excellent. In one retrospective study, there were no deaths in 313 SSRI-poisoned dogs. No characteristic or classic histopathologic lesions result from SSRI toxicosis. Differential diagnoses for SSRI overdose must include ingestions of other serotonergic medications such as phenylpiperidine opioids (fentanyl and tramadol), mirtazapine, buspirone, amitraz, and chlorpheniramine. PMID:23796482

Fitzgerald, Kevin T; Bronstein, Alvin C

2013-02-01

363

Juvenile hormone-dopamine systems for the promotion of flight activity in males of the large carpenter bee Xylocopa appendiculata  

NASA Astrophysics Data System (ADS)

The reproductive roles of dopamine and dopamine regulation systems are known in social hymenopterans, but the knowledge on the regulation systems in solitary species is still needed. To test the possibility that juvenile hormone (JH) and brain dopamine interact to trigger territorial flight behavior in males of a solitary bee species, the effects on biogenic amines of JH analog treatments and behavioral assays with dopamine injections in males of the large carpenter bee Xylocopa appendiculata were quantified. Brain dopamine levels were significantly higher in methoprene-treated males than in control males 4 days after treatment, but were not significantly different after 7 days. Brain octopamine and serotonin levels did not differ between methoprene-treated and control males at 4 and 7 days after treatment. Injection of dopamine caused significantly higher locomotor activities and a shorter duration for flight initiation in experimental versus control males. These results suggest that brain dopamine can be regulated by JH and enhances flight activities in males. The JH-dopamine system in males of this solitary bee species is similar to that of males of the highly eusocial honeybee Apis mellifera.

Sasaki, Ken; Nagao, Takashi

2013-12-01

364

Juvenile hormone-dopamine systems for the promotion of flight activity in males of the large carpenter bee Xylocopa appendiculata.  

PubMed

The reproductive roles of dopamine and dopamine regulation systems are known in social hymenopterans, but the knowledge on the regulation systems in solitary species is still needed. To test the possibility that juvenile hormone (JH) and brain dopamine interact to trigger territorial flight behavior in males of a solitary bee species, the effects on biogenic amines of JH analog treatments and behavioral assays with dopamine injections in males of the large carpenter bee Xylocopa appendiculata were quantified. Brain dopamine levels were significantly higher in methoprene-treated males than in control males 4 days after treatment, but were not significantly different after 7 days. Brain octopamine and serotonin levels did not differ between methoprene-treated and control males at 4 and 7 days after treatment. Injection of dopamine caused significantly higher locomotor activities and a shorter duration for flight initiation in experimental versus control males. These results suggest that brain dopamine can be regulated by JH and enhances flight activities in males. The JH-dopamine system in males of this solitary bee species is similar to that of males of the highly eusocial honeybee Apis mellifera. PMID:24240706

Sasaki, Ken; Nagao, Takashi

2013-12-01

365

Electrochemical investigation of dopamine at the water/1,2-dichloroethane interface.  

PubMed

Dopamine is an important neurotransmitter in mammalian central and peripheral nervous systems and is also a medicament to cure some neuropsychosis. In this work, ion transfer (IT), facilitated ion transfer (FIT) of protonated dopamine, and electron transfer (ET) between dopamine and ferrocene are investigated at the water/1,2-dichloroethane (W/DCE) interface. The IT and FIT reactions of protonated dopamine can be observed simultaneously within the same potential window. The experimental results demonstrate that dibenzo-18-crown-6, dibenzo-24-crown-8, and benzo-15-crown-5 work well with the protonated dopamine. The amperometric detection of dopamine based on either the IT or the FIT of protonated dopamine can get rid of the interference of ascorbic acid, and the lowest concentration that can be determined is approximately 0.05 microM by differential pulse voltammetry. For the ET reaction, its kinetics can be evaluated by scanning electrochemical microscopy, and the results show that the relationship between rate constants and driving force at the unmodified W/DCE interface obeys the Butler-Volmer equation in a rather wide potential region. When the W/DCE interface is modified by egg lecithin, the ET rate constants decrease with increasing concentration of egg lecithin, which indicates that egg lecithin hinders the ET reaction. When the driving force is increased to a certain degree, the linear relationship between ET rate constants and the driving force is distorted. These results will be helpful to understand both the pharmacodynamics and the neural signal transmission mechanism of dopamine at biological membranes and also provide a novel way to detect dopamine. PMID:15253653

Zhan, Dongping; Mao, Shuneng; Zhao, Qiang; Chen, Zhong; Hu, Hu; Jing, Ping; Zhang, Meiqin; Zhu, Zhiwei; Shao, Yuanhua

2004-07-15

366

Cortical trapping of ?-[ 11C]methyl- l-tryptophan, an index of serotonin synthesis, is lower in females than males  

Microsoft Academic Search

One neural system that may exhibit gender differences is serotonin (5-HT), a neurotransmitter implicated in the regulation of mood, cognitive processes, and impulse-control. However, most of the available evidence of gender-related differences in this system has been indirect and at times contradictory. The objective of the present study was to follow up on preliminary evidence that there are gender differences

Y. Sakai; M. Nishikawa; M. Leyton; C. Benkelfat; S. N. Young; M. Diksic

2006-01-01

367

Serotonin and inhibitory response control: Focusing on the role of 5-HT1A receptors.  

PubMed

Disturbances in behavioral inhibition are key features in several neurological and psychiatric disorders, such as attention-deficit/hyperactivity disorder, Parkinson?s disease and substance use disorders. Therefore, elucidating the neural correlates of inhibitory control processes is crucial for developing novel treatment strategies to ameliorate the symptomatology of these disorders and to improve the quality of life. The development of preclinical translational paradigms to study inhibitory control processes has greatly enhanced our neurobiological understanding of these cognitive processes. Over the last decades, emphasis has been mainly on monoamines including dopamine and serotonin and their contribution to behavioral inhibition. This short review will focus on the involvement of the serotonergic system, and in particular serotonin1A receptors, in inhibitory control processes. PMID:25094037

Pattij, Tommy; Schoffelmeer, Anton N M

2015-04-15

368

Microfabrication of biosensors for neurotransmitter analysis  

NASA Astrophysics Data System (ADS)

We have developed ultrasensitive biosensors for the analysis of neurotransmitters such as glutamate, GABA and lactate. These sensors have micrometer to submicrometer sizes. They are based on biomolecule immobilization on optical fiber probe surfaces. The miniaturized fiber probes are fabricated by either pulling or etching conventional optical fibers. For example, surface immobilized glutamate dehydrogenase (GDH) is being used for glutamate analysis. GDH has been directly immobilized onto an optical fiber probe surface through a new optical fiber sensor fabrication technique using covalent binding mechanisms. None of the direct or indirect physical confinement methods, such as mechanical confinement, gel trapping or membrane immobilization, has been used for the sensor preparation. An optical fiber surface is initially activated by silanization, which adds amine groups (-NH2) to the surface. We then affix functional groups -CHO to the optical fiber surface by employing a bifunctional cross-linking agent, glutaraldehyde. The amino acids of GDH enzyme molecules (or other biomolecules) readily attach to these free -CHO groups on the fiber surface. The sensor is able to detect its substrate, glutamate, by monitoring the fluorescence of reduced nicotinamide adenine dinucleotide (NADH), a product of the reaction between nicotinamide adenine dinucleotide (NAD+) and glutamate. Similar procedures and principle have been used for the development of lactate and GABA sensors. Our biomolecule based biosensors have been applied to the study of single living cell neurophysiological responses.

Tan, Weihong; Cordek, Julia; Liu, Xiaojing; Gross, Brooks; Liesenfeld, Bernd

1999-06-01

369

Role of 5-ht2c receptor density on behaviour in mice   

E-print Network

The neurotransmitters serotonin (5-HT) and dopamine (DA) play roles in eating disorders, mood disorders, such as depression and anxiety, and in the regulation of locomotion. The 5-HT2C receptor is one of fourteen 5-HT receptor subtypes...

Stevenson, Paula Louise

2011-07-05

370

Challenges and recent advances in mass spectrometric imaging of neurotransmitters  

PubMed Central

Mass spectrometric imaging (MSI) is a powerful tool that grants the ability to investigate a broad mass range of molecules, from small molecules to large proteins, by creating detailed distribution maps of selected compounds. To date, MSI has demonstrated its versatility in the study of neurotransmitters and neuropeptides of different classes toward investigation of neurobiological functions and diseases. These studies have provided significant insight in neurobiology over the years and current technical advances are facilitating further improvements in this field. neurotransmitters, focusing specifically on the challenges and recent Herein, we advances of MSI of neurotransmitters. PMID:24568355

Gemperline, Erin; Chen, Bingming; Li, Lingjun

2014-01-01

371

Dopamine regulation of human speech and bird song: A critical review  

PubMed Central

To understand the neural basis of human speech control, extensive research has been done using a variety of methodologies in a range of experimental models. Nevertheless, several critical questions about learned vocal motor control still remain open. One of them is the mechanism(s) by which neurotransmitters, such as dopamine, modulate speech and song production. In this review, we bring together the two fields of investigations of dopamine action on voice control in humans and songbirds, who share similar behavioral and neural mechanisms for speech and song production. While human studies investigating the role of dopamine in speech control are limited to reports in neurological patients, research on dopaminergic modulation of bird song control has recently expanded our views on how this system might be organized. We discuss the parallels between bird song and human speech from the perspective of dopaminergic control as well as outline important differences between these species. PMID:22284300

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

2012-01-01

372

The effects of dopamine on antioxidant enzymes activities and reactive oxygen species levels in soybean roots.  

PubMed

In the current work, we investigated the effects of dopamine, an neurotransmitter found in several plant species on antioxidant enzyme activities and ROS in soybean (Glycine max L. Merrill) roots. The effects of dopamine on SOD, CAT and POD activities, as well as H2O2, O2(•-), melanin contents and lipid peroxidation were evaluated. Three-day-old seedlings were cultivated in half-strength Hoagland nutrient solution (pH 6.0), without or with 0.1 to 1.0 mM dopamine, in a growth chamber (25°C, 12 h photoperiod, irradiance of 280 ?mol m(-2) s(-1)) for 24 h. Significant increases in melanin content were observed. The levels of ROS and lipid peroxidation decreased at all concentrations of dopamine tested. The SOD activity increased significantly under the action of dopamine, while CT activity was inhibited and POD activity was unaffected. The results suggest a close relationship between a possible antioxidant activity of dopamine and melanin and activation of SOD, reducing the levels of ROS and damage on membranes of soybean roots. PMID:25482756

Gomes, Bruno Ribeiro; Siqueira-Soares, Rita de Cássia; Dos Santos, Wanderley Dantas; Marchiosi, Rogério; Soares, Anderson Ricardo; Ferrarese-Filho, Osvaldo

2014-01-01

373

Breathing is affected by dopamine D2-like receptors in the basolateral amygdala.  

PubMed

The precise mechanisms underlying how emotions change breathing patterns remain unclear, but dopamine is a candidate neurotransmitter in the process of emotion-associated breathing. We investigated whether basal dopamine release occurs in the basolateral amygdala (BLA), where sensory-related inputs are received and lead to fear or anxiety responses, and whether D1- and D2-like receptor antagonists affect breathing patterns and dopamine release in the BLA. Adult male mice (C57BL/6N) were perfused with artificial cerebrospinal fluid, a D1-like receptor antagonist (SCH 23390), or a D2-like receptor antagonist ((S)-(-)-sulpiride) through a microdialysis probe in the BLA. Respiratory variables were measured using a double-chamber plethysmograph. Dopamine release was measured by an HPLC. Perfusion of (S)-(-)-sulpiride in the BLA, not SCH 23390, specifically decreased respiratory rate without changes in local release of dopamine. These results suggest that basal dopamine release in the BLA, at least partially, increases respiratory rates only through post-synaptic D2-like receptors, not autoreceptors, which might be associated with emotional responses. PMID:25281921

Sugita, Toshihisa; Kanamaru, Mitsuko; Iizuka, Makito; Sato, Kanako; Tsukada, Setsuro; Kawamura, Mitsuru; Homma, Ikuo; Izumizaki, Masahiko

2015-04-01

374

Amphetamine Paradoxically Augments Exocytotic Dopamine Release and Phasic Dopamine Signals  

PubMed Central

Drugs of abuse hijack brain reward circuitry during the addiction process by augmenting action potential-dependent phasic dopamine release events associated with learning and goal-directed behavior. One prominent exception to this notion would appear to be amphetamine (AMPH) and related analogs, which are proposed instead to disrupt normal patterns of dopamine neurotransmission by depleting vesicular stores and promoting non-exocytotic dopamine efflux via reverse transport. This mechanism of AMPH action, though, is inconsistent with its therapeutic effects and addictive properties - which are thought to be reliant on phasic dopamine signaling. Here we used fast-scan cyclic voltammetry in freely moving rats to interrogate principal neurochemical responses to AMPH in the striatum and relate these changes to behavior. First, we showed that AMPH dose-dependently enhanced evoked dopamine responses to phasic-like current pulse trains for up to two hours. Modeling the data revealed that AMPH inhibited dopamine uptake but also unexpectedly potentiated vesicular dopamine release. Second, we found that AMPH increased the amplitude, duration and frequency of spontaneous dopamine transients, the naturally occurring, non-electrically evoked, phasic increases in extracellular dopamine. Finally, using an operant sucrose reward paradigm, we showed that low-dose AMPH augmented dopamine transients elicited by sucrose-predictive cues. However, operant behavior failed at high-dose AMPH, which was due to phasic dopamine hyperactivity and the decoupling of dopamine transients from the reward predictive cue. These findings identify up-regulation of exocytotic dopamine release as a key AMPH action in behaving animals and support a unified mechanism of abused drugs to activate phasic dopamine signaling. PMID:23303926

Daberkow, DP; Brown, HD; Bunner, KD; Kraniotis, SA; Doellman, MA; Ragozzino, ME; Garris, PA; Roitman, MF

2013-01-01

375

m-Chlorophenylpiperazine: A central serotonin agonist causing powerful anorexia in rats  

Microsoft Academic Search

Meta-chlorophenylpiperazine inhibited serotonin and noradrenaline uptake by synaptosomes to the same extent with IC50 of 1.3×10-6 M and 5.8×10-6 M respectively. Dopamine uptake was lesss affected by meta-chlorophenylpiperazine (IC50 of 2.2×10-5 M). Unlike d-amphetamine and d-fenfluramine, the drug did not significantly increase monoamine release in synaptosomal preparations. On the other hand, metachlorophenylpiperazine showed an IC50 of 620 nM in displacing

R. Samanin; T. Mennini; A. Ferraris; C. Bendotti; F. Borsini; S. Garattini

1979-01-01

376

Novel and high affinity fluorescent ligands for the serotonin transporter based on (s)-citalopram.  

PubMed

Novel rhodamine-labeled ligands, based on (S)-citalopram, were synthesized and evaluated for uptake inhibition at the human serotonin, dopamine, and norepinephrine transporters (hSERT, hDAT, and hNET, respectively) and for binding at SERT, in transiently transfected COS7 cells. Compound 14 demonstrated high affinity binding and selectivity for SERT (K i = 3 nM). Visualization of SERT, using confocal laser scanning microscopy, validated compound 14 as a novel tool for studying SERT expression and distribution in living cells. PMID:24944746

Kumar, Vivek; Rahbek-Clemmensen, Troels; Billesbølle, Christian B; Jorgensen, Trine Nygaard; Gether, Ulrik; Newman, Amy Hauck

2014-06-12

377

Biochemical changes in tissue catecholamines and serotonin in duodenal ulceration caused by cysteamine or propionitrile in the rat  

SciTech Connect

Previous structure-activity and pharmacologic studies with duodenal ulcerogens cysteamine and propionitrile implicating catecholamines in the pathogenesis of duodenal ulceration have now been followed up by dose- and time-response biochemical investigations to assess the importance of monoamines in the development of duodenal ulcers. The concentrations of norepinephrine (noradrenaline), dopamine, serotonin and their metabolites were measured in total brain, brain regions, stomach, duodenum, pancreas and adrenals in the rat. Turnover of catecholamines was determined in rats pretreated with the inhibitor of tyrosine hydroxylase alpha-methyl-p-tyrosine. The duodenal ulcerogens caused a dose- and time-dependent depletion of norepinephrine in virtually all the tissues examined. The effect was maximal 4 or 7 hr after cysteamine or propionitrile, and norepinephrine levels returned to normal in 24 hr. Dopamine changes were selective and often biphasic, e.g., elevation in adrenals, biphasic in brain cortex, hippocampus and midbrain, but uniformly decreasing in glandular stomach and duodenum. In the median eminence dopamine levels decreased by 181 and 324% at 15 and 30 min, respectively, after cysteamine, but neither dopamine nor 3,4-dihydroxyphenylacetic acid was modified in the periventricular nucleus. Serotonin levels were relatively stable, revealing slight elevations or no changes in most of the tissues. The turnover of norepinephrine was accelerated by both chemicals in virtually all brain regions, but dopamine turnover was affected only in a few areas, e.g., in the corpus striatum and medulla oblongata cysteamine decreased dopamine turnover, whereas propionitrile first (at 1 hr) accelerated then (at 8 hr) significantly suppressed it.(ABSTRACT TRUNCATED AT 250 WORDS)

Szabo, S.; Horner, H.C.; Maull, H.; Schnoor, J.; Chiueh, C.C.; Palkovits, M.

1987-03-01

378

TEMPORAL NEUROTRANSMITTER CONDITIONING RESTORES THE FUNCTIONAL ACTIVITY OF ADULT SPINAL-CORD NEURONS IN LONG-TERM CULTURE  

PubMed Central

The ability to culture functional adult mammalian spinal-cord neurons represents an important step in the understanding and treatment of a spectrum of neurological disorders including spinal cord injury. Previously, the limited functional recovery of these cells, as characterized by a diminished ability to initiate action potentials and to exhibit repetitive firing patterns, has arisen as a major impediment to their physiological relevance. In this report we demonstrate that single temporal doses of the neurotransmitters serotonin, glutamate (N-acetyl-DL-glutamic acid) and acetylcholine-chloride leads to the full electrophysiological functional recovery of adult mammalian spinal-cord neurons, when they are cultured under defined serum-free conditions. Approximately 60% of the neurons treated regained their electrophysiological signature, often firing single, double and, most importantly, multiple action potentials. PMID:18005959

Das, Mainak; Bhargava, Neelima; Bhalkikar, Abhijeet; Kang, Jung Fong; Hickman, James J

2008-01-01

379

Serotonin in fear conditioning processes.  

PubMed

This review describes the latest developments in our understanding of how the serotonergic system modulates Pavlovian fear conditioning, fear expression and fear extinction. These different phases of classical fear conditioning involve coordinated interactions between the extended amygdala, hippocampus and prefrontal cortices. Here, I first define the different stages of learning involved in cued and context fear conditioning and describe the neural circuits underlying these processes. The serotonergic system can be manipulated by administering serotonin receptor agonists and antagonists, as well as selective serotonin reuptake inhibitors (SSRIs), and these can have significant effects on emotional learning and memory. Moreover, variations in serotonergic genes can influence fear conditioning and extinction processes, and can underlie differential responses to pharmacological manipulations. This research has considerable translational significance as imbalances in the serotonergic system have been linked to anxiety and depression, while abnormalities in the mechanisms of conditioned fear contribute to anxiety disorders. PMID:25078294

Bauer, Elizabeth P

2015-01-15

380

Serotonin Norepinephrine Reuptake Inhibitors: A Pharmacological Comparison  

PubMed Central

The serotonin norepinephrine reuptake inhibitors are a family of antidepressants that inhibit the reuptake of both serotonin and norepinephrine. While these drugs are traditionally considered a group of inter-related antidepressants based upon reuptake inhibition, they generally display different chemical structures as well as different pharmacological properties. In this article, we discuss these and other differences among the serotonin norepinephrine reuptake inhibitors, including the year of approval by the United States Food and Drug Administration, generic availability, approved clinical indications, half-lives, metabolism and excretion, presence or not of active metabolites, dosing schedules, proportionate effects on serotonin and norepinephrine, and the timing of serotonin and norepinephrine reuptake (i.e., sequential or simultaneous). Again, while serotonin norepinephrine reuptake inhibitors are grouped as a family of antidepressants, they exhibit a surprising number of differences— differences that may ultimately relate to clinical nuances in patient care. PMID:24800132

Sansone, Lori A.

2014-01-01

381

Depletion of serotonin and catecholamines block the acute behavioral response to different classes of antidepressant drugs in the mouse tail suspension test  

Microsoft Academic Search

Rationale  Few studies have investiga.ted whether the behavioral effects elicited by different types of antidepressant drugs are mediated\\u000a by either serotonin (5-HT) or the catecholamines norepinephrine (NE) and dopamine (DA).\\u000a \\u000a \\u000a \\u000a Objectives  By depleting 5-HT, or NE and DA, the present study investigated the contributions of these monoamines to the acute behavioral\\u000a effects of selective serotonin reuptake inhibitors (SSRIs; fluoxetine and citalopram) and

Olivia F. O’Leary; Anita J. Bechtholt; James J. Crowley; Tiffany E. Hill; Michelle E. Page; Irwin Lucki

2007-01-01

382

Hypoximimetic activity of N-acyl-dopamines. N-arachidonoyl-dopamine stabilizes HIF-1? protein through a SIAH2-dependent pathway.  

PubMed

The N-acyl conjugates of amino acids and neurotransmitters (NAANs) are a class of endogenous lipid messengers that are expressed in the mammalian central and peripheral nervous system. Hypoxia inducible factor-1? (HIF-1?) is a transcription factor that plays a key role in the cellular adaptation to hypoxia and ischemia, and hypoxic preconditioning through HIF-1? has been shown to be neuroprotective in ischemic models. This study showed that N-acyl-dopamines induce HIF-1? stabilization on human primary astrocytes and neurons as well as in transformed cell lines. N-arachidonoyl-dopamine (NADA)-induced HIF-1? stabilization depends on the dopamine moiety of the molecule and is independent of cannabinoid receptor-1 (CB1) and transient receptor potential vanilloid type I (TRPV1) activation. NADA increases the activity of the E3 ubiquitin ligase seven in absentia homolog-2 (SIAH2), inhibits prolyl-hydroxylase-3 (PHD3) and stabilizes HIF-1?. NADA enhances angiogenesis in endothelial vascular cells and promotes the expression of genes such as erythropoietin (EPO), vascular endothelial growth factor A (VEGFA), heme oxygenase 1 (HMOX-1), hexokinase 2 (HK2) and Bcl-2/E1B-nineteen kiloDalton interacting protein (BNIP3) in primary astrocytes. These findings indicate a link between N-acyl-dopamines and hypoxic preconditioning and suggest that modulation of the N-acyl-dopamine metabolism might prove useful for prevention against hypoxic diseases. PMID:25090972

Soler-Torronteras, Rafael; Lara-Chica, Maribel; García, Victor; Calzado, Marco A; Muñoz, Eduardo

2014-11-01

383

Interleukin1 Stimulates Hypothalamic Inhibitory Amino Acid Neurotransmitter Release  

Microsoft Academic Search

Interleukin-1 (IL-1), a polypeptide cytokine, has been postulated as a chemical messenger between the immune and the neuroendocrine system. IL-1 receptors and immunopositive neurons have been visualized in the human and rat hypothalamus, suggesting that IL-1 can act as a neurotransmitter within the brain. In the hypothalamus IL-1 and the amino acid neurotransmitters are known to modulate several functions, such

Carlos Feleder; Damián Refojo; Silvina Nacht; Jaime A. Moguilevsky

1998-01-01

384

Peptides and neurotransmitters that affect renin secretion  

NASA Technical Reports Server (NTRS)

Substance P inhibits renin secretion. This polypeptide is a transmitter in primary afferent neurons and is released from the peripheral as well as the central portions of these neurons. It is present in afferent nerves from the kidneys. Neuropeptide Y, which is a cotransmitter with norepinephrine and epinephrine, is found in sympathetic neurons that are closely associated with and presumably innervate the juxtagolmerular cells. Its effect on renin secretion is unknown, but it produces renal vasoconstriction and natriuresis. Vasoactive intestinal polypeptide (VIP) is a cotransmitter with acetylocholine in cholinergic neurons, and this polypeptide stimulates renin secretion. We cannot find any evidence for its occurence in neurons in the kidneys, but various stimuli increase plasma VIP to levels comparable to those produced by doses of exogenous VIP which stimulated renin secretion. Neostigmine increases plasma VIP and plasma renin activity, and