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Effects of antipsychotic drugs on dopamine and serotonin contents and metabolites, dopamine and serotonin transporters, and serotonin 1A receptors  

Microsoft Academic Search

Summary.   The effects of neuroleptics have been attributed to dopamine (DA) receptor blockade; however, other neurotransmitters, in\\u000a particular serotonin (5-HT), have also been implicated. In this study, we examined the effects of clozapine and haloperidol\\u000a on the distribution of DA and 5-HT transporters, on endogenous DA, 5-HT and their major metabolites, and on 5-HT1A receptors. Adult male Sprague-Dawley rats were

A. R. Ase; F. Amdiss; C. Hébert; N. Huang; N. M. van Gelder; T. A. Reader



Lymphocytes transport serotonin and dopamine: agony or ecstasy?  

Microsoft Academic Search

Lymphocytes apparently carry active transport systems for the neurotransmitters serotonin and dopamine. Meanwhile, pharmacological substrates for the transporters have been claimed to impinge on immune function: these include, commonly used antidepressants [such as fluoxetine (Prozac®)], appetite suppressants and the recreational drugs MDMA [3,4-Methylenedioxymethamphetamine (‘Ecstasy’)] and cocaine. Data on these issues can be patchy. Given the widespread use – or, abuse

John Gordon; Nicholas M. Barnes



Serotonin/dopamine interaction in learning.  


Dopamine (DA)-serotonin interactions dealing with learning and memory functions have been apparent from experimental approaches over the past decade. However, since the former evidence showing that these cerebral neurotransmitter systems are involved in the regulation of the same cognitive processes, few experimental studies have been done to further clarify the nature of DA-serotonin interactions for cognitive processes sharing common brain structures. Nevertheless, a regulatory role of 5-HT/DA interactions in cognition and the prefrontal cortex (PFC) and the striatum as a neuroanatomical substrate for these DA/5-HT interactions, are now recognized. Experimental evidence indicates that pharmacological disruption of serotonin neurotransmission results in a facilitative effect on the processing of mnemonic information by cerebral regions under strong, functional DA modulation, such as the striatum and the PFC; on the other hand, increased serotonin neurotransmission appears to have a detrimental effect on cognitive functions integrated in these structures. These effects seem to occur through the interaction of different pre- and postsynaptic DA and serotonin receptor subtypes acting as opposite systems underlying cognitive abilities. Some studies, focused on DA-serotonin interactions underlying the pathophysiology of neurological and psychiatric diseases, which evolve with cognitive dysfunctions in human beings, have shown that drugs that are able to modify DA or serotonin neurotransmission may exert beneficial effects on cognitive functions, even though improvement of motor, mood and behavioural disturbances are the main objectives of pharmacological treatment of these diseases. The complete significance of DA-serotonin interactions in cognitive functions could be addressed by future experimental and clinical studies. PMID:18772051

Olvera-Cortés, María Esther; Anguiano-Rodríguez, Patricia; López-Vázquez, Miguel Angel; Alfaro, José Miguel Cervantes



Synthesis of dopamine and serotonin derivatives for immobilization on a solid support.  


The two important neurotransmitters dopamine and serotonin are synthesized with short PEG tethers and immobilized on a magnetic solid support. The tether is attached to the aromatic moiety of the neurotransmitters to conserve their original functional groups. This approach causes minimal alteration of the original structure with the aim of optimizing the immobilized neurotransmitters for aptamer selection by SELEX. For the dopamine derivative, the tether is attached to the aromatic core of a dopamine precursor by the Sonogashira reaction. For serotonin, a link to the indole core is introduced by a Claisen rearrangement from the allylated phenol moiety of serotonin. The tethers are azide-functionalized, which enables coupling to alkyne-modified magnetic beads. The coupling to the magnetic beads is quantified by UV spectroscopy using Fmoc-monitoring of the immobilized dopamine and serotonin derivatives. PMID:22390263

Funder, Erik Daa; Jensen, Anne Bjørnskov; Tørring, Thomas; Kodal, Anne Louise Bank; Azcargorta, Ane Rebolledo; Gothelf, Kurt Vesterager



Carbon nanotube-modified microelectrodes for simultaneous detection of dopamine and serotonin in vivo.  


Dopamine and serotonin are important neurotransmitters that interact in the brain. While dopamine is easily detected with electrochemical sensors, the detection of serotonin is more difficult because reactive species formed after oxidation can adsorb to the electrode, reducing sensitivity. Carbon nanotube treatments of electrodes have been used to increase the sensitivity, promote electron transfer, and reduce fouling. Most methods have focused on nanotube coatings of large electrodes and slower electrochemical techniques that are not conducive to measurements in vivo. In this study, we investigated carbon-fiber microelectrodes modified with single-walled carbon nanotubes for the co-detection of dopamine and serotonin in vivo. Using fast-scan cyclic voltammetry, S/N ratios for the neurotransmitters increased after nanotube coating. Electrocatalytic effects of nanotubes were not apparent at fast scan rates but faster kinetics were observed with slower scanning. Nanotube-modified microelectrodes showed significantly less fouling after exposure to serotonin than bare electrodes. The nanotube-modified electrodes were used to monitor stimulated dopamine and serotonin changes simultaneously in the striatum of anesthetized rat after administration of a serotonin synthetic precursor. These studies show that nanotube-coated microelectrodes can be used with fast scanning techniques and are advantageous for in vivo measurements of neurotransmitters because of their greater sensitivity and resistance to fouling. PMID:17710262

Swamy, B E Kumara; Venton, B Jill



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

NASA Astrophysics Data System (ADS)

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

Schafer, William R.; Kenyon, Cynthia J.



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.



The role of serotonin in memory: interactions with neurotransmitters and downstream signaling.  


Serotonin, or 5-hydroxytryptamine (5-HT), is found to be involved in many physiological or pathophysiological processes including cognitive function. Seven distinct receptors (5-HT1-7), each with several subpopulations, have been identified for serotonin, which are different in terms of localization and downstream signaling. Because of the development of selective agonists and antagonists for these receptors as well as transgenic animal models of cognitive disorders, our understanding of the role of serotonergic transmission in learning and memory has improved in recent years. A large body of evidence indicates the interplay between serotonergic transmission and other neurotransmitters including acetylcholine, dopamine, ?-aminobutyric acid (GABA) and glutamate, in the neurobiological control of learning and memory. In addition, there has been an alteration in the density of serotonergic receptors in aging and Alzheimer's disease, and serotonin modulators are found to alter the process of amyloidogenesis and exert cognitive-enhancing properties. Here, we discuss the serotonin-induced modulation of various systems involved in mnesic function including cholinergic, dopaminergic, GABAergic, glutamatergic transmissions as well as amyloidogenesis and intracellular pathways. PMID:24430027

Seyedabadi, Mohammad; Fakhfouri, Gohar; Ramezani, Vahid; Mehr, Shahram Ejtemaei; Rahimian, Reza



Serotonin and Dopamine Protect from Hypothermia/Rewarming Damage through the CBS/ H2S Pathway  

PubMed Central

Biogenic amines have been demonstrated to protect cells from apoptotic cell death. Herein we show for the first time that serotonin and dopamine increase H2S production by the endogenous enzyme cystathionine-?-synthase (CBS) and protect cells against hypothermia/rewarming induced reactive oxygen species (ROS) formation and apoptosis. Treatment with both compounds doubled CBS expression through mammalian target of rapamycin (mTOR) and increased H2S production in cultured rat smooth muscle cells. In addition, serotonin and dopamine treatment significantly reduced ROS formation. The beneficial effect of both compounds was minimized by inhibition of their re-uptake and by pharmacological inhibition of CBS or its down-regulation by siRNA. Exogenous administration of H2S and activation of CBS by Prydoxal 5?-phosphate also protected cells from hypothermic damage. Finally, serotonin and dopamine pretreatment of rat lung, kidney, liver and heart prior to 24 h of hypothermia at 3°C followed by 30 min of rewarming at 37°C upregulated the expression of CBS, strongly reduced caspase activity and maintained the physiological pH compared to untreated tissues. Thus, dopamine and serotonin protect cells against hypothermia/rewarming induced damage by increasing H2S production mediated through CBS. Our data identify a novel molecular link between biogenic amines and the H2S pathway, which may profoundly affect our understanding of the biological effects of monoamine neurotransmitters. PMID:21829469

Talaei, Fatemeh; Bouma, Hjalmar R.; Van der Graaf, Adrianus C.; Strijkstra, Arjen M.; Schmidt, Martina; Henning, Robert H.



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


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

Microsoft Academic Search

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

Roshan Cools; Kae Nakamura; Nathaniel D Daw




Microsoft Academic Search

In this article the positive effects of massage therapy on biochemistry are re- viewed including decreased levels of cortisol and increased levels of serotonin and dopamine. The research reviewed includes studies on depression (including sex abuse and eating disorder studies), pain syndrome studies, research on auto- immune conditions (including asthma and chronic fatigue), immune studies (including HIV and breast cancer),




Serotonin, norepinephrine and dopamine involvement in the antidepressant action of hypericum perforatum.  


Hypericum perforatum is considered an effective alternative to the synthetic antidepressants in the treatment of mild-to-moderate depression. Recently, we showed that the effects on neurotransmitter contents in different brain regions of laboratory animals are more evident after administration of hypericum extracts containing a higher concentration of flavonoids, thus suggesting that these compounds are important in the antidepressant action of hypericum perforatum. We studied the effects of Ph-50, a hypericum extract standardized to flavonoids (50%) and containing 0.3% hypericin and 4.5% hyperforin on brain serotonin content, norepinephrine and dopamine by a high-performance liquid chromatography method in discrete brain areas (cortex, diencephalon and brainstem) in male Sprague-Dawley rats. Moreover, we evaluated the effects of Ph-50 alone or in association with sulpiride (a dopamine receptor antagonist), metergoline (a serotonin receptor antagonist) and 6-hydroxydopamine (6-OH-DA, destroying norepinephrine-containing neurons) using a forced-swimming test in the rat. Hypericum extract (Ph-50; 250-500 mg/kg) with acute oral administration enhanced serotonin, norepinephrine and dopamine content in the brain and reduced the immobility time of rats in the forced-swimming test. Sulpiride, metergoline and 6-OH-DA significantly increased the period of immobility in the forced-swimming test for the rats receiving hypericum extract (Ph-50). The results indicate that the neurotransmitters studied could be involved in the anti-immobility effects of hypericum, and suggest that its antidepressant action is probably mediated by serotonergic, noradrenergic and dopaminergic system activation. PMID:11302563

Calapai, G; Crupi, A; Firenzuoli, F; Inferrera, G; Squadrito, F; Parisi, A; De Sarro, G; Caputi, A



Temperature and 3,4-methylenedioxymethamphetamine alter human serotonin transporter-mediated dopamine uptake.  


Although studies have suggested that dopamine can be transported by serotonin transporters (SERTs), such activity has not been characterized at the cloned SERTs. Dopamine and serotonin uptake by human SERT expressed in HEK-293 cells was compared at 37 and 40 degrees C. Elevated temperature was found to alter serotonin transport, but had no significant effect on dopamine transport. These effects led to a 10-fold increase in the serotonin:dopamine transport ratio reflecting an increased preference of SERTs for dopamine as opposed to serotonin at the higher temperature. The effects of 3,4-methylenedioxymethamphetamine (MDMA) on SERT-mediated dopamine transport were also evaluated by pre-incubating SERT-expressing cells with MDMA. The presence of intracellular MDMA caused a decrease in [3H]dopamine uptake but had no effect on [3H]serotonin transport suggesting that intracellular MDMA may be capable of inhibiting transporter function. PMID:14700733

Saldaña, Shannon N; Barker, Eric L



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.



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



Monoamines (norepinephrine, dopamine, serotonin) in the rat medial vestibular nucleus: endogenous levels and turnover.  


Monoamine (norepinephrine, dopamine, serotonin) and metabolite endogenous levels were determined in the rat medial vestibular nucleus (MVN) using HPLC with electrochemical detection. As a comparison, the locus coeruleus (LC) and dorsal raphe nucleus (RD) which contain the cell bodies of MVN noradrenergic and serotoninergic neurons respectively were also analyzed. Norepinephrine (NE) and serotonin (5-HT) basal levels of MVN were high (33.8 and 39.2pmol/mg protein respectively) but lesser than in LC or RD. Great amounts of MHPG and 5-HIAA were also present in the MVN. The turnover of NE assessed both from the ratio MHPG/NE and by the decrease in the NE content after treatment with alpha-methylparatyrosine was faster in the MVN (half-life: 1.5h) than in LC (half-life: 3.6h). On the other hand, the ratio 5-HIAA/5-HT was lower in the MVN (0.58) than in the RD (0.85) indicating a smaller 5-HT turnover in the MVN. In addition, like LC and RD, the MVN contained meaningful amounts of dopamine (DA) and DOPAC. The high ratio DA/NE (0.27) suggests the presence of non precursor specific dopaminergic pools. However, individualized dopaminergic neurons have not yet been demonstrated. The data are discussed in line with the possible neurotransmitter function of monoamines in the MVN. PMID:9617784

Cransac, H; Cottet-Emard, J M; Pequignot, J M; Peyrin, L



Adenosine, dopamine and serotonin receptors imbalance in lymphocytes of Lesch-Nyhan patients.  


Lesch-Nyhan disease (LND) is caused by complete deficiency of the hypoxanthine-guanine phosphoribosyltransferase enzyme. It is characterized by overproduction of uric acid, jointly with severe motor disability and self-injurious behaviour which physiopathology is unknown. These neurological manifestations suggest a dysfunction in the basal ganglia, and three neurotransmitters have been implicated in the pathogenesis of the disease: dopamine, adenosine and serotonin. All of them are implicated in motor function and behaviour, and act by binding to specific G-protein coupled receptors in the synaptic membrane where they seem to be integrated through receptor-receptor interactions. In this work we have confirmed at protein level the previously reported increased expression of DRD5 and the variably aberrant expression of ADORA2A, in LND PBL respect to control PBL. We have also described, for the first time, a decreased expression and protein level of 5-HTR1A in LND PBL respect to control PBL. If these results were confirmed in the Lesch-Nyhan patients basal ganglia cells, this would support the hypothesis that pathogenesis of neurological manifestations of Lesch-Nyhan patients may be related to an imbalance of neurotransmitters, rather than to the isolated disturbance of one of the neurotransmitters, and this fact should be taken into account in the design of pharmacologic treatment for their motor and behavioural disturbances. PMID:22403020

García, Marta G; Puig, Juan G; Torres, Rosa J



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

PubMed Central

Methods to determine neurochemical concentrations in small samples of tissue are needed to map interactions among neurotransmitters. In particular, correlating physiological measurements of neurotransmitter release and the tissue content in a small region would be valuable. HPLC is the standard method for tissue content analysis but it requires microliter samples and the detector often varies by the class of compound being quantified; thus detecting molecules from different classes can be difficult. In this paper, we develop capillary electrophoresis with fast-scan cyclic voltammetry detection (CE-FSCV) for analysis of dopamine, serotonin, and adenosine content in tissue punches from rat brain slices. Using field-amplified sample stacking, the limit of detection was 5 nM for dopamine, 10 nM for serotonin, and 50 nM for adenosine. Neurotransmitters could be measured from a tissue punch as small as 7 µg (7 nL) of tissue, three orders of magnitude smaller than a typical HPLC sample. Tissue content analysis of punches in successive slices through the striatum revealed higher dopamine but lower adenosine content in the anterior striatum. Stimulated dopamine release was measured in a brain slice, then a tissue punch collected from the recording region. Dopamine content and release had a correlation coefficient of 0.71, which indicates much of the variance in stimulated release is due to variance in tissue content. CE-FSCV should facilitate measurements of tissue content in nanoliter samples, leading to a better understanding of how diseases or drugs affect dopamine, serotonin, and adenosine content. PMID:23795210

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



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


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

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



Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters.  


Major depressive disorder (MDD) which is supposed to result from a complex interaction of genetic and epigenetic, environmental and developmental factors is one of the most common debilitating public health problems. The molecular mechanisms underlying this disease are still largely unclear. Identifying common pathways for diverse antidepressants (ADs) as well as new drug targets and thereby developing more effective treatments are primary goals of research in this field. Major targets of ADs are the serotonin transporter (SERT), the noradrenaline transporter (NAT) and also the dopamine transporter (DAT) located in the plasma membrane of corresponding neurons. These monoamine transporters (MATs) are important regulators of the extracellular neurotransmitter concentration. Among the clinically important ADs are tricyclic ADs (e.g. imipramine), selective serotonin re-uptake inhibitors (SSRIs, e.g. fluoxetine), selective noradrenaline (NA) re-uptake inhibitors (SNRIs, e.g. reboxetine) and NAT/DAT inhibitors like bupropion. This review is focussing on brain changes in monoamine neurotransmitter systems, downstream targets of monoaminergic neurotransmission as well as of behaviours of mice with a conventional knockout (KO) of either the SERT, DAT or NAT. MAT knockout induces changes in behaviour and brain neurochemistry. Although at least NATKO and SERTKO mice were expected to show a phenotype like AD-treated wild-type mice, this holds true only for the NATKO mice whereas SERTKO mice show an anxiety-like phenotype. Chronic social or restraint stress-induced depression-like behaviour and concomitant changes in brain neurotrophins are prevented by pharmacologically diverse ADs and by NATKO. Thus, NATKO mice are an interesting tool to investigate the mechanisms beyond monoamines responsible for depression as well as for AD actions. PMID:21147164

Haenisch, Britta; Bönisch, Heinz



Motoneurons which may utilize dopamine as their neurotransmitter  

Microsoft Academic Search

1.Three neurons in the abdominal ganglion ofAplysia elicit gill movements similar to those observed when dopamine is added to a gill perfusate. One, which we designate L9, produces contractions of all medial and lateral external pinnule muscles, the circular and longitudinal muscles of the afferent vessel, and the circular muscles of the efferent vessel. The others produce identical contractions in

John W. Swann; C. Nelson Sinback; Procerfina R. Kebabian; David O. Carpenter



Dopamine and serotonin in rat striatum during in vivo hypoxic-hypoxia  

Microsoft Academic Search

Dopamine and serotonin were determined in extracellular fluid of rat striatum by semiderivativein vivo voltammetry during normoxia and a single or repeated exposure to 15% O2 (i.e., mild hypoxia) or 12.5% O2 (i.e., moderate hypoxia). A single exposure to 15% oxygen increased extracellular dopamine 76%. With reintroduction of air to the animals, dopamine values returned to baseline. During a second

Patricia A. Broderick; Gary E. Gibson



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.



The clozapine metabolite N-desmethylclozapine displays variable activity in diverse functional assays at human dopamine D? and serotonin 5-HT?A receptors.  


N-desmethylclozapine (NDMC or norclozapine) is the major active metabolite of the antipsychotic clozapine in humans. The activity of NDMC differs from clozapine at a number of neurotransmitter receptors, probably influencing the pharmacological effects of clozapine treatment. Here, we tested the properties of NDMC in comparison with clozapine at recombinant human dopamine D(2) and serotonin 5-HT(1A) receptors, using a panel of functional assays implicating diverse signalling pathways. At dopamine D(2) receptors, NDMC as well as clozapine did not display agonist activity in measures of G protein activation by [(35)S]GTP?S binding and in the sensitive Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) phosphorylation assay. In contrast, there were weak partial agonist actions of NDMC (but not of clozapine) for dopamine D(2)-dependent activation of Ca(2+) liberation via coexpressed chimeric G?(q/o) proteins and for G protein-coupled inward rectifier potassium channel (GIRK) current induction in Xenopus oocytes. Intriguingly, GIRK currents induced by NDMC via dopamine D(2) receptors showed a rapid and transient time course, strikingly different from currents recorded with other receptor agonists. At serotonin 5-HT(1A) receptors, NDMC was a more efficacious partial agonist than clozapine for [(35)S]GTP?S binding, ERK1/2 phosphorylation and GIRK activation. Respective low and moderate partial agonist properties of NDMC at dopamine D(2) and serotonin 5-HT(1A) receptors thus differentiate the metabolite from its parent drug and may contribute to the overall effects of clozapine pharmacotherapy. PMID:21835172

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



Sexual side effects of serotonergic antidepressants: mediated by inhibition of serotonin on central dopamine release?  


Antidepressant-induced sexual dysfunction adversely affects the quality of life of antidepressant users and reduces compliance with treatment. Animal models provide an instructive approach for examining potential sexual side effects of novel drugs. This review discusses the stability and reproducibility of our standardized test procedure that assesses the acute, subchronic and chronic effects of psychoactive compounds in a 30 minute mating test. In addition, we present an overview of the effects of several different (putative) antidepressants on male rat sexual behavior, as tested in our standardized test procedure. By comparing the effects of these mechanistically distinct antidepressants (paroxetine, venlafaxine, bupropion, buspirone, DOV 216,303 and S32006), this review discusses the putative mechanism underlying sexual side effects of antidepressants and their normalization. This review shows that sexual behavior is mainly inhibited by antidepressants that increase serotonin neurotransmission via blockade of serotonin transporters, while those that mainly increase the levels of dopamine and noradrenaline are devoid of sexual side effects. Those sexual disturbances cannot be normalized by simultaneously increasing noradrenaline neurotransmission, but are normalized by increasing both noradrenaline and dopamine neurotransmission. Therefore, it is hypothesized that the sexual side effects of selective serotonin reuptake inhibitors may be mediated by their inhibitory effects on dopamine signaling in sex brain circuits. Clinical development of novel antidepressants should therefore focus on compounds that simultaneously increase both serotonin and dopamine signaling. PMID:24128918

Bijlsma, Elisabeth Y; Chan, Johnny S W; Olivier, Berend; Veening, Jan G; Millan, Mark J; Waldinger, Marcel D; Oosting, Ronald S



Dopamine and Serotonin Transporter Availability During Acute Alcohol Withdrawal: Effects of Comorbid Tobacco Smoking  

Microsoft Academic Search

Tobacco smoking is highly comorbid with heavy alcohol drinking, yet the interaction of tobacco smoking and alcohol drinking on brain catecholaminergic synaptic markers is unexplored. Here we evaluate the effects of alcohol drinking alone from comorbid alcohol drinking and tobacco smoking on dopamine (DA) and serotonin (5-HT) transporter availability. A total of 14 heavy alcohol drinking smokers (n=6) and nonsmokers

Kelly P Cosgrove; Erica Krantzler; Erin B Frohlich; Stephanie Stiklus; Brian Pittman; Gilles D Tamagnan; Ronald M Baldwin; Frederic Bois; John P Seibyl; John H Krystal; Stephanie S O'Malley; Julie K Staley



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.



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



Interactions of the Novel Antipsychotic Aripiprazole (OPC14597) with Dopamine and Serotonin Receptor Subtypes  

Microsoft Academic Search

OPC-14597 {aripiprazole; 7-(4-(4-(2,3-dichlorophenyl)-1-piperazinyl)butyloxy)-3,4-dihydro-2(1H)-quinolinone} is a novel candidate antipsychotic that has high affinity for striatal dopamine D2-like receptors, but causes few extrapyramidal effects. These studies characterized the molecular pharmacology of OPC-14597, DM-1451 (its major rodent metabolite), and the related quinolinone derivative OPC-4392 at each of the cloned dopamine receptors, and at serotonin 5HT6 and 5HT7 receptors. All three compounds exhibited highest

Cindy P Lawler; Cassandra Prioleau; Mechelle M Lewis; Chun Mak; Dong Jiang; John A Schetz; Antonio M Gonzalez; David R Sibley; Richard B Mailman



Opponency Revisited: Competition and Cooperation Between Dopamine and Serotonin  

Microsoft Academic Search

Affective valence lies on a spectrum ranging from punishment to reward. The coding of such spectra in the brain almost always involves opponency between pairs of systems or structures. There is ample evidence for the role of dopamine in the appetitive half of this spectrum, but little agreement about the existence, nature, or role of putative aversive opponents such as

Y-Lan Boureau; Peter Dayan



Interaction effect of D4 dopamine receptor gene and serotonin transporter promoter polymorphism on the cortisol stress response.  


Genetic variation of the serotonin transporter (SCL6A4, 5-HTT) has been associated with fear- and anxiety-related behaviors, while a polymorphism in exon III of the D4 dopamine receptor gene (DRD4) has been linked to novelty seeking. The dopaminergic and the serotonergic neurotransmitter system have been found to modulate the amygdala-connected circuitries that are crucial in emotional modulation and response to fearful stimuli. Additionally, reactivity of amygdala-innervated effector systems is also essential for our understanding of anxiety-related behaviors. Here, we used the stress-induced activation of the hypothalamic-pituitary-adrenal axis to investigate the impact of 5-HTTLPR and DRD4 on the cortisol stress response in 84 healthy adults. Saliva cortisol was measured during and after the Trier Social Stress Test. We found a significant main effect of DRD4: Carriers of the 7R allele exhibited lower cortisol responses. Additionally, a DRD4 by 5-HTTLPR interaction emerged: 5-HTTLPR LA/LA homozygotes showed a lower cortisol response than did S or LG allele carriers but only if they possessed at least one copy of the DRD4 7R allele. The results point to independent and joint effects of these polymorphisms on stress responsivity. PMID:20001112

Armbruster, D; Mueller, A; Moser, D A; Lesch, K P; Brocke, B; Kirschbaum, C



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


Electrochemical methods are very often used to detect catecholamine and indolamine neurotransmitters separated by conventional reverse-phase high performance liquid chromatography (HPLC). The present paper presents the development of a chromatographic method to detect monoamines present in low-volume brain dialysis samples using a capillary column filled with sub-2?m particles. Several parameters (repeatability, linearity, accuracy, limit of detection) for this new ultrahigh performance liquid chromatography (UHPLC) method with electrochemical detection were examined after optimization of the analytical conditions. Noradrenaline, adrenaline, serotonin, dopamine and its metabolite 3-methoxytyramine were separated in 1?L of injected sample volume; they were detected above concentrations of 0.5-1nmol/L, with 2.1-9.5% accuracy and intra-assay repeatability equal to or less than 6%. The final method was applied to very low volume dialysates from rat brain containing monoamine traces. The study demonstrates that capillary UHPLC with electrochemical detection is suitable for monitoring dialysate monoamines collected at high sampling rate. PMID:24508677

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



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.



Association of dopamine, serotonin, and nicotinic gene polymorphisms with methylphenidate response in ADHD.  


Gene polymorphisms of the 3' untranslated region (3'-UTR) of the dopamine transporter (DAT1), Dopamine receptor exon 3 D4 variable number tandem repeat (DRD4VNTR), nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) and serotonin transporter promoter (SLC6A4-5HTTLPR) are under consideration as potential risk factors for attention-deficit/hyperactivity disorder (ADHD). A post-hoc attempt was made to investigate the association between the allelic variations of these candidate genes and retrospective parental report of response to methylphenidate in an ADHD-enriched, population-based twin sample. Subjects (N = 243) were selected from the twin sample based on parent report that the child had been treated with methylphenidate for ADHD symptoms. The functional polymorphisms screened were the VNTR located in the 3'-UTR of the dopamine transporter, DRD4 VNTR, CHRNA4 (rs1044396 and rs6090384) and the long (L(A) and L(G)) and short (S) forms of the serotonin transporter promoter region. Logistic regression did not demonstrate a significant association between methylphenidate treatment response and the relevant polymorphisms. The sample size had high power to detect effect sizes similar to those reported in some prior methylphenidate pharmacogenetic studies; however, the categorical (yes/no) measure of parent-reported treatment response may not have been sensitive enough to pick up statistically significant differences in treatment response based on genotype. Further studies including quantitative measures of treatment response are warranted. PMID:17948872

Tharoor, Hema; Lobos, Elizabeth A; Todd, Richard D; Reiersen, Angela M



Fluvoxamine, a selective serotonin reuptake inhibitor, suppresses tetrahydrobiopterin levels and dopamine as well as serotonin turnover in the mesoprefrontal system of mice  

Microsoft Academic Search

Rationale Tetrahydrobiopterin (BH 4) is a coenzyme of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), rate-limiting enzymes of monoamine biosynthesis. According to the monoamine hypothesis of depression, antidepressants will restore the function of the brain monoaminergic system, and BH 4 concentration. Objective To investigate the effects of fluvoxamine on BH 4 levels and dopamine (DA) and serotonin (5-HT) turnover in

H. Miura; H. Qiao; T. Kitagami; T. Ohta; N. Ozaki



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



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.



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


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



Allele and genotype frequencies of serotonin and dopamine transporter and receptor polymorphisms in a Norwegian population.  


Polymorphisms in genes coding for dopaminergic and serotonergic receptors and transporters have been associated with the clinical effects and adverse drug reactions of antipsychotic and antidepressant drugs. The objective of this study was to investigate the frequency and combinations of common polymorphisms in the dopamine transporter (DAT1), dopamine D(2) receptor (DRD2), dopamine D(3) receptor (DRD3), serotonin transporter (5HTT), and serotonin 2A receptor (5HTR2A) genes in a Norwegian population. To determine the background frequency in the population, 250 blood samples were consecutively collected from healthy Norwegian blood donors (125 men and 125 women; mean age: 48±11 years). Samples were tested for DAT1 VNTR, DRD2 Taq1A, DRD3 Ser9Gly, 5HTTLPR, and four polymorphisms (102 T>C, His452Tyr, 516 C>T, and Thr25Asn) in the 5HTR2A, using polymerase chain reaction and real-time polymerase chain reaction. We observed the frequency of the nine-repeat allele of DAT1 VNTR polymorphism as 20% (95% confidence interval [CI]: 0.18-0.23), the A1 allele of DRD2 Taq1A polymorphism as 21% (95% CI: 0.19-0.23), the A1 allele of DRD3 Ser9Gly polymorphism as 68% (95% CI: 0.66-0.70), the short allele of 5HTTLPR as 38% (95% CI: 0.36-0.40), and the T allele of 5HTR2A 102 T>C polymorphism as 41% (95% CI: 0.39-0.41), and the frequencies of 5HTR2A His452Tyr and 5HTR2A Thr25Asn were 93% and 95%, respectively. The tested polymorphisms showed differences compared with other European populations. Further studies are necessary to better understand the effect of these alleles and their combinations on personality, mental disorders, drug response, and adverse reactions of psychotropic drugs. PMID:21453053

Güzey, Cüneyt; Lopez-Rodriguez, Rosario; Myhre, Ronny; Spigset, Olav



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



Interaction between the dopamine D4 receptor and the serotonin transporter promoter polymorphisms in alcohol and tobacco use among 15-year-olds.  


Early onset of alcohol and tobacco use during adolescence increases the risk for establishing a substance use disorder in adulthood. Both alcohol and nicotine stimulate the dopamine (DA) and the serotonin (5-HT) systems. The DA system has been implicated in the mediation of the rewarding effects of self-administered drugs of abuse. A possible role of an interaction between these neurotransmitter systems in substance use behavior has been suggested but is as yet unknown. The present study was designed to examine the influence of the DA D4 receptor (DRD4) and the serotonin transporter (5-HTT) genotype and their interaction on adolescent alcohol and tobacco experimentation. Participants were from a longitudinal study of a birth cohort consisting initially of 384 children from a high-risk community sample. At the age of 15 years, adolescents completed a self-report questionnaire measuring tobacco and alcohol consumption. DNA was taken from 305 participants (146 boys, 159 girls) and genotyped for the DRD4 exon III and the 5-HTTLPR polymorphisms. The DRD4 7-repeat allele was associated with greater smoking and drinking involvement in boys. In girls, a significant DRD4 x 5-HTT interaction was detected. Girls without the DRD4 7-repeat allele and who were homozygous for the long allele of 5-HTTLPR displayed the highest smoking and drinking activity. The genetic and potential molecular background underlying adolescent vulnerability to substance abuse is discussed. PMID:16819620

Skowronek, M H; Laucht, M; Hohm, E; Becker, K; Schmidt, M H



Flow-injection analysis systems with different detection devices and other related techniques for the in vitro and in vivo determination of dopamine as neurotransmitter. A review.  


Dopamine (DA) is one of the most important catecholamine neurotransmitters in the human central nervous system in the brain and plays a key role in the functioning of the renal, hormonal, and cardiovascular systems. Abnormal levels of dopamine are related to neurological disorders, such as schizophrenia and Parkinson's disease and the control and fluctuations of the amount of dopamine are extremely important in monitoring with analytical systems in the human brain. This review covers the attributes of flow-injection analysis systems with different detection devices and other related techniques for the in vitro and in vivo determination of dopamine as neurotransmitter and points out the advantages and disadvantages in the implementation thereof. PMID:23182572

van Staden, Jacobus F; van Staden, Raluca I Stefan



Monoamines (noradrenaline, dopamine, serotonin) in the rat cochlear nuclei: endogenous levels and turnover.  


Noradrenaline (NA), dopamine (DA), serotonin (5-HT) and their metabolites, 3-methoxy,4-hydroxyphenylglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA), were determined using high-performance liquid chromatography with electrochemical detection in the rat anteroventral cochlear nucleus (AVCN), in the dorsal part of the nucleus including the dorsal cochlear nucleus (DCN) and the posteroventral cochlear nucleus (PVCN) and as a comparison, in the locus coeruleus (LC) and dorsal raphe nucleus (RD) which contain the corresponding noradrenergic and serotonergic cell bodies. In both cochlear nuclei (CN), the endogenous levels of NA, 5-HT and related metabolites were smaller than in LC or RD. NA turnover assessed from the ratio MHPG/NA or after treatment with alpha-methylparatyrosine was faster in the CN than in LC; in contrast, 5-HT turnover was lower in the CN than in RD as shown by the ratio 5-HIAA/5-HT. In agreement with previous histological findings, NA and 5-HT were more concentrated in AVCN than in DCN+PCVN; however, the turnover of both monoamines was faster in the dorsal nuclei. In addition, the CN contained small amounts of dopamine and DOPAC; both DA levels and the ratio DA/NA (0.10 vs. 0.04) were greater in the dorsal than in the ventral part suggesting the presence of non-precursor-specific DA pools. Our data suggest that the functional involvement of monoamines may be different in cochlear subnuclei. PMID:8975006

Cransac, H; Cottet-Emard, J M; Pequignot, J M; Peyrin, L



[Association between dopamine (DRD2) and serotonin (5HTR2A) gene polymorphisms with the indicators of adolescent behavior adaptiveness].  


The paper gives the results of a study of the impact of dopamine (DRD2) and serotonin (5HTR2A) genes on the development of personality characteristics in adolescents, by applying the Cattell (16PF) questionnaire. The study was performed in a group of 360 Moscow teenagers (185 girls and 175 boys) aged 14-17 years. The boys carrying the A1 allelle of the DRD2 gene were found to have a lower self-control, indiscipline, and impulsiveness. An association between the indicators of unconscientiousness, social introversion, and group independence was established in the girls with the G/G genotype of the 5HTR2A gene. Thus, gender differences have been revealed from the impact of dopamine and serotonin gene polymorphisms on the teenagers' personality characteristics that characterize the forms of disadaptive behavior, such as unconscientiousness, indiscipline, low self-control, and impulsiveness. PMID:21384582

Barski?, V I; Aksenova, M G; Kozlova, O B; Kirillov, A V; Demin, A A; Il'inykh, L M



Associations between polymorphisms in dopamine neurotransmitter pathway genes and pain response in healthy humans.  


Although evidence shows that several dopamine neurotransmission pathway genes are associated with specific clinical pain syndromes, such as fibromyalgia, chronic headache, and postoperative pain, the exact role of dopamine in pain processing is not fully understood. The aim of this study was to explore the relationship between functional polymorphisms in dopaminergic candidate genes and sensitivity to pain in healthy subjects. Healthy subjects (n=192; 105 F, 87 M) were exposed to experimental tonic cold pain (1 degrees C) and phasic heat pain (47 degrees C) stimuli. DNA samples were obtained from both participants and their parents. The relationships between pain response (intensity in response to heat and cold; threshold and tolerance in response to cold only) and the functional Variable Number of Tandem Repeat (VNTR) polymorphisms of three dopamine-related genes were investigated using a Transmission Disequilibrium Test (TDT). Specifically, 30-bp repeat in the promoter region of the monoamine oxidase-A gene (MAO-A), 40-bp repeat in the 3'-untranslated region of the dopamine transporter gene (DAT-1), and 48-bp repeat in the exon 3 of the dopamine receptor 4 gene (DRD4) were examined. Significant associations between cold pain tolerance and DAT-1 (p=0.008) and MAO-A (p=0.024) polymorphisms were found. Specifically, tolerance was shorter for carriers of allele 10 and the rarer allele 11, as compared to homozygous for allele 9, and for carriers of allele 4 as compared to homozygous for allele 3, respectively. These results, together with the known function of the investigated candidate gene polymorphisms, suggest that low dopaminergic activity can be associated with high pain sensitivity and vice versa. PMID:19796878

Treister, Roi; Pud, Dorit; Ebstein, Richard P; Laiba, Efrat; Gershon, Edith; Haddad, May; Eisenberg, Elon



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

Microsoft Academic Search

There is an increasing awareness that a psychosis, similar to that of schizophrenic psychosis, can be derived from cocaine addiction. Thus, the prototypical atypical antipsychotic medication, clozapine, a 5-HT2\\/DA2 antagonist, was studied for its effects on cocaine-induced dopamine (DA) and serotonin (5-HT) release in nucleus accumbens (NAcc) of behaving male Sprague–Dawley laboratory rats with In Vivo Microvoltammetry, while animals' locomotor

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



Analysis of intact glucuronides and sulfates of serotonin, dopamine, and their phase I metabolites in rat brain microdialysates by liquid chromatography-tandem mass spectrometry.  


A method for the analysis of intact glucuronides and sulfates of common neurotransmitters serotonin (5-HT) and dopamine (DA) as well as of 5-hydroxy-3-indoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in rat brain microdialysates by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. Enzyme-assisted synthesis using rat liver microsomes as a biocatalyst was employed for the production of 5-HT-, 5-HIAA-, DOPAC-, and HVA-glucuronides for reference compounds. The sulfate conjugates were synthesized either chemically or enzymatically using a rat liver S9 fraction. The LC-MS/MS method was validated by determining the limits of detection and quantitation, linearity, and repeatability for the quantitative analysis of 5-HT and DA and their glucuronides, as well as of 5-HIAA, DOPAC, and HVA and their sulfate-conjugates. In this study, 5-HT-glucuronide was for the first time detected in rat brain. The concentration of 5-HT-glucuronide (1.0-1.7 nM) was up to 2.5 times higher than that of free 5-HT (0.4-2.1 nM) in rat brain microdialysates, whereas the concentration of DA-glucuronide (1.0-1.4 nM) was at the same level or lower than the free DA (1.2-2.4 nM). The acidic metabolites of neurotransmitters, 5-HIAA, HVA, and DOPAC, were found in free and sulfated form, whereas their glucuronidation was not observed. PMID:19772284

Uutela, Päivi; Reinilä, Ruut; Harju, Kirsi; Piepponen, Petteri; Ketola, Raimo A; Kostiainen, Risto



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

PubMed Central

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

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



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


Existing studies of the effect on infant temperament of the 48 base pair variable number of tandem repeats polymorphism in exon 3 of the dopamine D4 receptor gene, DRD4 VNTR, and the serotonin transporter-linked polymorphic region, 5-HTTLPR, have provided contradictory results, and age seems to be an important factor. The present study investigated the effect of these two polymorphisms on the stability of infant temperament between 4 and 9 months of age. Furthermore, the effect of a recently discovered single nucleotide polymorphism which modulates the 5-HTTLPR (rs25531) was investigated in relation to infant temperament. The study sample consisted of 90 infants, who were assessed by parental report at the two ages under consideration using the Revised Infant Behavior Questionnaire. It was found that infants carrying the 7-repeat allele of the DRD4 VNTR had higher levels of Negative Affect. Furthermore, there was an interaction between DRD4 VNTR and 5-HTTLPR genotype such that infants with the DRD4 VNTR 7-repeat allele and the highest expressing 5-HTTLPR genotype (L(A) L(A) ) had the highest level of Negative Affect. These effects were largely driven by scores on the Falling Reactivity scale. Genetic effects were stable across age. The results emphasize the need for developmental studies of genetic effects on temperament. PMID:21166770

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



Effect of loxapine on peripheral dopamine-like and serotonin receptors in patients with schizophrenia  

PubMed Central

Objective To investigate the effect of loxapine on peripheral dopamine D2-like and serotonin receptor binding and on psychotic symptoms. Patients Patients (n = 24) meeting the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, for schizophrenia were selected from an outpatient clinic (age range 18–70 yr). Methods Patients were given loxapine (dose determined by a physician) for a period of 12 weeks. There were clinic visits at before treatment began and at 6 weeks and 12 weeks of treatment. Scores on a variety of efficacy and safety scales were recorded at each visit, and blood was drawn for receptor assays. Results Patients showed significant improvement on most psychiatric assessment scales after 6 and 12 weeks of treatment with loxapine, and both lymphocyte D2-like and 5-HT2A platelet receptor binding were down-regulated after 6 and 12 weeks. The degree of receptor down-regulation was not significantly correlated with improvements in psychotic symptoms, however. Conclusion Loxapine down-regulated both lymphocyte D2-like and platelet 5-HT2A receptors to the same extent, suggesting that both receptors are involved in the mechanism of action of loxapine in patients with schizophrenia. PMID:12587849

Singh, Amarendra N.; Barlas, Cia; Saeedi, Huma; Mishra, Ram K.



Risk Neurogenes for Long-Term Spaceflight: Dopamine and Serotonin Brain System.  


Mice were exposed to 1 month of spaceflight on Russian biosatellite BION-M1 to determine its effect on the expression of key genes in the brain dopamine (DA) and serotonin (5-HT) systems. Spaceflight decreased the expression of crucial genes involved in DA synthesis and degradation, as well as the D1 receptor. However, spaceflight failed to alter the expression of tryptophan hydroxylase-2, 5-HT transporter, 5-HT1A, and 5-HT3 receptor genes, though it reduced 5-HT2A receptor gene expression in the hypothalamus. We revealed risk DA and 5-HT neurogenes for long-term spaceflight for the first time, as well as microgravity-responsive genes (tyrosine hydroxylase, catechol-O-methyltransferase, and D1 receptor in the nigrostriatal system; D1 and 5-HT2A receptors in the hypothalamus; and monoamine oxidase A (MAO A) in the frontal cortex). Decreased genetic control of the DA system may contribute to the spaceflight-induced locomotor impairment and dyskinesia described for both humans and rats. PMID:25084757

Popova, N K; Kulikov, A V; Kondaurova, E M; Tsybko, A S; Kulikova, E A; Krasnov, I B; Shenkman, B S; Bazhenova, E Yu; Sinyakova, N A; Naumenko, V S



Subchronic effects of phencyclidine on dopamine and serotonin receptors: implications for schizophrenia.  


Changes in representative dopamine (D(1), D(2), and D(4)) and serotonin (5-HT(1A) and 5-HT(2A)) receptors that have been implicated in the pathophysiology and treatment of schizophrenia were autoradiographically quantified after subchronic phencyclidine (PCP) treatment (2 mg/kg for 7 days, bi-daily followed by 7 days drug free). This treatment has consistently induced robust and long-lasting cognitive deficits in adult rats, although the molecular mechanisms contributing to PCP-induced cognitive deficits remain undefined. Repeated PCP treatment significantly decreased labeling of D(1) receptors in the medial and lateral caudate-putamen (22% and 23%, respectively) and increased 5HT(1A) receptor binding in the medial-prefrontal (26%) and dorsolateral-frontal cortex (30%). No changes in D(1) or 5HT(1A) receptors were detected in other brain regions. These findings suggest that downregulation of striatal D(1) receptors and upregulation of cortical 5HT(1A) receptors may contribute to PCP-induced impairment of cognitive functions in rats. Subchronic PCP treatment did not alter levels of D(2), D(4), and 5HT(2A) receptors in all brain regions examined, which suggests a minimal role for these receptors in mediating subchronic actions of PCP in adult rats. PMID:19455435

Choi, Yong Kee; Snigdha, Shikha; Shahid, Mohammed; Neill, Jo C; Tarazi, Frank I



Altered Serotonin, Dopamine and Norepinepherine Levels in 15q Duplication and Angelman Syndrome Mouse Models  

PubMed Central

Childhood neurodevelopmental disorders like Angelman syndrome and autism may be the result of underlying defects in neuronal plasticity and ongoing problems with synaptic signaling. Some of these defects may be due to abnormal monoamine levels in different regions of the brain. Ube3a, a gene that causes Angelman syndrome (AS) when maternally deleted and is associated with autism when maternally duplicated has recently been shown to regulate monoamine synthesis in the Drosophila brain. Therefore, we examined monoamine levels in striatum, ventral midbrain, frontal cerebral cortex, cerebellar cortex and hippocampus in Ube3a deficient and Ube3a duplication animals. We found that serotonin (5HT), a monoamine affected in autism, was elevated in the striatum and cortex of AS mice. Dopamine levels were almost uniformly elevated compared to control littermates in the striatum, midbrain and frontal cortex regardless of genotype in Ube3a deficient and Ube3a duplication animals. In the duplication 15q autism mouse model, paternal but not maternal duplication animals showed a decrease in 5HT levels when compared to their wild type littermates, in accordance with previously published data. However, maternal duplication animals show no significant changes in 5HT levels throughout the brain. These abnormal monoamine levels could be responsible for many of the behavioral abnormalities observed in both AS and autism, but further investigation is required to determine if any of these changes are purely dependent on Ube3a levels in the brain. PMID:22916201

Farook, M. Febin; DeCuypere, Michael; Hyland, Keith; Takumi, Toru; LeDoux, Mark S.; Reiter, Lawrence T.



Dopamine D4 receptor and serotonin transporter promoter in the determination of neonatal temperament.  


Genetic effects on behavior were evaluated at a time in early development when we hypothesized that environmental influences are minimal and least likely to confound associations between temperament and genes. The behavioral effects of two common polymorphisms linked respectively in some, but not all, studies to novelty seeking (dopamine D4 receptor-D4DR) and neuroticism and harm avoidance (serotonin transporter promoter region-STPR) were examined in a group of 81 two-week-old neonates. Neonate temperament was evaluated using the Brazelton neonatal assessment scale (NBAS). Multivariate tests of significance showed a significant association of D4DR across four behavioral clusters pertinent to temperament including orientation, motor organization, range of state and regulation of state. A significant multivariate interaction was also observed between D4DR and STPR. The effect of the homozygous short STPR genotype (s/s) was to lower the orientation score for the group of neonates lacking the long form (L) of D4DR. When adult subjects were grouped by the STPR polymorphism there is no significant effect of L-D4DR in those subjects homozygous for the STPR short form (s/s) whereas in the group without the homozygous genotype the effect of L-D4DR is significant and accounts for 13% of the variance in novelty seeking scores between groups. PMID:9672899

Ebstein, R P; Levine, J; Geller, V; Auerbach, J; Gritsenko, I; Belmaker, R H



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


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

Howell, Leonard L; Cunningham, Kathryn A



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


Psilocin (3-[2-(dimethylamino)ethyl]-1H-indol-4-ol) is a hallucinogenic component of the Mexican mushroom Psilocybe mexicana and a skeletal serotonin (5-HT) analogue. Psilocin is the active metabolite of psilocybin (3-[2-(dimethylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate). In the present study, we examined the effects of systemically administered psilocin on extracellular dopamine and 5-HT concentrations in the ventral tegmental area (VTA), nucleus accumbens, and medial prefrontal cortex of the dopaminergic pathway in awake rats using in vivo microdialysis. Intraperitoneal administration of psilocin (5 and 10 mg/kg) significantly increased extracellular dopamine levels in the nucleus accumbens. Psilocin did not affect the extracellular 5-HT level in the nucleus accumbens. Conversely, systemic administration of psilocin (10 mg/kg) significantly increased extracellular 5-HT levels in the medial prefrontal cortex of rats, but dopamine was decreased in this region. However, neither extracellular dopamine nor 5-HT levels in the VTA were altered by administration of psilocin. Behaviorally, psilocin significantly increased the number of head twitches. Thus, psilocin affects the dopaminergic system in the nucleus accumbens. In the serotonergic system, psilocin contribute to a crucial effect in the medial prefrontal cortex. The present data suggest that psilocin increased both the extracellular dopamine and 5-HT concentrations in the mesoaccumbens and/or mesocortical pathway. PMID:25342005

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



Role of Serotonin and Dopamine System Interactions in the Neurobiology of Impulsive Aggression and its Comorbidity with other Clinical Disorders  

PubMed Central

Impulsive aggression is characterized by an inability to regulate affect as well as aggressive impulses, and is highly comorbid with other mental disorders including depression, suicidal behavior, and substance abuse. In an effort to elucidate the neurobiological underpinnings of impulsive aggression and to help account for its connections with these other disorders, this paper reviews relevant biochemical, brain imaging, and genetic studies. The review suggests that dysfunctional interactions between serotonin and dopamine systems in the prefrontal cortex may be an important mechanism underlying the link between impulsive aggression and its comorbid disorders. Specifically, serotonin hypofunction may represent a biochemical trait that predisposes individuals to impulsive aggression, with dopamine hyperfunction contributing in an additive fashion to the serotonergic deficit. The current paper proposes a modified diathesis-stress model of impulsive aggression in which the underlying biological diathesis may be deficient serotonergic function in the ventral prefrontal cortex. This underlying disposition can be manifested behaviorally as impulsive aggression towards oneself and others, and as depression under precipitating life stressors. Substance abuse associated with impulsive aggression is understood in the context of dopamine dysregulation resulting from serotonergic deficiency. Also discussed are future research directions in the neurobiology of impulsive aggression and its comorbid disorders. PMID:19802333

Seo, Dongju; Patrick, Christopher J.; Kennealy, Patrick J.



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


Bacopa monnieri (BM) has been used in Ayurvedic medicine as a nootropic, anxiolytic, antiepileptic and antidepressant. An n-butanol extract of the plant (nBt-ext BM) was analysed and found to contain Bacoside A (Bacoside A3, Bacopaside II and Bacopasaponin C). The effects of the BM extract were then studied on morphine-induced hyperactivity as well as dopamine and serotonin turnover in the striatum since these parameters have a role in opioid sensitivity and dependence. Mice were pretreated with saline or nBt-ext BM (5, 10 and 15 mg/kg, orally), 60 min before morphine administration and locomotor activity was subsequently recorded. Immediately after testing, striatal tissues were analysed for dopamine (DA), serotonin (5HT) and their metabolites using HPLC coupled with electrochemical detection. The results indicated that nBt-ext BM significantly (p < 0.001) decreased locomotor activity in both the saline and morphine treated groups. Additionally, nBt-ext BM significantly lowered morphine-induced dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-H1AA) upsurges in the striatum but failed to affect DA, 5-HT and their metabolites in the saline treated group. These findings suggest that nBt-ext BM has an antidopaminergic/serotonergic effect and may have potential beneficial effects in the treatment of morphine dependence. PMID:22105846

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



Brexpiprazole II: antipsychotic-like and procognitive effects of a novel serotonin-dopamine activity modulator.  


Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel serotonin-dopamine activity modulator with partial agonist activity at serotonin 1A (5-HT1A) and D2/3 receptors, combined with potent antagonist effects on 5-HT2A, ?1B-, and ?2C-adrenergic receptors. Brexpiprazole inhibited conditioned avoidance response (ED50 = 6.0 mg/kg), apomorphine- or d-amphetamine-induced hyperactivity (ED50 = 2.3 and 0.90, respectively), and apomorphine-induced stereotypy (ED50 = 2.9) in rats at clinically relevant D2 receptor occupancies. Brexpiprazole also potently inhibited apomorphine-induced eye blinking in monkeys. The results suggest that brexpiprazole has antipsychotic potential. Brexpiprazole induced catalepsy (ED50 = 20) well above clinically relevant D2 receptor occupancies, suggesting a low risk for extrapyramidal side effects. Subchronic treatment with phencyclidine (PCP) induced cognitive impairment in both novel object recognition (NOR) and attentional set-shifting (ID-ED) tests in rats. Brexpiprazole reversed the PCP-induced cognitive impairment in the NOR test at 1.0 and 3.0 mg/kg, and in the ID-ED test at 1.0 mg/kg. However, aripiprazole (10 mg/kg) was ineffective in both tests, despite achieving relevant D2 occupancies. In the NOR test, the 5-HT1A agonist buspirone and the 5-HT2A antagonist M100907 [(R)-(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)piperidin-4-yl]methanol] partially but significantly reversed PCP-induced impairment. Furthermore, the effect of brexpiprazole was reversed by cotreatment with the 5-HT1A antagonist WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate). The results indicate that brexpiprazole has antipsychotic-like activity and robust efficacy in relevant models of cognitive impairment associated with schizophrenia. The effects of brexpiprazole in the cognitive tests are superior to those of aripiprazole. We propose that the pharmacologic profile of brexpiprazole be based on its balanced effects on 5-HT1A, D2, and 5-HT2A receptors, with possible modulating activity through additional monoamine receptors. PMID:24947464

Maeda, Kenji; Lerdrup, Linda; Sugino, Haruhiko; Akazawa, Hitomi; Amada, Naoki; McQuade, Robert D; Stensbøl, Tine Bryan; Bundgaard, Christoffer; Arnt, Jørn; Kikuchi, Tetsuro



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))



Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission  

PubMed Central

Rationale Schizophrenia remains among the most prevalent neuropsychiatric disorders, and current treatment options are accompanied by unwanted side effects. New treatments that better address core features of the disease with minimal side effects are needed. Objectives As a new therapeutic approach, 1-(4-fluoro-phenyl)-4-((6bR, 10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro- 1H,7H-pyrido[3?,4?:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)- butan-1-one (ITI-007) is currently in human clinical trials for the treatment of schizophrenia. Here, we characterize the preclinical functional activity of ITI-007. Results ITI-007 is a potent 5-HT2A receptor ligand (Ki = 0.5 nM) with strong affinity for dopamine (DA) D2 receptors (Ki = 32 nM) and the serotonin transporter (SERT) (Ki = 62 nM) but negligible binding to receptors (e.g., H1 histaminergic, 5-HT2C, and muscarinic) associated with cognitive and metabolic side effects of antipsychotic drugs. In vivo it is a 5-HT 2A antagonist, b lock ing (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)-induced headtwitch in mice with an inhibitory dose 50 (ID50)=0.09 mg/kg, per oral (p.o.), and has dual properties at D2 receptors, acting as a postsynaptic D2 receptor antagonist to block D-amphetamine hydrochloride (D-AMPH) hyperlocomotion (ID50 = 0.95 mg/kg, p.o.), yet acting as a partial agonist at presynaptic striatal D2 receptors in assays measuring striatal DA neuro- transmission. Further, in microdialysis studies, this compound significantly and preferentially enhances mesocortical DA release. At doses relevant for antipsychotic activity in rodents, ITI-007 has no demonstrable cataleptogenic activity. ITI-007 indirectly modulates glutamatergic neurotransmission by in- creasing phosphorylation of GluN2B-type N-methyl-d-aspartate (NMDA) receptors and preferentially increases phosphorylation of glycogen synthase kinase 3? (GSK-3?) in mesolimbic/mesocortical dopamine systems. Conclusion The combination of in vitro and in vivo activities of this compound support its development for the treatment of schizophrenia and other psychiatric and neurologic disorders. PMID:25120104

Snyder, Gretchen L.; Vanover, Kimberly E.; Zhu, Hongwen; Hendrick, Joseph P.; Wennogle, Lawrence P.; Mates, Sharon; Tomesch, John; Li, Peng; Zhang, Qiang; Miller, Diane B.; O’Callaghan, James P.; Krishnan, Vaishnav; Nestler, Eric J.; Davis, Robert E.



Interaction between serotonin transporter promoter and dopamine receptor D4 polymorphisms on decision making.  


Appropriate decision making is an important brain function to maintain our lives. The Iowa gambling task (IGT) is a tool for decision making under ambiguity. The aims of this study were to evaluate the influence of serotonin transporter linked polymorphic region (5-HTTLPR) and dopamine receptor D4 (DRD4) polymorphisms and their interaction on IGT performance. One hundred fifty-nine normal subjects were involved in this study. All subjects performed the IGT and were genotyped for the triallelic 5-HTTLPR and DRD4 48 bp uVNTR polymorphisms. After controlling for gender, age, and impulsiveness, there were no main effects of 5-HTTLPR and DRD4 gene polymorphisms on total IGT score. However, there was a significant effect on the interaction between 5-HTTLPR and DRD4 on total IGT score. In the presence of the 5-HTTLPR S'S' (SS+SL(G)+L(G)L(G)), subjects with the DRD4 2R+ (2 repeat carrier) had higher total IGT score compared to those with the DRD4 2R-. In contrast, in the absence of the 5-HTTLPR S'S', subjects with the DRD4 2R- had higher total IGT score than those with the DRD4 2R+. When we divided IGT scores into the first and second half of trials, the 5-HTTLPRxDRD4 interaction effects were stronger in the second half block (decision under risk) than in the first half block (decision under ambiguity). In conclusion, the DRD4 genotypes might influence decision-making performance differently according to the background genotypes of 5-HTTLPR. PMID:19615421

Ha, Ra Yeon; Namkoong, Kee; Kang, Jee In; Kim, Yang Tae; Kim, Se Joo



Serotonin and dopamine receptors in motivational and cognitive disturbances of schizophrenia  

PubMed Central

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

Sumiyoshi, Tomiki; Kunugi, Hiroshi; Nakagome, Kazuyuki



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


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



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

PubMed Central

The prefrontal cortex (PFC) is implicated to play an important role in cognitive control. Abnormal PFC activities and rhythms have been observed in some neurological and neuropsychiatric disorders, and evidences suggest influences from the neuromodulators dopamine (DA) and serotonin (5-HT). Despite the high level of interest in these brain systems, the combined effects of DA and 5-HT modulation on PFC dynamics remain unknown. In this work, we build a mathematical model that incorporates available experimental findings to systematically study the comodulation of DA and 5-HT on the network behavior, focusing on beta and gamma band oscillations. Single neuronal model shows pyramidal cells with 5-HT1A and 2A receptors can be non-monotonically modulated by 5-HT. Two-population excitatory-inhibitory type network consisting of pyramidal cells with D1 receptors can provide rich repertoires of oscillatory behavior. In particular, 5-HT and DA can modulate the amplitude and frequency of the oscillations, which can emerge or cease, depending on receptor types. Certain receptor combinations are conducive for the robustness of the oscillatory regime, or the existence of multiple discrete oscillatory regimes. In a multi-population heterogeneous model that takes into account possible combination of receptors, we demonstrate that robust network oscillations require high DA concentration. We also show that selective D1 receptor antagonists (agonists) tend to suppress (enhance) network oscillations, increase the frequency from beta toward gamma band, while selective 5-HT1A antagonists (agonists) act in opposite ways. Selective D2 or 5-HT2A receptor antagonists (agonists) can lead to decrease (increase) in oscillation amplitude, but only 5-HT2A antagonists (agonists) can increase (decrease) the frequency. These results are comparable to some pharmacological effects. Our work illustrates the complex mechanisms of DA and 5-HT when operating simultaneously through multiple receptors. PMID:23935568

Wang, Da-Hui; Wong-Lin, KongFatt



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

PubMed Central

Most of the current techniques for in vivo detection of dopamine exploit the ease of oxidation of this compound. The major problem during the detection is the presence of a high concentration of ascorbic acid that is oxidized at nearly the same potential as dopamine on bare electrodes. Furthermore, the oxidation product of dopamine reacts with ascorbic acid present in samples and regenerates dopamine again, which severely limits the accuracy of the detection. Meanwhile, the product could also form a melanin-like insulating film on the electrode surface, which decreases the sensitivity of the electrode. Various surface modifications on the electrode, new materials for making the electrodes, and new electrochemical techniques have been exploited to solve these problems. Recently we developed a new electrochemical detection method that did not rely on direct oxidation of dopamine on electrodes, which may naturally solve these problems. This approach takes advantage of the high performance of our newly developed poly(anilineboronic acid)/carbon nanotube composite and the excellent permselectivity of the ion-exchange polymer Nafion. The high affinity binding of dopamine to the boronic acid groups of the polymer affects the electrochemical properties of the polyaniline backbone, which act as the basis for the transduction mechanism of this non-oxidative dopamine sensor. The unique reduction capability and high conductivity of single-stranded DNA functionalized single-walled carbon nanotubes greatly improved the electrochemical activity of the polymer in a physiologically-relevant buffer, and the large surface area of the carbon nanotubes increased the density of the boronic acid receptors. The high sensitivity and selectivity of the sensor show excellent promise toward molecular diagnosis of Parkinson's disease. In this review, we will focus on the discussion of this novel detection approach, the new interferences in this detection approach, and how to eliminate these interferences toward in vivo and in vitro detection of the neurotransmitter dopamine.

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



Neurotrophic actions of dopamine on the development of a serotonergic feeding circuit in Drosophila melanogaster  

PubMed Central

Background In the fruit fly, Drosophila melanogaster, serotonin functions both as a neurotransmitter to regulate larval feeding, and in the development of the stomatogastric feeding circuit. There is an inverse relationship between neuronal serotonin levels during late embryogenesis and the complexity of the serotonergic fibers projecting from the larval brain to the foregut, which correlate with perturbations in feeding, the functional output of the circuit. Dopamine does not modulate larval feeding, and dopaminergic fibers do not innervate the larval foregut. Since dopamine can function in central nervous system development, separate from its role as a neurotransmitter, the role of neuronal dopamine was assessed on the development, and mature function, of the 5-HT larval feeding circuit. Results Both decreased and increased neuronal dopamine levels in late embryogenesis during development of this circuit result in depressed levels of larval feeding. Perturbations in neuronal dopamine during this developmental period also result in greater branch complexity of the serotonergic fibers innervating the gut, as well as increased size and number of the serotonin-containing vesicles along the neurite length. This neurotrophic action for dopamine is modulated by the D2 dopamine receptor expressed during late embryogenesis in central 5-HT neurons. Animals carrying transgenic RNAi constructs to knock down both dopamine and serotonin synthesis in the central nervous system display normal feeding and fiber architecture. However, disparate levels of neuronal dopamine and serotonin during development of the circuit result in abnormal gut fiber architecture and feeding behavior. Conclusions These results suggest that dopamine can exert a direct trophic influence on the development of a specific neural circuit, and that dopamine and serotonin may interact with each other to generate the neural architecture necessary for normal function of the circuit. PMID:22413901



Detection and Monitoring of Neurotransmitters - a Spectroscopic Analysis  

PubMed Central

Objectives We demonstrate that confocal Raman mapping spectroscopy provides rapid, detailed and accurate neurotransmitter analysis, enabling millisecond time resolution monitoring of biochemical dynamics. As a prototypical demonstration of the power of the method, we present real-time in vitro serotonin, adenosine, and dopamine detection, and dopamine diffusion in an inhomogeneous organic gel, which was used as a substitute for neurologic tissue. Materials and Methods Dopamine, adenosine and serotonin were used to prepare neurotransmitter solutions in DI water. The solutions were applied to the surfaces of glass slides, where they inter-diffused. Raman mapping was achieved by detecting non-overlapping spectral signatures characteristic of the neurotransmitters with an alpha 300 WITec confocal Raman system, using 532 nm Nd:YAG laser excitation. Every local Raman spectrum was recorded in milliseconds and complete Raman mapping in a few seconds. Results Without damage, dyeing, or preferential sample preparation, confocal Raman mapping provided positive detection of each neurotransmitter, allowing association of the high-resolution spectra with specific micro-scale image regions. Such information is particularly important for complex, heterogeneous samples, where changes in composition can influence neurotransmission processes. We also report an estimated dopamine diffusion coefficient two orders of magnitude smaller than that calculated by the flow-injection method. Conclusions Accurate nondestructive characterization for real-time detection of neurotransmitters in inhomogeneous environments without the requirement of sample labeling is a key issue in neuroscience. Our work demonstrates the capabilities of Raman spectroscopy in biological applications, possibly providing a new tool for elucidating the mechanism and kinetics of deep brain stimulation. PMID:22989218

Manciu, Felicia S.; Lee, Kendall H.; Durrer, William G.; Bennet, Kevin E.



Simultaneous measurement of dopamine, serotonin, their metabolites and tryptophan in mouse brain homogenates by high-performance liquid chromatography with dual coulometric detection.  


A new rapid and sensitive high-performance liquid chromatography (HPLC) method for the simultaneous determination of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine, 5-hydroxytryptamine (serotonin), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid and tryptophan has been developed and applied to mouse frontal cortex, caudate nucleus and dorsal raphe assays. A dual coulometric detector was used with detection at +0.25 and +0.55 V, which allowed the determination of tryptophan. Detection limits for all compounds (0.8-9.0 pg per injection, depending on the compounds) were useful for this application. Owing to great sensitivity of the method, the brain tissue samples can be very small, less than 2 mg. Linearity of standards was excellent (r > 0.999 in all cases). Intraday and interday precisions for samples analytes were generally acceptable (intraday assay CV < 8.7% and interday assay CV < 7.0% except for DOPAC and 5-HIAA, which was 11.4% for the low concentrations). Average recoveries of standard additions to sample analytes were > 90%. Attention was paid to stability of standard and sample analytes when stored at +4 degrees C or at -70 degrees C with two different homogenizing agents (0.1 M HClO4 with 10(-7) M ascorbic acid and 0.05 M HClO4 without ascorbic acid). This simple, rapid and efficient method can be used as a basic research tool for modification of brain neurotransmitters in experimental pharmacological protocols for following psychotropic drug treatments in animals. PMID:10416063

Alvarez, J C; Bothua, D; Collignon, I; Advenier, C; Spreux-Varoquaux, O



Acute and subacute effects of risperidone and cocaine on accumbens dopamine and serotonin release using in vivo microvoltammetry on line with open-field behavior  

Microsoft Academic Search

In vivo microvoltammetry was used to detect dopamine (DA) and serotonin (5-HT) release from nucleus accumbens (NAcc) of freely moving, male, Sprague–Dawley laboratory rats, while animals' locomotor (forward ambulations) and stereotypic behavior (fine movements of sniffing and grooming) were monitored at the same time with infrared photobeams. Monoamine release mechanisms were determined by using a depolarization blocker (?-butyrolactone, ?BL). Miniature

Patricia A Broderick; David N Rahni; Yueping Zhou



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.  


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



Recreational Ecstasy\\/MDMA, the serotonin syndrome, and serotonergic neurotoxicity  

Microsoft Academic Search

The ring-substituted amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) or “Ecstasy” is widely used a recreational drug. It stimulates the release and inhibits the reuptake of serotonin (5-HT) and other neurotransmitters such as dopamine to a lesser extent. The acute boost in monoamine activity can generate feelings of elation, emotional closeness, and sensory pleasure. In the hot and crowded conditions of raves\\/dances, mild

A. C. Parrott



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.



Polyethylenimine carbon nanotube fiber electrodes for enhanced detection of neurotransmitters.  


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

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



A neural network of obsessive– compulsive disorder: modelling cognitive disinhibition and neurotransmitter dysfunction  

Microsoft Academic Search

While significant advances have been made in documenting both neurotransmitter and neuropsychological dysfunction in obsessive–compulsive disorder (OCD), there remains a need for theoretical models to account for their relationship. A neural network model of OCD was developed to provide a rigorous simulation of the relationship between the cognitive disinhibition and serotonin\\/dopamine dysfunction that characterize this disorder. An architecture-specific recurrent neural

D. J. Stein; J. Ludik



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

PubMed Central

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

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



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


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

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



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.




PubMed Central

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

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



The serotonin system: a potential target for anti-dyskinetic treatments and biomarker discovery.  


L-DOPA-induced dyskinesia is a major problem in the treatment of Parkinson's disease. Today there are few anti-dyskinetic treatments available for the patients, and all of them have major limitations. Recent findings have revealed an important role of the serotonin system in L-DOPA-induced dyskinesia. In the parkinsonian brain, serotonin axon terminals can compensate for the dopamine loss by converting L-DOPA into dopamine and releasing it as a false neurotransmitter. However, the terminals represent an aberrant source of dopamine release, increasing the risk for dyskinesia. In line with this, a relatively high density of serotonin axon fibres in striatum has been reported in dyskinetic animals and patients. Furthermore, serotonin can influence dyskinesia by modulating glutamate or GABA signalling in the basal ganglia via receptors located on non-serotonergic neurons. Through either mechanism, modulation of certain serotonin receptors has been shown to reduce the severity of dyskinetic movements. The serotonin system represents an interesting target for developing anti-dyskinetic treatments. Future therapies may take advantage of the synergistic effect produced by the modulation of different serotonin receptors or pursue a region-specific modulation of certain receptors. Moreover, morphological or biochemical features of the serotonin system could be used to develop biomarkers for patient stratification in clinical trials of anti-dyskinetic compounds. PMID:22166409

Rylander, Daniella



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.



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.



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



The methylation, neurotransmitter, and antioxidant connections between folate and depression.  


Depression is common - one-fourth of the U.S. population will have a depressive episode sometime in life. Folate deficiency is also relatively common in depressed people, with approximately one-third of depressed individuals having an outright deficiency. Folate is a water-soluble B-vitamin necessary for the proper biosynthesis of the monoamine neurotransmitters serotonin, epinephrine, and dopamine. The active metabolite of folate, 5-methyltetrahydrofolate (5-MTHF, L-methylfolate), participates in re-methylation of the amino acid metabolite homocysteine, creating methionine. S-adenosylmethionine (SAMe), the downstream metabolite of methionine, is involved in numerous biochemical methyl donation reactions, including reactions forming monoamine neurotransmitters. Without the participation of 5-MTHF in this process, SAMe and neurotransmitter levels decrease in the cerebrospinal fluid, contributing to the disease process of depression. SAMe supplementation was shown to improve depressive symptoms. 5-MTHF also appears to stabilize, enhance production of, or possibly act as a substitute for, tetrahydrobiopterin (BH4), an essential cofactor in monoamine neurotransmitter biosynthesis. There are few intervention studies of folic acid or 5-MTHF as a stand-alone treatment for depression related to folate deficiency; however, the studies that have been conducted are promising. Depressed individuals with low serum folate also tend to not respond well to selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Correcting the insufficiency by dosing folate along with the SSRI results in a significantly better antidepressant response. PMID:18950248

Miller, Alan L



Electrophoretic separation of neurotransmitters on a polystyrene nano-sphere\\/polystyrene sulphonate coated poly(dimethylsiloxane) microchannel  

Microsoft Academic Search

In this paper, a poly(dimethylsiloxane) microchip with amperometric detector was developed for the electrophoretic separation and determination of neurotransmitters. For increasing the separation efficiency, the microchannel is modified by polystyrene sulphonate\\/polystyrene nano-sphere self-assembly coating. A stable electro-osmotic flow (EOF) and higher separation efficiency are obtained in proposed modified microchannel. Under optimized conditions, dopamine, epinephrine, catechol, and serotonin are acceptably baseline

Jinjin Zhao; Qianli Zhang; Huijuan Yang; Yifeng Tu



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


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



Lack of association between down syndrome and polymorphisms in dopamine receptor D4 and serotonin transporter genes.  


Down Syndrome (DS) patients suffer from cognitive dysfunction, depression, hyperactivity, irritability etc. Dopamine (DA) and serotonin (5HT) are known to control cognitive and behavioral attributes. An increased number of the DA receptor 4 (DRD4) is detected in brain regions primarily involved in cognition. Impairments in executive function have also been reported with depletion in 5HT. A variable number of tandem repeat (VNTR) in the exon 3 of DRD4 and an insertion/deletion polymorphism in the promoter region of 5HT transporter (5HTTLPR) have been found to be associated with different neurobehavioral disorders; however, association of these polymorphisms with DS has never been explored. The present family-based analysis on DS revealed significant over-transmission of a DRD4 VNTR allele which encodes for D4 receptor with average activity. No association was noticed for the 5HTTLPR. We may conclude that these genetic polymorphisms are not contributing to the neuromotor and cognitive dysfunctions observed in DS. PMID:18270821

Das Bhowmik, Aneek; Dutta, Samikshan; Sinha, Swagata; Chattopadhyay, Anindita; Mukhopadhyay, Kanchan



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

PubMed Central

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

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



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.



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

PubMed Central

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, in most cases the causal mechanisms are unknown. The scientific issues are daunting but important for human health because of the use of selective serotonin reuptake inhibitors and other pharmacological agents to treat disorders in the serotonergic signaling system. Methods We construct a mathematical model of serotonin synthesis, release, and reuptake in a single serotonergic neuron terminal. The model includes the effects of autoreceptors, the transport of tryptophan into the terminal, and the metabolism of serotonin, as well as the dependence of release on the firing rate. The model is based on real physiology determined experimentally and is compared to experimental data. Results We compare the variations in serotonin and dopamine synthesis due to meals and find that dopamine synthesis is insensitive to the availability of tyrosine but serotonin synthesis is sensitive to the availability of tryptophan. We conduct in silico experiments on the clearance of extracellular serotonin, normally and in the presence of fluoxetine, and compare to experimental data. We study the effects of various polymorphisms in the genes for the serotonin transporter and for tryptophan hydroxylase on synthesis, release, and reuptake. We find that, because of the homeostatic feedback mechanisms of the autoreceptors, the polymorphisms have smaller effects than one expects. We compute the expected steady concentrations of serotonin transporter knockout mice and compare to experimental data. Finally, we study how the properties of the the serotonin transporter and the autoreceptors give rise to the time courses of extracellular serotonin in various projection regions after a dose of fluoxetine. Conclusions Serotonergic systems must respond robustly to important biological signals, while at the same time maintaining homeostasis in the face of normal biological fluctuations in inputs, expression levels, and firing rates. This is accomplished through the cooperative effect of many different homeostatic mechanisms including special properties of the serotonin transporters and the serotonin autoreceptors. Many difficult questions remain in order to fully understand how serotonin biochemistry affects serotonin electrophysiology and vice versa, and how both are changed in the presence of selective serotonin reuptake inhibitors. Mathematical models are useful tools for investigating some of these questions. PMID:20723248



Discovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors: design, synthesis, and effects on behavior.  


Dopamine D(3) antagonism combined with serotonin 5-HT(1A) and 5-HT(2A) receptor occupancy may represent a novel paradigm for developing innovative antipsychotics. The unique pharmacological features of 5i are a high affinity for dopamine D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors, together with a low affinity for dopamine D(2) receptors (to minimize extrapyramidal side effects), serotonin 5-HT(2C) receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacological and biochemical data, including specific c-fos expression in mesocorticolimbic areas, confirmed an atypical antipsychotic profile of 5i in vivo, characterized by the absence of catalepsy at antipsychotic dose. PMID:19072656

Butini, Stefania; Gemma, Sandra; Campiani, Giuseppe; Franceschini, Silvia; Trotta, Francesco; Borriello, Marianna; Ceres, Nicoletta; Ros, Sindu; Coccone, Salvatore Sanna; Bernetti, Matteo; De Angelis, Meri; Brindisi, Margherita; Nacci, Vito; Fiorini, Isabella; Novellino, Ettore; Cagnotto, Alfredo; Mennini, Tiziana; Sandager-Nielsen, Karin; Andreasen, Jesper Tobias; Scheel-Kruger, Jorgen; Mikkelsen, Jens D; Fattorusso, Caterina



Cytokine Targets in the Brain: Impact on Neurotransmitters and Neurocircuits  

PubMed Central

Increasing attention has been paid to the role of inflammation in a host of illnesses including neuropsychiatric disorders such as depression and anxiety. Activation of the inflammatory response leads to release of inflammatory cytokines and mobilization of immune cells both of which have been shown to access the brain and alter behavior. The mechanisms of the effects of inflammation on the brain have become an area of intensive study. Data indicate that cytokines and their signaling pathways including p38 mitogen activated protein kinase have significant effects on the metabolism of multiple neurotransmitters such as serotonin, dopamine and glutamate through impact on their synthesis, release and reuptake. Cytokines also activate the kynurenine pathway which not only depletes tryptophan, the primary amino acid precursor of serotonin, but also generates neuroactive metabolites that can significantly influence the regulation of dopamine and glutamate. Through their effects on neurotransmitter systems, cytokines impact neurocircuits in the brain including the basal ganglia and anterior cingulate cortex, leading to significant changes in motor activity and motivation as well as anxiety, arousal and alarm. In the context of environmental challenge from the microbial world, these effects of inflammatory cytokines on the brain represent an orchestrated suite of behavioral and immune responses that subserve evolutionary priorities to shunt metabolic resources away from environmental exploration to fighting infection and wound healing, while also maintaining vigilance against attack, injury and further pathogen exposure. Chronic activation of this innate behavioral and immune response may lead to depression and anxiety disorders in vulnerable individuals. PMID:23468190

Miller, Andrew H.; Haroon, Ebrahim; Raison, Charles L.; Felger, Jennifer C.



Combined effect of promoter polymorphisms in the dopamine D4 receptor and the serotonin transporter genes in heroin dependence.  


Dopamine D4 receptor (DRD4) and serotonin transporter (SERT) gene polymorphisms were studied, as possible genetic risk factors for substance dependence. The case-control study involved a large cohort (n = 362) of healthy Caucasian population, and an initial sample of 73 substance dependent patients (including a subgroup of 53 heroin dependents). Improved methods were applied for genotype detection of the DRD4 polymorphisms (exon 3 48 bp VNTR; -521 C/T SNP and 120 bp duplication in the 5' flanking region) and the SERT gene polymorphisms (5-hydroxytriptamin transporter linked polymorphic region [5-HTTLPR] in the 5' flanking region and the intron 2 VNTR [STin2]). Association between the -521 C/T SNP of the DRD4 promoter region and substance dependence was significant in the subgroup of heroin dependents (p = 0.044). The other analyzed polymorphisms did not show any significant association, but an interaction between -521 C/T SNP of DRD4 and the 5-HTTLPR polymorphisms was observed. Association between the -521 CC vs. CT or TT genotypes and heroin dependence was enhanced in the presence of short (s or 14-repeat) 5-HTTLPR allele (p 0.01). The odds ratio of 2.14 observed for the -521 CC genotype increased to 4.82 in double homozygotes of -521 CC and 5-HTTLPR ss, emphasizing the importance of combined analysis of polymorphisms in the dopaminergic and serotonergic systems in heroin dependence. However, due to the limited size of our sample these results should be interpreted with caution. PMID:16167465

Szilagyi, Agnes; Boór, Krisztina; Székely, Anna; Gaszner, Péter; Kalász, Huba; Sasvári-Székely, Mária; Barta, Csaba



Serotonin, Dopamine and Noradrenaline Adjust Actions of Myelinated Afferents via Modulation of Presynaptic Inhibition in the Mouse Spinal Cord  

PubMed Central

Gain control of primary afferent neurotransmission at their intraspinal terminals occurs by several mechanisms including primary afferent depolarization (PAD). PAD produces presynaptic inhibition via a reduction in transmitter release. While it is known that descending monoaminergic pathways complexly regulate sensory processing, the extent these actions include modulation of afferent-evoked PAD remains uncertain. We investigated the effects of serotonin (5HT), dopamine (DA) and noradrenaline (NA) on afferent transmission and PAD. Responses were evoked by stimulation of myelinated hindlimb cutaneous and muscle afferents in the isolated neonatal mouse spinal cord. Monosynaptic responses were examined in the deep dorsal horn either as population excitatory synaptic responses (recorded as extracellular field potentials; EFPs) or intracellular excitatory postsynaptic currents (EPSCs). The magnitude of PAD generated intraspinally was estimated from electrotonically back-propagating dorsal root potentials (DRPs) recorded on lumbar dorsal roots. 5HT depressed the DRP by 76%. Monosynaptic actions were similarly depressed by 5HT (EFPs 54%; EPSCs 75%) but with a slower time course. This suggests that depression of monosynaptic EFPs and DRPs occurs by independent mechanisms. DA and NA had similar depressant actions on DRPs but weaker effects on EFPs. IC50 values for DRP depression were 0.6, 0.8 and 1.0 µM for 5HT, DA and NA, respectively. Depression of DRPs by monoamines was nearly-identical in both muscle and cutaneous afferent-evoked responses, supporting a global modulation of the multimodal afferents stimulated. 5HT, DA and NA produced no change in the compound antidromic potentials evoked by intraspinal microstimulation indicating that depression of the DRP is unrelated to direct changes in the excitability of intraspinal afferent fibers, but due to metabotropic receptor activation. In summary, both myelinated afferent-evoked DRPs and monosynaptic transmission in the dorsal horn are broadly reduced by descending monoamine transmitters. These actions likely integrate with modulatory actions elsewhere to reconfigure spinal circuits during motor behaviors. PMID:24587177

García-Ramírez, David L.; Calvo, Jorge R.; Hochman, Shawn; Quevedo, Jorge N.



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


In this investigation, gene-environment interaction effects in predicting resilience in adaptive functioning among maltreated and nonmaltreated low-income children (N = 595) were examined. A multicomponent index of resilient functioning was derived and levels of resilient functioning were identified. Variants in four genes (serotonin transporter linked polymorphic region, corticotropin releasing hormone receptor 1, dopamine receptor D4-521C/T, and oxytocin receptor) were investigated. In a series of analyses of covariance, child maltreatment demonstrated a strong negative main effect on children's resilient functioning, whereas no main effects for any of the genotypes of the respective genes were found. However, gene-environment interactions involving genotypes of each of the respective genes and maltreatment status were obtained. For each respective gene, among children with a specific genotype, the relative advantage in resilient functioning of nonmaltreated compared to maltreated children was stronger than was the case for nonmaltreated and maltreated children with other genotypes of the respective gene. Across the four genes, a composite of the genotypes that more strongly differentiated resilient functioning between nonmaltreated and maltreated children provided further evidence of genetic variations influencing resilient functioning in nonmaltreated children, whereas genetic variation had a negligible effect on promoting resilience among maltreated children. Additional effects were observed for children based on the number of subtypes of maltreatment children experienced, as well as for abuse and neglect subgroups. Finally, maltreated and nonmaltreated children with high levels of resilience differed in their average number of differentiating genotypes. These results suggest that differential resilient outcomes are based on the interaction between genes and developmental experiences. PMID:22559122

Cicchetti, Dante; Rogosch, Fred A



Orquestic regulation of neurotransmitters on reward-seeking behavior  

PubMed Central

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



Analysis of Neurotransmitter Tissue Content of Drosophila melanogaster in Different Life Stages.  


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



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



Memory, Mood, Dopamine, and Serotonin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Lesioned Mouse Model of Basal Ganglia Injury  

PubMed Central

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse serves as a model of basal ganglia injury and Parkinson’s disease. The present study investigated the effects of MPTP-induced lesioning on associative memory, conditioned fear, and affective behavior. Male C57BL/6 mice were administered saline or MPTP and separate groups were evaluated at either 7 or 30 days post-lesioning. In the social transmission of food preference test, mice showed a significant decrease in preference for familiar food 30 days post-MPTP compared to controls. Mice at both 7 and 30 days post-MPTP-lesioning had increased fear extinction compared to controls. HPLC analysis of tissues homogenates showed dopamine and serotonin were depleted in the striatum, frontal cortex, and amygdala. No changes in anxiety or depression were detected by the tail suspension, sucrose preference, light-dark preference, or hole-board tests. In conclusion, acute MPTP-lesioning regimen in mice causes impairments in associative memory and conditioned fear, no mood changes, and depletion of dopamine and serotonin throughout the brain. PMID:18718537

Vu?kovi?, Marta G.; Wood, Ruth I.; Holschneider, Daniel P.; Abernathy, Avery; Togasaki, Daniel M.; Smith, Alexsandra; Petzinger, Giselle M.; Jakowec, Michael W.



[Neurotransmitters, calcium signalling and neuronal communication].  


In this article we show some recent findings that constitute a great progress in the molecular knowledge of synaptic dynamics. To communicate, neurons use a code that includes electrical (action potentials) and chemical signals (neurotransmitters, neuromodulators). At the moment a great variety of molecules are known, whose neurotransmitter function in brain and the peripheral nervous system are out of question. Monoamines like acetylcholine, dopamine, noradrenaline, adrenaline, histamine, serotonin, glutamate, aspartate, glycine, ATP and GABA are good examples. Opioid neuropeptides, vasoactive intestinal peptide (VIP), neurokinines (substance P), somatostatin, neurotensin, neuropeptide Y, cholecystokinine, vasopressin or oxitocin have been related to the control of the stress response, sexual behaviour, food intake, pain, learning and memory, qualities that are also related to nitric oxide (NO). A great part of the molecular structure of the secretory machinery is known to be responsible for fast neurotransmitter release at the synapse, in response to action potentials. Proteins like sinaptobrevin (located in the membrane of the synaptic vesicle), sintaxin and SNAP-25 (both located at the presynaptic plasma membrane) constitute a trimeric complex which is responsible of the vesicular docking at the active sites for exocytosis. From this strategic location, vesicles release their neurotransmitter within few milliseconds, when the action potential invades the nerve terminal and activates the opening of the different subtypes of voltage-dependent Ca2+ channels. The asymmetric geographical distribution of each type of channel, in different neurons, rose the hypothesis that Ca2+ that enters through each subtype of channel is compartmentalised, thus favouring the generation of Ca2+ microdomains, in the cytosol and the nucleus, involved in different cellular functions. This great biochemical synaptic heterogeneity is facilitating the selection of many biological targets to develop drugs with potential therapeutic applications in neuropsychiatric diseases i.e. Alzheimer's, Parkinson, epilepsies, stroke, vascular dementia, depression, schizophrenia, anxiety and so on. PMID:15159788

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



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



Brain serotonin and dopamine modulators, perceptual responses and endurance performance during exercise in the heat following creatine supplementation  

PubMed Central

Background The present experiment examined the responses of peripheral modulators and indices of brain serotonin (5-HT) and dopamine (DA) function and their association with perception of effort during prolonged exercise in the heat after creatine (Cr) supplementation. Methods Twenty one endurance-trained males performed, in a double-blind fashion, two constant-load exercise tests to exhaustion at 63 ± 5% V?O2 max in the heat (ambient temperature: 30.3 ± 0.5 °C, relative humidity: 70 ± 2%) before and after 7 days of Cr (20 g·d-1 Cr + 140 g·d-1 glucose polymer) or placebo (Plc) (160 g·d-1 glucose polymer) supplementation. Results 3-way interaction has shown that Cr supplementation reduced rectal temperature, heart rate, ratings of perceived leg fatigue (P < 0.05), plasma free-tryptophan (Trp) (P < 0.01) and free-Trp:tyrosine ratio (P < 0.01) but did not influence the ratio of free-Trp:large neutral amino acids or contribute in improving endurance performance (Plc group, n = 10: 50.4 ± 8.4 min vs. 51.2 ± 8.0 min, P > 0.05; Cr group, n = 11: 47.0 ± 4.7 min vs. 49.7 ± 7.5 min, P > 0.05). However, after dividing the participants into "responders" and "non-responders" to Cr, based on their intramuscular Cr uptake, performance was higher in the "responders" relative to "non-responders" group (51.7 ± 7.4 min vs.47.3 ± 4.9 min, p < 0.05). Conclusion although Cr influenced key modulators of brain 5-HT and DA function and reduced various thermophysiological parameters which all may have contributed to the reduced effort perception during exercise in the heat, performance was improved only in the "responders" to Cr supplementation. The present results may also suggest the demanding of the pre-experimental identification of the participants into "responders" and "non-responders" to Cr supplementation before performing the main experimentation. Otherwise, the possibility of the type II error may be enhanced. PMID:18826587

Hadjicharalambous, Marios; Kilduff, Liam P; Pitsiladis, Yannis P



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



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.  


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



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



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



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

NASA Astrophysics Data System (ADS)

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

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



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


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



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


Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple congenital anomaly syndrome with cognitive impairment and a distinct behavioral phenotype that includes autistic features. SLOS is caused by a defect in 3?-hydroxysterol ?(7)-reductase which leads to decreased cholesterol levels and elevated cholesterol precursors, specifically 7- and 8-dehydrocholesterol. However, the pathological processes contributing to the neurological abnormalities in SLOS have not been defined. In view of prior data suggesting defects in SLOS in vesicular release and given the association of altered serotonin metabolism with autism, we were interested in measuring neurotransmitter metabolite levels in SLOS to assess their potential to be used as biomarkers in therapeutic trials. We measured cerebral spinal fluid levels of serotonin and dopamine metabolites, 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) respectively, in 21 SLOS subjects. Results were correlated with the SLOS anatomical severity score, Aberrant Behavior Checklist scores and concurrent sterol biochemistry. Cerebral spinal fluid (CSF) levels of both 5HIAA and HVA were significantly reduced in SLOS subjects. In individual patients, the levels of both 5HIAA and HVA were reduced to a similar degree. CSF neurotransmitter metabolite levels did not correlate with either CSF sterols or behavioral measures. This is the first study demonstrating decreased levels of CSF neurotransmitter metabolites in SLOS. We propose that decreased levels of neurotransmitters in SLOS are caused by a sterol-related defect in synaptic vesicle formation and that CSF 5HIAA and HVA will be useful biomarkers in development of future therapeutic trials. PMID:24500076

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



New discoveries in the development of antipsychotics with novel mechanisms of action: beyond the atypical antipsychotics with serotonin dopamine antagonism  

Microsoft Academic Search

\\u000a Antipsychotic innovation can be divided into three eras. The first era began with the serendipitous discovery of the classical\\u000a antipsychotic neuroleptics, later found to mediate their therapeutic actions by blocking D2 dopamine receptors, particularly\\u000a in the mesolimbic dopamine pathway [1]. From the late 1950s through the 1980s, a large number of effective compounds sharing this mechanism of action were thus

Stephen M. Stahl; Darius K. Shayegan


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.



Targeting Dopamine D3 and Serotonin 5-HT1A and 5-HT2A Receptors for Developing Effective Antipsychotics: Synthesis, Biological Characterization, and Behavioral Studies.  


Combination of dopamine D3 antagonism, serotonin 5-HT1A partial agonism, and antagonism at 5-HT2A leads to a novel approach to potent atypical antipsychotics. Exploitation of the original structure-activity relationships resulted in the identification of safe and effective antipsychotics devoid of extrapyramidal symptoms liability, sedation, and catalepsy. The potential atypical antipsychotic 5bb was selected for further pharmacological investigation. The distribution of c-fos positive cells in the ventral striatum confirmed the atypical antipsychotic profile of 5bb in agreement with behavioral rodent studies. 5bb administered orally demonstrated a biphasic effect on the MK801-induced hyperactivity at dose levels not able to induce sedation, catalepsy, or learning impairment in passive avoidance. In microdialysis studies, 5bb increased the dopamine efflux in the medial prefrontal cortex. Thus, 5bb represents a valuable lead for the development of atypical antipsychotics endowed with a unique pharmacological profile for addressing negative symptoms and cognitive deficits in schizophrenia. PMID:25343529

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



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



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


Aspartame is one of the most widely used artificial sweeteners globally. Data concerning acute neurotoxicity of aspartame is controversial, and knowledge on its chronic effect is limited. In the current study, we investigated the chronic effects of aspartame on ionic homeostasis and regional monoamine neurotransmitter concentrations in the brain. Our results showed that aspartame at high dose caused a disturbance in ionic homeostasis and induced apoptosis in the brain. We also investigated the effects of aspartame on brain regional monoamine synthesis, and the results revealed that there was a significant decrease of dopamine in corpus striatum and cerebral cortex and of serotonin in corpus striatum. Moreover, aspartame treatment significantly alters the tyrosine hydroxylase activity and amino acids levels in the brain. Our data suggest that chronic use of aspartame may affect electrolyte homeostasis and monoamine neurotransmitter synthesis dose dependently, and this might have a possible effect on cognitive functions. PMID:24872471

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



Association between tridimensional personality questionnaire (TPQ) traits and three functional polymorphisms: dopamine receptor D4 (DRD4), serotonin transporter promoter region (5-HTTLPR) and catechol O-methyltransferase (COMT)  

Microsoft Academic Search

Dopamine D4 receptor (DRD4), serotonin transporter promoter regulatory region (5-HTTLPR) and catechol O-methyltransferase (COMT) polymorphisms were examined for association with TPQ personality factors in 455 subjects. Significant interactions were observed by multivariate analysis, (COMT × 5-HTTLPR: Hotelling's Trace = 2.3, P = 0.02) and by subsequent univariate 3-way ANOVA when Novelty Seeking (NS) was the dependent variable: 5-HTTLPR × D4DR

J Benjamin; Y Osher; M Kotler; I Gritsenko; L Nemanov; R H Belmaker; R P Ebstein



Dopamine elicits feeding motor program in Limax maximus.  


A neural system within the cerebral and buccal ganglia of the terrestrial mollusc Limax maximus responds to lip chemostimulation by emitting a feeding motor program (FMP) in vivo and in vitro. We have analyzed chemically the cerebral and buccal ganglia of Limax for neurotransmitters involved in controlling expression of FMP. Dopamine was found in clusters of cells in and the neuropil of the cerebral ganglia at a concentration of 62 pmol/ganglion; a large proportion of such dopamine-containing cells projected to the lips. The buccal ganglia contained several small dopaminergic cells and large amounts of dopamine in the neuropil; the measured concentration was 10 pmol/ganglion. Exogenous dopamine applied to the cerebral and buccal ganglia in vitro between 10(-7) M and 3 X 10(-6) M excited an autoactive salivary duct motor neuron (FB) and inhibited an autoactive secretomotor neuron (BSN). Concentrations of dopamine between 3 X 10(-6) M and 3 X 10(-5) M triggered FMP output, with an increased probability of triggering at higher concentrations of dopamine. ADTN and SK&F38393 were potent agonists in this system, whereas ergonovine was the only potent antagonist found; none of the neuroleptics tested was effective. Thus, the Limax system shows agonist responses similar to the vertebrate D1 receptors, but its antagonist-binding properties appear to have requirements quite different from vertebrate receptors. The effects of exogenous serotonin differed from dopamine's effects; serotonin excited BSN and several buccal motor neurons, could not elicit synchronized motor program cycling, and was not efficiently blocked by ergonovine. These data suggest that dopamine is a good candidate as an endogenous triggering and sustaining transmitter for the Limax feeding motor program. PMID:6886743

Wieland, S J; Gelperin, A



Regulation of embryonic neurotransmitter and tyrosine hydroxylase protein levels by ascorbic acid  

PubMed Central

Scope: Ascorbic acid (ascorbate) is required to recycle tetrahydrobiopterin, which is necessary for neurotransmitter synthesis by the rate-limiting enzymes tyrosine and tryptophan hydroxylases. We sought to determine whether ascorbate might regulate embryonic brain cortex monoamine synthesis utilizing transgenic mouse models with varying intracellular ascorbate levels. Methods and Results: In embryos lacking the sodium-dependent vitamin C transporter 2 (SVCT2), very low levels of brain ascorbate decreased cortex levels of norepinephrine and dopamine by approximately 33%, but had no effect on cortex serotonin or its metabolite, 5-hydroxyindole acetic acid. This decrease in ascorbate also led to a decrease in protein levels of tyrosine hydroxylase, but not of tryptophan hydroxylase. Increased cortex ascorbate in embryos carrying extra copies of the SVCT2 resulted in increased levels of dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), as well as serotonin and 5-hydroxyindole acetic acid. Conclusion: The dependence of embryonic brain cortex neurotransmitter synthesis and tyrosine hydroxylase expression on intracellular ascorbate emphasizes the importance of receiving adequate ascorbate during development. PMID:24095796

Meredith, M. Elizabeth; May, James M.



MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment  

Microsoft Academic Search

Rationale  3,4-Methylenedioxymethamphetamine (MDMA, designated as “Ecstasy” if illicitly marketed in tablet form) induces significant decrements in neuronal serotonin (5-HT) markers in humans, nonhuman primates, and rats as a function of dosing and dosing regimen. In rats, MDMA-mediated effects are attributed, in part, to selective high-affinity transport of MDMA into 5-HT neurons by the 5-HT transporter (SERT), followed by extensive 5-HT release.Objectives  To

Christopher D. Verrico; Gregory M. Miller; Bertha K. Madras



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.



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


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

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



Chronic and acute regulation of Na+/Cl- -dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems.  


Na+/Cl- -dependent neurotransmitter transporters, which constitute a gene superfamily, are crucial for limiting neurotransmitter activity. Thus, it is critical to understand their regulation. This review focuses primarily on the norepinephrine transporter, the dopamine transporter, the serotonin transporter, and the gamma-aminobutyric acid transporter GAT1. Chronic administration of drugs that alter neurotransmitter release or inhibit transporter activity can produce persistent compensatory changes in brain transporter number and activity. However, regulation has not been universally observed. Transient alterations in norepinephrine transporter, dopamine transporter, serotonin transporter, and GAT1 function and/or number occur in response to more acute manipulations, including membrane potential changes, substrate exposure, ethanol exposure, and presynaptic receptor activation/inhibition. In many cases, acute regulation has been shown to result from a rapid redistribution of the transporter between the cell surface and intracellular sites. Second messenger systems involved in this rapid regulation include protein kinases and phosphatases, of which protein kinase C has been the best characterized. These signaling systems share the common characteristic of altering maximal transport velocity and/or cell surface expression, consistent with regulation of transporter trafficking. Although less well characterized, arachidonic acid, reactive oxygen species, and nitric oxide also alter transporter function. In addition to post-translational modifications, cytoskeleton interactions and transporter oligomerization regulate transporter activity and trafficking. Furthermore, promoter regions involved in transporter transcriptional regulation have begun to be identified. Together, these findings suggest that Na+/Cl- -dependent neurotransmitter transporters are regulated both long-term and in a more dynamic manner, thereby providing several distinct mechanisms for altering synaptic neurotransmitter concentrations and neurotransmission. PMID:11750035

Zahniser, N R; Doolen, S



Generation of nitro radical anions of some 5-nitrofurans, 2- and 5-nitroimidazoles by norepinephrine, dopamine, and serotonin. A possible mechanism for neurotoxicity caused by nitroheterocyclic drugs.  


Catecholamine neurotransmitters such as norepinephrine, dopamine, and related catecholamine derivatives reduce nitroheterocyclic drugs such as nitrofurantoin, nifurtimox, nifuroxime, nitrofurazone, misonidazole, and metronidazole in slightly alkaline solutions. Drugs which contain 5-nitrofurans are reduced at lower pH than drugs which contain 2- and 5-nitroimidazoles. 5-Nitroimidazole derivatives such as metronidazole and ronidazole are known to be more difficult to reduce than 2-nitroimidazole derivatives, due to their lower redox potential. Catecholamines, when reducing nitro drugs, undergo concomitant oxidation to form semiquinone radicals. Both semiquinone radicals and nitro anion radicals formed in a reaction of nitro drug and catecholamine derivative were detected by electron spin resonance spectroscopy. Oxygen consumption studies in solutions containing nitro drug and catecholamine derivative showed that nitro anion radicals formed under aerobic conditions reduce oxygen to form the superoxide radical and hydrogen peroxide. Quinones formed in the reaction of catecholamine and nitro drug were detected by optical spectroscopy. Biosynthetic precursors and some metabolic products of catecholamines were also used in these studies, and they all exhibited reactions similar to catecholamines. Bovine chromaffin granules which synthesize and store catecholamines produced the nitrofurantoin anion radical when intact granules were treated with nitrofurantoin. These radicals formed inside the granules were observed by ESR spectroscopy. The formation of nitrofurantoin radical, semiquinone radicals of catecholamines, and oxygen-derived radicals by chromaffin granules is proposed to cause damage to adrenal medulla, and this process may lead to neurotoxicity. PMID:2887562

Rao, D N; Mason, R P



The association of the dopamine D4 receptor gene (DRD4) and the serotonin transporter promoter gene (5-HTTLPR) with temperament in 12-month-old infants.  


This study examined the association between two common polymorphisms, the dopamine D4 receptor (DRD4) gene and the serotonin transporter promoter (5-HTTLPR) gene and temperament in 61 infants aged 12 months. Twenty-two infants had a least one copy of the 6-8 repeat DRD4 alleles (L-DRD4) and 39 had two copies of the 2-5 repeat allele (S-DRD4). Twenty infants were homozygous for the short form (s/s) of 5-HTTLPR while 41 were either heterozygous for the short and the long form (l/s) or were homozygous for the long form (l/l). The infants were observed in a series of standard temperament episodes that elicited fear, anger, pleasure, interest, and activity. L-DRD4 infants showed less interest in a structured block play situation and more activity in a free play situation. They also displayed less anger in an episode of mild physical restraint. Infants with s/s 5-HTTLPR showed less fearful distress to stranger approach and less pleasure in a structured play situation than infants with l/l or l/s 5-HTTLPR. Duration of looking during block play was affected by a significant interaction between DRD4 and 5-HTTLPR. Shortest duration of looking was associated with the L-DRD4 and s/s 5-HTTLPR genotypes. The implications and limitations of these findings are discussed. PMID:11583250

Auerbach, J G; Faroy, M; Ebstein, R; Kahana, M; Levine, J



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


This investigation examined the extent to which polymorphisms of the serotonin transporter linked promoter region (5-HTTLPR) and the dopamine receptor D4 (DRD4) genes differentially influenced the development of attachment security and disorganization in maltreated and nonmaltreated infants at age 13 months, and the extent to which the efficacy of preventive interventions to promote attachment security were influenced by genetic variation. The sample consisted of 106 infants from maltreating families, participating in a randomized control trial evaluating the efficacy of two interventions, child-parent psychotherapy and psychoeducational parenting intervention, and 47 infants from nonmaltreating families. DNA samples were genotyped for polymorphisms of 5-HTTLPR, DRD4 exon III variable number tandem repeat, and DRD4-521. Attachment organization at age 1 and at age 2 was assessed with the Strange Situation for all participants, prior to and following the completion of the interventions. High rates of disorganized attachment were observed in the maltreatment compared to the nonmaltreatment group, and both interventions resulted in increased rates of attachment security at age 2. Genetic variation did not influence improvement in attachment organization among maltreated infants. Among maltreated infants, genetic variation had minimal effect on attachment organization. In contrast, among nonmaltreated infants, 5-HTTLPR and DRD4 polymorphisms influenced attachment security and disorganization at age 2 and the stability of attachment disorganization over time. PMID:23786683

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



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.



Neurotransmitter receptor density changes in Pitx3(ak) mice - A model relevant to Parkinson's disease.  


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



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.



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


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



Lack of involvement of dopamine and serotonin during the orphanin FQ/Nociceptin (OFQ/N)-induced prolactin secretory response.  


The purpose of these studies was to examine possible mechanisms of Orphanin FQ/Nociceptin (OFQ/N)-induced prolactin release. We investigated the involvement of the dopaminergic neurons by quantifying DOPAC:DA levels in the median eminence and neurointermediate lobe following central administration of OFQ/N to female Sprague-Dawley rats. To specifically determine the involvement of the tuberoinfundibular dopaminergic neurons, immunocytochemical studies were conducted to visualize c-fos protein expression in the arcuate nucleus following central administration of OFQ/N. In addition, the role of serotonergic activation was examined in dose response studies using the selective serotonin antagonist ritansarin and the nonselective antagonist metergoline. Finally, the pharmacological specificity of the prolactin response was examined by pretreating animals with [Nphe1] NC (1-13)NH2, a drug reported to antagonize OFQ/N effects. The results of these studies indicate that the increase in prolactin release following central administration of OFQ/N does not inhibit tuberoinfundibular, tuberohypophyseal or periventricular hypophysial dopaminergic neuronal activity at 10 min after drug administration, a time when prolactin levels were significantly elevated. Furthermore, serotonergic activation is not involved since pharmacological blockade of serotonergic receptors did not alter the prolactin secretory response to OFQ/N. NC (1-13)NH2 did not antagonize the stimulatory effects of OFQ/N on prolactin secretion. The neural effects of OFQ/N on dopaminergic neuronal activity may occur following a different time course than that of the prolactin increase. PMID:15996688

Kraska, Amy; Bryant, Winnifred; Murphree, Emily; Callahan, Phyllis; Janik, James



Neurotransmitter Transporters  

E-print Network

Neurotransmitter Transporters Dwight E Bergles,Johns Hopkins University, Baltimore, Maryland, USA of these chemical signals are terminated through active uptake by transporters that are located in the plasma membrane of neurons and glial cells. Transporters harness electrochemical gradients to force the movement

Bergles, Dwight


Polymorphisms in genes implicated in dopamine, serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis  

PubMed Central

Background Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major monoamine metabolites in the central nervous system (CNS). Their cerebrospinal fluid (CSF) concentrations, reflecting the monoamine turnover rates in CNS, are partially under genetic influence and have been associated with schizophrenia. We have hypothesized that CSF monoamine metabolite concentrations represent intermediate steps between single nucleotide polymorphisms (SNPs) in genes implicated in monoaminergic pathways and psychosis. Methods We have searched for association between 119 SNPs in genes implicated in monoaminergic pathways [tryptophan hydroxylase 1 (TPH1), TPH2, tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), dopamine beta-hydroxylase (DBH), catechol-O-methyltransferase (COMT), monoamine oxidase A (MAOA) and MAOB] and monoamine metabolite concentrations in CSF in 74 patients with psychotic disorder. Results There were 42 nominally significant associations between SNPs and CSF monoamine metabolite concentrations, which exceeded the expected number (20) of nominal associations given the total number of tests performed. The strongest association (p =?0.0004) was found between MAOB rs5905512, a SNP previously reported to be associated with schizophrenia in men, and MHPG concentrations in men with psychotic disorder. Further analyses in 111 healthy individuals revealed that 41 of the 42 nominal associations were restricted to patients with psychosis and were absent in healthy controls. Conclusions The present study suggests that altered monoamine turnover rates in CNS reflect intermediate steps in the associations between SNPs and psychosis. PMID:25073638



Synthesis of 8-thiabicyclo[3.2.1]octanes and Their Binding Affinity for the Dopamine and Serotonin Transporters  

PubMed Central

Cocaine is a potent stimulant of the central nervous system. Its reinforcing and stimulant properties have been associated with inhibition of the dopamine transporter (DAT) on presynaptic neurons. In the search for medications for cocaine abuse, we have prepared 2-carbomethoxy-3-aryl-8-thiabicyclo[3.2.1]octane analogues of cocaine. We report that this class of compounds provides potent and selective inhibitors of the DAT and SERT. The selectivity resulted from reduced activity at the SERT. The 3?-(3,4-dichlorophenyl) analogue inhibits the DAT and SERT with a potency of IC50 = 5.7 nM and 8.0 nM respectively. The 3-(3,4-dichlorophenyl)-2,3-unsaturated analogue inhibits the DAT potently (IC50 = 4.5 nM) and selectively (>800-fold vs. SERT). Biological enantioselectivity of DAT inhibition was limited for both the 3-aryl-2,3-unsaturated and the 3?-aryl analogues (2-fold), but more robust (> 10-fold) for the 3?-aryl analogues. The (1R)-configuration provided the eutomers. PMID:17070057

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



Positron Emission Tomographic Studies of Brain Dopamine and Serotonin Transporters in Abstinent (±) 3,4-Methylenedioxymethamphetamine (“Ecstasy”) Users: Relationship to Cognitive Performance  

PubMed Central

Rationale (±)3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) is a recreational drug and brain serotonin (5-HT) neurotoxin. Under certain conditions, MDMA damages brain dopamine (DA) neurons, at least in rodents. Human MDMA users have been found to have reduced brain 5-HT transporter (SERT) density and cognitive deficits, although it is not known whether these are related. We sought to determine whether MDMA users who take closely spaced sequential doses develop DA transporter (DAT) deficits, in addition to SERT deficits, and whether there is a relationship between transporter binding and cognitive performance. Methods Sixteen abstinent MDMA users with a history of sequential MDMA use (two or more doses over a 3-12 hour period) and sixteen age and gender- matched controls participated. Subjects underwent positron emission tomography with the DAT and SERT radioligands, [11C]WIN 35,428 and [11C]DASB, respectively. Subjects also underwent formal neuropsychiatric testing. Results MDMA users had reduced SERT binding in multiple brain regions but no reductions in striatal DAT binding. Memory performance in the aggregate subject population was correlated with SERT binding in the dorsolateral prefrontal cortex, orbitofrontal cortex and parietal cortex, brain regions implicated in memory function. Prior exposure to MDMA significantly diminished the strength of this relationship. Conclusions Sequential MDMA use is associated with lasting decreases in brain SERT, but not DAT. Memory performance is associated with SERT binding in brain regions involved in memory function. Prior MDMA exposure appears to disrupt this relationship. These data are the first to directly relate memory performance to brain SERT density. PMID:18661256

McCann, Una D.; Szabo, Zsolt; Vranesic, Melin; Palermo, Michael; Mathews, William B.; Ravert, Hayden T.; Dannals, Robert F.; Ricaurte, George A.



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.



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


The serotonin2C receptor (5-HT2CR) 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-HT2CRs 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-HT2CR 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-HT2CR 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-HT2CRs 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



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.



Dopamine function in Lesch-Nyhan disease.  

PubMed Central

Lesch-Nyhan disease is a disorder of purine metabolism resulting from mutations in the gene for hypoxanthine guanine phosphoribosyl transferase on the X chromosome. It is characterized by hyperuricemia and all of its consequences, as in gout; but in addition, patients have impressive disease of the central nervous system. This includes spasticity, involuntary movements, and retardation of motor development. The behavioral phenotype is best remembered by self-injurious biting behavior with attendant destruction of tissue. The connection between aberrant metabolism of purines and these neurologic and behavioral features of the disease is not clear. Increasing evidence points to imbalance of neurotransmitters. There is increased excretion of the serotonin metabolite 5-hydroxyindoleacetic acid in the urine. There are decreased quantities and activities of a number of dopaminergic functions. Positron emission tomography scanning has indicated deficiency in the dopamine transporter. PMID:10852837

Nyhan, W L



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



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


Cholinesterase inhibitors including donepezil, rivastigmine, and galantamine and the N-methyl-D-aspartate (NMDA) antagonist, memantine are the medications currently approved for the treatment of Alzheimer's disease (AD). In addition to their beneficial effects on cognitive and functional domains typically disrupted in AD, these agents have also been shown to slow down the emergence of behavioral and psychotic symptoms associated with this disease. However, the underlying mechanisms for these therapeutic effects remain poorly understood and could involve effects of these medications on non-cholinergic or non-glutamatergic neurotransmitter systems respectively. These considerations prompted us to initiate a series of investigations to examine the acute and chronic effects of donepezil (Aricept (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-1 hydrochloride and memantine (1-amino-3,5-dimethyladamantane hydrochloride C12H21N.HCl)). The present study focuses on the acute effects of donepezil and memantine on brain extracellular levels of acetylcholine, dopamine, serotonin, norepinephrine and their metabolites. We assayed changes in the ventral and dorsal hippocampus and the prefrontal and medial temporal cortex by microdialysis. Memantine resulted in significant increases in extracellular dopamine (DA), norepinephrine (NE), and their metabolites, in the cortical regions, and in a reduction of DA in the hippocampus. Donepezil produced an increase in extracellular DA in the cortex and in the dorsal hippocampus. Norepinephrine increased in the cortex; with donepezil it increased in the dorsal hippocampus and the medial temporal cortex, and decreased in the ventral hippocampus. Interestingly both compounds decreased extracellular serotonin (5HT) levels. The metabolites of the neurotransmitters were increased in most areas. We also found an increase in extracellular acetylcholine (ACh) by memantine in the nucleus accumbens and the ventral tegmental area. Our results suggest both region and drug specific neurotransmitter effects of these agents as well as some similarities. We conclude that drugs influencing cognitive mechanisms induce changes in a number of neurotransmitters with the changes being both region and drug specific. Release and metabolism are altered and extracellular neurotransmitter levels can be increased or decreased by the drugs. Other studies are in progress to determine the pharmacological effects associated with chronic treatment with these compounds, which may be more pertinent to the clinical situation in which patients take these medications for months or years. PMID:16533671

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



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



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


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



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.



[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



Molecular determinants of ligand interaction with serotonin transporters  

Microsoft Academic Search

The serotonin transporter (SERT) is a protein responsible for limiting the spatial and temporal actions of the neurotransmitter serotonin (5-HT) by regulating the concentration of 5-HT in the synapse through a reuptake mechanism. SERT is a target for a variety of drugs, including tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and the abused drugs cocaine and amphetamine. The two aims

David Lance Roman



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.



Serotonin and endocrine rhythms.  


The biological rhythms belong partly to the genetic patrimony and partly to the environmental patterns. The main results have been obtained on the hormonal fluctuations which are mostly controlled by the hypothalamopituitary system. Thus they include modulations of neurotransmitters activity especially serotonin. Experimental facts have been gathered in different species for ACTH, growth hormone, prolactin TSH and gonadotropins rhythms. These phenomenona are integrated in a general organization which includes sleep-waking cycle. PMID:6258661

Mornex, R; Jordan, D



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.


Surface enhanced Raman spectroscopy of neurotransmitters  

NASA Astrophysics Data System (ADS)

The surface-enhanced Raman spectra (SERS) of neurotransmitters in biological matrices and synthetic solutions are described. The effects of protein adsorption on cathecholamine SERS intensity are discussed. Techniques for obtaining dopamine SERS spectra in cerebrospinal fluid and rat brain dialysate are demonstrated. Preliminary SERS of histamine and tel-methylhistamine are presented.

McGlashen, Michael L.; Davis, Kevin L.; Morris, Michael D.



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



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

PubMed Central

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

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



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


Data drawn from the in-home subsample of the PROSPER intervention dissemination trial were used to investigate the moderation of intervention effects on underage alcohol use by maternal involvement and candidate genes. The primary gene examined was dopamine receptor D4 (DRD4). Variation in this gene and maternal involvement were hypothesized to moderate the influence of intervention status on alcohol use. The PROSPER data used were drawn from 28 communities randomly assigned to intervention or comparison conditions. Participating youth were assessed in five in-home interviews from sixth to ninth grades. A main effect of sixth-grade pretest maternal involvement on ninth-grade alcohol use was found. Neither intervention status nor DRD4 variation was unconditionally linked to ninth-grade drinking. However, moderation analyses revealed a significant three-way interaction among DRD4 status, maternal involvement, and intervention condition. Follow-up analyses revealed that prevention reduced drinking risk, but only for youth with at least one DRD4 seven-repeat allele who reported average or greater pretest levels of maternal involvement. To determine if this conditional pattern was limited to the DRD4 gene, we repeated analyses using the serotonin transporter linked polymorphic region site near the serotonin transporter gene. The results for this supplemental analysis revealed a significant three-way interaction similar but not identical to that found for DRD4. PMID:25640830

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



Transcranial electrostimulation effects on rat opioid and neurotransmitter levels.  


A specific form of Transcranial Electrostimulation Treatment (TCET) has been shown to induce analgesia, alleviate symptoms of opiate withdrawal and alter nociceptive responses in neurons in the midbrain and hypothalamus of rats. TCET consists of a 10Hz, charge balanced, 10 mu A current passed for 30 minutes between electrodes placed in the ears. Both serotonin (5HT) and endogenous opioids have been strongly implicated in TCET responses. This study directly measured brain levels of several neurotransmitters and their metabolites in anesthetized rats stimulated with either 10 mu A TCET or 0 mu A (Sham). Neurotransmitters measured in selected homogenized brain areas by high performance liquid chromatography were 5HT and its metabolite, 5-hydroxyindolacetic acid (5HIAA); norepinephrine (NE) and its metabolite, 3-methoxy-4-hydroxyphenethyleneglycol (MHPG); and dopamine (DA). Levels of NE and DA were significantly higher in the hypothalamic region of TCET rats than of control rats. The midbrains of TCET rats contained significantly elevated levels of DA, MHPG, 5HT and 5HIAA. In the hindbrain no significant differences were observed. Thus, TCET appears to cause an increase in the synthesis or release of 5HT, DA and NE in the midbrain and DA and 5HT in the hypothalamus. In a separate experiment, beta-endorphin-like immunoreactivity was measured in blood plasma taken from rats at intervals before, during and after a 30 minute TCET treatment, but no demonstrable TCET effect was observed. The lack of change in serum endorphin levels suggests that TCET-induced opioid activity may be confined to the central nervous system, a reasonable theory because the current passes only through the head. PMID:7906003

Warner, R L; Johnston, C; Hamilton, R; Skolnick, M H; Wilson, O B



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


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



Acute exposure to zinc oxide nanoparticles does not affect the cognitive capacity and neurotransmitters levels in adult rats.  


With the industrialization and increasing public exposure, nano-sized materials have received much more concerns. However, the impact of zinc oxide nanoparticles (ZnO-NPs) on the human body, especially on the central nervous system is extremely limited. The aim of this study is to investigate the effects of ZnO-NPs on the behavioral performances and the brain contents of some monoamines neurotransmitters. Male Wistar rats were treated with a single intravenous injection of a suspension of ZnO-NPs (25?mg/kg body weight). Subsequently, 14 days after nanoparticles injection, the rats were sacrificed. During that period, Morris water maze and open-field tests were performed, respectively, for the spatial working memory and the analysis of locomotor activity of the rats. The data showed that plasma and brain zinc concentrations increased after administration of ZnO-NPs. However, brain content of neurotransmitters such as norepinephrine, epinephrine, dopamine and serotonin remained unchanged in ZnO-NPs-treated rats compared with control group. The results showed also that the working memory, locomotor activity and exploratory behavior were not impaired in ZnO-NPs exposed groups. These data revealed that acute intravenous injection of ZnO-NPs does not affect neurotransmitter contents, locomotor activity and spatial working memory in adult rats. Thus, the effect of nanoparticles on the behavioral performances is still a new topic that requires more attention. PMID:24524369

Amara, Salem; Ben-Slama, Imen; Mrad, Imen; Rihane, Naima; Jeljeli, Mustapha; El-Mir, Lassaad; Ben-Rhouma, Khemais; Rachidi, Walid; Sève, Michel; Abdelmelek, Hafedh; Sakly, Mohsen



Electrophoretic separation of neurotransmitters on a polystyrene nano-sphere?polystyrene sulphonate coated poly(dimethylsiloxane) microchannel.  


In this paper, a poly(dimethylsiloxane) microchip with amperometric detector was developed for the electrophoretic separation and determination of neurotransmitters. For increasing the separation efficiency, the microchannel is modified by polystyrene sulphonate?polystyrene nano-sphere self-assembly coating. A stable electro-osmotic flow (EOF) and higher separation efficiency are obtained in proposed modified microchannel. Under optimized conditions, dopamine, epinephrine, catechol, and serotonin are acceptably baseline separated in this 3.5 cm length separation channel with the theoretical plate number from 4.6?×?10(4) to 2.1?×?10(5) per meter and resolution from 1.29 to 12.5. The practicability of proposed microchip is validated by the recovery test with cerebrospinal fluid as real sample which resulted from 91.7% to 106.5%. PMID:21918677

Zhao, Jinjin; Zhang, Qianli; Yang, Huijuan; Tu, Yifeng



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

PubMed Central

Food reinforcement, or the motivation to eat, has been associated with increased energy intake, greater body weight and prospective weight gain. Much of the previous research on the reinforcing value of food has focused on the role of dopamine, but it may be worthwhile to examine genetic polymorphisms in the serotonin and opioid systems as these neurotransmitters have been shown to be related to reinforcement processes and to influence energy intake. We examined the relationship among 44 candidate genetic polymorphisms in the dopamine, serotonin and opioid systems, and food reinforcement and body mass index (BMI) in a sample of 245 individuals. Polymorphisms in the Monoamine oxidase A (MAOA-LPR) and serotonin receptor 2A genes (rs6314) moderated the effect of food reinforcement on BMI, accounting for an additional 5-10% variance and revealed a potential role of the single nucleotide polymorphism, rs6314 in the serotonin 2A receptor as a differential susceptibility factor for obesity. Differential susceptibility describes a factor that can confer either risk or protection depending on a second variable, such that rs6314 is predictive of both high and low BMI based on the level of food reinforcement, while the diathesis stress or dual-gain model influences only one end of the outcome measure. The interaction with MAOA-LPR better fit the dual-risk or diathesis stress model, with the 3.5R/4R allele conferring protection for individuals low in food reinforcement. These results provide new insight into genes theoretically involved in obesity and support the hypothesis that genetics moderate the association between food reinforcement on BMI. PMID:23544600

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



Quantitative determination of neurotransmitters, metabolites and derivates in microdialysates by UHPLC-tandem mass spectrometry.  


The main objective of the present work is to study the time-course of rat brain neurotransmitters in vivo after an oral challenge with a nutritional ingredient or an external stimulus, such as a chemical agent. An ultrahigh performance liquid chromatography-tandem mass spectrometry method for the identification and quantification of neurotransmitters, metabolites and derivates in microdialysates from rat brain was previously developed. Betaine, glutamine, glutamic acid, gamma-aminobutyric acid, phosphocholine, glycerophosphocholine, cytidine 5'-diphosphocholine, choline, acetylcholine, dopamine, norepinephrine, serotonin, tyrosine, epinephrine, tryptophan and 5-hydroxyindoleacetic acid were selected as analytes. The method involves direct injection of samples of microdialysates from rat brain onto the chromatographic equipment and quantification with a triple quadrupole mass spectrometer detector using an electrospray ionization interface in positive mode. The limits of detection ranged from 0.1 to 50 ng mL(-1) and the limits of quantification from 0.3 to 200 ng mL(-1). The inter- and intra-day variability were lower than 15%. Recovery rates ranged from 85% to 115%. PMID:23953445

Santos-Fandila, A; Zafra-Gómez, A; Barranco, A; Navalón, A; Rueda, R; Ramírez, M



CSF neurotransmitter metabolites and short-term outcome of patients in coma after head injury.  


The main metabolites of the neurotransmitters noradrenaline, dopamine, and serotonin, methoxy-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA) respectively, were estimated by HPLC with electrochemical detection in CSF samples from 24 patients in coma after head injury, 1 to 12 (mean 3.0) days from accident, and from 24 age- and sex-matched subjects undergoing myelography for possible herniated disk. Analysis of variance with age as covariate, revealed significantly elevated levels of all three metabolites in the patients group. The concentrations of 5HIAA were negatively correlated to the score in the Glasgow Coma Scale. Fourteen patients who recovered with no or minor neurological deficits, had significantly lower CSF 5HIAA levels compared to the ten patients who had a bad outcome (death), while there were no differences regarding HVA or MHPG concentrations. The possibility of a connection of the high neurotransmitter turnover during coma to the development of post-traumatic depression is discussed. PMID:1384260

Markianos, M; Seretis, A; Kotsou, S; Baltas, I; Sacharogiannis, H



Post-mortem changes of neurotransmitter concentrations in the rat brain regions.  


Using High Performance Liquid Chromatography coupled with electrochemical detection the post-mortem stability of noradrenaline (NA), dopamine (DA), serotonin (5-HT) and 5-hydroxy indole acetic acid (5-HIAA) were examined in the rat hypothalamus, amygdala, cerebral cortex, cerebellum and corpus striatum over an 8 hour time period. Changes in concentrations of the different neurotransmitters were less than it might be expected. The significant changes were: a. A fall in NA levels in the cerebral cortex by 4 hours and in the hypothalamus at 8 hours. b. A reduction in DA concentrations in the corpus striatum at 8 hours but a two fold rise of levels in the hypothalamus at 1 and 2 hours. c. A four-fold increase in 5-HT concentrations in the amygdala throughout the 8 hours studied. The results indicate that for comparative studies on post-mortem brain tissue correction factors should be employed to take into account differential changes in the concentrations of the various neurotransmitters. PMID:1975469

Siddiqui, A; Clark, J S; Gilmore, D P



Serotonin and stress coping.  


Coping is the necessary outcome of any stressful situation and the major determinant of stress resilience. Coping strategies can be divided into two broad categories, based on the presence (active) or absence (passive) of attempts to act upon the stressor. The role of brain serotonin (5-hydroxytryptamine, 5-HT) in coping behavior that is emerging from studies in animals and humans is the subject of this article. We have focused attention on studies that consider the coping behavior exhibited when the individual is faced with a new stressful experience. Coping styles characterize different species with different evolutionary histories, from fishes to mammals, and evidence shows that serotonin transmission in the central nervous system, with differences in transporter, receptor types and hormone or neurotransmitter influences is critical in determining coping behavior. Moreover, a major role of environmental challenges throughout the lifespan affects brain systems that control coping outcomes through 5-HT transmission. In particular early experiences, for their long-term effects in adulthood, and social experiences throughout the life span, for the effects on serotonin functioning, received attention in preclinical research because of their parallelism in humans and animals. Based on growing evidence pointing to a medial prefrontal cortex-amygdala system in mediating adaptive and maladaptive stress responses, we propose a brain circuit in which serotonin neurons in the dorsal raphe depending on the CRF (corticotropin releasing factor) regulatory action engage a prefrontal cortical-amygdala pathway through 5-HT1A receptors, GABA and Glutamate to moderate coping behavior. PMID:25108244

Puglisi-Allegra, Stefano; Andolina, Diego



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



Long-term effects of a high-dose methamphetamine regimen on subsequent methamphetamine-induced dopamine release in vivo.  


Rats were treated with a high-dose methamphetamine (METH) regimen (40 mg/kg/injection, four times at 2-h intervals) or a saline regimen (four injections at 2-h intervals). Temperature related measures taken during the high-dose METH treatment were maximum core temperature and minimum chamber temperature. Fourteen rats (METH N=7; Saline N=7) were implanted with in-vivo dialysis probes 4-7 weeks post-regimen (average=6 weeks). The next day, they received a challenge dose of METH (4.0 mg/kg) and dopamine release was measured. Results showed a significant decrease in challenge-induced dopamine release in rats previously treated with the high-dose METH regimen. These findings demonstrate a functional deficit in the dopamine system 6 weeks after high-dose METH treatment. Temperature-related measures taken during the high-dose regimen were not correlated with METH-induced dopamine release 6 weeks later. An additional group of rats were sacrificed 6 weeks after the high-dose regimen (METH N=12; Saline N=10), and their brains was analyzed for dopamine and serotonin concentrations. Tissue concentrations of dopamine were significantly depleted in striatum and nucleus accumbens/olfactory tubercle, but not septum, hypothalamus, or ventral mid-brain 6 weeks after the high-dose regimen. Tissue concentrations of serotonin were also significantly depleted in striatum, nucleus accumbens/olfactory tubercle, hippocampus, somatosensory cortex, but not septum, hypothalamus or ventral mid-brain. Significant correlations between the temperature-related measures and post-mortem neurotransmitter tissue concentrations were region and transmitter dependent. PMID:11172757

Sabol, K E; Roach, J T; Broom, S L; Ferreira, C; Preau, M M



Expression of neurotransmitter transport from rat brain mRNA in Xenopus laevis oocytes.  

PubMed Central

To permit a molecular characterization of neurotransmitter transporter proteins, we have studied uptake activities induced in Xenopus laevis oocytes after injection of adult rat forebrain, cerebellum, brainstem, and spinal cord poly(A)+ RNA. L-Glutamate uptake could be observed as early as 24 hr after injection, was linearly related to the quantity of mRNA injected, and could be induced after injection of as little as 1 ng of cerebellar mRNA. Transport of radiolabeled L-glutamate, gamma-aminobutyric acid, glycine, dopamine, serotonin, and choline could be measured in single microinjected oocytes with a regional profile consistent with the anatomical distribution of particular neurotransmitter synthesizing soma. Forebrain L-glutamate and dopamine uptake, as well as cerebellar L-glutamate transport, were found to be Na+-dependent. Cerebellar mRNA-induced L-glutamate transport was both time and temperature-dependent, was saturable by substrate, suggesting a single activity with an apparent transport Km of 14.2 microM and a Vmax of 15.2 pmol/hr per oocyte, and was sensitive to inhibitors of brain L-glutamate transport. Thus, the oocyte L-glutamate transport induced by injection of adult rat cerebellar mRNA appears essentially identical to the high-affinity, Na+-dependent L-glutamate uptake found in brain slices and nerve terminals. Experiments with size-fractionated cerebellar mRNA reveal single, comigrating peaks for cerebellar L-glutamate and gamma-aminobutyric acid transport, with peak activity obtained in fractions of approximately 2.7 kilobases, suggesting the presence of single or similarly sized mRNAs encoding each of these activities. Images PMID:2904681

Blakely, R D; Robinson, M B; Amara, S G



Drosophila 5HT_2 Serotonin Receptor: Coexpression with Fushi-Tarazu During Segmentation  

Microsoft Academic Search

Serotonin, first described as a neurotransmitter in invertebrates, has been investigated mostly for its functions in the mature central nervous system of higher vertebrates. Serotonin receptor diversity has been described in the mammalian brain and in insects. We report the isolation of a cDNA coding for a Drosophila melanogaster serotonin receptor that displays a sequence, a gene organization, and pharmacological

Jean-Francois Colas; Jean-Marie Launay; Odile Kellermann; Philippe Rosay; Luc Maroteaux



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


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



Membrane Organization and Function of the Serotonin 1A Receptor  

Microsoft Academic Search

(1) The serotonin1A receptor is a G-protein coupled receptor involved in several cognitive, behavioral, and developmental functions. It binds\\u000a the neurotransmitter serotonin and signals across the membrane through its interactions with heterotrimeric G-proteins. (2)\\u000a Lipid–protein interactions in membranes play an important role in the assembly, stability, and function of membrane proteins.\\u000a The role of membrane environment in serotonin1A receptor function

Shanti Kalipatnapu; Amitabha Chattopadhyay



Too much dopamine can be bad for you: 1I. Latent inhibition and schizophrenia  

E-print Network

· treatment: antipsychotics (D2 blockers; also called neuroleptics) + psychotherapy & vocational and social rehabilitation (also: atypical antipsychotics, which affect serotonin more than dopamine) 7 Outline

Niv, Yael


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


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



Social stress and the polymorphic region of the serotonin reuptake transporter gene modify estradiol-induced changes on central monoamine concentrations in female rhesus monkeys  

PubMed Central

Psychosocial stress exposure is linked to a disruption of emotional regulation that can manifest as anxiety and depression. Women are more likely to suffer from such psychopathologies than men, indicating that gender-based differences in gonadal steroids may be a key factor in the etiology of stress-induced adverse health outcomes. Estradiol (E2) positively influences mood and cognition in females, an effect likely related to E2’s ability to modulate the serotonin and dopamine neurotransmitter systems. Furthermore, genetic variation due to the polymorphism in the promoter region of the gene (SLC6A4) encoding the serotonin transporter (5HTTLPR) also can influence E2’s ability to modulate behavior and physiology. However, it remains uncertain whether exposure to social stress interacts with the 5HTTLPR to influence E2-induced changes in behavior and physiology. The present study used ovariectomized adult female rhesus monkeys to investigate acute and chronic effects of E2 on central monoamine metabolite concentrations using CSF sampling. We further assessed how E2-induced changes in monoamine metabolite levels are modified by the unpredictable stress of social subordination and the 5HTTLPR polymorphism. Levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA) decreased significantly during chronic E2 treatment only in dominant females with the long promoter length of SLC6A4. Chronic administration of E2 decreased levels of the dopamine metabolite dihydrophenylacetic acid (DOPAC) in a manner independent of the social status, 5HTTLPR genotype, or their interactions. Overall levels of dopamine and serotonin metabolites were increased in subordinate females but this effect of social stress was not influenced by 5HTTLPR genotype. Together, these data emphasize how E2 can modulate central neurotransmitter systems and indicate that social subordination in female monkeys is a valid model for examining how chronic psychosocial stress alters sensitivity to E2. Future studies are necessary to elaborate how changes in central neurotransmitter metabolism due to E2 and prolonged exposure to stress affect behavior and physiology. PMID:23253112

Asher, Jennifer; Michopoulos, Vasiliki; Reding, Katherine M; Wilson, Mark E; Toufexis, Donna



Neurotransmitter changes in the pathophysiology of Lesch–Nyhan syndrome  

Microsoft Academic Search

The neurological symptoms of Lesch–Nyhan syndrome (LNS) are assumed to result from the neurotransmitter changes in this disorder. Among them, the dopaminergic system is believed to play a role in the self-injurious behavior through receptor supersensitivity. However, the precise mechanism underlying the dopamine supersensitivity remains unclear. An increased serotonergic action in the striatum may be crucial for the appearance of

Yoshiaki Saito; Sachio Takashima



Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner  

Microsoft Academic Search

The serotonin type 3 (5-HT3) receptor is the only ligand-gated ion channel receptor for serotonin (5-HT). 5-HT3 receptors play an important role in modulating the inhibitory action of dopamine in mesocorticolimbic brain regions. Neuroleptic drugs are commonly thought to exert their psychopharmacological action mainly through dopamine and serotonin type 2 (5-HT2) receptors. Except for clozapine, a direct pharmacological interaction of

G Rammes; B Eisensamer; U Ferrari; M Shapa; G Gimpl; K Gilling; C Parsons; K Riering; G Hapfelmeier; B Bondy; W Zieglgänsberger; F Holsboer; R Rupprecht



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


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 27d: one control, one ethanol control, and two low environmental concentrations of endosulfan (0.1 and 1?gL(-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




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


Neural Modelling of Cognitive Disinhibition and Neurotransmitter Dysfunction in OCD  

Microsoft Academic Search

In this paper an Elman recurrent neural network model of obsessive-compulsive disorder (OCD) is developed to provide a simulation of the relationship between the cognitive disinhibition and serotonin\\/dopamine dysfunction that characterize this disorder. Cognitive disinhibition in OCD is apparent when OCD patients are compared with other anxiety disorder patients on a Temporal Stroop test, with OCD patients showing reduced negative

Jacques Ludik; Dan J. Stein



Neurotransmitters - Duration: 0:20.  

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...


Central serotonin4 receptors selectively regulate the impulse-dependent exocytosis of dopamine in the rat striatum: in vivo studies with morphine, amphetamine and cocaine.  


In vivo microdialysis and single-cell extracellular recordings were used to assess the involvement of serotonin(4) (5-HT(4)) receptors in the effects induced by morphine, amphetamine and cocaine on nigrostriatal and mesoaccumbal dopaminergic (DA) pathway activity. The increase in striatal DA release induced by morphine (2.5 mg/kg, s.c.) was significantly reduced by the selective 5-HT(4) antagonists GR 125487 (0.1 and 1 mg/kg, i.p.) or SB 204070 (1 mg/kg, i.p.), and potentiated by the 5-HT(4) agonist prucalopride (5 mg/kg, i.p.). Neither of these compounds affected morphine-stimulated DA release in the nucleus accumbens. In both regions, amphetamine (2 mg/kg, i.p.) and cocaine (15 mg/kg, i.p.) induced DA release was affected neither by GR 125487 nor by prucalopride. None of the 5-HT agents used modified basal DA release in either brain region. Finally, GR 125487 (445 microg/kg, i.v.), whilst not affecting basal firing of DA neurons within either the substantia nigra pars compacta nor the ventral tegmental area, significantly reduced morphine (0.1-10 mg/kg, i.v.) stimulated firing of nigrostriatal DA neurons only. These results confirm that 5-HT(4) receptors exert a state-dependent facilitatory control restricted to the nigrostriatal DA pathway, and indicate that 5-HT(4) receptors selectively modulate DA exocytosis associated with increased DA neuron firing rate. PMID:12504916

Porras, Grégory; Di Matteo, Vincenzo; De Deurwaerdère, Philippe; Esposito, Ennio; Spampinato, Umberto



Transport of biogenic amine neurotransmitters at the mouse blood–retina and blood–brain barriers by uptake1 and uptake2  

PubMed Central

Uptake1 and uptake2 transporters are involved in the extracellular clearance of biogenic amine neurotransmitters at synaptic clefts. We looked for them at the blood–brain barrier (BBB) and blood–retina barriers (BRB), where they could be involved in regulating the neurotransmitter concentration and modulate/terminate receptor-mediated effects within the neurovascular unit (NVU). Uptake2 (Oct1-3/Slc22a1-3, Pmat/Slc29a4) and Mate1/Slc47a1 transporters are also involved in the transport of xenobiotics. We used in situ carotid perfusion of prototypic substrates like [3H]-1-methyl-4-phenylpyridinium ([3H]-MPP+), [3H]-histamine, [3H]-serotonin, and [3H]-dopamine, changes in ionic composition and genetic deletion of Oct1-3 carriers to detect uptake1 and uptake2 at the BBB and BRB. We showed that uptake1 and uptake2 are involved in the transport of [3H]-dopamine and [3H]-MPP+ at the blood luminal BRB, but not at the BBB. These functional studies, together with quantitative RT-PCR and confocal imaging, suggest that the mouse BBB lacks uptake1 (Net/Slc6a2, Dat/Slc6a3, Sert/Slc6a4), uptake2, and Mate1 on both the luminal and abluminal sides. However, we found evidence for functional Net and Oct1 transporters at the luminal BRB. These heterogeneous transport properties of the brain and retina NVUs suggest that the BBB helps protect the brain against biogenic amine neurotransmitters in the plasma while the BRB has more of a metabolic/endocrine role. PMID:22850405

André, Pascal; Saubaméa, Bruno; Cochois-Guégan, Véronique; Marie-Claire, Cynthia; Cattelotte, Julie; Smirnova, Maria; Schinkel, Alfred H; Scherrmann, Jean-Michel; Cisternino, Salvatore



Neurotransmitters and microglial-mediated neuroinflammation.  


Reciprocal interactions between cells caused by release of soluble factors are essential for brain function. So far, little attention has been paid to interactions between neurons and glia. However, in the last few decades, studies regarding such interactions have given us some important clues about possible mechanisms underlying degenerative processes in neurological diseases such as Alzheimer's disease and Parkinson's disease. Activated microglia and markers of inflammatory reactions have been consistently found in the post-mortem brains of diseased patients. But it has not been clearly understood how microglia respond to neurotransmitters released from neurons during disease progression. The main purpose of this review is to summarize studies performed on neurotransmitter receptor expression in microglia, and the effects of their activation on microglial-mediated neuroinflammation. A possible mechanism underlying transmitter-mediated modulation of microglial response is also suggested. Microglia express receptors for neurotransmitters such as ATP, adenosine, glutamate, GABA, acetylcholine, dopamine and adrenaline. Activation of GABA, cholinergic and adrenergic receptors suppresses microglial responses, whereas activation of ATP or adenosine receptors activates them. This latter effect may be due primarily to activation of a Ca(2+)-signaling pathway which, in turn, results in activation of MAP kinases and NFkB proteins with the release of proinflammatory factors. However, glutamate and dopamine are both pro- and anti-inflammatory depending on the receptor subtypes expressed in microglia. More detailed studies on downstream receptor-signaling cascades are needed to understand the roles of neurotransmitters in controlling neuron-microglia interactions during inflammatory processes in disease progression. Such knowledge may suggest new methods of treatment. PMID:23441898

Lee, Moonhee



Serotonin-Labeled CdSe Nanocrystals: Applications for Neuroscience  

NASA Astrophysics Data System (ADS)

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

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



Neurochemical, pharmacokinetic, and behavioral effects of the novel selective serotonin reuptake inhibitor BMS-505130  

Microsoft Academic Search

BMS-505130 is a potent and selective serotonin transport inhibitor; Ki for binding to the serotonin transporter=0.18 nM (Ki values for binding to the norepinephrine and dopamine transporters=4.6 and 2.1 ?M, respectively). In platelet serotonin uptake studies BMS-505130 (5 mg\\/kg, p.o.) produced a robust inhibition of serotonin uptake. In microdialysis studies oral dosing with BMS-505130 produced a dose-dependent increase in cortical

Matthew T. Taber; Robert N. Wright; Thaddeus F. Molski; Wendy J. Clarke; Patrick J. Brassil; Derek J. Denhart; Ronald J. Mattson; Nicholas J. Lodge



Chromosome 11: gene for dopamine receptors, Matt RidleySite: DNA Interactive (  

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.




PubMed Central

Background Moderate prenatal alcohol exposure can contribute to neurodevelopmental impairments and disrupt several neurotransmitter systems. We examined the timing of moderate level alcohol exposure, serotonin transporter gene polymorphic region variation (rh5-HTTLPR), and levels of primary serotonin and dopamine metabolites in cerebrospinal fluid (CSF) in rhesus monkeys. Methods Thirty-two 30-month old rhesus monkeys (Macaca mulatta) from four groups of females were assessed: (1) early alcohol-exposed group (n = 9), in which mothers voluntarily consumed 0.6 g/kg/day alcohol solution on gestational days 0 – 50; (2) middle-to-late gestation alcohol-exposed group (n = 6), mothers consumed 0.6 g/kg/day alcohol solution on gestational days 50 – 135; (3) a continuous-exposure group (n = 8), mothers consumed 0.6 g/kg/day alcohol solution on gestational days 0 – 135; and (4) controls (n = 9), mothers consumed an isocaloric control solution on gestational days 0 – 50, 50 – 135, or 0 – 135. Serotonin transporter promoter region allelic variants (homozygous s/s or heterozygous s/l versus homozygous l/l) were determined. We examined CSF concentrations of the 5-HT and DA metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), respectively, at baseline and 50 hours after separation from cage-mates, when the monkeys were 30 months old. Results Early- and middle-to-late gestation-alcohol exposed monkeys carrying the short allele had lower concentrations of 5-HIAA in CSF relative to other groups. Concentrations of 5-HIAA in CSF were lower for s allele carriers and increased from baseline relative to pre-separation values, while 5-HIAA levels in l/l allele carriers were not affected by separation. Monkeys carrying the short allele had lower basal concentrations of HVA in CSF compared to monkeys homozygous for the long allele. Conclusion Carrying the s allele of the 5-HT transporter increased the probability of reduced 5-HIAA in early- and middle-to-late gestation alcohol-exposed monkeys and reduced HVA at baseline. These findings that prenatal alcohol exposure altered central 5-HT activity in genetically sensitive monkeys raise questions about whether abnormal serotonin biological pathways could underlie some of the psychiatric disorders reported in fetal alcohol spectrum disorder (FASD). PMID:21294753

Schneider, Mary L.; Moore, Colleen F.; Barr, Christina S.; Larson, Julie A.; Kraemer, Gary W.



Body Mass Index in Multiple Sclerosis: Associations with CSF Neurotransmitter Metabolite Levels  

PubMed Central

Body weight and height of patients with relapsing-remitting multiple sclerosis (RRMS) or clinically isolated syndrome suggesting MS (CIS) in the age range 18 to 60 years (154 males and 315 females) were compared with those of subjects (146 males and 212 females) free of any major neurological disease. In drug-free patients, CSF levels of the metabolites of noradrenaline (MHPG), serotonin (5-HIAA), and dopamine (HVA), neurotransmitters involved in eating behavior, were estimated in searching for associations with body mass index (BMI). Statistical evaluations were done separately for males and females. Lower BMI was found in female MS patients compared to female controls, more pronounced in RRMS. BMI was not associated with duration of illness, smoking, present or previous drug treatment, or disability score. Body height showed a shift towards greater values in MS patients compared to controls. Patients in the lower BMI quartile (limits defined from control subjects) had lower 5-HIAA and HVA compared to patients in the upper quartile. The results provide evidence for weight reduction during disease process in MS, possibly related to deficits in serotoninergic and dopaminergic activities that develop during disease course, resulting in impairments in food reward capacity and in motivation to eat. PMID:24205443

Evangelopoulos, Maria-Eleftheria; Davaki, Panagiota; Sfagos, Constantinos



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

PubMed Central

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

Martínez-Torres, Ataúlfo; Miledi, Ricardo



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.



Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism.  


Salvinorin A (SalA), a selective ?-opioid receptor (KOR) agonist, produces dysphoria and pro-depressant like effects. These actions have been attributed to inhibition of striatal dopamine release. The dopamine transporter (DAT) regulates dopamine transmission via uptake of released neurotransmitter. KORs are apposed to DAT in dopamine nerve terminals suggesting an additional target by which SalA modulates dopamine transmission. SalA produced a concentration-dependent, nor-binaltorphimine (BNI)- and pertussis toxin-sensitive increase of ASP(+) accumulation in EM4 cells coexpressing myc-KOR and YFP-DAT, using live cell imaging and the fluorescent monoamine transporter substrate, trans 4-(4-(dimethylamino)-styryl)-N-methylpyridinium) (ASP(+)). Other KOR agonists also increased DAT activity that was abolished by BNI pretreatment. While SalA increased DAT activity, SalA treatment decreased serotonin transporter (SERT) activity and had no effect on norepinephrine transporter (NET) activity. In striatum, SalA increased the Vmax for DAT mediated DA transport and DAT surface expression. SalA up-regulation of DAT function is mediated by KOR activation and the KOR-linked extracellular signal regulated kinase-½ (ERK1/2) pathway. Co-immunoprecipitation and BRET studies revealed that DAT and KOR exist in a complex. In live cells, DAT and KOR exhibited robust FRET signals under basal conditions. SalA exposure caused a rapid and significant increase of the FRET signal. This suggests that the formation of KOR and DAT complexes is promoted in response to KOR activation. Together, these data suggest that enhanced DA transport and decreased DA release resulting in decreased dopamine signalling may contribute to the dysphoric and pro-depressant like effects of SalA and other KOR agonists. PMID:25107591

Kivell, Bronwyn; Uzelac, Zeljko; Sundaramurthy, Santhanalakshmi; Rajamanickam, Jeyaganesh; Ewald, Amy; Chefer, Vladimir; Jaligam, Vanaja; Bolan, Elizabeth; Simonson, Bridget; Annamalai, Balasubramaniam; Mannangatti, Padmanabhan; Prisinzano, Thomas E; Gomes, Ivone; Devi, Lakshmi A; Jayanthi, Lankupalle D; Sitte, Harald H; Ramamoorthy, Sammanda; Shippenberg, Toni S



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.



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



Serotonin in antipsychotic drugs action.  


Antipsychotic drugs are the treatment of choice in schizophrenia. Since the discovery of chlorpromazine, several generations of antipsychotic drugs have been developed with disparate mechanism of action and complex binding profile. Although the modifications of their mechanisms have translated into decreased side effects, their superior therapeutic efficacy is often debated. Furthermore, the lack of clear criteria to define antipsychotic drugs as typical or atypical is delaying the development of new compounds with innovative mechanisms of actions. There is general agreement that we are abusing dopaminergic based criteria to evaluate the newly available compounds although they are targeting several other neurotransmitter systems. The present work will overview the antipsychotic drugs effects on serotonin levels as measured with microdialysis in the rat brain. A functional association among therapeutic mechanisms of antipsychotic drugs, their serotonin receptors affinities and serotonin level changes will be attempted. The primary ambition of this investigation is to provide an exhaustive reference for who is interested, at any levels, in antipsychotic drugs effects on cortical and subcortical serotonin output. PMID:25078293

Amato, Davide



Analyzing a Discrete Model of Aplysia Central Pattern Generator  

E-print Network

neurons in the CPG. The individual neurons are inter- connected through excitatory and inhibitory synaptic specialized molecules, the neurotransmitters, such as glutamate, serotonin, and dopamine. A neurotransmitter

Tiwari, Ashish


Transsynaptic (GABA-dopamine) modulation of cocaine induced dopamine release: A potential therapeutic strategy for cocaine abuse  

Microsoft Academic Search

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

S. L. Dewey; R. Straughter-Moore; R. Chen



Analysis of drug effects on neurotransmitter release  

SciTech Connect

The release of neurotransmitter is routinely studied in a superfusion system in which serial samples are collected and the effects of drugs or other treatments on the amount of material in the superfusate is determined. With frequent sampling interval, this procedure provides a mechanism for dynamically characterizing the release process itself. Using automated data collection in conjunction with polyexponential computer analysis, the equation which describes the release process in each experiment is determined. Analysis of the data during the nontreated phase of the experiment allows an internal control to be used for accurately assessing any changes in neurotransmitter release which may occur during a subsequent treatment phase. The use of internal controls greatly improves the signal to noise ratio and allows determinations of very low concentrations of drugs on small amounts of tissue to be made. In this presentation, the effects of 10 nicotine on /sup 3/H-dopamine release in rat nucleus accumbens is described. The time course, potency and efficacy of the drug treatment is characterized using this system. Determinations of the exponential order of the release as well as the rate constants allow one to study the mechanism of the release process. A description of /sup 3/H-dopamine release in normal as well as Ca/sup + +/-free medium is presented.

Rowell, P.; Garner, A.



Role of serotonin in seasonal affective disorder.  


This review was prepared with an aim to show role of serotonin in seasonal affective disorder. Seasonal affective disorder, which is also called as winter depression or winter blues, is mood disorder in which persons with normal mental health throughout most of the year will show depressive symptoms in the winter or, less commonly, in the summer. Serotonin is an important endogenous neurotransmitter which also acts as neuromodulator. The least invasive, natural, and researched treatment of seasonal affective disorder is natural or otherwise is light therapy. Negative air ionization, which acts by liberating charged particles on the sleep environment, has also become effective in treatment of seasonal affective disorder.   PMID:23329523

Gupta, A; Sharma, P K; Garg, V K; Singh, A K; Mondal, S C



Development of a simple and rapid solid phase microextraction-gas chromatography-triple quadrupole mass spectrometry method for the analysis of dopamine, serotonin and norepinephrine in human urine.  


The work aims at developing a simple and rapid method for the quantification of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) in human urine. The urinary levels of these biogenic amines can be correlated with several pathological conditions concerning heart disease, stress, neurological disorders and cancerous tumors. The proposed analytical approach is based on the use of solid phase microextraction (SPME) combined with gas chromatography-triple quadrupole mass spectrometry (GC-QqQ-MS) after a fast derivatization of both aliphatic amino and phenolic moieties by propyl chloroformate. The variables influencing the derivatization reaction were reliably optimized by the multivariate approach of "Experimental design". The optimal conditions were obtained by performing derivatization with 100?L of propyl chloroformate and 100?L of pyridine. The extraction ability of five commercially available SPME fibers was evaluated in univariate mode and the best results were obtained using the polyacrylate fiber. The variables affecting the efficiency of SPME analysis were again optimized by the multivariate approach of "Experimental design" and, in particular, a central composite design (CCD) was applied. The optimal values were extraction in 45min at room temperature, desorption temperature at 300°C, no addition of NaCl. Assay of derivatized analytes was performed by using a gas chromatography-triple quadrupole mass spectrometry (GC-QqQ-MS) system in selected reaction monitoring (SRM) acquisition. An evaluation of all analytical parameters demonstrates that the developed method provides satisfactory results. Indeed, very good linearities were achieved in the tested calibration range with correlation coefficient values of 0.9995, 0.9999 and 0.9997 for DA, 5-HT and NE, respectively. Accuracies and RSDs calculated for between-run and tested at concentrations of 30, 200, and 800?g L(-1) were in the range from 92.8% to 103.0%, and from 0.67 to 4.5%, respectively. Finally, the LOD values obtained can be considered very good (0.587, 0.381 and 1.23?g L(-1) for DA, 5-HT and NE, respectively). PMID:24439500

Naccarato, Attilio; Gionfriddo, Emanuela; Sindona, Giovanni; Tagarelli, Antonio



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.



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



Serotonin syndrome  


... you must have been taking a drug that changes the body's serotonin levels (serotonergic drug) and have at least three of the following signs or symptoms: Agitation Diarrhea Heavy sweating not due to activity Fever Mental status changes such as confusion or ...


Quantitative analysis of immunolabeling for serotonin and for glutamate transporters after administration of imipramine and citalopram  

Microsoft Academic Search

Serotonin (5-hydroxytryptamine, 5-HT) is an amine neurotransmitter derived from tryptophan and is important in brain systems regulating mood, emotional behavior, and sleep. Selective serotonin reuptake inhibitor (SSRI) drugs are used to treat disorders such as depression, stress, eating disorders, autism, and schizophrenia. It is thought that these drugs act to prolong the action of 5-HT by blocking reuptake. This may

Susan M. Williams; Lesley J. Bryan-Lluka; David V. Pow



Turn up the heat: circulating serotonin tunes our internal heating system.  


Serotonin acts as neurotransmitter in the brain and as a multifaceted signaling molecule coordinating many physiological processes in the periphery. In a recent issue of Nature Medicine, Crane et al. (2014) find that peripheral serotonin controls thermogenesis in adipose tissue by modulating ?-adrenergic stimulation of UCP-1, thereby affecting glucose homeostasis and weight gain. PMID:25651169

Schneider, Jochen G; Nadeau, Joseph H



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


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



A Standardized Chinese Herbal Decoction, Kai-Xin-San, Restores Decreased Levels of Neurotransmitters and Neurotrophic Factors in the Brain of Chronic Stress-Induced Depressive Rats  

PubMed Central

Kai-xin-san (KXS), a Chinese herbal decoction being prescribed by Sun Simiao in Beiji Qianjin Yaofang about 1400 years ago, contains Ginseng Radix et Rhizoma, Polygalae Radix, Acori tatarinowii Rhizoma, and Poria. KXS has been used to treat stress-related psychiatric disease with the symptoms of depression and forgetfulness in ancient China until today. However, the mechanism of its antidepression action is still unknown. Here, the chronic mild-stress-(CMS-) induced depressive rats were applied in exploring the action mechanisms of KXS treatment. Daily intragastric administration of KXS for four weeks significantly alleviated the CMS-induced depressive symptoms displayed by enhanced sucrose consumption. In addition, the expressions of those molecular bio-markers relating to depression in rat brains were altered by the treatment of KXS. These KXS-regulated brain biomarkers included: (i) the levels of dopamine, norepinephrine, and serotonin (ii) the transcript levels of proteins relating to neurotransmitter metabolism; (iii) the transcript levels of neurotrophic factors and their receptors. The results suggested that the anti-depressant-like action of KXS might be mediated by an increase of neurotransmitters and expression of neurotrophic factors and its corresponding receptors in the brain. Thus, KXS could serve as alternative medicine, or health food supplement, for patients suffering from depression. PMID:22973399

Zhu, Kevin Yue; Mao, Qing-Qiu; Ip, Siu-Po; Choi, Roy Chi-Yan; Dong, Tina Ting-Xia; Lau, David Tai-Wai; Tsim, Karl Wah-Keung



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



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




Beta-amyloid peptides undergo regulated co-secretion with neuropeptide and catecholamine neurotransmitters  

PubMed Central

Beta-amyloid (A?) peptides are secreted from neurons, resulting in extracellular accumulation of A? and neurodegeneration of Alzheimer's disease. Because neuronal secretion is fundamental for the release of neurotransmitters, this study assessed the hypothesis that A? undergoes co-release with neurotransmitters. Model neuronal-like chromaffin cells were investigated, and results illustrate regulated, co-secretion of A?(1–40) and A?(1–42) with peptide neurotransmitters (galanin, enkephalin, and NPY) and catecholamine neurotransmitters (dopamine, norepinephrine, and epinephrine). Regulated secretion from chromaffin cells was stimulated by KCl depolarization and nicotine. Forskolin, stimulating cAMP, also induced co-secretion of A? peptides with peptide and catecholamine neurotransmitters. These data suggested the co-localization of A? with neurotransmitters in dense core secretory vesicles (DCSV) that store and secrete such chemical messengers. Indeed, A? was demonstrated to be present in DCSV with neuropeptide and catecholamine transmitters. Furthermore, the DCSV organelle contains APP and its processing proteases, ?- and ?-secretases, that are necessary for production of A?. Thus, A? can be generated in neurotransmitter-containing DCSV. Human IMR32 neuroblastoma cells also displayed regulated secretion of A?(1–40) and A?(1–42) with the galanin neurotransmitter. These findings illustrate that A? peptides are present in neurotransmitter-containing DCSV, and undergo co-secretion with neuropeptide and catecholamine neurotransmitters that regulate brain functions. PMID:23747840

Toneff, Thomas; Funkelstein, Lydiane; Mosier, Charles; Abagyan, Armen; Ziegler, Michael; Hook, Vivian



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



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.



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...


Modulation of CYP1A2 enzyme activity by indoleamines: inhibition by serotonin and tryptamine.  


Recent evidence supports a role for the CYP2D6 enzyme in the metabolism of tryptamine. Because of the partial overlapping between substrate and inhibitor specificities that characterize some cytochrome P450 enzymes, these finding raise the possibility that other cytochrome P450 enzymes may be modulated by endogenous compounds. In the present study, the occurrence of modulatory effect of 17 neurotransmitters, precursors and metabolites on the cytochrome P450 1A2 (CYP1A2) enzyme activity was studied in human liver microsomes. Two indoleamines, serotonin and tryptamine, showed a competitive inhibitory effect on the high-affinity component of the phenacetin O-de-ethylase activity. Both substances induced an inhibition of 100% of the activity, with Ki values of 35 and 45 microns for serotonin and tryptamine, respectively. The inhibitors did not affect the microsomal NADPH-reductase activity. Other substances, which were either poor or partial inhibitors, were dopamine, L-tyrosine, tryptophol, 5-hydroxytryptophol, adrenaline, indole-3-acetaldehyde, 5-hydroxytryptophan, noradrenaline, vanillylmandelic acid, indole-3-acetic acid, dihydroxyphenylacetic acid, and homovanillic acid. L-tryptophan, dihydroxyphenylalanine and 5-hyroxyindole acetic acid induced very low or no inhibitory effect. Tryptamine and serotonin metabolism in human liver microsomes was studied after inhibition of monoamine oxidase activity with the unspecific MAO inhibitor pargyline. Both serotonin and tryptamine were metabolized in human liver microsomes. However, the metabolism of both indoleamines was not significantly inhibited with the CYP1A2-specific inhibitor furafylline, thus indicating that the inhibition of CYP1A2 was not related to metabolic activity of the CYP1A2 enzyme on serotonin or tryptamine. The CYP1A2 enzyme is expressed in brain and is involved in the metabolism of psychoactive drugs. Therefore, the fact that endogenous compounds could modulate the CYP1A2 activity suggests that local activity of brain CYP1A2 might be susceptible to local regulatory mechanisms. This may have important clinical implications, one of them being that CYP1A2 activity in brain tissue might correlate poorly with that of liver, as observed in vivo. In addition, the influence of indoleamines on CYP1A2 activity might be partly responsible for a number of associations of CYP1A2 activity with nutritional and environmental factors. PMID:9682270

Agúndez, J A; Gallardo, L; Martínez, C; Gervasini, G; Benítez, J



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


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



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.



Cognitive effects of genetic variation in monoamine neurotransmitter systems: A population-based study of COMT, MAOA, and 5HTTLPR  

PubMed Central

Individual differences in cognitive function are highly heritable and most likely driven by multiple genes of small effect. Well-characterized common functional polymorphisms in the genes MAOA, COMT, and 5HTTLPR each have predictable effects on the availability of the monoamine neurotransmitters dopamine, noradrenaline, and serotonin. We hypothesized that 5HTTLPR genotype would show little association with prefrontal cognitive performance, but that COMT and MAOA would have interacting effects on cognition through their shared influence on prefrontal catecholamine availability. We assessed the individual and epistatic effects of functional polymorphisms in COMT, MAOA, and 5HTTLPR on children's prefrontal cognitive function in nearly 6,000 children from the population-based Avon Longitudinal Study of Parents and Children (ALSPAC). Neither MAOA nor 5HTTLPR polymorphisms showed significant effects on cognitive function. In boys but not girls, there was a modest but statistically significant interaction between MAOA and COMT genotypes such that increased prefrontal catecholamine availability was associated with better working memory. These results suggest that assessment of multiple genes within functionally related systems may improve our understanding of the genetic basis of cognition. © 2010 Wiley-Liss, Inc. PMID:21302344

Barnett, Jennifer H; Xu, Ke; Heron, Jon; Goldman, David; Jones, Peter B



Determination of monoamine and amino acid neurotransmitters and their metabolites in rat brain samples by UFLC-MS/MS for the study of the sedative-hypnotic effects observed during treatment with S. chinensis.  


Schisandra chinensis (Turcz.) Baill. has been used as a sedative and hypnotic agent in traditional Chinese medicine for centuries. The purpose of this study was to reveal the influence of insomnia on the levels of the neurotransmitters: glutamate (Glu), ?-aminobutyric acid (GABA), noradrenaline (NE), dopamine (DA), serotonin (5-HT) and their metabolites (5-HIAA, DOPAC and HVA), and to study the role of S. chinensis in the treatment of insomnia. To achieve this goal, an efficient, sensitive and selective method was developed and validated for the simultaneous determination of these five neurotransmitters and their metabolites in rat brain samples using ultra fast liquid chromatography/tandem mass spectrometry (UFLC-MS/MS). The analysis was performed on a Synergi Fusion-RP 80A ODS column (150mm×2.0mm, 4.0?m) using gradient elution, with the mobile phase consisting of acetonitrile and 0.05% formic acid in water. The method was validated using rat brain homogenate samples and showed a good linearity over a wide concentration range (r(2)>0.99) with a lower limit of quantification (LLOQ) at 4-16ngmL(-1). The intra and inter-day assay variability was less than 15% for all analytes. The results indicated that the condition of insomnia elevated GABA, NE, DA, DOPAC and HVA, and reduced 5-HT, 5-HIAA levels in rat brain. The oral administration of S. chinensis (7.5gkg(-1)day(-1), eight days) influenced insomnia by significantly increasing or reducing the levels of the neurotransmitters parameters mentioned above. These results suggested that S. chinensis could alter the levels of these brain neurotransmitters and their metabolites through its sedative-hypnotic effects. PMID:24176746

Wei, Binbin; Li, Qing; Fan, Ronghua; Su, Dan; Chen, Xiaohui; Jia, Ying; Bi, Kaishun



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



Serotonin controlling feeding and satiety.  


Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked to serotonin has stimulated interest in and research into the role of this neurotransmitter in satiety. Various rodent models, including transgenic models, have been developed to identify the involved 5-HT receptor subtypes. This approach also required the availability of receptor ligands of different selectivity, and behavioural techniques had to be developed simultaneously which allow differentiating between unspecific pharmacological effects of these ligands and 'true' satiation and satiety. Currently, 5-HT1B, 5-HT2C and 5-HT6 receptors have been identified to mediate serotonergic satiety in different ways. The recently approved anti-obesity drug lorcaserin is a 5-HT2C receptor agonist. In brain, both hypothalamic (arcuate nucleus, paraventricular nucleus) and extrahypothalamic sites (parabrachial nucleus, nucleus of the solitary tract) have been identified to mediate the serotonergic control of satiety. Serotonin interacts within the hypothalamus with endogenous orexigenic (Neuropeptide Y/Agouti related protein) and anorectic (?-melanocyte stimulating hormone) peptides. In the nucleus of the solitary tract serotonin integrates peripheral satiety signals. Here, the 5-HT3, but possibly also the 5-HT2C receptor play a role. It has been found that 5-HT acts in concert with such peripheral signals as cholecystokinin and leptin. Despite the recent advances of our knowledge, many of the complex interactions between 5-HT and other satiety factors are not fully understood yet. Further progress in research will also advance the development of new serotonergic anti-obesity drugs. PMID:25217810

Voigt, Jörg-Peter; Fink, Heidrun



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

PubMed Central

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

Özel, R?fat Emrah; Wallace, Kenneth N.; Andreescu, Silvana



Snapshot of antidepressants at work: the structure of neurotransmitter transporter proteins.  


In the sweet spot: Cocrystal structures of engineered neurotransmitter transporters reveal the binding mode of commonly prescribed antidepressants, providing a basis for a rational drug design for this class of proteins. The picture shows the structure of the dopamine transporter of Drosophila melanogaster in complex with the antidepressant nortriptyline. PMID:24729171

Cuboni, Serena; Hausch, Felix



Dopamine and Norepinephrine Transporter Inhibition in Cocaine Addiction: Using Mice Expressing Cocaine-Insensitive Transporters.  

E-print Network

??Cocaine’s effects are predominately mediated by inhibiting the reuptake transporters for dopamine, serotonin, and norepinephrine. How each of these transporters contributes to cocaine’s effects is… (more)

Martin, Bradley J.



Circulating serotonin in vertebrates.  


The role of circulating serotonin is unclear and whether or not serotonin is present in the blood of non-mammalian species is not known. This study provides the first evidence for the presence of serotonin in thrombocytes of birds and three reptilian species, the endothermic leatherback sea turtle, the green sea turtle and the partially endothermic American alligator. Thrombocytes from a fresh water turtle, American bullfrog, Yellowfin tuna, and Chinook salmon did not contain serotonin. Serotonin is a vasoactive substance that regulates skin blood flow, a major mechanism for endothermic body temperature regulation, which could explain why circulating serotonin is present in warm-blooded species. The temperature sensitivity of human blood platelets with concomitant changes in serotonin content further supports a link between circulating serotonin and thermoregulation. Phylogenetic comparison of the presence of circulating serotonin indicated an evolutionary divergence within reptilian species that might coincide with the emergence of endothermy. PMID:16041566

Maurer-Spurej, E



Relationship of CSF neurotransmitter metabolite levels to disease severity and disability in multiple sclerosis.  


Axonal degeneration and brain tissue loss occur during disease progression in multiple sclerosis (MS) and are expected to influence neurotransmitter activities, with consequences on neurologic and psychiatric symptomatology. We searched for relationships of disease duration, disability, and severity of MS patients to CSF levels of the major metabolites of noradrenaline, dopamine, and serotonin, MHPG, methoxyhydroxyphenylglycol (MHPG), homovanillic acid, and 5-hydroxyindoleacetic acid (5-HIAA), respectively, in 39 patients with relapsing-remitting (RR) MS in remission, and 26 patients with progressive (PR) MS. Disability and Disease Severity were assessed by the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Severity Score (MSSS). Compared with the levels of 50 control subjects, MHPG levels were not different in either MS group, correlated negatively to duration of illness and number of relapses in the RRMS group, but not to EDSS score or to MSSS. Homovanillic acid levels were significantly lower only in the PRMS group, with a negative correlation to duration of illness, and a strong negative correlation to EDSS score, but not to MSSS. 5-HIAA was significantly lower in both RRMS and PRMS groups. In the RRMS group, 5-HIAA levels were negatively related to EDSS and to MSSS. Multiple regression analyses revealed a significant association of MHPG to duration of illness, and a strong negative association of 5-HIAA to MSSS rather than to EDSS. The strong negative correlation of MSSS to CSF 5-HIAA levels in RRMS group of patients indicates that deficits in central serotonergic activity are related to the rate of disability accumulation in RRMS, and could be linked to the reported reduction of disease activity by serotonergic drugs. PMID:19014375

Markianos, Manolis; Koutsis, Georgios; Evangelopoulos, Maria-Eleftheria; Mandellos, Dimitrios; Karahalios, Georgios; Sfagos, Constantin



Dopamine Transporter Blockade Increases LTP in the CA1 Region of the Rat Hippocampus via Activation of the D3 Dopamine Receptor  

ERIC Educational Resources Information Center

Dopamine has been demonstrated to be involved in the modulation of long-term potentiation (LTP) in the CA1 region of the hippocampus. As monoamine transporter blockade will increase the actions of endogenous monoamine neurotransmitters, the effect of a dopamine transporter (DAT) antagonist on LTP was assessed using field excitatory postsynaptic…

Swant, Jarod; Wagner, John J.



Development and validation of an ultra-high performance liquid chromatography-tandem mass-spectrometry (UHPLC-MS/MS) method for the simultaneous determination of neurotransmitters in rat brain samples.  


A simple method for the simultaneous determination of glutamate, ?-aminobutyric acid (GABA), choline, acetylcholine, dopamine, 5-hydroxyindole-3-acetic (5-HIAA), serotonin, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) was developed by using ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). These compounds are analysed in a single chromatographic run in less than 8 min, adding heptafluorobutyric acid (HFBA) in the mobile phase to improve the separation of the selected neurotransmitters. The analytes were detected using electrospray ionization (ESI)-MS/MS in positive mode with multiple reaction monitoring (MRM). Good linearity was obtained (R² > 0.98) and the intra and inter-day precision of the method (expressed as relative standard deviation) were lower than 26%. Limits of quantification were lower than 2.440 ?g/g of brain in all the cases, allowing the sensitive determination of these compounds in rat brain extracts. Therefore, the method was successfully applied for the quantitative determination of neurotransmitters in several rat brain regions (prefrontal cortex, striatum, nucleus accumbens and amygdala), detecting glutamate, GABA and choline at concentrations higher than 1000 ?g/g, 30 ?g/g and 100 ?g/g respectively, whereas the other compounds were found at lower concentrations. PMID:21459108

González, Roberto Romero; Fernández, Remedios Fernández; Vidal, José Luis Martínez; Frenich, Antonia Garrido; Pérez, María Luz Gómez



Life without brain serotonin: Reevaluation of serotonin function with mice deficient in brain serotonin synthesis.  


Tryptophan hydroxylase (TPH) is a rate limiting enzyme in the synthesis of serotonin (5-HT), a monoamine which works as an autacoid in the periphery and as a neurotransmitter in the central nervous system. In 2003 we have discovered the existence of a second Tph gene, which is expressed exclusively in the brain, and, therefore, is responsible for the 5-HT synthesis in the central nervous system. In the following years several research groups have independently generated Tph2-deficient mice. In this review we will summarize the data gained from the existing mouse models with constitutive or conditional deletion of the Tph2 gene, focusing on biochemical, developmental, and behavioral consequences of Tph2-deficiency. PMID:24928769

Mosienko, Valentina; Beis, Daniel; Pasqualetti, Massimo; Waider, Jonas; Matthes, Susann; Qadri, Fatimunnisa; Bader, Michael; Alenina, Natalia



Variable Dopamine Release Probability and Short-Term Plasticity between Functional Domains of the Primate Striatum  

Microsoft Academic Search

Release of the neuromodulator dopamine (DA) is critical to the control of locomotion, motivation, and reward. However, the probability of DA release is not well understood. Current understanding of neurotransmitter release probability in the CNS is limited to the conven- tional synaptic amino acid transmitters (e.g., glutamate and GABA). These fast neurotransmitters are released with a repertoire of probabilities according

Stephanie J. Cragg



Serotonin is critical for rewarded olfactory short-term memory in Drosophila.  


The biogenic amines dopamine, octopamine, and serotonin are critical in establishing normal memories. A common view for the amines in insect memory performance has emerged in which dopamine and octopamine are largely responsible for aversive and appetitive memories. Examination of the function of serotonin begins to challenge the notion of one amine type per memory because altering serotonin function also reduces aversive olfactory memory and place memory levels. Could the function of serotonin be restricted to the aversive domain, suggesting a more specific dopamine/serotonin system interaction? The function of the serotonergic system in appetitive olfactory memory was examined. By targeting the tetanus toxin light chain (TNT) and the human inwardly rectifying potassium channel (Kir2.1) to the serotonin neurons with two different GAL4 driver combinations, the serotonergic system was inhibited. Additional use of the GAL80(ts1) system to control expression of transgenes to the adult stage of the life cycle addressed a potential developmental role of serotonin in appetitive memory. Reduction in appetitive olfactory memory performance in flies with these transgenic manipulations, without altering control behaviors, showed that the serotonergic system is also required for normal appetitive memory. Thus, serotonin appears to have a more general role in Drosophila memory, and implies an interaction with both the dopaminergic and octopaminergic systems. PMID:22436011

Sitaraman, Divya; LaFerriere, Holly; Birman, Serge; Zars, Troy



Common drugs inhibit human organic cation transporter 1 (OCT1)-mediated neurotransmitter uptake.  


The human organic cation transporter 1 (OCT1) is a polyspecific transporter involved in the uptake of positively charged and neutral small molecules in the liver. To date, few endogenous compounds have been identified as OCT1 substrates; more importantly, the effect of drugs on endogenous substrate transport has not been examined. In this study, we established monoamine neurotransmitters as substrates for OCT1, specifically characterizing serotonin transport in human embryonic kidney 293 cells. Kinetic analysis yielded a Km of 197 micomolar and a Vmax of 561 pmol/mg protein/minute for serotonin. Furthermore, we demonstrated that serotonin uptake was inhibited by diphenhydramine, fluoxetine, imatinib, and verapamil, with IC50 values in the low micromolar range. These results were recapitulated in primary human hepatocytes, suggesting that OCT1 plays a significant role in hepatic elimination of serotonin and that xenobiotics may alter the elimination of endogenous compounds as a result of interactions at the transporter level. PMID:24688079

Boxberger, Kelli H; Hagenbuch, Bruno; Lampe, Jed N



Dopamine Signaling Regulates Fat Content through ?-Oxidation in Caenorhabditis elegans  

PubMed Central

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

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



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

E-print Network

for the psychostimulant and reinforcing effects of drugs of abuse [1]. Dopamine (DA) increase in the NAcc plays a criticalRole of Serotonin via 5-HT2B Receptors in the Reinforcing Effects of MDMA in Mice Ste´phane Doly1, respectively, in regions of the brain that have been implicated in reward. However, the role of serotonin

Paris-Sud XI, Université de


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



A Conserved Salt Bridge between Transmembrane Segments 1 and 10 Constitutes an Extracellular Gate in the Dopamine Transporter.  


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



Automated mass spectrometric analysis of urinary and plasma serotonin.  


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



Research update on serotonin function in bulimia nervosa and anorexia nervosa.  


The extent to which dysregulation of serotonin function in the central nervous system may contribute to core symptoms in patients with bulimia nervosa and anorexia nervosa is currently an area of intensive psychobiological investigation. Preclinical and clinical studies have demonstrated the involvement of the neurotransmitter serotonin in the regulation of food intake, suggesting that impaired serotonin-mediated satiety signals could contribute to patterns of recurrent binge eating. Other symptom patterns in patients with eating disorders, including mood dysregulation, impulsivity, and obsessionality, as well as therapeutic response to serotonergic agents, suggest involvement of serotonergic pathways. With a primary focus on serotonin function, this article reviews clinical studies of neuroendocrine and behavioral response to pharmacological challenges, levels of neurotransmitter metabolite in cerebrospinal fluid, and platelet studies. Controlled clinical trials involving pharmacological treatment with serotonergic medications are summarized. Considerations for future research are discussed. PMID:9550877

Wolfe, B E; Metzger, E; Jimerson, D C



Mimicking subsecond neurotransmitter dynamics with femtosecond laser stimulated nanosystems  

PubMed Central

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. PMID:24954021

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.



Mimicking subsecond neurotransmitter dynamics with femtosecond laser stimulated nanosystems.  


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. PMID:24954021

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



Neurotransmitter signaling in white matter.  


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



Development and sensitivity to serotonin of Drosophila serotonergic varicosities in the central nervous system  

PubMed Central

Serotonin is a classical small-molecule neurotransmitter with known effects on developmental processes. Previous studies have shown a developmental role for serotonin in the fly peripheral nervous system. In this study, we show that serotonin can modulate the development of serotonergic varicosities within the fly central nervous system. We have developed a system to examine the development of serotonergic varicosities in the larval CNS. We use this method to describe the normal serotonergic development in the A7 abdominal ganglion. From first to third instar larvae, the volume of the neuropil and number of serotonergic varicosities increase substantially while the varicosity density remains relatively constant. We hypothesize that serotonin is an autoregulator for serotonergic varicosity density. We tested the sensitivity of serotonergic varicosities to serotonin by adding neurotransmitter at various stages to isolated larval ventral nerve cords. Addition of excess exogenous serotonin decreases native varicosity density in older larvae, and these acute effects are reversible. The effects of serotonin appear to be selective for serotonergic varicosities, as dopaminergic and corazonergic varicosities remain qualitatively intact following serotonin application. PMID:16122730

Sykes, Paul A.; Condron, Barry G.



Thyroid hormones as neurotransmitters.  


During brain development, before the apparatus of neurotransmission has been set into place, many neurotransmitters act as growth regulators. In adult brain, their role in neurotransmission comes to the fore but neuronal plasticity and other growth-related processes are their continuing responsibility. This has been clearly demonstrated for catecholamines. Previous as well as recent evidence now indicates that thyroid hormones may participate in the developing and adult brain through similar mechanisms. Immunohistochemical mapping of brain triiodothyronine (antibody specificity established by numerous appropriate tests) demonstrated that the hormone was concentrated in both noradrenergic centers and noradrenergic projection sites. In the centers (locus coeruleus and lateral tegmental system) triiodothyronine staining, like that of tyrosine hydroxylase, was heavily concentrated in cytosol and cell processes. By contrast, in noradrenergic targets, label was most prominent in cell nuclei. Combined biochemical and morphologic data allows a construct of thyroid hormone circuitry to unfold: The locus coeruleus is conveniently located just beneath the ependyma of the 4th ventricle. Thyroxine, entering the brain via the choroid plexus, is preferentially delivered to subependymal brain structures. High concentrations of locus coeruleus norepinephrine promote active conversion of thyroxine to triiodothyronine, leading to the preeminence of the locus coeruleus as a site of triiodothyronine concentration. Results of treatment with the locus coeruleus neurotoxin DSP-4 established that axonal transport accounts for delivery of both triiodothyronine and norepinephrine from locus coeruleus to noradrenergic terminal fields. The apparatus for transduction of thyronergic and noradrenergic signals at both membrane and nuclear sites resides in the postsynaptic target cells. Upon internalization of hormone in post-synaptic target cells, genomic effects of triiodothyronine, norepinephrine, and/or their second messengers are possible and expected. The evidence establishes a direct morphologic connection between central thyronergic and noradrenergic systems, supporting earlier proposals that triiodothyronine or its proximate metabolites may serve as cotransmitters with norepinephrine in the adrenergic nervous system. PMID:9001201

Dratman, M B; Gordon, J T



Autoradiographic Evaluation of Electomagnetic Field Effects on Serotonin (5HT1A) Receptors in Rat Brain  

Microsoft Academic Search

Serotonin (5HT1A) is a chemical mediator of inflammation and the largest single neurotransmitter system of the brain. Its secretion and physiological actions mediate stress and pain, affecting both immune and nervous system functions through the hypothalamic-pituitary-adrenal axis. Serotonin receptor dysfunction is well-characterized in mental disturbances like depression and anxiety. Transcranial magnetic stimulation has been used therapeutically to treat refractory disorders

Mary T. Johnson; Jane McCullough; Gabi Nindl; Jack K. Chamberlain


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



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



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

PubMed Central

Part I describes important contributions made by some Japanese pioneers in the field of neurotransmitters: (their achievements in parentheses) J. Takamine (isolation and crystallization of adrenaline); K. Shimidzu (early hint for acetylcholine as a neurotransmitter); F. Kanematsu (donation of the Kanematsu Memorial Institute in Sydney); T. Hayashi (discovery of the excitatory action of glutamate and the inhibitory action of GABA); and I. Sano (discovery of a high concentration of dopamine in striatum, its reduction in a patient with Parkinson’s disease and the treatment with DOPA). In Part II, I present some of my reflections on my research on neurotransmitters. The work of my colleagues and myself has made some significant contributions to the establishment of neurotransmitter roles played by GABA and substance P, the first amino acid and the first peptide neurotransmitters, respectively. By the early 1960s, 3 substances, i.e., acetylcholine, noradrenaline, and adrenaline, had been established as neurotransmitters. Now the number of neurotransmitters is believed to be as many as 50 or even more mainly due to the inclusion of several amino acids and a large number of peptide transmitters. PMID:24019584

Otsuka, Masanori



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.



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


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



Rapid analysis of neurotransmitters in rat brain using ultra-fast liquid chromatography and tandem mass spectrometry: application to a comparative study in normal and insomnic rats.  


Neurotransmitters and their metabolites in central nervous system were known to play a significant role in sedation and hypnosis. A rapid and sensitive UFLC-MS/MS method for simultaneous determination of serotonin, 5-hydroxyindole acetic acid (5-HIAA), tryptophan (Try), dopamine (DA), norepinephrine (NE), ?-aminobutyric acid (GABA), glutamic acid (Glu) and acetylcholine (Ach) in rat brain without derivatization, ion-pairing reagent or pre-concentration was developed. Analytes and IS were separated on a Inertsil ODS-EP column (150?mm?×?4.6?mm, 5?µm particles) and analyzed in a single chromatographic run in less than 9.0?min, using gradient elution with the mobile phase consisting of methanol and 0.01% acetic acid in water at a flow rate of 1.2?ml?min(-1) . The detection of the analytes was performed on 4000Q UFLC-MS/MS system with turbo ion spray source in positive ion and multiple reaction monitoring mode. The developed method provided excellent linear calibration curves for the assay of analytes (R(2) ???0.9915). Limits of quantification were in the range of 1.0?ng?ml(-1) to 1.0?µg?ml(-1) for the analytes in rat brain. Intra- and inter-day precision and accuracy of analytes were well within acceptance criteria (15%). Mean extraction recoveries of analytes and IS from rat brain were all more than 80.0%. Furthermore, the validated method was successfully applied to comparing profiles of analytes in normal and insomnic rat brains. Results indicated that there were statistically significant differences for serotonin, 5-HIAA, DA, NE, Glu and Ach, but no significant difference for Try and GABA between two groups. PMID:23893645

He, Bosai; Bi, Kaishun; Jia, Ying; Wang, Jiahong; Lv, Chunxiao; Liu, Ran; Zhao, Longshan; Xu, Huarong; Chen, Xiaohui; Li, Qing



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

PubMed Central

Background Previous reports suggest that omega-3 (n-3) polyunsaturated fatty acids (PUFA) supplements may reduce ADHD-like behaviour. Our aim was to investigate potential effects of n-3 PUFA supplementation in an animal model of ADHD. Methods We used spontaneously hypertensive rats (SHR). SHR dams were given n-3 PUFA (EPA and DHA)-enriched feed (n-6/n-3 of 1:2.7) during pregnancy, with their offspring continuing on this diet until sacrificed. The SHR controls and Wistar Kyoto (WKY) control rats were given control-feed (n-6/n-3 of 7:1). During postnatal days (PND) 25–50, offspring were tested for reinforcement-dependent attention, impulsivity and hyperactivity as well as spontaneous locomotion. The animals were then sacrificed at PND 55–60 and their neostriata were analysed for monoamine and amino acid neurotransmitters with high performance liquid chromatography. Results n-3 PUFA supplementation significantly enhanced reinforcement-controlled attention and reduced lever-directed hyperactivity and impulsiveness in SHR males whereas the opposite or no effects were observed in females. Analysis of neostriata from the same animals showed significantly enhanced dopamine and serotonin turnover ratios in the male SHRs, whereas female SHRs showed no change, except for an intermediate increase in serotonin catabolism. In contrast, both male and female SHRs showed n-3 PUFA-induced reduction in non-reinforced spontaneous locomotion, and sex-independent changes in glycine levels and glutamate turnover. Conclusions Feeding n-3 PUFAs to the ADHD model rats induced sex-specific changes in reinforcement-motivated behaviour and a sex-independent change in non-reinforcement-associated behaviour, which correlated with changes in presynaptic striatal monoamine and amino acid signalling, respectively. Thus, dietary n-3 PUFAs may partly ameliorate ADHD-like behaviour by reinforcement-induced mechanisms in males and partly via reinforcement-insensitive mechanisms in both sexes. PMID:23228189



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


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



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



Dopamine Modulates Cholinergic Cortical Excitability in Alzheimer's Disease Patients  

Microsoft Academic Search

In Alzheimer's disease (AD) patients dysfunction of cholinergic neurons is considered a typical hallmark, leading to a rationale for the pharmacological treatment in use based on drugs that enhance acetylcholine neurotransmission. However, besides altered acetylcholine transmission, other neurotransmitter systems are involved in cognitive dysfunction leading to dementia. Among others, dopamine seems to be particularly involved in the regulation of cognitive

Alessandro Martorana; Francesco Mori; Zaira Esposito; Hajime Kusayanagi; Fabrizia Monteleone; Claudia Codecà; Giuseppe Sancesario; Giorgio Bernardi; Giacomo Koch




Microsoft Academic Search

A neural system within the cerebral and buccal ganglia of the terrestrial mollusc Limax maximus responds to lip chemostimulation by emitting a feeding motor program (FMP) in uiuo and in uitro. We have analyzed chemically the cerebral and buccal ganglia of Limax for neurotransmitters involved in controlling expression of FMP. Dopamine was found in clusters of cells and in the



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



Trafficking of Vesicular Neurotransmitter Transporters  

PubMed Central

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

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



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



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



Role of the serotonin transporter gene in temperament and character.  


The biosocial model postulates that personality is comprised of two broad domains: temperament, which is largely due to inherited variations in specific monoamine neurotransmitter systems; and character, which arises from socioculturally learned differences in values, goals, and self-concepts and is the strongest predictor of personality disorders. The model also proposes that serotonin modulates the temperament trait of harm avoidance. We analyzed the association of temperament and character traits with the 5-HTTLPR, an inherited variation that modulates serotonin transporter gene expression, in 634 volunteer subjects. Contrary to theory, the 5-HTTLPR was most strongly associated with the character traits of cooperativeness and self-directedness. Associations with the temperament traits of reward dependence and harm avoidance were weaker and could be attributable largely to cross-correlations with the character traits and demographic variables. Psychometric analysis indicated that the serotonin transporter influences two broad areas of personality, negative affect and social disaffiliation, that are consistent across inventories but are more concisely described by the 5-factor model of personality than by the biosocial model. These results suggest that there is no fundamental mechanistic distinction between character and temperament in regard to the serotonin transporter gene, and that a single neurotransmitter can influence multiple personality traits. PMID:10633313

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



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




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.



Dopamine Dysfunction in Borderline Personality Disorder: A Hypothesis  

Microsoft Academic Search

Research on the biological basis of borderline personality disorder (BPD) has focused primarily on the serotonin model of impulsive aggression. However, there is evidence that dopamine (DA) dysfunction may also be associated with BPD. Pertinent research and review articles, identified by Medline searches of relevant topics, books, references from bibliographies, and conference proceedings from 1975 to 2003, were reviewed. Evidence

Robert O Friedel



Near-infrared surface-enhanced Raman scattering (NIR-SERS) of neurotransmitters in colloidal silver solutions  

Microsoft Academic Search

NIR-SERS spectra are measured for the neurotransmitters dopamine and norepinephrine at concentrations as low as 5 × 10?9 M in colloidal silver solutions with accumulation times as short as 25 ms. The detection range and acquisition time are on the order of physiologically relevant concentrations and the time scale of neuronal processes, respectively. The spectra are obtained using a CCD

Katrin Kneipp; Yang Wang; Ramachandra R. Dasari; Michael S. Feld



Effect of neurotransmitters on NADPH-cytochrome P450 reductase in vitro activity.  


Three neurotransmitters, namely adrenaline, serotonin and tryptamine inhibit the in vitro activity of several cytochrome P450 (CYP) isozymes (CYP1A2, CYP2C9, CYP2D6 and CYP3A). In order to test whether this effect is related to inhibition of the CYP-coupled NADPH reductase activity, we assayed the potential inhibitory effect of these neurotransmitters and their main metabolites on the NADPH reductase activity. Of the five compounds analyzed: tryptamine, tryptophol, serotonin, 5-hydroxytryptamine and adrenaline, only adrenaline significantly decreased NADPH reductase activity at the fixed concentration of 500 microM. However, the effect became negligible when adrenaline concentration was decreased to 100 microM: whereas a high inhibitory effect was observed in CYP2D6, CYP2C9 and CYP3A4 enzyme activities, the NADPH reductase activity remains unchanged. This study indicates that the effect of these endogenous neurotransmitters on CYP enzymes is not related to changes in the reductase activity. In the light of these findings further studies on the inhibitory effect of these neurotransmitters on CYP enzymes can be designed ruling out the modulation of the coupled NADPH reductase activity as a confounding factor. PMID:19356039

Gervasini, Guillermo; Martinez, Carmen; Benitez, Julio; Agúndez, Jose A G



Boosting serotonin in the brain: is it time to revamp the treatment of depression?  

PubMed Central

Abnormalities in serotonin systems are presumably linked to various psychiatric disorders including schizophrenia and depression. Medications intended for these disorders aim to either block the reuptake or the degradation of this neurotransmitter. In an alternative approach, efforts have been made to enhance serotonin levels through dietary manipulation of precursor levels with modest clinical success. In the last 30 years, there has been little improvement in the pharmaceutical management of depression, and now is the time to revisit therapeutic strategies for the treatment of this disease. Tryptophan hydroxylase (TPH) catalyzes the first and rate-limiting step in the biosynthesis of serotonin. A recently discovered isoform, TPH2, is responsible for serotonin biosynthesis in the brain. Learning how to activate this enzyme (and its polymorphic versions) may lead to a new, more selective generation of antidepressants, able to regulate the levels of serotonin in the brain with fewer side effects. PMID:22158544

Torrente, Mariana P; Gelenberg, Alan J; Vrana, Kent E



Interaction of curcumin with manganese may compromise metal and neurotransmitter homeostasis in the hippocampus of young mice.  


Manganese (Mn) exposure is related to industrial activities, where absorption by inhalation has high relevance. Manganism, a syndrome caused as a result of excessive accumulation of Mn in the central nervous system, has numerous symptoms similar to those seen in idiopathic Parkinson disease (IPD). Some of these symptoms, such as learning, memory, sensorial, and neurochemical changes, appear before the onset of motor deficits in both manganism and IPD. The aim of this study was to evaluate the possible neuroprotective effects of curcumin against behavioral deficits induced by Mn toxicity in young (2 months old) Swiss mice. We evaluated the effect of chronic inhalation of a Mn mixture [Mn(OAc)3 and MnCl2 (20:40 mM)], 1 h/session, three times a week, over a 14-week period on behavioral and neurochemical parameters. Curcumin was supplemented in the diet (500 or 1,500 ppm in food pellets). The Mn disrupted the motor performance evaluated in the single-pellet reach task, as well as the short- and long-term spatial memory evaluated in the step-down inhibitory avoidance task. Surprisingly, curcumin also produced similar deleterious effects in such behavioral tests. Moreover, the association of Mn plus curcumin significantly increased the levels of Mn and iron, and decreased the levels of dopamine and serotonin in the hippocampus. These alterations were not observed in the striatum. In conclusion, the current Mn treatment protocol resulted in mild deficits in motor and memory functions, resembling the early phases of IPD. Additionally, curcumin showed no beneficial effects against Mn-induced disruption of hippocampal metal and neurotransmitter homeostasis. PMID:24723215

Schmitz, Ariana Ern; de Oliveira, Paulo Alexandre; de Souza, Luiz F; da Silva, Danilo Grünig Humberto; Danielski, Samara; Santos, Danúbia Bonfanti; de Almeida, Eduardo Alves; Prediger, Rui Daniel; Fisher, Andrew; Farina, Marcelo; Dafre, Alcir Luiz



Very low doses of delta 8-THC increase food consumption and alter neurotransmitter levels following weight loss.  


We have investigated the effect of 0.001 mg/kg delta(8)-tetrahydrocannabinol (THC) on food consumption, cognitive function, and neurotransmitters in mice. Sabra mice were treated with vehicle, THC, or THC+CB1 antagonist (SR141716A). The mice were fed for 2.5 h a day for 9 or 50 days. In the 9-day schedule, THC-treated mice showed a 16% increase in food intake compared with controls (P<.001). This effect was reversed by the antagonist (P<.01). In the long-term schedule a 22% increase in intake (P<.05) was recorded. During the course of the 9- and 50-day experimental protocol, all mice lost about 20% and 10% of their original weight, respectively, to reach approximately the same weights, which were not significantly different between the different treatment groups. In addition, THC caused an increase in activity (P<.05). Cognitive function showed a tendency to improve (P<.06) in the THC-treated mice, which was reversed by the antagonist for Days 4 and 5 of the maze (P<.01, and P<.05, respectively). Significant decreases in dopamine and serotonin (5-HT) levels were found both in the hypothalamus (P<.01) and the hippocampus (P<.01, P<.05), respectively, while norepinephrine (NE) levels showed tendency to increase in both the hypothalamus and hippocampus. Delta(8)-THC increased food intake significantly more (P<.05) than did delta(9)-THC, while performance and activity were similar. Thus, delta(8)-THC (0.001 mg/kg) caused increased food consumption and tendency to improve cognitive function, without cannabimimetic side effects. Hence, a low dose of THC might be a potential therapeutic agent in the treatment of weight disorders. PMID:15099912

Avraham, Yosefa; Ben-Shushan, Dikla; Breuer, Aviva; Zolotarev, Olga; Okon, Avital; Fink, Nir; Katz, Vered; Berry, Elliot M



Influence of serotonin on the immune response.  

PubMed Central

The present study investigates the influence of pharmacological agents known to regulate biosynthesis of the neurotransmitter, serotonin (5-hydroxytryptamine, 5-HT) on the primary antibody response to sheep red blood cells (SRBC) in the CBA mouse. Systemic administration of 5-HT (4-100 mg/kg) or its precursor, 5-hydroxytryptophan (5-HTP, 50-400 mg/kg), 30-60 min before immunization resulted in dose-dependent suppression of both the IgM and IgG plaque-forming cell (PFC) response to SRBC. Conversely, para-chlorophenylalanine (PCPA, 250 mg/kg), which inhibits the rate-limiting enzyme (tryptophan hydroxylase) in 5-HT biosynthesis, markedly enhanced IgM and IgG antibody production when injected 48 hr prior to antigen. Effects of these drugs on immune processes appeared independent of observed changes in plasma corticosterone levels. Further, immune function was preserved following selective depletion of brain serotonin through intracisternal injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) in mice pretreated with desmethylimipramine (DMI). Thus, immunomodulation by serotonin appears to be mediated via peripheral mechanism(s). PMID:3156091

Jackson, J C; Cross, R J; Walker, R F; Markesbery, W R; Brooks, W H; Roszman, T L



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...


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...


Prospects for serotonin 5HT 2R pharmacotherapy in psychostimulant abuse  

Microsoft Academic Search

The serotonin (5-HT) neurotransmitter system provides fundamental modulatory regulation of the limbic-corticostriatal circuitry known to be vital in the development of addiction as well as the aspects of addiction that hinder recovery and contribute to relapse. Thus, components of the 5-HT system may provide novel targets for the development of pharmacological treatments for psychostimulant dependence, which is associated with significant

Marcy J. Bubar; Kathryn A. Cunningham



A peripheral marker for schizophrenia: Increased levels of D3 dopamine receptor mRNA in blood lymphocytes  

Microsoft Academic Search

Dopamine is a major neurotransmitter in the central nervous system, and its receptors are associated with a number of neuropathological disorders such as Parkinson's disease and schizophrenia. Although the precise pathophysiology of schizophrenia remains unknown, the dopaminergic hypothesis of the illness assumes that the illness results from excessive activity at dopamine synapses in the brain. Because, at present, the diagnosis

Tal Ilani; Dorit Ben-Shachar; Rael D. Strous; Marina Mazor; Ala Sheinkman; Moshe Kotler; Sara Fuchs



The Serotonin Connection  

Microsoft Academic Search

Serotonin metabolism is disordered in a variety of clinical states. These include ad- dictions, attention deficit disorder, chronic pain, depression, dysthymia, eating disorders, headache, obsessive-compulsive disorders, panic, poor impulse control, post-traumatic stress disorders, premenstrual syndrome, sleep disorders, stress disorders, sudden cardiac death and violence. A decreased serotonin state has also been implicated in sleep disorders which may then progress into

Robert A. Nash


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.



Redox reactions of neurotransmitters possibly involved in the progression of Parkinson's Disease  

Microsoft Academic Search

In Parkinson’s Disease the neuromelanin in the substania nigra is known to contain considerably increased amounts of iron suggesting the presence of free, unprotected iron ions during its formation. Iron(II) is known to interact with peroxide via Fenton’s reaction producing OH-radicals or ferryl (Fe(IV)) species. This can readily oxidize the neurotransmitter dopamine to the neurotoxic 6-hydroxydopamine (6-OHDA) which is a

W. Linert; G. N. L. Jameson



Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling  

Microsoft Academic Search

Catecholamines are important regulators of homeostasis, yet their functions in hematopoiesis are poorly understood. Here we report that immature human CD34+ cells dynamically expressed dopamine and ?2-adrenergic receptors, with higher expression in the primitive CD34+CD38lo population. The myeloid cytokines G-CSF and GM-CSF upregulated neuronal receptor expression on immature CD34+ cells. Treatment with neurotransmitters increased the motility, proliferation and colony formation

Asaf Spiegel; Shoham Shivtiel; Alexander Kalinkovich; Aya Ludin; Neta Netzer; Polina Goichberg; Yaara Azaria; Igor Resnick; Izhar Hardan; Herzel Ben-Hur; Arnon Nagler; Menachem Rubinstein; Tsvee Lapidot



Effects of Drugs on Brain Neurotransmitter and Pituitary-Testicular Function in Male Rats  

Microsoft Academic Search

The effects of different drugs influencing brain neurotransmitter contents have been tested on the pituitary-testicular function in male rats. L-dopa (200 mg\\/kg body weight, i.p.) increased the dopamine and noradrenaline contents of the hypothalamus, amygdala, striatum and mesencephalon, but it was ineffective as regards the 5-hydroxytryptamine contents of the same brain areas, and increased the plasma testosterone level. ?-Methyl-p-tyrosine (250

I. Vermes; É. K. Tóth; G. Telegdy



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



Local modulation of striatal glutamate efflux by serotonin 1A receptor stimulation in dyskinetic, hemiparkinsonian rats  

Microsoft Academic Search

Serotonin 1A receptor (5-HT1AR) agonists reduce both l-DOPA- and D1 receptor (D1R) agonist-mediated dyskinesia, but their anti-dyskinetic mechanism of action is not fully understood. Given that 5-HT1AR stimulation reduces glutamatergic neurotransmission in the dopamine-depleted striatum, 5-HT1AR agonists may diminish dyskinesia in part through modulation of pro-dyskinetic striatal glutamate levels. To test this, rats with unilateral medial forebrain bundle dopamine or

Kristin B. Dupre; Corinne Y. Ostock; Karen L. Eskow Jaunarajs; Thomas Button; Lisa M. Savage; William Wolf; Christopher Bishop



Topic 4 -Neurotransmitters 1. Criteria and types  

E-print Network

) - Asparate - GABA (widespread) - Glycine excitatory inhibitory 1. Small-molecule neurotransmitters Biogenic1 Topic 4 - Neurotransmitters 1. Criteria and types 2. Synthesis, release and re-uptake 3. Drug interactions and poisons 4. Disorders Neurotransmitter vs. Neuromodulator?? Criteria for classification as a NT

Sergio, Lauren E.


The role of dopamine in motor flexibility.  


Humans carry out many daily tasks in a seemingly automatic fashion. However, when unexpected changes in the environment occur, we have the capacity to inhibit prepotent behavior and replace it with an alternative one. Such behavioral flexibility is a hallmark of executive functions. The neurotransmitter dopamine is known to be crucial for fast, efficient, and accurate cognitive flexibility. Despite the perceived similarities between cognitive and motor flexibility, less is known regarding the role of dopamine within the motor domain. Therefore, the aim of this study was to determine the role of dopamine in motor flexibility. In a double-blind, five-session, within-subject pharmacological experiment, human participants performed an RT task within a probabilistic context that was either predictable or unpredictable. The probabilistic nature of the predictable context resulted in prediction errors. This required participants to replace the prepotent or prepared action with an unprepared action (motor flexibility). The task was overlearned, and changes in context were explicitly instructed, thus controlling for contributions from other dopamine-related processes such as probabilistic or reversal learning and interactions with other types of uncertainty. We found that dopamine receptor blockade by high-dose haloperidol (D1/D2 dopamine receptors) impaired participants' ability to react to unexpected events occurring in a predictable context, which elicit large prediction errors and necessitate motor flexibility. This effect was not observed with selective D2 receptor blockade (sulpiride), with a general increase in tonic dopamine levels (levodopa), or during an unpredictable context, which evoked minimal prediction error. We propose that dopamine is vital in responding to low-level prediction errors about stimulus outcome that requires motor flexibility. PMID:25170792

Bestmann, Sven; Ruge, Diane; Rothwell, John; Galea, Joseph M



The Role of Serotonin in Antipsychotic Drug Action  

Microsoft Academic Search

Recent interest in the role of serotonin (5-HT) in antipsychotic drug action is based mainly upon the fact that antipsychotic drugs such as clozapine, olanzapine, quetiapine, risperidone, sertindole, and ziprasidone are potent 5-HT2a receptor antagonists and relatively weaker dopamine D2 antagonists. These agents share in common low extrapyramidal side effects at clinically effective doses and possibly greater efficacy to reduce

Herbert Y Meltzer



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



Dopamine Inhibits Mitochondrial Motility in Hippocampal Neurons  

PubMed Central

Background The trafficking of mitochondria within neurons is a highly regulated process. In an earlier study, we found that serotonin (5-HT), acting through the 5-HT1A receptor subtype, promotes axonal transport of mitochondria in cultured hippocampal neurons by increasing Akt activity, and consequently decreasing glycogen synthase kinase (GSK3?) activity. This finding suggests a critical role for neuromodulators in the regulation of mitochondrial trafficking in neurons. In the present study, we investigate the effects of a second important neuromodulator, dopamine, on mitochondrial transport in hippocampal neurons. Methodology/Principal Findings Here, we show that dopamine, like 5-HT, regulates mitochondrial motility in cultured hippocampal neurons through the Akt-GSK3? signaling cascade. But, in contrast to the stimulatory effect of 5-HT, administration of exogenous dopamine or bromocriptine, a dopamine 2 receptor (D2R) agonist, caused an inhibition of mitochondrial movement. Moreover, pretreatment with bromocriptine blocked the stimulatory effect of 5-HT on mitochondrial movement. Conversely, in cells pretreated with 5-HT, no further increases in movement were observed after administration of haloperidol, a D2R antagonist. In contrast to the effect of the D2R agonist, addition of SKF38393, a dopamine 1 receptor (D1R) agonist, promoted mitochondrial transport, indicating that the inhibitory effect of dopamine was actually the net summation of opposing influences of the two receptor subtypes. The most pronounced effect of dopamine signals was on mitochondria that were already moving directionally. Western blot analysis revealed that treatment with either a D2R agonist or a D1R antagonist decreased Akt activity, and conversely, treatment with either a D2R antagonist or a D1R agonist increased Akt activity. Conclusions/Significance Our observations strongly suggest a role for both dopamine and 5-HT in regulating mitochondrial movement, and indicate that the integrated effects of these two neuromodulators may be important in determining the distribution of energy sources in neurons. PMID:18665222

Chen, Sigeng; Owens, Geoffrey C.; Edelman, David B.



Sampling phasic dopamine signaling with fast-scan cyclic voltammetry in awake, behaving rats.  


Fast-scan cyclic voltammetry (FSCV) is an electrochemical technique that permits the in vivo measurement of extracellular fluctuations in multiple chemical species. The technique is frequently utilized to sample sub-second (phasic) concentration changes of the neurotransmitter dopamine in awake and behaving rats. Phasic dopamine signaling is implicated in reinforcement, goal-directed behavior, and locomotion, and FSCV has been used to investigate how rapid changes in striatal dopamine concentration contribute to these and other behaviors. This unit describes the instrumentation and construction, implantation, and use of components required to sample and analyze dopamine concentration changes in awake rats with FSCV. © 2015 by John Wiley & Sons, Inc. PMID:25559005

Fortin, S M; Cone, J J; Ng-Evans, S; McCutcheon, J E; Roitman, M F



Decreased vigilance and neurotransmitter synthesis after discontinuation of dietary treatment for phenylketonuria in adolescents  

Microsoft Academic Search

Four adolescent or young adult patients with phenylketonuria were examined before and after discontinuation of dietary treatment. Plasma and CSF phenylalanine concentrations increased about two-fold in three patients. In these patients the CSF concentration of the dopamine and serotonin metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) decreased markedly; 5-HIAA to extremely low values. The reaction time variability increased in

H. C. Lou; F. Giittler; C. Lykkelund; P. Bruhn; A. Niederwieser



Gintonin, a novel ginseng-derived lysophosphatidic acid receptor ligand, stimulates neurotransmitter release.  


Gintonin is a novel ginseng-derived G protein-coupled lysophosphatidic acid (LPA) receptor ligand. Gintonin elicits an intracellular calcium concentration [Ca(2+)]i transient via activation of LPA receptors and regulates calcium-dependent ion channels and receptors. [Ca(2+)]i elevation by neurotransmitters or depolarization is usually coupled to neurotransmitter release in neuronal cells. Little is known about whether gintonin-mediated [Ca(2+)]i transients are also coupled to neurotransmitter release. The PC12 cell line is derived from a pheochromocytoma of the rat adrenal medulla and is widely used as a model for catecholamine release. In the present study, we examined the effects of gintonin on dopamine release in PC12 cells. Application of gintonin to PC12 cells induced [Ca(2+)]i transients in concentration-dependent and reversible manners. However, ginsenoside Rg3, another active ingredient of ginseng, induced a lagged and irreversible [Ca(2+)]i increase. The induction of gintonin-mediated [Ca(2+)]i transients was attenuated or blocked by the LPA1/3 receptor antagonist Ki16425, a phospholipase C inhibitor, an inositol 1,4,5-triphosphate receptor antagonist, and an intracellular Ca(2+) chelator. Repeated treatment with gintonin induced homologous desensitization of [Ca(2+)]i transients. Gintonin treatment in PC12 cells increased the release of dopamine in a concentration-dependent manner. Intraperitoneal administration of gintonin to mice also increased serum dopamine concentrations. The present study shows that gintonin-mediated [Ca(2+)]i transients are coupled to dopamine release via LPA receptor activation. Finally, gintonin-mediated [Ca(2+)]i transients and dopamine release via LPA receptor activation might explain one mechanism of gintonin-mediated inter-neuronal modulation in the nervous system. PMID:25445364

Hwang, Sung-Hee; Lee, Byung-Hwan; Choi, Sun-Hye; Kim, Hyeon-Joong; Jung, Seok-Won; Kim, Hyun-Sook; Shin, Ho-Chul; Park, Hyun Jin; Park, Keun Hong; Lee, Myung Koo; Nah, Seung-Yeol



Serotonin neuronal function and selective serotonin reuptake inhibitor treatment in anorexia and bulimia nervosa.  


Anorexia nervosa (AN) and bulimia nervosa (BN) are disorders characterized by aberrant patterns of feeding behavior and weight regulation, and disturbances in attitudes toward weight and shape and the perception of body shape. Emerging data support the possibility that substantial biologic and genetic vulnerabilities contribute to the pathogenesis of AN and BN. Multiple neuroendocrine and neurotransmitter abnormalities have been documented in AN and BN, but for the most part, these disturbances are state-related and tend to normalize after symptom remission and weight restoration; however, elevated concentrations of 5-hydroxyindoleacetic acid in the cerebrospinal fluid after recovery suggest that altered serotonin activity in AN and BN is a trait-related characteristic. Elevated serotonin activity is consistent with behaviors found after recovery from AN and BN, such as obsessionality with symmetry and exactness, harm avoidance, perfectionism, and behavioral over control. In BN, serotonergic modulating antidepressant medications suppress symptoms independently of their antidepressant effects. Selective serotonin reuptake inhibitors (SSRIs) are not useful when AN subjects are malnourished and under-weight; however, when given after weight restoration, fluoxetine may significantly reduce the extremely high rate of relapse normally seen in AN. Nonresponse to SSRI medication in ill AN subjects could be a consequence of an inadequate supply of nutrients, which are essential to normal serotonin synthesis and function. These data raise the possibility that a disturbance of serotonin activity may create a vulnerability for the expression of a cluster of symptoms that are common to both AN and BN and that nutritional factors may affect SSRI response in depression, obsessive-compulsive disorder, or other conditions characterized by disturbances in serotonergic pathways. PMID:9807638

Kaye, W; Gendall, K; Strober, M



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


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



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.  


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



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



X-ray structure of dopamine transporter elucidates antidepressant mechanism.  


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

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



Effects of delayed treatment with nebracetam on neurotransmitters in brain regions after microsphere embolism in rats  

PubMed Central

The effects of delayed treatment with nebracetam, a novel nootropic drug, on neurotransmitters of brain regions were examined in rats with microsphere embolism-induced cerebral ischaemia. Cerebral ischaemia was induced by administration of 900 microspheres (48??m) into the internal carotid artery. The rats with stroke-like symptoms were treated p.o. with 30?mg?kg?1 nebracetam twice daily. The levels of acetylcholine, dopamine, noradrenaline, 5-hydroxytryptamine (5-HT) and their metabolites in the cerebral cortex, striatum and hippocampus of animals with microsphere embolism were determined by high performance liquid chromatography (h.p.l.c.) on the 3rd and 7th days after the operation. Although the microsphere embolism induced significant changes in most of the neurotransmitters and some of their metabolites in the brain regions, the delayed treatment with nebracetam partially restored only the hippocampal 5-HT and the striatal dopamine metabolite contents on the 3rd day. The hippocampal in vivo 5-HT synthesis, but not the striatal dopamine synthesis, was attenuated in rats with microsphere embolism on the 3rd day, but was restored by treatment with nebracetam. In vivo striatal dopamine turnover rate of the rats with microsphere embolism was inhibited on the 3rd day irrespective of treatment with nebracetam. The present study provides evidence for a possible action of nebracetam on 5-HT metabolism in the ischaemic brain. PMID:9179389

Takeo, Satoshi; Hayashi, Hideki; Miyake, Keiko; Takagi, Kaori; Tadokoro, Mina; Takagi, Norio; Oshikawa, Sayuri



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.



Regulated expression and function of the somatodendritic catecholamine neurotransmitter transporters.  


Termination of neurotransmission at catecholaminergic synapses is well documented by the transporters for dopamine and norepinephrine, members of the Na(+)/Cl(-)-dependent neurotransmitter transporter family, which accumulates released transmitters within their nerve endings, respectively. Although somatodendritic expression of the transporters and the effects of cocaine and amphetamine on those have been reported, their role is still obscure. Recent findings of the transporter function as an ion channel and/or its reverse transport property provide a clue to identify the role of these transporters in the somatodendrites and their consequential interaction with uptake inhibitors. Differences in ionic environment and maturity of the release machinery in the somatodendrites at developmental stages influence the transporter functions, resulting in the formation of both positive and negative feedback loop of catecholaminergic neurons. PMID:16217145

Kitayama, Shigeo; Sogawa, Chiharu



Neural Circuits, Neurotransmitters, and Behavior  

Microsoft Academic Search

\\u000a In bulimia nervosa (BN), and in related binge–purge syndromes, factors affecting central serotonin (5-hydroxytryptamine, 5-HT)\\u000a function appear to contribute not only to appetitive dysregulation but also to temperamental and personality manifestations.\\u000a Drawing upon findings from neurobiological, molecular-genetic, and brain-imaging studies, we present an integrative model\\u000a of the role of 5-HT function in bulimic syndromes. At the core of our model

Howard Steiger; Kenneth R. Bruce; Patricia Groleau


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



[ 123I] ?-CIT and single photon emission computed tomography reveal reduced brain serotonin transporter availability in bulimia nervosa  

Microsoft Academic Search

Background: Impaired serotonin transmission has been implicated in the pathophysiology of eating disorders. We investigated the in vivo availability of brain serotonin transporters and dopamine transporters in bulimia nervosa patients.Methods: Approximately 24 hours after injection of [123I]-2?-carbomethoxy-3?-(4-iodophenyl)tropane ([123I] ?-CIT), single photon emission computed tomography scans were performed in 10 medication-free, female bulimic patients and 10 age-matched, healthy females. For quantification

Johannes Tauscher; Walter Pirker; Matthäus Willeit; Martina de Zwaan; Ursula Bailer; Alexander Neumeister; Susanne Asenbaum; Claudia Lennkh; Nicole Praschak-Rieder; Thomas Brücke; Siegfried Kasper



Serotonin, but not N-Methyltryptamines, activates the Serotonin 2A Receptor via a ?arrestin2/Src/Akt signaling complex in vivo  

PubMed Central

Hallucinogens mediate many of their psychoactive effects by activating serotonin 2A receptors (5-HT2AR). While serotonin is the cognate endogenous neurotransmitter and is not considered hallucinogenic, metabolites of serotonin also have high affinity at 5-HT2AR and can induce hallucinations in humans. Here we report that serotonin differs from the psychoactive N-methyltryptamines by its ability to engage a ?arrestin2-mediated signaling cascade in the frontal cortex. Serotonin and 5-hydroxy-L-tryptophan (5-HTP) induce a head twitch response in wild-type (WT) mice which is a behavioral proxy for 5-HT2AR activation. The response in ?arrestin2 knockout (?arr2-KO) mice is greatly attenuated until the doses are elevated, at which point, ?arr2-KO mice display a head twitch response that can exceed that of WT mice. Direct administration of N-methyltryptamines also produces a greater response in ?arr2-KO mice. Moreover, the inhibition of N-methyltransferase blocks 5-HTP-induced head twitches in ?arr2-KO mice indicating that N-methyltrypatmines, rather than serotonin, primarily mediate this response. Biochemical studies demonstrate that serotonin stimulates Akt phosphorylation in the frontal cortex and in primary cortical neurons through the activation of a ?arrestin2/PI3-K/Src/Akt cascade, while N-methyltryptamines do not. Further, disruption of any of the components of this cascade prevents 5-HTP-, but not N-methyltryptamine-induced, head twitches. We propose that there is a bifurcation of 5-HT2AR signaling that is neurotransmitter- and ?arrestin2-dependent. This demonstration of agonist-directed 5-HT2AR signaling in vivo, may significantly impact drug discovery efforts for the treatment of disorders wherein hallucinations are part of the etiology, such as schizophrenia, or manifest as side effects of treatment, such as depression. PMID:20926677

Schmid, Cullen L.; Bohn, Laura M.



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

PubMed Central

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

Small, D H; Wurtman, R J



Serotonin regulates rhythmic whisking.  


Many rodents explore their environment by rhythmically palpating objects with their mystacial whiskers. These rhythmic whisker movements ("whisking"; 5-9 Hz) are thought to be regulated by an unknown brainstem central pattern generator (CPG). We tested the hypothesis that serotonin (5-HT) inputs to whisking facial motoneurons (wFMNs) are part of this CPG. In response to exogenous serotonin, wFMNs recorded in vitro fire rhythmically at whisking frequencies, and selective 5-HT2 or 5-HT3 receptor antagonists suppress this rhythmic firing. In vivo, stimulation of brainstem serotonergic raphe nuclei evokes whisker movements. Unilateral infusion of selective 5-HT2 or 5-HT3 receptor antagonists suppresses ipsilateral whisking and substantially alters the frequencies and symmetry of whisker movements. These findings suggest that serotonin is both necessary and sufficient to generate rhythmic whisker movements and that serotonergic premotoneurons are part of a whisking CPG. PMID:12873389

Hattox, Alexis; Li, Ying; Keller, Asaf



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.



From galactorrhea to osteopenia: rethinking serotonin-prolactin interactions.  


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 as galactorrhea, which may be accompanied by impaired fertility. Long-term clinical sequelae include decreased bone density and the possibility of an increased risk of breast cancer. Through literature review, we explore the possible pathways involved in serotonin-induced PRL release. While the classic mechanism of antipsychotic-induced hyperprolactinemia directly involves dopamine cells in the tuberoinfundibular pathway, SSRIs may act on this system indirectly through GABAergic neurons. Alternate pathways involve serotonin stimulation of vasoactive intestinal peptide (VIP) and oxytocin (OT) release. We conclude with a comprehensive review of clinical sequelae associated with hyperprolactinemia, and the potential role of SSRIs in this phenomenon. PMID:14997175

Emiliano, Ana B F; Fudge, Julie L



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.



[Simultaneous detection of 8 monoamine neurotransmitters in the different sections of rat brains by high performance liquid chromatography with fluorescence detection].  


A method for the simultaneous detection of L-dihydroxyphenylalanine, norepinephrine, epinephrine, dopamine, 3,4-dihydroxyphenylacetic acid, serotonin hydrochloride, 5-hydroxyindole-3-acetic acid and homovanillic acid in the different sections of mouse brains was established by using high performance liquid chromatography (HPLC) with fluorescence detection and isocratic elution. Before analysis, the sample was deproteinized by 0.60 mol/L perchloric acid, followed by adjusting pH value of the sample with 1.20 mol/L K2HPO4, addition of 0.1 g/L L-cysteine as antioxidant and 0.50 mmol/L Na2EDTA as complexing agent. The separation column was a Shim-pack C18 column (250 mm x 4.6 mm, 5 microm) and the mobile phase (pH 3.8) was 13% methanol containing 50 mmol/L citric acid, 50 mmol/L sodium acetate, 0.5 mmol/L 1-heptanesulfonic acid sodium salt, 5 mmol/L triethylamine and 0.5 mmol/L Na2EDTA. The flow rate was 1.0 mL/min. The injection volume was 10 microL. The emission and excitation wavelengths were 330 nm and 280 nm, respectively. Under the optimized separation conditions, the calibration curves showed good linearity within the concentrations of 1.25 - 5000 microg/L (r > 0.9999). The limits of detection were between 0.20 - 5.00 microg/L, the average recoveries were between 94.83% and 99.19%, and the relative standard deviations (RSDs) were between 0.08% and 2.51%. The advantages of the method include easy and prompt operation, high recovery, low detection limit, good separation effect, high accuracy and precision. The method has practical value for detecting 8 monoamine neurotransmitters in biological samples. PMID:21598515

Zhao, Yanyan; Liu, Liyan; Han, Yuanyuan; Bai, Jie; Du, Guangling; Gao, Qian



Hypoxia. 3. Hypoxia and neurotransmitter synthesis  

PubMed Central

Central and peripheral neurons as well as neuroendocrine cells express a variety of neurotransmitters/modulators that play critical roles in regulation of physiological systems. The synthesis of several neurotransmitters/modulators is regulated by O2-requiring rate-limiting enzymes. Consequently, hypoxia resulting from perturbations in O2 homeostasis can affect neuronal functions by altering neurotransmitter synthesis. Two broad categories of hypoxia are frequently encountered: continuous hypoxia (CH) and intermittent hypoxia (IH). CH is often seen during high altitude sojourns, whereas IH is experienced in sleep-disordered breathing with recurrent apneas (i.e., brief, repetitive cessations of breathing). This article presents what is currently known on the effects of both forms of hypoxia on neurotransmitter levels and neurotransmitter synthesizing enzymes in the central and peripheral nervous systems. PMID:21270298



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)



Serotonin and beyond: therapeutics for major depression.  


The serotonin (5-HT, 5-hydroxytryptamine) system has been implicated in the pathogenesis of major depressive disorder (MDD). The case for its contribution to the therapeutic efficacy of a wide variety of antidepressant treatments is, however, much stronger. All antidepressant strategies have been shown to enhance 5-HT transmission in the brain of laboratory animals. Catecholamines, norepinephrine (NE) and dopamine (DA) can also play a pivotal role in the mechanism of action of certain antidepressant strategies. The enhancement of 5-HT transmission by selective serotonin reuptake inhibitors, which leads to a dampening of the activity of NE and DA neurons, may account in part for the low remission rate achieved with these medications and/or the residuals symptoms after remission is achieved. The functional connectivity between the 5-HT, NE and DA systems can be used to understand the mechanism of action of a wide variety of augmentation strategies in treatment-resistant MDD. Proof-of-concept studies have shown that antidepressant medications with complementary mechanisms of action on monoaminergic systems can double the remission rate achieved in a trial of standard duration. Novel approaches are also being used to treat MDD, which also appear to involve the monoaminergic system(s) to a varying extent. PMID:23440470

Blier, Pierre; El Mansari, Mostafa



Nonparametric extraction of transient changes in neurotransmitter concentration from dynamic PET data.  


We have developed a nonparametric approach to the analysis of dynamic positron emission tomography (PET) data for extracting temporal characteristics of the change in endogenous neurotransmitter concentration in the brain. An algebraic method based on singular value decomposition (SVD) was applied to simulated data under both rest (neurotransmitter at baseline) and activated (transient neurotransmitter release) conditions. The resulting signals are related to the integral of the change in free neurotransmitter concentration in the tissue. Therefore, a specially designed minimum mean-square error (MMSE) filter must be applied to the signals to recover the desired temporal pattern of neurotransmitter change. To test the method, we simulated sets of realistic time activity curves representing uptake of [11C]raclopride, a dopamine (DA) receptor antagonist, in brain regions, under baseline and dopamine-release conditions. Our tests considered two scenarios: 1) a spatially homogeneous pattern with all voxels in the activated state presenting an identical DA signal; 2) a spatially heterogeneous pattern in which different DA signals were contained in different families of voxels. In the first case, we demonstrated that the timing of a single DA peak can be accurately identified to within 1 min and that two distinct neurotransmitter peaks can be distinguished. In the second case, separate peaks of activation separated by as little as 5 min can be distinguished. A decrease in blood flow during activation could not account for our findings. We applied the method to human PET data acquired with [11C]raclopride in the presence of transiently elevated DA due to intravenous (IV) alcohol. Our results for an area of the nucleus accumbens-a region relevant to alcohol consumption-agreed with a model-based method for estimating the DA response. SVD-based analysis of dynamic PET data promises a completely noninvasive and model-independent technique for determining the dynamics of a neurotransmitter response to cognitive or pharmacological stimuli. Our results indicate that the method is robust enough for application to voxel-by-voxel data. PMID:17354641

Constantinescu, Cristian C; Bouman, Charles; Morris, Evan D



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

PubMed Central

First-line treatment of major depression includes administration of a selective serotonin reuptake inhibitor (SSRI), yet studies suggest that remission rates following two trials of an SSRI are <50%. The authors examine the putative biological substrates underlying “treatment resistant depression (TRD)” with the goal of elucidating novel rationales to treat TRD. We look at relevant articles from the preclinical and clinical literature combined with clinical exposure to TRD patients. A major focus was to outline pathophysiological mechanisms whereby the serotonin system becomes impervious to the desired enhancement of serotonin neurotransmission by SSRIs. A complementary focus was to dissect neurotransmitter systems, which serve to inhibit the dorsal raphe. We propose, based on a body of translational studies, TRD may not represent a simple serotonin deficit state but rather an excess of midbrain peri-raphe serotonin and subsequent deficit at key fronto-limbic projection sites, with ultimate compromise in serotonin-mediated neuroplasticity. Glutamate, serotonin, noradrenaline, and histamine are activated by stress and exert an inhibitory effect on serotonin outflow, in part by “flooding” 5-HT1A autoreceptors by serotonin itself. Certain factors putatively exacerbate this scenario – presence of the short arm of the serotonin transporter gene, early-life adversity and comorbid bipolar disorder – each of which has been associated with SSRI-treatment resistance. By utilizing an incremental approach, we provide a system for treating the TRD patient based on a strategy of rescuing serotonin neurotransmission from a state of SSRI-induced dorsal raphe stasis. This calls for “stacked” interventions, with an SSRI base, targeting, if necessary, the glutamatergic, serotonergic, noradrenergic, and histaminergic systems, thereby successively eliminating the inhibitory effects each are capable of exerting on serotonin neurons. Future studies are recommended to test this biologically based approach for treatment of TRD. PMID:24904340

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



Screening for molecules essential in activity-mediated neurotransmitter specification  

E-print Network

excitatory and inhibitory neurotransmitters in the centralneurotransmitters while decreasing the number of neurons expressing inhibitoryNeurotransmitters can be excitatory, increasing the production of action potentials, or inhibitory,

Su, Jennifer Jeeye



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.



Tyrosine 402 phosphorylation of Pyk2 is involved in ionomycin-induced neurotransmitter release.  


Protein tyrosine kinases, which are highly expressed in the central nervous system, are implicated in many neural processes. However, the relationship between protein tyrosine kinases and neurotransmitter release remains unknown. In this study, we found that ionomycin, a Ca²? ionophore, concurrently induced asynchronous neurotransmitter release and phosphorylation of a non-receptor protein tyrosine kinase, proline-rich tyrosine kinase 2 (Pyk2), in clonal rat pheochromocytoma PC12 cells and cerebellar granule cells, whereas introduction of Pyk2 siRNA dramatically suppressed ionomycin-induced neurotransmitter release. Further study indicated that Tyr-402 (Y402) in Pyk2, instead of other tyrosine sites, underwent rapid phosphorylation after ionomycin induction in 1 min to 2 min. We demonstrated that the mutant of Pyk2 Y402 could abolish ionomycin-induced dopamine (DA) release by transfecting cells with recombinant Pyk2 and its mutants (Y402F, Y579F, Y580F, and Y881F). In addition, Src inhibition could prolong phosphorylation of Pyk2 Y402 and increase DA release. These findings suggested that Pyk2 was involved in ionomycin-induced neurotransmitter release through phosphorylation of Y402. PMID:24718602

Zhang, Zhao; Zhang, Yun; Mou, Zheng; Chu, Shifeng; Chen, Xiaoyu; He, Wenbin; Guo, Xiaofeng; Yuan, Yuhe; Takahashi, Masami; Chen, Naihong



Tyrosine 402 Phosphorylation of Pyk2 Is Involved in Ionomycin-Induced Neurotransmitter Release  

PubMed Central

Protein tyrosine kinases, which are highly expressed in the central nervous system, are implicated in many neural processes. However, the relationship between protein tyrosine kinases and neurotransmitter release remains unknown. In this study, we found that ionomycin, a Ca2+ ionophore, concurrently induced asynchronous neurotransmitter release and phosphorylation of a non-receptor protein tyrosine kinase, proline-rich tyrosine kinase 2 (Pyk2), in clonal rat pheochromocytoma PC12 cells and cerebellar granule cells, whereas introduction of Pyk2 siRNA dramatically suppressed ionomycin-induced neurotransmitter release. Further study indicated that Tyr-402 (Y402) in Pyk2, instead of other tyrosine sites, underwent rapid phosphorylation after ionomycin induction in 1 min to 2 min. We demonstrated that the mutant of Pyk2 Y402 could abolish ionomycin-induced dopamine (DA) release by transfecting cells with recombinant Pyk2 and its mutants (Y402F, Y579F, Y580F, and Y881F). In addition, Src inhibition could prolong phosphorylation of Pyk2 Y402 and increase DA release. These findings suggested that Pyk2 was involved in ionomycin-induced neurotransmitter release through phosphorylation of Y402. PMID:24718602

Zhang, Zhao; Zhang, Yun; Mou, Zheng; Chu, Shifeng; Chen, Xiaoyu; He, Wenbin; Guo, Xiaofeng; Yuan, Yuhe; Takahashi, Masami; Chen, Naihong



Dopamine, learning and motivation  

Microsoft Academic Search

The hypothesis that dopamine is important for reward has been proposed in a number of forms, each of which has been challenged. Normally, rewarding stimuli such as food, water, lateral hypothalamic brain stimulation and several drugs of abuse become ineffective as rewards in animals given performance-sparing doses of dopamine antagonists. Dopamine release in the nucleus accumbens has been linked to

Roy A. Wise



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



Low Extracellular Dopamine Levels Are Maintained in the Anoxic Turtle (Trachemys scripta) Striatum  

Microsoft Academic Search

The uncontrolled increase of extracellular dopamine (DA) has been implicated in the pathogenesis of hypoxic\\/ischemic damage in the mammalian brain. But unlike the harmful release of excitatory neurotransmitters such as glutamate and aspartate, which occurs on brain depolarization, excessive extracellular DA levels occur even with mild hypoxia in the mammalian brain. The purpose of this study was to determine whether

Sarah L. Milton; Peter L. Lutz



Dual dopamine–5HT releasers: potential treatment agents for cocaine addiction  

Microsoft Academic Search

Biogenic amine transporters (BATs) are integral membrane proteins that translocate biogenic amine neurotransmitters (norepinephrine, dopamine (DA) and 5-hydroxytryptamine (5-HT)) across cell mem- branes. BATs are the principal sites of action for many psychotropic drugs, including abused stimulants such as cocaine and methamphetamine. Preclinical and human data demonstrate that withdrawal from long-term cocaine administration produces a dual deficit of synap- tic

Richard B. Rothman; Bruce E. Blough; Michael H. Baumann



Dopamine Deficiency in a Genetic Mouse Model of Lesch-Nyhan Disease  

Microsoft Academic Search

We have examined several aspects of neurotransmitter function in the brains of mice carrying a deletion mutation in the gene encoding the purine salvage enzyme hypoxan- thine-guanine phosphoribosyltransferase (HPRT). During the first 6 weeks of postnatal development, dopamine levels in whole-brain extracts from the mutant mice (HPRT-) failed to increase at rates comparable to normal animals, resulting in 40% lower

H. A. Jinnah; E. Wojcik; M. Hunt; N. Narang; K. Y. Lee; M. Goldstein; J. K. Wamsley; P. J. Langlais; T. Friedmann


Neurotransmitter GABA Activates Muscle but Not ?7 Nicotinic Receptors.  


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



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.



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


Dopamine is an important neurotransmitter in the central nervous system of vertebrates and invertebrates. Despite their evolutionary distance, striking parallels exist between deuterostomian and protostomian dopaminergic systems. In both, signalling is achieved via a complement of functionally distinct dopamine receptors. In this study, we investigated the sequence, pharmacology and tissue distribution of a D2-like dopamine receptor from the red flour beetle Tribolium castaneum (TricaDop3) and compared it with related G protein-coupled receptors in other invertebrate species. The TricaDop3 receptor-encoding cDNA shows considerable sequence similarity with members of the Dop3 receptor class. Real time qRT-PCR showed high expression in both the central brain and the optic lobes, consistent with the role of dopamine as neurotransmitter. Activation of TricaDop3 expressed in mammalian cells increased intracellular Ca(2+) signalling and decreased NKH-477 (a forskolin analogue)-stimulated cyclic AMP levels in a dose-dependent manner. We studied the pharmacological profile of the TricaDop3 receptor and demonstrated that the synthetic vertebrate dopamine receptor agonists, 2 - amino- 6,7 - dihydroxy - 1,2,3,4 - tetrahydronaphthalene hydrobromide (6,7-ADTN) and bromocriptine acted as agonists. Methysergide was the most potent of the antagonists tested and showed competitive inhibition in the presence of dopamine. This study offers important information on the Dop3 receptor from Tribolium castaneum that will facilitate functional analyses of dopamine receptors in insects and other invertebrates. PMID:25449128

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



Neuromolecular Imaging Shows Temporal Synchrony Patterns between Serotonin and Movement within Neuronal Motor Circuits in the Brain  

PubMed Central

The present discourse links the electrical and chemical properties of the brain with neurotransmitters and movement behaviors to further elucidate strategies to diagnose and treat brain disease. Neuromolecular imaging (NMI), based on electrochemical principles, is used to detect serotonin in nerve terminals (dorsal and ventral striata) and somatodendrites (ventral tegmentum) of reward/motor mesocorticolimbic and nigrostriatal brain circuits. Neuronal release of serotonin is detected at the same time and in the same animal, freely moving and unrestrained, while open-field behaviors are monitored via infrared photobeams. The purpose is to emphasize the unique ability of NMI and the BRODERICK PROBE® biosensors to empirically image a pattern of temporal synchrony, previously reported, for example, in Aplysia using central pattern generators (CPGs), serotonin and cerebral peptide-2. Temporal synchrony is reviewed within the context of the literature on central pattern generators, neurotransmitters and movement disorders. Specifically, temporal synchrony data are derived from studies on psychostimulant behavior with and without cocaine while at the same time and continuously, serotonin release in motor neurons within basal ganglia, is detected. The results show that temporal synchrony between the neurotransmitter, serotonin and natural movement occurs when the brain is NOT injured via, e.g., trauma, addictive drugs or psychiatric illness. In striking contrast, in the case of serotonin and cocaine-induced psychostimulant behavior, a different form of synchrony and also asynchrony can occur. Thus, the known dysfunctional movement behavior produced by cocaine may well be related to the loss of temporal synchrony, the loss of the ability to match serotonin in brain with motor activity. The empirical study of temporal synchrony patterns in humans and animals may be more relevant to the dynamics of motor circuits and movement behaviors than are studies of static parameters currently relied upon within the realms of science and medicine. There are myriad applications for the use of NMI to discover clinically relevant diagnoses and treatments for brain disease involving the motor system. PMID:24961434

Broderick, Patricia A.



Serotonin and the sleep\\/wake cycle: special emphasis on microdialysis studies  

Microsoft Academic Search

Several areas in the brainstem and forebrain are important for the modulation and expression of the sleep\\/wake cycle. Even if the first observations of biochemical events in relation to sleep were made only 40years ago, it is now well established that several neurotransmitters, neuropeptides, and neurohormones are involved in the modulation of the sleep\\/wake cycle.Serotonin has been known for many

Chiara M Portas; Bjørn Bjorvatn; Reidun Ursin



Regulation of gene expression in cultured embryonic mouse mandibular mesenchyme by serotonin antagonists  

Microsoft Academic Search

During murine embryogenesis, uptake sites for the neurotransmitter serotonin (5-HT) are transiently expressed in craniofacial\\u000a epithelial structures. Based on malformations produced in cultured mouse embryos exposed to uptake inhibitors or receptor\\u000a ligands, we have proposed that 5-HT acts as a dose-dependent morphogenetic signal during critical periods of craniofacial\\u000a development. Several 5-HT receptor subtypes are co-distributed with tenascin and the calcium

Julian R. D. Moiseiwitsch; J. M. Lauder



Behavioral effects of tryptophan depletion in seasonal affective disorder associated with the serotonin transporter gene?  

Microsoft Academic Search

There is some evidence that the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) may be involved in the pathogenesis of seasonal affective disorder (SAD). Short-term tryptophan (TRP) depletion was carried out in 18 drug-free remitted patients who met DSM-IV criteria for SAD. Behavioral effects were measured with the Hamilton Depression Rating Scale (HDRS) both 24 h before and 24 h after TRP depletion.

Elisabeth Lenzinger; Alexander Neumeister; Nicole Praschak-Rieder; Karoline Fuchs; Elisabeth Gerhard; Mattheus Willeit; Werner Sieghart; Siegfried F Kasper; Kurt Hornik; Harald N. Aschauer



Developmental origins of brain disorders: roles for dopamine  

PubMed Central

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

Money, Kelli M.; Stanwood, Gregg D.



Elevated brain dopamine levels associated with ovary development in queenless worker honey bees ( Apis mellifera L.)  

Microsoft Academic Search

Brain levels of octopamine (OA), dopamine (DA) and serotonin (5HT) were compared between worker honey bees (Apis mellifera L.) kept with or without queens in various experiments. Levels of DA were significantly higher in queenless bees than in their sisters that had been kept with queens either (1) in small field colonies for 30 days or (2) in incubator cages

Jeffrey W. Harris; Joseph Woodring



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.



Modeling Dopamine and Serotonin Systems in a Visual Recognition Network  

E-print Network

recognition settings to investigate how such a system can learn through interactions with a teacher, who does computation and neuronal learning. This work proposes a neuromorphic motivational system, which includes two that are intrinsically aversive (e.g., stress or pain). The latter signals a large class of stimuli


Serotonin stimulates secretion of exosomes from microglia cells.  


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



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


The brain-gut axis is a bidirectional communication system between the central nervous system and the gastrointestinal tract. Serotonin functions as a key neurotransmitter at both terminals of this network. Accumulating evidence points to a critical role for the gut microbiome in regulating normal functioning of this axis. In particular, it is becoming clear that the microbial influence on tryptophan metabolism and the serotonergic system may be an important node in such regulation. There is also substantial overlap between behaviours influenced by the gut microbiota and those which rely on intact serotonergic neurotransmission. The developing serotonergic system may be vulnerable to differential microbial colonisation patterns prior to the emergence of a stable adult-like gut microbiota. At the other extreme of life, the decreased diversity and stability of the gut microbiota may dictate serotonin-related health problems in the elderly. The mechanisms underpinning this crosstalk require further elaboration but may be related to the ability of the gut microbiota to control host tryptophan metabolism along the kynurenine pathway, thereby simultaneously reducing the fraction available for serotonin synthesis and increasing the production of neuroactive metabolites. The enzymes of this pathway are immune and stress-responsive, both systems which buttress the brain-gut axis. In addition, there are neural processes in the gastrointestinal tract which can be influenced by local alterations in serotonin concentrations with subsequent relay of signals along the scaffolding of the brain-gut axis to influence CNS neurotransmission. Therapeutic targeting of the gut microbiota might be a viable treatment strategy for serotonin-related brain-gut axis disorders. PMID:25078296

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



Serotonin uptake inhibition during treatment of depression with nortriptyline caused by parent drug and not by 10-hydroxymetabolites  

Microsoft Academic Search

Treatment of endogenous depression with nortriptyline (NT), at a daily dose of 150 mg, resulted in a pronounced improvement of seven of ten patients investigated. The concentration of the norepinephrine metabolite HMPG in cerebrospinal fluid (CSF) decreased by 29% (P<0.01) after 3 weeks of treatment. There was no significant effect of treatment on the serotonin and dopamine metabolites 5-HIAA and

R. Malmgren; A. Åberg-Wistedt; L. Bertilsson



Impulsive Choice and Altruistic Punishment Are Correlated and Increase in Tandem With Serotonin Depletion  

PubMed Central

Human cooperation may partly depend on the presence of individuals willing to incur personal costs to punish noncooperators. The psychological factors that motivate such 'altruistic punishment' are not fully understood; some have argued that altruistic punishment is a deliberate act of norm enforcement that requires self-control, while others claim that it is an impulsive act driven primarily by emotion. In the current study, we addressed this question by examining the relationship between impulsive choice and altruistic punishment in the ultimatum game. As the neurotransmitter serotonin has been implicated in both impulsive choice and altruistic punishment, we investigated the effects of manipulating serotonin on both measures. Across individuals, impulsive choice and altruistic punishment were correlated and increased following serotonin depletion. These findings imply that altruistic punishment reflects the absence rather than the presence of self control, and suggest that impulsive choice and altruistic punishment share common neural mechanisms. PMID:21171757

Crockett, Molly J.; Clark, Luke; Lieberman, Matthew D.; Tabibnia, Golnaz; Robbins, Trevor W.



Dopamine Modulates Reward-Related Vigor  

PubMed Central

Subjects routinely control the vigor with which they emit motoric responses. However, the bulk of formal treatments of decision-making ignores this dimension of choice. A recent theoretical study suggested that action vigor should be influenced by experienced average reward rate and that this rate is encoded by tonic dopamine in the brain. We previously examined how average reward rate modulates vigor as exemplified by response times and found a measure of agreement with the first suggestion. In the current study, we examined the second suggestion, namely the potential influence of dopamine signaling on vigor. Ninety healthy subjects participated in a double-blind experiment in which they received one of the following: placebo, L-DOPA (which increases dopamine levels in the brain), or citalopram (which has a selective, if complex, effect on serotonin levels). Subjects performed multiple trials of a rewarded odd-ball discrimination task in which we varied the potential reward over time in order to exercise the putative link between vigor and average reward rate. Replicating our previous findings, we found that a significant fraction of the variance in subjects' responses could be explained by our experimentally manipulated changes in average reward rate. Crucially, this relationship was significantly stronger under L-Dopa than under Placebo, suggesting that the impact of average reward levels on action vigor is indeed subject to a dopaminergic influence. PMID:23419875

Beierholm, Ulrik; Guitart-Masip, Marc; Economides, Marcos; Chowdhury, Rumana; Düzel, Emrah; Dolan, Ray; Dayan, Peter



Dopamine modulates reward-related vigor.  


Subjects routinely control the vigor with which they emit motoric responses. However, the bulk of formal treatments of decision-making ignores this dimension of choice. A recent theoretical study suggested that action vigor should be influenced by experienced average reward rate and that this rate is encoded by tonic dopamine in the brain. We previously examined how average reward rate modulates vigor as exemplified by response times and found a measure of agreement with the first suggestion. In the current study, we examined the second suggestion, namely the potential influence of dopamine signaling on vigor. Ninety healthy subjects participated in a double-blind experiment in which they received one of the following: placebo, L-DOPA (which increases dopamine levels in the brain), or citalopram (which has a selective, if complex, effect on serotonin levels). Subjects performed multiple trials of a rewarded odd-ball discrimination task in which we varied the potential reward over time in order to exercise the putative link between vigor and average reward rate. Replicating our previous findings, we found that a significant fraction of the variance in subjects' responses could be explained by our experimentally manipulated changes in average reward rate. Crucially, this relationship was significantly stronger under L-Dopa than under Placebo, suggesting that the impact of average reward levels on action vigor is indeed subject to a dopaminergic influence. PMID:23419875

Beierholm, Ulrik; Guitart-Masip, Marc; Economides, Marcos; Chowdhury, Rumana; Düzel, Emrah; Dolan, Ray; Dayan, Peter



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


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



Cloning, expression, and localization of a chloride-facilitated, cocaine-sensitive serotonin transporter from Drosophila melanogaster.  

PubMed Central

We report here on the isolation and characterization of a serotonin (5HT) transporter from Drosophila melanogaster. A 3.1-kb complementary DNA clone (dSERT) was found to encode a protein of 622 amino acid residues with a predicted molecular mass of approximately 69 kDa and a putative transmembrane topology characteristic of cloned members of the mammalian Na+/Cl- neurotransmitter cotransporter gene family. dSERT displays highest overall amino acid sequence identity with the mammalian 5HT (51%), norepinephrine (47%), and dopamine (47%) transporters and shares with all transporters 104 absolutely conserved amino acid residues. Upon transient expression in HeLa cells, dSERT exhibited saturable, high-affinity, and sodium-dependent [3H]5HT uptake with estimated Km and Vmax values of approximately 500 nM and 5.2 x 10(-18) mol per cell per min, respectively. In marked contrast to the human SERT (hSERT), 5HT-mediated transport by dSERT was not absolutely dependent on extracellular Cl-, while the sodium-dependent uptake of 5HT was facilitated by increased extracellular Cl- concentrations. dSERT displays a pharmacological profile and rank order of potency consistent with, but not identical to, mammalian 5HT transporters. Comparison of the affinities of various compounds for the inhibition of 5HT transport by both dSERT and hSERT revealed that antidepressants were 3- to 300-fold less potent on dSERT than on hSERT, while mazindol displayed approximately 30-fold greater potency for dSERT. Both cocaine and RTI-55 inhibited 5HT uptake by dSERT with estimated inhibition constants of approximately 500 nM, while high concentrations (> 10 microM) of dopamine, norepinephrine, octopamine, tyramine, and histamine failed to inhibit transport. In situ hybridization reveals the selective expression of dSERT mRNA to specific cell bodies in the ventral ganglion of the embryonic and larval Drosophila nervous system with a distribution pattern virtually identical to that of 5HT-containing neurons. The dSERT gene was mapped to position 60C on chromosome 2. The availability of the gene encoding the unique ion dependence and pharmacological characteristics of dSERT may allow for identification of those amino acid residues and structural motifs that confer the pharmacologic specificity and genetic regulation of the 5HT transport process. Images PMID:8197200

Demchyshyn, L L; Pristupa, Z B; Sugamori, K S; Barker, E L; Blakely, R D; Wolfgang, W J; Forte, M A; Niznik, H B



Neurotransmitter control of islet hormone pulsatility.  


Pulsatile secretion is an inherent property of hormone-releasing pancreatic islet cells. This secretory pattern is physiologically important and compromised in diabetes. Neurotransmitters released from islet cells may shape the pulses in auto/paracrine feedback loops. Within islets, glucose-stimulated ?-cells couple via gap junctions to generate synchronized insulin pulses. In contrast, ?- and ?-cells lack gap junctions, and glucagon release from islets stimulated by lack of glucose is non-pulsatile. Increasing glucose concentrations gradually inhibit glucagon secretion by ?-cell-intrinsic mechanism/s. Further glucose elevation will stimulate pulsatile insulin release and co-secretion of neurotransmitters. Excitatory ATP may synchronize ?-cells with ?-cells to generate coinciding pulses of insulin and somatostatin. Inhibitory neurotransmitters from ?- and ?-cells can then generate antiphase pulses of glucagon release. Neurotransmitters released from intrapancreatic ganglia are required to synchronize ?-cells between islets to coordinate insulin pulsatility from the entire pancreas, whereas paracrine intra-islet effects still suffice to explain coordinated pulsatile release of glucagon and somatostatin. The present review discusses how neurotransmitters contribute to the pulsatility at different levels of integration. PMID:25200303

Gylfe, E; Tengholm, A



Distribution of serotonin and FMRF-amide in the brain of Lymnaea stagnalis with respect to the visual system.  


Despite serotonin's and FMRF-amide's wide distribution in the nervous system of invertebrates and their importance as neurotransmitters, the exact roles they play in neuronal networks leaves many questions. We mapped the presence of serotonin and FMRF-amide-immunoreactivity in the central nervous system and eyes of the pond snail Lymnaea stagnalis and interpreted the results in connection with our earlier findings on the central projections of different peripheral nerves. Since the chemical nature of the intercellular connections in the retina of L. stagnalis is still largely unknown, we paid special attention to clarifying the role of serotonin and FMRF-amide in the visual system of this snail and compared our findings with those reported from other species. At least one serotonin- and one FMRF-amidergic fibre were labeled in each optic nerve, and since no cell bodies in the eye showed immunoreactivity to these neurotransmitters, we believe that efferent fibres with somata located in the central ganglia branch at the base of the eye and probably release 5HT and FMRF-amide as neuro-hormones. Double labelling revealed retrograde transport of neurobiotin through the optic nerve, allowing us to conclude that the central pathways and serotonin- and FMRF-amide-immunoreactive cells and fibres have different locations in the CNS in L. stagnalis. The chemical nature of the fibres, which connect the two eyes in L. stagnalis, is neither serotoninergic nor FMRF-amidergic. PMID:22653864

Tuchina, Oksana P; Zhukov, Valery V; Meyer-Rochow, Victor B



Single cell measurement of dopamine release with simultaneous voltage-clamp and amperometry.  


After its release into the synaptic cleft, dopamine exerts its biological properties via its pre- and post-synaptic targets(1). The dopamine signal is terminated by diffusion(2-3), extracellular enzymes(4), and membrane transporters(5). 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 dopamine(5). 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 homeostasis(6). 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 volume(7). 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



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



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.



Homeostatic control of presynaptic neurotransmitter release.  


It is well established that the active properties of nerve and muscle cells are stabilized by homeostatic signaling systems. In organisms ranging from Drosophila to humans, neurons restore baseline function in the continued presence of destabilizing perturbations by rebalancing ion channel expression, modifying neurotransmitter receptor surface expression and trafficking, and modulating neurotransmitter release. This review focuses on the homeostatic modulation of presynaptic neurotransmitter release, termed presynaptic homeostasis. First, we highlight criteria that can be used to define a process as being under homeostatic control. Next, we review the remarkable conservation of presynaptic homeostasis at the Drosophila, mouse, and human neuromuscular junctions and emerging parallels at synaptic connections in the mammalian central nervous system. We then highlight recent progress identifying cellular and molecular mechanisms. We conclude by reviewing emerging parallels between the mechanisms of homeostatic signaling and genetic links to neurological disease. PMID:25386989

Davis, Graeme W; Müller, Martin



Activation of nicotinic receptors on GABAergic amacrine cells in the rabbit retina indirectly stimulates dopamine release.  


The retina possesses subpopulations of amacrine cells, which utilize different transmitters, including acetylcholine (ACh), GABA, and dopamine. We have examined interactions between these neurones by studying the effects of nicotinic agonists on GABA and dopamine release. Isolated rabbit retinas were incubated with [3H]dopamine and then superfused. Fractions of the superfusate (2 min) were collected and the [3H]dopamine in each sample was measured. Endogenous GABA release was examined by incubating retinas in a small chamber. At 5-min intervals, the medium was changed and the GABA measured by high-pressure liquid chromatography (HPLC). Exposure of the retina to nicotine, epibatidine, and other nicotinic agonists increased the release of both GABA and dopamine. The effects of nicotine and epibatidine were blocked by mecamylamine, confirming an action on nicotinic receptors. The action of epibatidine on dopamine release was unaffected by glutamate antagonists but was blocked by picrotoxin and gabazine. These results suggested that nicotine might increase dopamine release indirectly by stimulating the release of GABA, which in turn inhibited the release of an inhibitory transmitter acting tonically on the dopaminergic amacrines. Exposure of the retina to GABA caused a small increase in dopamine release. This hypothetical inhibitory transmitter was not GABA, an opioid, adenosine, glycine, nociceptin, a cannabinoid, or nitric oxide because appropriate antagonists did not affect the resting release of dopamine. However, metergoline, a 5HT1/5HT2 receptor antagonist, and ketanserin, a 5HT2A receptor antagonist, but not the 5HT1A antagonist WAY100635, increased the resting release of dopamine and blocked the effects of nicotine. The 5HT1A/5HT7 agonist 8-hydroxy DPAT inhibited both the nicotine and GABA-evoked release of dopamine. We conclude that nicotinic agonists directly stimulate the release of GABA, but the evoked release of dopamine is indirect, and arises from GABA inhibiting the input of an inhibitory transmitter, which we tentatively identify as serotonin. PMID:11347816

Neal, M J; Cunningham, J R; Matthews, K L



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, 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.



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


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. Five 5-HT receptor subtypes have been reported in Drosophila that share high similarity with mammalian 5-HT1A , 5-HT1B , 5-HT2A , 5-HT2B , and 5-HT7 receptors. We isolated a cDNA (Pr5-HT8 ) from larval Pieris rapae, which shares relatively low similarity to the known 5-HT receptor classes. After heterologous expression in HEK293 cells, Pr5-HT8 mediated increased [Ca(2+) ]i in response to low concentrations (< 10 nM) of 5-HT. The receptor did not affect [cAMP]i even at high concentrations (> 10 ?M) of 5-HT. Dopamine, octopamine, and tyramine did not influence receptor signaling. Pr5-HT8 was also activated by various 5-HT receptor agonists including 5-methoxytryptamine, (±)-8-Hydroxy-2-(dipropylamino) tetralin, and 5-carboxamidotryptamine. Methiothepin, a non-selective 5-HT receptor antagonist, activated Pr5-HT8 . WAY 10635, a 5-HT1A antagonist, but not SB-269970, SB-216641, or RS-127445, inhibited 5-HT-induced [Ca(2+) ]i increases. We infer that Pr5-HT8 represents the first recognized member of a novel 5-HT receptor class with a unique pharmacological profile. We found orthologs of Pr5-HT8 in some insect pests and vectors such as beetles and mosquitoes, but not in the genomes of honeybee or parasitoid wasps. This is likely to be an invertebrate-specific receptor because there were no similar receptors in mammals. We isolated a cDNA (Pr5-HT8 ) from larval Pieris rapae, which shares relatively low similarity to the known GPCRs. After heterologous expression in HEK293 cells, Pr5-HT8 mediated increased [Ca(2+) ]i in response to low concentrations (< 10 nM) of 5-HT and various 5-HT receptor agonists. We found orthologs of Pr5-HT8 in some insect pests and vectors such as beetles and mosquitoes, but not in the genomes of honeybee, parasitoid wasps, or mammals. PMID:25187179

Qi, Yi-Xiang; Xia, Ren-Ying; Wu, Ya-Su; Stanley, David; Huang, Jia; Ye, Gong-Yin



The (B)link Between Creativity and Dopamine: Spontaneous Eye Blink Rates Predict and Dissociate Divergent and Convergent Thinking  

ERIC Educational Resources Information Center

Human creativity has been claimed to rely on the neurotransmitter dopamine, but evidence is still sparse. We studied whether individual performance (N=117) in divergent thinking (alternative uses task) and convergent thinking (remote association task) can be predicted by the individual spontaneous eye blink rate (EBR), a clinical marker of…

Chermahini, Soghra Akbari; Hommel, Bernhard



Dopamine Enhances a Glutamate-gated Ionic Current in OFF Bipolar Cells of the Tiger Salamander Retina  

Microsoft Academic Search

The transmitter glutamate is thought to be used by all ver- tebrate photoreceptors to drive the second-order neurons of the retina, horizontal and bipolar neurons. Dopamine, an endogenous retinal neurotransmitter localized to amacrine and interplexiform cells, has previously been shown to en- hance glutamate-gated currents in retinal horizontal cells. In the present study we demonstrate that bipolar cells, like horizontal

Greg Maguirelz; Frank Werblin


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.



Increased dopamine tone during meditation-induced change of consciousness.  


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



Serotonin metabolism in cystic fibrosis.  

PubMed Central

The average blood serotonin level of 67 children with cystic fibrosis was found to be about twice that of age-matched normal children. There was no corresponding increase in the urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA). Children with cystic fibrosis were well able to metabolize serotonin taken by mouth. No significant correlations were found between the blood serotonin level and the platelet count, height, weight, skinfold thickness, and pulmonary function test, 5 out of 44 patients had raised serum IgE levels, and their mean blood serotonin was higher than in those with normal IgE levels. No explanation for this emerged. Comparable findings (raised blood serotonin normal platelet count, normal urinary 5-HIAA) have been reported only in severe mental retardation. Further study of this phenomenon is warranted because (a) a raised blood serotonin level is sufficiently characteristic of cystic fibrosis to explore its use in diagnosis, and (b) it may help to explain the pathogenesis of cystic fibrosis and (c) the metabolism and function of serotonin. PMID:869568

Partington, M W; Ferguson, A C



The dopamine system and alcohol dependence  

PubMed Central

summary Alcohol dependence is a common mental disorder that is associated with substantial disease burden. Current efforts at prevention and treatment of alcohol dependence are of very limited effectiveness. A better understanding of the biological mechanisms underlying dependence is essential to improving the outcomes of treatment and prevention initiatives. To date, most of the efforts have focused on the key role of the dopamine system in the complex etiological network of alcohol dependence. This review summarizes current research about the relationships between alcohol consumption and the dopaminergic system. We find that many of the currently available studies have contradictory results, presumably due to differences in methodology, non-linear dosage effects, use of different samples, and the possible confounding effects of other neurotransmitter systems. PMID:25092951

MA, Hui; ZHU, Gang



Chronic Citalopram Administration Causes a Sustained Suppression of Serotonin Synthesis in the Mouse Forebrain  

PubMed Central

Background Serotonin (5-HT) is a neurotransmitter with important roles in the regulation of neurobehavioral processes, particularly those regulating affect in humans. Drugs that potentiate serotonergic neurotransmission by selectively inhibiting the reuptake of serotonin (SSRIs) are widely used for the treatment of psychiatric disorders. Although the regulation of serotonin synthesis may be an factor in SSRI efficacy, the effect of chronic SSRI administration on 5-HT synthesis is not well understood. Here, we describe effects of chronic administration of the SSRI citalopram (CIT) on 5-HT synthesis and content in the mouse forebrain. Methodology/Principal Findings Citalopram was administered continuously to adult male C57BL/6J mice via osmotic minipump for 2 days, 14 days or 28 days. Plasma citalopram levels were found to be within the clinical range. 5-HT synthesis was assessed using the decarboxylase inhibition method. Citalopram administration caused a suppression of 5-HT synthesis at all time points. CIT treatment also caused a reduction in forebrain 5-HIAA content. Following chronic CIT treatment, forebrain 5-HT stores were more sensitive to the depleting effects of acute decarboxylase inhibition. Conclusions/Significance Taken together, these results demonstrate that chronic citalopram administration causes a sustained suppression of serotonin synthesis in the mouse forebrain. Furthermore, our results indicate that chronic 5-HT reuptake inhibition renders 5-HT brain stores more sensitive to alterations in serotonin synthesis. These results suggest that the regulation of 5-HT synthesis warrants consideration in efforts to develop novel antidepressant strategies. PMID:19710918

Honig, Gerard; Jongsma, Minke E.; van der Hart, Marieke C. G.; Tecott, Laurence H.



Tyrosine administration enhances dopamine synthesis and release in light-activated rat retina  

NASA Technical Reports Server (NTRS)

Exposure of dark-adapted albino rats to light (350 lux) significantly elevated retinal levels of the dopamine metabolite dihydroxyphenyl acetic acid during the next hour; their return to a dark environment caused dihydroxyphenyl acetic acid levels to fall. Retinal dopamine levels were increased slightly by light exposure, suggesting that the increase in dihydroxyphenyl acetic acid reflected accelerated dopamine synthesis. Administration of tyrosine (100 mg/kg, i.p.) further elevated retinal dihydroxyphenyl acetic acid among light-exposed animals, but failed to affect dopamine release among animals in the dark. These observations show that a physiological stimulus - light exposure - can cause catecholaminergic neurons to become tyrosine-dependent; they also suggest that food consumption may affect neurotransmitter release within the retina.

Gibson, C. J.; Watkins, C. J.; Wurtman, R. J.



Vesicular Glutamate Transport Promotes Dopamine Storage and Glutamate Corelease In Vivo  

PubMed Central

SUMMARY Dopamine neurons in the ventral tegmental area (VTA) play an important role in the motivational systems underlying drug addiction, and recent work has suggested that they also release the excitatory neurotransmitter glutamate. To assess a physiological role for glutamate corelease, we disrupted the expression of vesicular glutamate transporter 2 selectively in dopamine neurons. The conditional knockout abolishes glutamate release from midbrain dopamine neurons in culture and severely reduces their excitatory synaptic output in mesoaccumbens slices. Baseline motor behavior is not affected, but stimulation of locomotor activity by cocaine is impaired, apparently through a selective reduction of dopamine stores in the projection of VTA neurons to ventral striatum. Glutamate co-entry promotes monoamine storage by increasing the pH gradient that drives vesicular monoamine transport. Remarkably, low concentrations of glutamate acidify synaptic vesicles more slowly but to a greater extent than equimolar Cl?, indicating a distinct, presynaptic mechanism to regulate quantal size. PMID:20223200

Hnasko, Thomas S.; Chuhma, Nao; Zhang, Hui; Goh, Germaine Y.; Sulzer, David; Palmiter, Richard D.; Rayport, Stephen; Edwards, Robert H.



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



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



Central neurotransmitters and control of prolactin secretion  

E-print Network

Central neurotransmitters and control of prolactin secretion C. KORDON A. ENJALBERT L. CARBONELL of this control is the existence of a predominant inhibitory regulation, as demonstrated by a number of older and Tixier- Vidal, 1966), such stimulatory effects even appear more important than the inhibitory component

Boyer, Edmond


Regulation of Neurotransmitter Release by Metabotropic Glutamate Receptors  

E-print Network

receptors--Neurotransmitters--Synaptic transmission--Excitatory amino acids--Inhibitory amino acidsReview Regulation of Neurotransmitter Release by Metabotropic Glutamate Receptors Jayne Cartmell, such as excitatory and inhibitory amino acids, monoamines, and neuropeptides. Key Words: Metabo- tropic glutamate

Alford, Simon


Title : Involvement of D1 dopamine receptor in MDMA-induced locomotor activity and striatal gene expression in mice.  

E-print Network

, France Abstract 3,4-Methylenedioxymethamphetamine (MDMA), a widely used recreational drug with psychoactive properties, induces both serotonin and dopamine release in the brain. In rats and mice MDMA induces behavioural changes and has rewarding effects but little is known about its cellular effects. We

Paris-Sud XI, Université de


Modeling the glutamate–glutamine neurotransmitter cycle  

PubMed Central

Glutamate is the principal excitatory neurotransmitter in brain. Although it is rapidly synthesized from glucose in neural tissues the biochemical processes for replenishing the neurotransmitter glutamate after glutamate release involve the glutamate–glutamine cycle. Numerous in vivo 13C magnetic resonance spectroscopy (MRS) experiments since 1994 by different laboratories have consistently concluded: (1) the glutamate–glutamine cycle is a major metabolic pathway with a flux rate substantially greater than those suggested by early studies of cell cultures and brain slices; (2) the glutamate–glutamine cycle is coupled to a large portion of the total energy demand of brain function. The dual roles of glutamate as the principal neurotransmitter in the CNS and as a key metabolite linking carbon and nitrogen metabolism make it possible to probe glutamate neurotransmitter cycling using MRS by measuring the labeling kinetics of glutamate and glutamine. At the same time, comparing to non-amino acid neurotransmitters, the added complexity makes it more challenging to quantitatively separate neurotransmission events from metabolism. Over the past few years our understanding of the neuronal-astroglial two-compartment metabolic model of the glutamate–glutamine cycle has been greatly advanced. In particular, the importance of isotopic dilution of glutamine in determining the glutamate–glutamine cycling rate using [1?13C] or [1,6-13C2] glucose has been demonstrated and reproduced by different laboratories. In this article, recent developments in the two-compartment modeling of the glutamate–glutamine cycle are reviewed. In particular, the effects of isotopic dilution of glutamine on various labeling strategies for determining the glutamate–glutamine cycling rate are analyzed. Experimental strategies for measuring the glutamate–glutamine cycling flux that are insensitive to isotopic dilution of glutamine are also suggested. PMID:23372548

Shen, Jun



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)



Novel repeat polymorphisms of the dopaminergic neurotransmitter genes among dogs and wolves.  


Genetic polymorphisms of the neurotransmission systems are intensively studied in the human because of a possible influence on personality traits and the risk of psychiatric disorders. The investigation of genetic variations of the dog genome has recently been a promising approach, as a considerable similarity can be observed between dogs and humans, in both genetic and social aspects, suggesting that the dog could become an appropriate animal model of human behavioral genetic studies. The aim of our study was the identification and analysis of variable number of tandem repeats polymorphisms (VNTRs) in the genes of the dopaminergic neurotransmitter system of dogs. The in silico search was followed by the development of PCR-based techniques for the analysis of the putative VNTRs. Highly variable repetitive sequence regions were found in the tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine beta-hydroxylase (DBH) genes. Allele frequency and genotype distribution of these novel polymorphisms together with the exon 3 and exon 1 VNTR of the dopamine D4 receptor gene were determined in a large sample involving four dog breeds (German Shepherd, Belgian Tervueren, Groenandael, and Malinois) and European Grey Wolves. A significant difference of allele and genotype frequencies was demonstrated among the analyzed breeds; therefore, an association analysis was also carried out between the activity-impulsivity phenotype and the described VNTRs. Preliminary findings are presented that polymorphisms of the DRD4, DBH, and DAT genes can be associated with attention deficit among Belgian Tervuerens. PMID:18049838

Hejjas, Krisztina; Vas, Judit; Kubinyi, Eniko; Sasvari-Szekely, Maria; Miklosi, Adam; Ronai, Zsolt



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



Glutamate is an inhibitory neurotransmitter in the Drosophila olfactory system  

E-print Network

Glutamate is an inhibitory neurotransmitter in the Drosophila olfactory system Wendy W. Liu acts as an inhibitory neurotransmitter in the antennal lobe, broadly similar to the role of GABA GABA and glycine serve as the major inhibitory neurotransmitters. Like the vertebrate CNS

Wilson, Rachel


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


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



Human iPSC Neurons Display Activity-Dependent Neurotransmitter Secretion: Aberrant Catecholamine Levels in Schizophrenia Neurons  

PubMed Central

Summary This study investigated human-induced pluripotent stem cell (hiPSC) -derived neurons for their ability to secrete neurotransmitters in an activity-dependent manner, the fundamental property required for chemical neurotransmission. Cultured hiPSC neurons showed KCl stimulation of activity-dependent secretion of catecholamines—dopamine (DA), norepinephrine (NE), and epinephrine (Epi)—and the peptide neurotransmitters dynorphin and enkephlain. hiPSC neurons express the biosynthetic enzymes for catecholamines and neuropeptides. Because altered neurotransmission contributes to schizophrenia (SZ), we compared SZ to control cultures of hiPSC neurons and found that SZ cases showed elevated levels of secreted DA, NE, and Epi. Consistent with increased catecholamines, the SZ neuronal cultures showed a higher percentage of tyrosine hydroxylase (TH)-positive neurons, the first enzymatic step for catecholamine biosynthesis. These findings show that hiPSC neurons possess the fundamental property of activity-dependent neurotransmitter secretion and can be advantageously utilized to examine regulation of neurotransmitter release related to brain disorders. PMID:25358781

Hook, Vivian; Brennand, Kristen J.; Kim, Yongsung; Toneff, Thomas; Funkelstein, Lydiane; Lee, Kelly C.; Ziegler, Michael; Gage, Fred H.



Determination of isatin and monoamine neurotransmitters in rat brain with liquid chromatography using palladium hexacyanoferrate modified electrode.  


The fabrication and application of a novel electrochemical detector (ED) with palladium hexacyanoferrate (PdHCF) chemically modified electrode (CME) for liquid chromatography (LC) were described. The electrochemical behaviors of isatin, monoamine neurotransmitters and their metabolites at this CME were investigated by cyclic voltammetry. It was found that the CME exhibited efficiently electrocatalytic of isatin and showed high sensitivity and stability for determination of monoamine neurotransmitters. The linear ranges were over three orders of magnitude and the detection limits were 2.5 x 10(-8) mol L(-1) for isatin, 2.5 x 10(-10) mol L(-1) for norepinephrine (NE), 2.5 x 10(-10) mol L(-1) for 5-hydroxyindoleacetic acid (5-HIAA), 5.0 x 10(-10) mol L(-1) for dopamine (DA), 1.0 x 10(-9)mol L(-1) for 3,4-dihydroxyphenylacetic acid (DOPAC), 1.2 x 10(-10) mol L(-1) for 5-hydroxytryptamine (5-HT) and 2.5 x 10(-9)mol L(-1) for homovanillic acid (HVA). Combined with microdialysis, the method was successfully applied to study the effect of isatin on the levels of monoamine neurotransmitters in experimental Parkinsonian rats. The results showed that isatin could significantly increase striatal monoamine neurotransmitters release to the basal level. PMID:17723673

Xu, Haihong; Wang, Dan; Zhang, Wen; Zhu, Wei; Yamamoto, Katsunobu; Jin, Litong



6R-Tetrahydrobiopterin induces dopamine synthesis in a human neuroblastoma cell line, LA-N-1. A cellular model of DOPA-responsive dystonia.  


Dopa-responsive dystonia (DRD) is an extrapyramidal disorder caused by deficit of 5,6,7,8-tetrahydrobiopterin (BH4), cofactor for tyrosine hydroxylase (TH). In these patients the nigrostriatal dopaminergic neurons normally express TH and the cellular machinery for the dopamine uptake. LA-N-1 is a human neuroblastoma cell line expressing tyrosine hydroxylase. Here we show that LA-N-1 cells are able to take up exogenous dopamine (DA) by an high-affinity mechanism; significant amounts of serotonin and its metabolite 5HIAA, but neither DA nor its metabolites, DOPAC and HVA, could be measured in the cell culture homogenate. 5,6,7,8-Tetrahydrobiopterin, cofactor for both tyrosine and tryptophan hydroxylases, is able to activate dopamine synthesis and also decreases the content of 5HIAA by 50%, indicating that LA-N-1 might be a useful model for studying dopamine-serotonin interaction in cultured cells and the neuronal mechanism of DRD. PMID:12101048

Zuddas, Alessandro; Mancosu, Cristina; Lilliu, Vanessa; Sorrentino, Giuseppe; di Porzio, Umberto; Cianchetti, Carlo



Dopamine Controls Systemic Inflammation through Inhibition of NLRP3 Inflammasome.  


Inflammasomes are involved in diverse inflammatory diseases, so the activation of inflammasomes needs to be tightly controlled to prevent excessive inflammation. However, the endogenous regulatory mechanisms of inflammasome activation are still unclear. Here, we report that the neurotransmitter dopamine (DA) inhibits NLRP3 inflammasome activation via dopamine D1 receptor (DRD1). DRD1 signaling negatively regulates NLRP3 inflammasome via a second messenger cyclic adenosine monophosphate (cAMP), which binds to NLRP3 and promotes its ubiquitination and degradation via the E3 ubiquitin ligase MARCH7. Importantly, in vivo data show that DA and DRD1 signaling prevent NLRP3 inflammasome-dependent inflammation, including neurotoxin-induced neuroinflammation, LPS-induced systemic inflammation, and monosodium urate crystal (MSU)-induced peritoneal inflammation. Taken together, our results reveal an endogenous mechanism of inflammasome regulation and suggest DRD1 as a potential target for the treatment of NLRP3 inflammasome-driven diseases. PMID:25594175

Yan, Yiqing; Jiang, Wei; Liu, Lei; Wang, Xiaqiong; Ding, Chen; Tian, Zhigang; Zhou, Rongbin



Studies on possible mechanisms of action of electroconvulsive therapy; effects of repeated electrically induced seizures on rat brain receptors for monoamines and other neurotransmitters  

Microsoft Academic Search

There is evidence that repeated electroconvulsive shocks (ECS) in rats potentiate dopamine (DA)-, serotonin (5HT)- and a-noradrenergic (a-NA)-mediated drug-induced behaviour and reduce opiate-induced behaviours. These studies suggest changes at the level of the receptor or beyond. However, high affinity in vitro 3H-ligand binding studies in brain membranes from ECS-treated control rats failed to demonstrate generalized ECS-induced changes in 5HT, DA,

J. F. W. Deakin; F. Owen; A. J. Cross; M. J. Dashwood



Effects of Delta9Tetrahydrocannabinol, Cannabinol and Cannabidiol, Alone and in Combinations, on Luteinizing Hormone and Prolactin Release and on Hypothalamic Neurotransmitters in the Male Rat  

Microsoft Academic Search

The acute effects of low oral doses of ?9-tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiol (CBD) administered alone or in combinations on LH and prolactin (PRL) secretion and on hypothalamic norepinephrine (NE), dopamine (DA) and serotonin (5-HI) dynamics were examined in adult male rats. Plasma LH levels were significantly reduced 60 min after administration of 0.5 mgTHC\\/kg body weight and 30,

Laura L. Murphy; Richard W. Steger; Susan Smith; Andrzej Bartke



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


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



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.


Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo  

PubMed Central

Disruption of neurotransmitter vesicle dynamics (transport, capacity, release) has been implicated in a variety of neurodegenerative and neuropsychiatric conditions. Here, we report a novel mouse model of enhanced vesicular function via bacterial artificial chromosome (BAC)-mediated overexpression of the vesicular monoamine transporter 2 (VMAT2; Slc18a2). A twofold increase in vesicular transport enhances the vesicular capacity for dopamine (56%), dopamine vesicle volume (33%), and basal tissue dopamine levels (21%) in the mouse striatum. The elevated vesicular capacity leads to an increase in stimulated dopamine release (84%) and extracellular dopamine levels (44%). VMAT2-overexpressing mice show improved outcomes on anxiety and depressive-like behaviors and increased basal locomotor activity (41%). Finally, these mice exhibit significant protection from neurotoxic insult by the dopaminergic toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), as measured by reduced dopamine terminal damage and substantia nigra pars compacta cell loss. The increased release of dopamine and neuroprotection from MPTP toxicity in the VMAT2-overexpressing mice suggest that interventions aimed at enhancing vesicular capacity may be of therapeutic benefit in Parkinson disease. PMID:24979780

Lohr, Kelly M.; Bernstein, Alison I.; Stout, Kristen A.; Dunn, Amy R.; Lazo, Carlos R.; Alter, Shawn P.; Wang, Minzheng; Li, Yingjie; Fan, Xueliang; Hess, Ellen J.; Yi, Hong; Vecchio, Laura M.; Goldstein, David S.; Guillot, Thomas S.; Salahpour, Ali; Miller, Gary W.



Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo.  


Disruption of neurotransmitter vesicle dynamics (transport, capacity, release) has been implicated in a variety of neurodegenerative and neuropsychiatric conditions. Here, we report a novel mouse model of enhanced vesicular function via bacterial artificial chromosome (BAC)-mediated overexpression of the vesicular monoamine transporter 2 (VMAT2; Slc18a2). A twofold increase in vesicular transport enhances the vesicular capacity for dopamine (56%), dopamine vesicle volume (33%), and basal tissue dopamine levels (21%) in the mouse striatum. The elevated vesicular capacity leads to an increase in stimulated dopamine release (84%) and extracellular dopamine levels (44%). VMAT2-overexpressing mice show improved outcomes on anxiety and depressive-like behaviors and increased basal locomotor activity (41%). Finally, these mice exhibit significant protection from neurotoxic insult by the dopaminergic toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), as measured by reduced dopamine terminal damage and substantia nigra pars compacta cell loss. The increased release of dopamine and neuroprotection from MPTP toxicity in the VMAT2-overexpressing mice suggest that interventions aimed at enhancing vesicular capacity may be of therapeutic benefit in Parkinson disease. PMID:24979780

Lohr, Kelly M; Bernstein, Alison I; Stout, Kristen A; Dunn, Amy R; Lazo, Carlos R; Alter, Shawn P; Wang, Minzheng; Li, Yingjie; Fan, Xueliang; Hess, Ellen J; Yi, Hong; Vecchio, Laura M; Goldstein, David S; Guillot, Thomas S; Salahpour, Ali; Miller, Gary W



Membrane receptors for hormones and neurotransmitters  

PubMed Central

Receptors for peptide hormones and neurotransmitters are integral components of the plasma membrane of cells which serve to couple the external milieu to the intracellular regulators of metabolism. These macromolecules are usually high molecular weight glycoproteins, and in many cases appear to have more than one subunit capable of binding the hormone. The interaction of the hormone or neurotransmitter with its receptor is rapid, reversible, and of high affinity and specificity. Many receptors exhibit cooperative properties in hormone binding or biological function. The concentration of receptors on the membrane is a function of continued synthesis and degradation, and may be altered by a variety of factors including the hormone itself. The fluid mosaic nature of the membrane may allow hormone receptors and effectors to exist in free floating states. Further investigations of the hormone- receptor interaction will no doubt yield new insights into both the mechanism of hormone action and membrane structure and function. PMID:7569



The Iowa Gambling Task and the three fallacies of dopamine in gambling disorder  

PubMed Central

Gambling disorder sufferers prefer immediately larger rewards despite long term losses on the Iowa Gambling Task (IGT), and these impairments are associated with dopamine dysfunctions. Dopamine is a neurotransmitter linked with temporal and structural dysfunctions in substance use disorder, which has supported the idea of impaired decision-making and dopamine dysfunctions in gambling disorder. However, evidence from substance use disorders cannot be directly transferred to gambling disorder. This article focuses on three hypotheses of dopamine dysfunctions in gambling disorder, which appear to be “fallacies,” i.e., have not been supported in a series of positron emission tomography (PET) studies. The first “fallacy” suggests that gambling disorder sufferers have lower dopamine receptor availability, as seen in substance use disorders. However, no evidence supported this hypothesis. The second “fallacy” suggests that maladaptive decision-making in gambling disorder is associated with higher dopamine release during gambling. No evidence supported the hypothesis, and the literature on substance use disorders offers limited support for this hypothesis. The third “fallacy” suggests that maladaptive decision-making in gambling disorder is associated with higher dopamine release during winning. The evidence did not support this hypothesis either. Instead, dopaminergic coding of reward prediction and uncertainty might better account for dopamine dysfunctions in gambling disorder. Studies of reward prediction and reward uncertainty show a sustained dopamine response toward stimuli with maximum uncertainty, which may explain the continued dopamine release and gambling despite losses in gambling disorder. The findings from the studies presented here are consistent with the notion of dopaminergic dysfunctions of reward prediction and reward uncertainty signals in gambling disorder. PMID:24115941

Linnet, Jakob



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.



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



Serotonin is a Sword and a Shield of the Bowel: Serotonin Plays Offense and Defense  

PubMed Central

The gut contains the bulk of the body's serotonin (5-hydroxytryptamine, 5-HT); nevertheless, the physiological role that enteric 5-HT plays has not been determined. 5-HT is linked to gastrointestinal (GI) motility; increased intraluminal pressure causes enterochromaffin (EC) cells to secrete 5-HT, which stimulates intrinsic primary afferent neurons that initiate peristaltic reflexes. 5-HT is also an enteric neurotransmitter. Surprisingly, deletion of tryptophan hydroxylase-1 (TPH1), upon which 5-HT biosynthesis in EC cells depends, does not alter constitutive GI motility, whereas deletion of TPH2, upon which biosynthesis of neuronal 5-HT depends, slows intestinal transit and accelerates gastric emptying. TPH1 deletion, however, protects mice from experimental inflammation; 5-HT potentiation and TPH2 deletion each make inflammation more severe. Neuronal 5-HT is neuroprotective and recruits stem cells to give rise to new enteric neurons in adult mice. Mucosal 5-HT, therefore, may mobilize inflammatory effectors, which protect the gut from invasion, whereas neuronal 5-HT shields enteric neurons from inflammatory damage. PMID:23303993

Gershon, Michael D.



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



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.



Serotonin neurotransmission in anorexia nervosa.  


Patients with anorexia nervosa (AN) show extreme dieting weight loss, hyperactivity, depression/anxiety, self-control, and behavioral impulsivity. 5-Hydroxytryptamine (5-HT; serotonin) is involved in almost all the behavioral changes observed in AN patients. Both genetic and environmental factors contribute toward the pathogenesis of AN. It is a frequent disorder among adolescent girls and young women and starts as an attempt to lose weight to look beautiful and attractive. Failure to see the turning point when fasting becomes unreasonable leads to malnutrition and AN. Tryptophan, the precursor of serotonin and an essential amino acid, is only available in the diet. It is therefore likely that excessive diet restriction and malnutrition decrease brain serotonin stores because the precursor is less available to the rate-limiting enzyme of 5-HT biosynthesis, which normally exists unsaturated with its substrate. Evidence shows that diet restriction-induced exaggerated feedback control over 5-HT synthesis and the smaller availability of tryptophan decreases serotonin neurotransmission at postsynaptic sites, leading to hyperactivity, depression, and behavioral impulsivity. A compensatory upregulation of postsynaptic 5-HT-1A receptors and hypophagic serotonin receptors may be involved in anxiety and suppression of appetite. It is suggested that tryptophan supplementation may improve pharmacotherapy in AN. PMID:22854305

Haleem, Darakhshan Jabeen



MicroRNA-132 dysregulation in Toxoplasma gondii infection has implications for dopamine signaling pathway  

PubMed Central

Congenital toxoplasmosis and toxoplasmic encephalitis can be associated with severe neuropsychiatric symptoms. However, which host cell processes are regulated and how Toxoplasma gondii affects these changes remain unclear. MicroRNAs (miRNAs) are small noncoding RNA sequences critical to neurodevelopment and adult neuronal processes by coordinating the activity of multiple genes within biological networks. We examined the expression of over 1000 miRNAs in human neuroepithelioma cells in response to infection with Toxoplasma. MiR-132, a cyclic AMP-responsive element binding (CREB)-regulated miRNA, was the only miRNA that was substantially upregulated by all three prototype Toxoplasma strains. The increased expression of miR-132 was also documented in mice following infection with Toxoplasma. To identify cellular pathways regulated by miR-132, we performed target prediction followed by pathway enrichment analysis in the transcriptome of Toxoplasma-infected mice. This led us to identify 20 genes and dopamine receptor signaling was their strongest associated pathway. We then examined myriad aspects of the dopamine pathway in the striatum of Toxoplasma infected mice 5 days after infection. Here we report decreased expression of D1-like dopamine receptors (DRD1, DRD5), metabolizing enzyme (MAOA) and intracellular proteins associated with the transduction of dopamine-mediated signaling (DARPP-32 phosphorylation at Thr34 and Ser97). Increased concentrations of dopamine and its metabolites, serotonin and 5-hydroxyindoleacetic acid were documented by HPLC analysis; however, the metabolism of dopamine was decreased and serotonin metabolism was unchanged. Our data show that miR-132 is upregulated following infection with Toxoplasma and is associated with changes in dopamine receptor signaling. Our findings provide a possible mechanism for how the parasite contributes to the neuropathology of infection. PMID:24657774

Xiao, Jianchun; Li, Ye; Prandovszky, Emese; Karuppagounder, Senthilkumar S.; Talbot, C. Conover; Dawson, Valina L.; Dawson, Ted M.; Yolken, Robert H.



Asenapine Increases Dopamine, Norepinephrine, and Acetylcholine Efflux in the Rat Medial Prefrontal Cortex and Hippocampus  

Microsoft Academic Search

Atypical antipsychotic drugs, which are more potent direct acting antagonists of brain serotonin (5-HT)2A than dopamine (DA) D2 receptors, preferentially enhance DA and acetylcholine (ACh) efflux in the rat medial prefrontal cortex (mPFC) and hippocampus (HIP), compared with the nucleus accumbens (NAc). These effects may contribute to their ability, albeit limited, to improve cognitive function and negative symptoms in patients

Mei Huang; Zhu Li; Jin Dai; Mohammed Shahid; Erik H F Wong; Herbert Y Meltzer



Azepines and Piperidines with Dual Norepinephrine Dopamine Uptake Inhibition and Antidepressant Activity  

PubMed Central

Herein, we describe the discovery of inhibitors of norepinephrine (NET) and dopamine (DAT) transporters with reduced activity relative to serotonin transporters (SERT). Two compounds, 8b and 21a, along with nomifensine were tested in a rodent receptor occupancy study and demonstrated dose-dependent displacement of radiolabeled NET and DAT ligands. These compounds were efficacious in a rat forced swim assay (model of depression) and also had activity in rat spontaneous locomotion assay. PMID:24900562



Dopamine uptake in platelets: Two different low-affinity, saturable mechanisms  

Microsoft Academic Search

Uptake of dopamine (DA) in human blood platelets was found to encompass two different saturable components, one chloride-dependent and one non-chloride-dependent. The chloride-dependent uptake had an apparentKm of about 4×10?5M, was strongly inhibited by serotonin (5HT), and moderately inhibited by ouabain, PHMB and by substituting K+ for Na+ in the incubation medium. The antidepressants imipramine, clomipramine, desipramine and nomifensine showed

O. Lingjærde; O. Kildemo



Comparative quantitative aspects of putative neurotransmitters in the central nervous system of spiders (Arachnida: Araneida).  


The amounts of eight putative neurotransmitters or modulators (acetylcholine, dopamine, noradrenaline, adrenaline, GABA, taurine, glutamic acid, glycine) were determined from the CNS of 12 species of five different spider families (Theraphosidae, Agelenidae, Araneidae, Lycosidae, Salticidae). Comparatively high contents of acetylcholine and noradrenaline could be found in the CNS of hunting spiders, higher contents of GABA and taurine were visible in the web-building spider families, while extraordinarily high amounts of glutamic acid were confined to the Theraphosidae. The results obtained are compared with findings from other arthropod groups and the role of putative transmitters or modulators in the spider CNS is discussed in relation to behavioural differences within the families investigated. PMID:6149080

Meyer, W; Schlesinger, C; Poehling, H M; Ruge, W



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



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.



Restoration of Dopamine Release Deficits during Object Recognition Memory Acquisition Attenuates Cognitive Impairment in a Triple Transgenic Mice Model of Alzheimer's Disease  

ERIC Educational Resources Information Center

Previous findings indicate that the acquisition and consolidation of recognition memory involves dopaminergic activity. Although dopamine deregulation has been observed in Alzheimer's disease (AD) patients, the dysfunction of this neurotransmitter has not been investigated in animal models of AD. The aim of this study was to assess, by in vivo…

Guzman-Ramos, Kioko; Moreno-Castilla, Perla; Castro-Cruz, Monica; McGaugh, James L.; Martinez-Coria, Hilda; LaFerla, Frank M.; Bermudez-Rattoni, Federico



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



A mechanism for intracellular release of Na+ by neurotransmitter/sodium symporters.  


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



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.



The gut-brain dopamine axis: a regulatory system for caloric intake.  


Post-ingestive factors are known to strongly modulate feeding behavior by providing feedback signals to the central nervous system on the current physiological state of the organism. Of particular interest is the identification of the physiological pathways that permit the brain to sense post-ingestive signals. We will review recent evidence supporting the concept that direct stimulation of the gastrointestinal tract with nutrients induces release of the catecholamine neurotransmitter dopamine. In addition, changes in dopamine efflux produced by direct stimulation of the gastrointestinal tract were found to reflect the caloric load of the infusates, suggesting that dopamine signaling may function as a central caloric sensor that mediates adjustments in intake according to the caloric density of a meal. Consistent with the above, blockade of dopamine signaling disrupts flavor-nutrient associations and impairs the regulatory capacity to maintain constant caloric intake during intra-gastric feeding. Future research must determine the exact pathways linking gut nutrient administration to dopamine efflux. Current evidence points to parallel contributions by pre- and post-absorptive pathways, indicating that dopamine systems constitute a site of convergence through which distinct physiological signals can exert control over ingestive behaviors. PMID:22406348

de Araujo, Ivan E; Ferreira, Jozélia G; Tellez, Luis A; Ren, Xueying; Yeckel, Catherine W



Dopamine Controls the Neural Dynamics of Memory Signals and Retrieval Accuracy  

PubMed Central

The human brain is capable of differentiating between new and already stored information rapidly to allow optimal behavior and decision-making. Although the neural mechanisms of novelty discrimination were often described as temporally constant (ie, with specific latencies), recent electrophysiological studies have demonstrated that the onset of neural novelty signals (ie, differences in event-related responses to new and old items) can be accelerated by reward motivation. While the precise physiological mechanisms underlying this acceleration remain unclear, the involvement of the neurotransmitter dopamine in both novelty and reward processing suggests that enhanced dopamine levels in the context of reward prospect may have a role. To investigate this hypothesis, we used magnetoencephalography (MEG) in combination with an old/new recognition memory task in which correct discrimination between old and new items was rewarded. Importantly, before the task, human subjects received either 150?mg of the dopamine precursor levodopa or placebo. For the placebo group, old/new signals peaked at ?100?ms after stimulus onset over left temporal/occipital sensors. In contrast, after levodopa administration earliest old/new effects only emerged after ?400?ms and retrieval accuracy was reduced as expressed in lower d? values. As such, our results point towards a previously unreported role of dopamine in controlling the chronometry of neural processes underlying the distinction between old and new information. They also suggest that this relationship follows a nonlinear function whereby slightly enhanced dopamine levels accelerate neural/cognitive processes and excessive dopamine levels impair them. PMID:23728140

Apitz, Thore; Bunzeck, Nico