Lung damage and pulmonary uptake of serotonin in intact dogs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dawson, C.A.; Christensen, C.W.; Rickaby, D.A.

1985-06-01

The authors examined the influence of glass bead embolization and oleic acid, dextran, and imipramine infusion on the pulmonary uptake of trace doses of (/sup 3/H)serotonin and the extravascular volume accessible to (/sup 14/C)antipyrine in anesthetized dogs. Embolization and imipramine decreased serotonin uptake by 53 and 61%, respectively, but no change was observed with oleic acid or dextran infusion. The extravascular volume accessible to the antipyrine was reduced by 77% after embolization and increased by 177 and approximately 44% after oleic acid and dextran infusion, respectively. The results suggest that when the perfused endothelial surface is sufficiently reduced, as withmore » embolization, the uptake of trace doses of serotonin will be depressed. In addition, decreases in serotonin uptake in response to imipramine in this study and in response to certain endothelial toxins in other studies suggest that serotonin uptake can reveal certain kinds of changes in endothelial function. However, the lack of a response to oleic acid-induced damage in the present study suggests that serotonin uptake is not sensitive to all forms of endothelial damage.« less

Serotonin release varies with brain tryptophan levels

NASA Technical Reports Server (NTRS)

Schaechter, Judith D.; Wurtman, Richard J.

1990-01-01

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.

Serotonin uptake inhibitors: uses in clinical therapy and in laboratory research.

PubMed

Fuller, R W

1995-01-01

Fluoxetine, zimelidine, sertraline, paroxetine, fluvoxamine, indalpine and citalopram are the selective inhibitors of serotonin uptake that have been most widely studied. Some of these compounds are or have been used clinically in the treatment of mental depression, obsessive-compulsive disorder and bulimia, and therapeutic benefit has been claimed in additional diseases as well. By blocking the membrane uptake carrier which transports serotonin from the extracellular space to inside the serotonin nerve terminals, these compounds increase extracellular concentrations of serotonin and amplify signals sent by serotonin neurons. Because serotonin neurons are widespread in the central nervous system, the functional consequences of blocking serotonin uptake are diverse, but are generally subtle. Animals treated with serotonin uptake inhibitors look normal in gross appearance, but effects such as reduced aggressive behavior, decreased food intake and altered food selection, analgesia, anticonvulsant activity, endocrine changes and neurochemical changes have been demonstrated and characterized. Serotonin uptake inhibitors have helped in revealing some dynamics of serotonin neurons; for example, when uptake is inhibited and extracellular serotonin concentration increases, presynaptic as well as postsynaptic receptors for serotonin are activated to a greater degree. A consequence of increased activation of autoreceptors on serotonin cell bodies and nerve terminals is a reduction in firing of serotonin neurons and a decrease in serotonin synthesis and release. The result is a limit on the degree to which extracellular serotonin and serotonergic neurotransmission are increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Type I Interferon-Mediated Skewing of the Serotonin Synthesis Is Associated with Severe Disease in Systemic Lupus Erythematosus

PubMed Central

Lood, Christian; Tydén, Helena; Gullstrand, Birgitta; Klint, Cecilia; Wenglén, Christina; Nielsen, Christoffer T.; Heegaard, Niels H. H.; Jönsen, Andreas; Kahn, Robin; Bengtsson, Anders A.

2015-01-01

Serotonin, a highly pro-inflammatory molecule released by activated platelets, is formed by tryptophan. Tryptophan is also needed in the production of kynurenine, a process mediated by the type I interferon (IFN)-regulated rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO). The aim of this study was to investigate levels of serotonin in patients with the autoimmune disease systemic lupus erythematosus (SLE), association to clinical phenotype and possible involvement of IDO in regulation of serotonin synthesis. Serotonin levels were measured in serum and plasma from patients with SLE (n=148) and healthy volunteers (n=79) by liquid chromatography and ELISA, as well as intracellularly in platelets by flow cytometry. We found that SLE patients had decreased serotonin levels in serum (p=0.01) and platelets (p<0.0001) as compared to healthy individuals. SLE patients with ongoing type I IFN activity, as determined by an in-house reporter assay, had decreased serum levels of serotonin (p=0.0008) as well as increased IDO activity (p<0.0001), as determined by the kynurenine/tryptophan ratio measured by liquid chromatography. Furthermore, SLE sera induced IDO expression in WISH cells in a type I IFN-dependent manner (p=0.008). Also platelet activation contributed to reduce overall availability of serotonin levels in platelets and serum (p<0.05). Decreased serum serotonin levels were associated with severe SLE with presence of anti-dsDNA antibodies and nephritis. In all, reduced serum serotonin levels in SLE patients were related to severe disease phenotype, including nephritis, suggesting involvement of important immunopathological processes. Further, our data suggest that type I IFNs, present in SLE sera, are able to up-regulate IDO expression, which may lead to decreased serum serotonin levels. PMID:25897671

Serotonin Neuron Abnormalities in the BTBR Mouse Model of Autism

PubMed Central

Guo, Yue-Ping; Commons, Kathryn G.

2017-01-01

The inbred mouse strain BTBR T+ Itpr3tf/J (BTBR) i studied as a model of idiopathic autism because they are less social and more resistant to change than other strains. Forebrain serotonin receptors and the response to serotonin drugs are altered in BTBR mice, yet it remains unknown if serotonin neurons themselves are abnormal. In this study, we found that serotonin tissue content and the density of serotonin axons is reduced in the hippocampus of BTBR mice in comparison to C57BL/6J (C57) mice. This was accompanied by possible compensatory changes in serotonin neurons that were most pronounced in regions known to provide innervation to the hippocampus: the caudal dorsal raphe (B6) and the median raphe. These changes included increased numbers of serotonin neurons and hyperactivation of Fos expression. Metrics of serotonin neurons in the rostral 2/3 of the dorsal raphe and serotonin content of the prefrontal cortex were less impacted. Thus, serotonin neurons exhibit region-dependent abnormalities in the BTBR mouse that may contribute to their altered behavioral profile. PMID:27478061

Melatonin and its precursors in Y79 human retinoblastoma cells: Effect of sodium butyrate

NASA Technical Reports Server (NTRS)

Deng, Mei Hua; Coviella, Ignacio Lopez G.; Lynch, Harry J.; Wurtman, Richard J.

1991-01-01

The release of melatonin and the production of its precursors, S-hydroxytryptophan and serotonin, in cultured Y79 human retinoblastoma cells were studied. This biosynthetic capability was found to be dependent on cell differentiation, which was initiated by culturing Y79 cells for 7 days in dishes coated with poly-D-lysine to promote cell adhesion to the surface of the culture dishes. Differentiation was further induced by exposing the cell monolayer to sodium butyrate (3 mM) for 3 days. This protocol dramatically increased the release of melatonin, and the syntheses of 5-hydroxytryptophan and serotonin in response to forskolin stimulation. Exposure to dopamine (10 micro-M) or L-DOPA (100 micro-M) markedly diminished the forskolin-stimulated release of melatonin, as well as the production of 5-hydroxytryptophan and serotonin. These observations indicate that Y79 cells represent a primitive cell line which, following appropriate differentiation (e.g. treatment with sodium butyrate) can display biochemical characteristics similar to those of the human retina. Moreover, serotonin synthesis and melatonin release appear to be coupled in Y79 cells. The inhibition of melatonin release by dopamine supports the hypothesis that in these cells, melatonin and dopamine are components of a retinal feedback loop.

The serotonergic system and anxiety.

PubMed

Gordon, Joshua A; Hen, Rene

2004-01-01

The wide use of serotonin reuptake inhibitors and serotonin receptor agonists in anxiety disorders has suggested a key role for the modulatory neurotransmitter in anxiety. However, serotonin's specific role is still uncertain. This article reviews the literature concerning how and where serotonergic agents modulate anxiety. Varying and sometimes conflicting data from human and animal studies argue for both anxiolytic and anxiogenic roles for serotonin, depending on the specific disorder, structure, or behavioral task studied. However, recent data from molecular genetic studies in the mouse point toward two important roles for the serotonin 1A receptor. In development, serotonin acts through this receptor to promote development of the circuitry necessary for normal anxiety-like behaviors. In adulthood, serotonin reuptake inhibitors act through the same receptor to stimulate neurogenesis and reduce anxiety-like behaviors. These studies highlight that the complex serotonin system likely plays various roles in the regulation of anxiety both during development and in adulthood.

Acute pharmacologically induced shifts in serotonin availability abolish emotion-selective responses to negative face emotions in distinct brain networks.

PubMed

Grady, Cheryl L; Siebner, Hartwig R; Hornboll, Bettina; Macoveanu, Julian; Paulson, Olaf B; Knudsen, Gitte M

2013-05-01

Pharmacological manipulation of serotonin availability can alter the processing of facial expressions of emotion. Using a within-subject design, we measured the effect of serotonin on the brain's response to aversive face emotions with functional MRI while 20 participants judged the gender of neutral, fearful and angry faces. In three separate and counterbalanced sessions, participants received citalopram (CIT) to raise serotonin levels, underwent acute tryptophan depletion (ATD) to lower serotonin, or were studied without pharmacological challenge (Control). An analysis designed to identify distributed brain responses identified two brain networks with modulations of activity related to face emotion and serotonin level. The first network included the left amygdala, bilateral striatum, and fusiform gyri. During the Control session this network responded only to fearful faces; increasing serotonin decreased this response to fear, whereas reducing serotonin enhanced the response of this network to angry faces. The second network involved bilateral amygdala and ventrolateral prefrontal cortex, and these regions also showed increased activity to fear during the Control session. Both drug challenges enhanced the neural response of this set of regions to angry faces, relative to Control, and CIT also enhanced activity for neutral faces. The net effect of these changes in both networks was to abolish the selective response to fearful expressions. These results suggest that a normal level of serotonin is critical for maintaining a differentiated brain response to threatening face emotions. Lower serotonin leads to a broadening of a normally fear-specific response to anger, and higher levels reduce the differentiated brain response to aversive face emotions. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

Serotonin neuron abnormalities in the BTBR mouse model of autism.

PubMed

Guo, Yue-Ping; Commons, Kathryn G

2017-01-01

The inbred mouse strain BTBR T + Itpr3 tf /J (BTBR) is studied as a model of idiopathic autism because they are less social and more resistant to change than other strains. Forebrain serotonin receptors and the response to serotonin drugs are altered in BTBR mice, yet it remains unknown if serotonin neurons themselves are abnormal. In this study, we found that serotonin tissue content and the density of serotonin axons is reduced in the hippocampus of BTBR mice in comparison to C57BL/6J (C57) mice. This was accompanied by possible compensatory changes in serotonin neurons that were most pronounced in regions known to provide innervation to the hippocampus: the caudal dorsal raphe (B6) and the median raphe. These changes included increased numbers of serotonin neurons and hyperactivation of Fos expression. Metrics of serotonin neurons in the rostral 2/3 of the dorsal raphe and serotonin content of the prefrontal cortex were less impacted. Thus, serotonin neurons exhibit region-dependent abnormalities in the BTBR mouse that may contribute to their altered behavioral profile. Autism Res 2017, 10: 66-77. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Brain Histamine Is Crucial for Selective Serotonin Reuptake Inhibitors‘ Behavioral and Neurochemical Effects

PubMed Central

Munari, Leonardo; Provensi, Gustavo; Passani, Maria Beatrice; Galeotti, Nicoletta; Cassano, Tommaso; Benetti, Fernando; Corradetti, Renato

2015-01-01

Backgound: The neurobiological changes underlying depression resistant to treatments remain poorly understood, and failure to respond to selective serotonin reuptake inhibitors may result from abnormalities of neurotransmitter systems that excite serotonergic neurons, such as histamine. Methods: Using behavioral (tail suspension test) and neurochemical (in vivo microdialysis, Western-blot analysis) approaches, here we report that antidepressant responses to selective serotonin reuptake inhibitors (citalopram or paroxetine) are abolished in mice unable to synthesize histamine due to either targeted disruption of histidine decarboxylase gene (HDC-/-) or injection of alpha-fluoromethylhistidine, a suicide inhibitor of this enzyme. Results: In the tail suspension test, all classes of antidepressants tested reduced the immobility time of controls. Systemic reboxetine or imipramine reduced the immobility time of histamine-deprived mice as well, whereas selective serotonin reuptake inhibitors did not even though their serotonergic system is functional. In in vivo microdialysis experiments, citalopram significantly increased histamine extraneuronal levels in the cortex of freely moving mice, and methysergide, a serotonin 5-HT1/5-HT2 receptor antagonist, abolished this effect, thus suggesting the involvement of endogenous serotonin. CREB phosphorylation, which is implicated in the molecular mechanisms of antidepressant treatment, was abolished in histamine-deficient mice treated with citalopram. The CREB pathway is not impaired in HDC-/- mice, as administration of 8-bromoadenosine 3’, 5’-cyclic monophosphate increased CREB phosphorylation, and in the tail suspension test it significantly reduced the time spent immobile by mice of both genotypes. Conclusions: Our results demonstrate that selective serotonin reuptake inhibitors selectively require the integrity of the brain histamine system to exert their preclinical responses. PMID:25899065

Symptoms of depression and anxiety in anorexia nervosa: links with plasma tryptophan and serotonin metabolism.

PubMed

Gauthier, Claire; Hassler, Christine; Mattar, Lama; Launay, Jean-Marie; Callebert, Jacques; Steiger, Howard; Melchior, Jean-Claude; Falissard, Bruno; Berthoz, Sylvie; Mourier-Soleillant, Virginie; Lang, François; Delorme, Marc; Pommereau, Xavier; Gerardin, Priscille; Bioulac, Stephanie; Bouvard, Manuel; Godart, Nathalie

2014-01-01

Depressive, anxiety and obsessive symptoms frequently co-occur with anorexia nervosa (AN). The relationship between these clinical manifestations and the biological changes caused by starvation is not well understood. It has been hypothesised that reduced availability of tryptophan (TRP) could reduce serotonin activity and thus trigger these comorbid symptoms. The aim of this study, during re-feeding in individuals with AN, was to analyse covariations across measures of nutritional status, depressive and anxiety symptoms, and peripheral serotonin markers. Depressive and anxiety symptoms, nutritional status and serotonin markers--whole blood serotonin content, plasma TRP and the ratio between TRP and large neutral amino acids--were assessed for 42 AN participants at admission to inpatient treatment and after re-feeding. Biological measures were compared to those obtained in 42 non-eating disordered subjects. For those with AN, psychological, nutritional and biological parameters improved significantly during hospitalisation. Levels of serotonin markers were significantly lower in the AN group compared to the control group, at admission and at discharge. Increase in the TRP/LNAA ratio was correlated with a decrease in depressive symptoms. In addition, there was a positive correlation between serotonin levels and symptoms of both anxiety and depression at discharge. We speculate that enhanced TRP availability during re-feeding, as a result of the increase in the TRP/LNAA ratio, could restore serotonin neurotransmission and lead to a decrease in depressive symptoms. The association between serotonin and anxiety and depressive symptoms would be consistent with numerous observations indicating abnormal functioning of the serotoninergic system in AN. Copyright © 2013 Elsevier Ltd. All rights reserved.

Aging and depression vulnerability interaction results in decreased serotonin innervation associated with reduced BDNF levels in hippocampus of rats bred for learned helplessness.

PubMed

Aznar, Susana; Klein, Anders B; Santini, Martin A; Knudsen, Gitte M; Henn, Fritz; Gass, Peter; Vollmayr, Barbara

2010-07-01

Epidemiological studies have revealed a strong genetic contribution to the risk for depression. Both reduced hippocampal serotonin neurotransmission and brain-derived neurotrophic factor (BDNF) levels have been associated with increased depression vulnerability and are also regulated during aging. Brains from young (5 months old) and old (13 months old) congenital Learned Helplessness rats (cLH), and congenital Non Learned Helplessness rats (cNLH) were immunohistochemically stained for the serotonin transporter and subsequently stereologically quantified for estimating hippocampal serotonin fiber density. Hippocampal BDNF protein levels were measured by ELISA. An exacerbated age-related loss of serotonin fiber density specific for the CA1 area was observed in the cLH animals, whereas reduced hippocampal BDNF levels were seen in young and old cLH when compared with age-matched cNLH controls. These observations indicate that aging should be taken into account when studying the neurobiological factors behind the vulnerability for depression and that understanding the effect of aging on genetically predisposed individuals may contribute to a better understanding of the pathophysiology behind depression, particularly in the elderly.

Effect of grazing seedhead-suppressed tall fescue pasture on the vasoactivity of serotonin receptors

USDA-ARS?s Scientific Manuscript database

Previous research has demonstrated that exposure to ergot alkaloids reduces vasoactivity of serotonin (5HT) receptors. Chemical suppression of tall fescue seedhead production is a tool to reduce the level of exposure to ergot alkaloids by a grazing animal. Therefore, the objective was to evaluate co...

Clinical Effects of Fenfluramine in Ten Autistic Subjects. Brief Report.

ERIC Educational Resources Information Center

Klykylo, William M.; And Others

1985-01-01

Use of the drug Fenfluramine, which reduces blood serotonin levels and possible problem behaviors, was evaluated. Nine of 10 Ss showed reduced serotonin; none showed significant differences on intelligence tests; and at least two Ss showed marked behavioral changes in less echolalia, perseveration, and motoric disturbance and more increases in…

Brain serotonin content regulates the manifestation of tramadol-induced seizures in rats: disparity between tramadol-induced seizure and serotonin syndrome.

PubMed

Fujimoto, Yohei; Funao, Tomoharu; Suehiro, Koichi; Takahashi, Ryota; Mori, Takashi; Nishikawa, Kiyonobu

2015-01-01

Tramadol-induced seizures might be pathologically associated with serotonin syndrome. Here, the authors investigated the relationship between serotonin and the seizure-inducing potential of tramadol. Two groups of rats received pretreatment to modulate brain levels of serotonin and one group was treated as a sham control (n = 6 per group). Serotonin modulation groups received either para-chlorophenylalanine or benserazide + 5-hydroxytryptophan. Serotonin, dopamine, and histamine levels in the posterior hypothalamus were then measured by microdialysis, while simultaneously infusing tramadol until seizure onset. In another experiment, seizure threshold with tramadol was investigated in rats intracerebroventricularly administered with either a serotonin receptor antagonist (methysergide) or saline (n = 6). Pretreatment significantly affected seizure threshold and serotonin fluctuations. The threshold was lowered in para-chlorophenylalanine group and raised in benserazide + 5-hydroxytryptophan group (The mean ± SEM amount of tramadol needed to induce seizures; sham: 43.1 ± 4.2 mg/kg, para-chlorophenylalanine: 23.2 ± 2.8 mg/kg, benserazide + 5-hydroxytryptophan: 59.4 ± 16.5 mg/kg). Levels of serotonin at baseline, and their augmentation with tramadol infusion, were less in the para-chlorophenylalanine group and greater in the benserazide + 5-hydroxytryptophan group. Furthermore, seizure thresholds were negatively correlated with serotonin levels (correlation coefficient; 0.71, P < 0.01), while intracerebroventricular methysergide lowered the seizure threshold (P < 0.05 vs. saline). The authors determined that serotonin-reduced rats were predisposed to tramadol-induced seizures, and that serotonin concentrations were negatively associated with seizure thresholds. Moreover, serotonin receptor antagonism precipitated seizure manifestation, indicating that tramadol-induced seizures are distinct from serotonin syndrome.

Increased release of brain serotonin reduces vulnerability to ventricular fibrillation in the cat

NASA Technical Reports Server (NTRS)

Lehnert, Hendrik; Lombardi, Federico; Raeder, Ernst A.; Lorenzo, Antonio V.; Verrier, Richard L.; Lown, Bernard; Wurtman, Richard J.

1987-01-01

The effect of administering the serotonin precursor 5-l-hydroxytryptophan, in conjunction with a monamine oxidase inhibitor phenelzine and a l-amino acid decarboxylase inhibitor carbidopa, on neurochemical changes in the concentrations of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid of the cat were investigated. Results showed that this drug regimen led to increases of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the cerebrospinal fluid by 330 and 830 percent, respectively. Concomitantly, the threshold of ventricular fibrillation was found to be elevated by 42 percent and the effective refractory period was prolonged by 7 percent; the efferent sympathetic neural activity was suppressed in the normal heart. The results indicate that the enhancement of central serotoninergic neurotransmission can reduce the susceptibility of the heart to ventricular fibrillation mediated through a decline in sympathetic neural traffic to the heart.

The external gate of the human and Drosophila serotonin transporters requires a basic/acidic amino acid pair for 3,4-methylenedioxymethamphetamine (MDMA) translocation and the induction of substrate efflux.

PubMed

Sealover, Natalie R; Felts, Bruce; Kuntz, Charles P; Jarrard, Rachel E; Hockerman, Gregory H; Lamb, Patrick W; Barker, Eric L; Henry, L Keith

2016-11-15

The substituted amphetamine, 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy), is a widely used drug of abuse that induces non-exocytotic release of serotonin, dopamine, and norepinephrine through their cognate transporters as well as blocking the reuptake of neurotransmitter by the same transporters. The resulting dramatic increase in volume transmission and signal duration of neurotransmitters leads to psychotropic, stimulant, and entactogenic effects. The mechanism by which amphetamines drive reverse transport of the monoamines remains largely enigmatic, however, promising outcomes for the therapeutic utility of MDMA for post-traumatic stress disorder and the long-time use of the dopaminergic and noradrenergic-directed amphetamines in treatment of attention-deficit hyperactivity disorder and narcolepsy increases the importance of understanding this phenomenon. Previously, we identified functional differences between the human and Drosophila melanogaster serotonin transporters (hSERT and dSERT, respectively) revealing that MDMA is an effective substrate for hSERT but not dSERT even though serotonin is a potent substrate for both transporters. Chimeric dSERT/hSERT transporters revealed that the molecular components necessary for recognition of MDMA as a substrate was linked to regions of the protein flanking transmembrane domains (TM) V through IX. Here, we performed species-scanning mutagenesis of hSERT, dSERT and C. elegans SERT (ceSERT) along with biochemical and electrophysiological analysis and identified a single amino acid in TM10 (Glu394, hSERT; Asn484, dSERT, Asp517, ceSERT) that is primarily responsible for the differences in MDMA recognition. Our findings reveal that an acidic residue is necessary at this position for MDMA recognition as a substrate and serotonin releaser. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of exercise on depressive behavior and striatal levels of norepinephrine, serotonin and their metabolites in sleep-deprived mice.

PubMed

Daniele, Thiago Medeiros da Costa; de Bruin, Pedro Felipe Carvalhedo; Rios, Emiliano Ricardo Vasconcelos; de Bruin, Veralice Meireles Sales

2017-08-14

Exercise is a promising adjunctive therapy for depressive behavior, sleep/wake abnormalities, cognition and motor dysfunction. Conversely, sleep deprivation impairs mood, cognition and functional performance. The objective of this study is to evaluate the effects of exercise on anxiety and depressive behavior and striatal levels of norepinephrine (NE), serotonin and its metabolites in mice submitted to 6h of total sleep deprivation (6h-TSD) and 72h of Rapid Eye Movement (REM) sleep deprivation (72h-REMSD). Experimental groups were: (1) mice submitted to 6h-TSD by gentle handling; (2) mice submitted to 72h-REMSD by the flower pot method; (3) exercise (treadmill for 8 weeks); (4) exercise followed by 6h-TSD; (5) exercise followed by 72h-REMSD; (6) control (home cage). Behavioral tests included the Elevated Plus Maze and tail-suspension. NE, serotonin and its metabolites were determined in the striatum using high-performance liquid chromatography (HPLC). Sleep deprivation increased depressive behavior (time of immobilization in the tail-suspension test) and previous exercise hindered it. Sleep deprivation increased striatal NE and previous exercise reduced it. Exercise only was associated with higher levels of serotonin. Furthermore, exercise reduced serotonin turnover associated with sleep deprivation. In brief, previous exercise prevented depressive behavior and reduced striatal high NE levels and serotonin turnover. The present findings confirm the effects of exercise on behavior and neurochemical alterations associated with sleep deprivation. These findings provide new avenues for understanding the mechanisms of exercise. Copyright © 2017 Elsevier B.V. All rights reserved.

Myocardial serotonin exchange: negligible uptake by capillary endothelium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moffett, T.C.; Chan, I.S.; Bassingthwaighte, J.B.

1988-03-01

The extraction of serotonin from the blood during transorgan passage through the heart was studied using Langendorff-perfused rabbit hearts. Outflow dilution curves of /sup 131/I- or /sup 125/I-labeled albumin, (/sup 14/C)sucrose, and (3H)serotonin injected simultaneously into the inflow were fitted with an axially distributed blood-tissue exchange model to examine the extraction process. The model fits of the albumin and sucrose outflow dilution curves were used to define flow heterogeneity, intravascular dispersion, capillary permeability, and the volume of the interstitial space, which reduced the degrees of freedom in fitting the model to the serotonin curves. Serotonin extractions, measured against albumin, duringmore » single transcapillary passage, ranged from 24 to 64%. The ratio of the capillary permeability-surface area products for serotonin and sucrose, based on the maximum instantaneous extraction, was 1.37 +/- 0.2 (n = 18), very close to the predicted value of 1.39, the ratio of free diffusion coefficients calculated from the molecular weights. This result shows that the observed uptake of serotonin can be accounted for solely on the basis of diffusion between endothelial cells into the interstitial space. Thus it appears that the permeability of the luminal surface of the endothelial cell is negligible in comparison to diffusion through the clefts between endothelial cells. In 18 sets of dilution curves, with and without receptor and transport blockers or competitors (ketanserin, desipramine, imipramine, serotonin), the extractions and estimates of the capillary permeability-surface area product were not reduced, nor were the volumes of distribution. The apparent absence of transporters and receptors in rabbit myocardial capillary endothelium contrasts with their known abundance in the pulmonary vasculature.« less

Is Serum Serotonin Involved in the Bone Loss of Young Females with Anorexia Nervosa?

PubMed

Maïmoun, L; Guillaume, S; Lefebvre, P; Philibert, P; Bertet, H; Picot, M-C; Courtet, P; Mariano-Goulart, D; Renard, E; Sultan, C

2016-03-01

Recent experimental data suggest that circulating serotonin interacts with bone metabolism, although this is less clear in humans. This study investigated whether serum serotonin interferes with bone metabolism in young women with anorexia nervosa (AN), a clinical model of energy deprivation. Serum serotonin, markers of bone turnover [osteocalcin (OC), procollagen type I N-terminal propeptide (PINP), type I-C telopeptide breakdown products (CTX)], leptin, soluble leptin receptor (sOB-R), and insulin-like growth factor-1 (IGF-1) and its binding protein (IGFBP-3) were assessed. Whole body, spine, hip, and radius areal bone mineral density BMD (aBMD) were assessed by dual-energy X-ray absorptiometry in 21 patients with AN and 19 age-matched controls. Serum serotonin, leptin, IGF-1, IGFBP-3, OC, PINP, and aBMD at all sites, radius excepted, were significantly reduced in AN whereas CTX and sOB-R were increased compared with controls. Serum serotonin levels were positively correlated with weight, body mass index, whole body fat mass, leptin, and IGF-1, and negatively with CTX for the entire population. Low serum serotonin levels are observed in patients with AN. Although no direct link between low serum serotonin levels and bone mass was identified in these patients, the negative relationship between serotonin and markers of bone resorption found in all population nevertheless suggests the implication of serotonin in bone metabolism. Impact of low serum serotonin on bone in AN warrants further studies. © Georg Thieme Verlag KG Stuttgart · New York.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

1988-05-01

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

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

PubMed

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

2012-06-01

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

Characterization and regulation of (/sup 3/H)-serotonin uptake and release in rodent spinal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stauderman, K.A.

1986-01-01

The uptake and release of (/sup 3/H)-serotonin were investigated in rat spinal cord synaptosomes. In the uptake experiments, sodium-dependent and sodium-independent (/sup 3/H)-serotonin accumulation processes were found. Sodium-dependent (/sup 3/H)-serotonin accumulation was: linear with sodium concentrations up to 180 mM; decreased by disruption of membrane integrity or ionic gradients; associated with purified synaptosomal fractions; and reduced after description of descending serotonergic neurons in the spinal cord. Of the uptake inhibitors tested, the most potent was fluoxetine (IC/sub 50/ 75 nM), followed by desipramine (IC/sub 50/ 430 nM) and nomifensine (IC/sub 50/ 950 nM). The sodium-independent (/sup 3/H)-serotonin accumulation process wasmore » insensitive to most treatments and probably represents nonspecific membrane binding. Thus, only sodium-dependent (/sup 3/H)-serotonin uptake represents the uptake process of serotonergic nerve terminals in rat spinal cord homogenates. In the release experiments, K/sup +/-induced release of previously accumulated (/sup 3/H)-serotonin was Ca/sup 2 +/-dependent, and originated from serotonergic synaptosomes. Exogenous serotonin and 5-methyoxy-N,N-dimethyltryptamine inhibited (/sup 3/H)-serotonin release in a concentration-dependent way. Of the antagonists tested, only methiothepin effectively blocked the effect of serotonin. These data support the existence of presynaptic serotonin autoreceptors on serotonergic nerve terminals in the rat spinal cord that act to inhibit a voltage and Ca/sup 2 +/-sensitive process linked to serotonin release. Alteration of spinai cord serotonergic function may therefore be possible by drugs acting on presynaptic serotonin autoreceptors in the spinal cord.« less

Tramadol and another atypical opioid meperidine have exaggerated serotonin syndrome behavioral effects, but decreased analgesic effects, in genetically-deficient serotonin transporter (SERT) mice

PubMed Central

Fox, Meredith A.; Jensen, Catherine L.; Murphy, Dennis L.

2009-01-01

The serotonin syndrome is a potential side effect of serotonin-enhancing drugs, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs). We recently reported a genetic mouse model for the serotonin syndrome, as serotonin transporter (SERT)-deficient mice have exaggerated serotonin syndrome behavioral responses to the MAOI tranylcypromine and the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP). As numerous case reports implicate the atypical opioids tramadol and meperidine in the development of the human serotonin syndrome, we examined tramadol and meperidine as possible causative drugs in the rodent model of the serotonin syndrome in SERT wildtype (+/+), heterozygous (+/−) and knockout (−/−) mice. Comparisons were made to SERT mice treated with either vehicle or morphine, an opioid not implicated in the serotonin syndrome in humans. Here we show that tramadol and meperidine, but not morphine, induce serotonin syndrome-like behaviors in mice, and we show that this response is exaggerated in mice lacking one or two copies of SERT. The exaggerated response to tramadol in SERT −/− mice was blocked by pretreatment with the 5-HT1A antagonist WAY 100635. Further, we show that morphine-, meperidine- and tramadol-induced analgesia is markedly decreased in SERT −/− mice. These studies suggest that caution seems warranted in prescribing or not warning patients receiving SSRIs or MAOIs, that dangerous side effects may occur during concurrent use of tramadol and similar agents. These findings suggest that it is conceivable that there might be increased vulnerability in individuals with SERT polymorphisms that may reduce SERT by more than 50%, the level in SERT +/− mice. PMID:19275775

Involvement of serotoninergic pathways in the control of luteinizing hormone secretion in red deer hinds.

PubMed

Villa-Diaz, L G; Barrell, G K

1999-01-01

Two experiments were conducted to determine whether serotoninergic pathways, which are implicated in the neuroendocrine regulation of luteininzing hormone (LH) secretion in domestic animals, have a similar action in red deer hinds. In the non-breeding season (August), ovariectomized (n = 5) and ovariectomized-thyroidectomized (n = 5) hinds received a vehicle solution followed 4 h later by either serotonin (66 microg kg(-1) i.v.) every 10 min for a further 4 h or the serotonin antagonist, cyproheptadine (3 mg kg(-1) i.v.) as a single injection. This procedure was repeated in the breeding season (June). In the non-breeding season serotonin was without effect, but cyproheptadine reduced LH pulse frequency and amplitude in ovariectomized-thyroidectomized hinds (P<0.01). During the breeding season, serotonin reduced LH pulse amplitude in ovariectomized hinds (P<0.05) and cyproheptadine reduced LH pulse frequency in both ovariectomized and ovariectomized-thyroidectomized hinds (P<0.05 and P<0.01, respectively). On each occasion, cyproheptadine increased (P<0.01) plasma prolactin concentration, whereas serotonin had no effect. These results indicate a stimulatory role for serotoninergic neurons on the hypothalamic GnRH pulse generator mechanism of red deer hinds during the breeding season. In a second experiment, the LH response to GnRH (5 microg i.v.) was examined in ovariectomized hinds (n = 5) following administration of a serotonin infusion (6.6 microg kg(-1) min(-1) i.v. for 15 min), cyproheptadine (3 mg kg(-1) i.v. as a single dose) or vehicle, in the breeding season (July) after induction of halothane anaesthesia and in the non-breeding season (December) without anaesthesia. Halothane anaesthesia eliminated endogenous pulses of LH. In comparison with the vehicle-treated controls, the response of plasma LH to exogenous GnRH was not altered by serotonin or cyproheptadine in either season, which shows that serotonin has no effect on LH release at the pituitary gland level in these animals. It was concluded that in the regulation of LH release in red deer hinds, serotoninergic pathways have a stimulatory role operating at the hypothalamic level.

Serotonin shapes risky decision making in monkeys.

PubMed

Long, Arwen B; Kuhn, Cynthia M; Platt, Michael L

2009-12-01

Some people love taking risks, while others avoid gambles at all costs. The neural mechanisms underlying individual variation in preference for risky or certain outcomes, however, remain poorly understood. Although behavioral pathologies associated with compulsive gambling, addiction and other psychiatric disorders implicate deficient serotonin signaling in pathological decision making, there is little experimental evidence demonstrating a link between serotonin and risky decision making, in part due to the lack of a good animal model. We used dietary rapid tryptophan depletion (RTD) to acutely lower brain serotonin in three macaques performing a simple gambling task for fluid rewards. To confirm the efficacy of RTD experiments, we measured total plasma tryptophan using high-performance liquid chromatography (HPLC) with electrochemical detection. Reducing brain serotonin synthesis decreased preference for the safe option in a gambling task. Moreover, lowering brain serotonin function significantly decreased the premium required for monkeys to switch their preference to the risky option, suggesting that diminished serotonin signaling enhances the relative subjective value of the risky option. These results implicate serotonin in risk-sensitive decision making and, further, suggest pharmacological therapies for treating pathological risk preferences in disorders such as problem gambling and addiction.

Physical exercise-induced fatigue: the role of serotonergic and dopaminergic systems

PubMed Central

Cordeiro, L.M.S.; Rabelo, P.C.R.; Moraes, M.M.; Teixeira-Coelho, F.; Coimbra, C.C.; Wanner, S.P.; Soares, D.D.

2017-01-01

Brain serotonin and dopamine are neurotransmitters related to fatigue, a feeling that leads to reduced intensity or interruption of physical exercises, thereby regulating performance. The present review aims to present advances on the understanding of fatigue, which has recently been proposed as a defense mechanism instead of a “physiological failure” in the context of prolonged (aerobic) exercises. We also present recent advances on the association between serotonin, dopamine and fatigue. Experiments with rodents, which allow direct manipulation of brain serotonin and dopamine during exercise, clearly indicate that increased serotoninergic activity reduces performance, while increased dopaminergic activity is associated with increased performance. Nevertheless, experiments with humans, particularly those involving nutritional supplementation or pharmacological manipulations, have yielded conflicting results on the relationship between serotonin, dopamine and fatigue. The only clear and reproducible effect observed in humans is increased performance in hot environments after treatment with inhibitors of dopamine reuptake. Because the serotonergic and dopaminergic systems interact with each other, the serotonin-to-dopamine ratio seems to be more relevant for determining fatigue than analyzing or manipulating only one of the two transmitters. Finally, physical training protocols induce neuroplasticity, thus modulating the action of these neurotransmitters in order to improve physical performance. PMID:29069229

Implications of genetic research on the role of the serotonin in depression: emphasis on the serotonin type 1A receptor and the serotonin transporter.

PubMed

Neumeister, Alexander; Young, Theresa; Stastny, Juergen

2004-08-01

Serotonin systems appear to play a key role in the pathophysiology of major depressive disorder. Consequently, ongoing research determines whether serotonin related genes account for the very robust differential behavioral and neural mechanisms that discriminate patients with depression from healthy controls. Serotonin type 1(A) receptors and the serotonin transporters are reduced in depression, and recent genetic research in animals and humans has implicated both in depression. Preclinical studies have utilized a variety of animal models that have been used to explain pathophysiological mechanisms in humans, although it is not clear at all whether these models constitute relevant models for depression in humans. However, data from preclinical studies can generate hypotheses that are tested in humans by combining genetic data with behavioral and physiological challenge paradigms and neuroimaging. These studies will enhance our understanding about combined influences from multiple interacting genes, as well as from environmental factors on brain circuits and their function, and about how these mechanisms may contribute to the pathophysiology of neuropsychiatric disorders.

Sleep and rhythm consequences of a genetically induced loss of serotonin.

PubMed

Leu-Semenescu, Smaranda; Arnulf, Isabelle; Decaix, Caroline; Moussa, Fathi; Clot, Fabienne; Boniol, Camille; Touitou, Yvan; Levy, Richard; Vidailhet, Marie; Roze, Emmanuel

2010-03-01

A genetic deficiency in sepiapterin reductase leads to a combined deficit of serotonin and dopamine. The motor phenotype is characterized by a dopa-responsive fluctuating generalized dystonia-parkinsonism. The non-motor symptoms are poorly recognized. In particular, the effects of brain serotonin deficiency on sleep have not been thoroughly studied. We examine the sleep, sleep-wake rhythms, CSF neurotransmitters, and melatonin profile in a patient with sepiapterin reductase deficiency. The patient was a 28-year-old man with fluctuating generalized dystonia-parkinsonism caused by sepiapterin reductase deficiency. A sleep interview, wrist actigraphy, sleep log over 14 days, 48-h continuous sleep and core temperature monitoring, and measurement of CSF neurotransmitters and circadian serum melatonin and cortisol levels before and after treatment with 5-hydroxytryptophan (the precursor of serotonin) and levodopa were performed. Before treatment, the patient had mild hypersomnia with long sleep time (704 min), ultradian sleep-wake rhythm (sleep occurred every 11.8 +/- 5.3 h), organic hyperphagia, attentionlexecutive dysfunction, and no depression. The serotonin metabolism in the CSF was reduced, and the serum melatonin profile was flat, while cortisol and core temperature profiles were normal. Supplementation with 5-hydroxytryptophan, but not with levodopa, normalized serotonin metabolism in the CSF, reduced sleep time to 540 min, normalized the eating disorder and the melatonin profile, restored a circadian sleep-wake rhythm (sleep occurred every 24 +/- 1.7 h, P < 0.0001), and improved cognition. In this unique genetic paradigm, the melatonin deficiency (caused by a lack of its substrate, serotonin) may cause the ultradian sleep-wake rhythm.

Tryptophan depletion disinhibits punishment but not reward prediction: implications for resilience.

PubMed

Robinson, Oliver J; Cools, Roshan; Sahakian, Barbara J

2012-01-01

We have previously shown that tryptophan depletion enhances punishment but not reward prediction (Cools et al. in Neuropsychopharmacology 33:2291-2299, 2008b). This provided evidence for a valence-specific role of serotonin (which declines under depleted tryptophan) in aversive processing. Recent theoretical (Dayan and Huys in PLoS Comput Biol 4:e4, 2008) and experimental (Crockett et al. in J Neurosci 29:11993-11999, 2009) approaches have, however, further specified this role by showing that serotonin is critical for punishment-induced inhibition. We sought to examine the role of serotonin in punishment-induced inhibition. We also examined the impact of induced mood on this effect to assess whether effects of tryptophan depletion on affective inhibition are moderated by mood. Healthy females consumed a balanced amino acid mixture with (N = 20) or without (N = 21) the serotonin precursor tryptophan. Each subject completed either negative or neutral mood induction. All subjects completed the reward and punishment reversal learning task adopted in the previous study. We demonstrate a punishment prediction impairment in individuals who consumed tryptophan which was absent in individuals who were depleted of tryptophan. This effect was impervious to mood state. Our results suggest that serotonin promotes the inhibition of responses to punishing outcomes. This may lead to reduced punishment prediction accuracy in the presence of tryptophan and may contribute to resilience to affective disorders. Reduction of serotonin via tryptophan depletion then removes this inhibition. As such, we highlight a mechanism by which reduced serotonin can contribute to disorders of impulsivity and compulsivity as well as disorders of emotion.

The role of serotonin in impulsive aggression, suicide, and homicide in adolescents and adults: a literature review.

PubMed

Glick, Amy R

2015-05-01

This is a literature review discussing previous studies on the associations between impulsive aggression and the serotonergic system in adults, adolescents, and children. The review demonstrates that there is a clear association between low cerebrospinal fluid serotonin and impulsive aggression. However, studies on neurotransmitter receptor profiles, functional imaging, genetics, and epigenetics reviewed in this article suggest a more complicated picture that includes consideration of gene vs. environment in the evaluation of risk. Serotonin supplementation studies suggest that selective serotonin reuptake inhibitors may reduce impulsive aggression in some adults but are less effective in adults with pathological aggression and also in children and adolescents. Child and adolescent studies are less conclusive, in part due to the heterogeneous physiologic and psychosocial changes occurring over the course of development. The author thus concludes that psychiatrists can reduce risk in these special patient populations by creating safer environments in the form of changes in policy and increased support services.

Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion from Alpha Cells.

PubMed

Almaça, Joana; Molina, Judith; Menegaz, Danusa; Pronin, Alexey N; Tamayo, Alejandro; Slepak, Vladlen; Berggren, Per-Olof; Caicedo, Alejandro

2016-12-20

In the pancreatic islet, serotonin is an autocrine signal increasing beta cell mass during metabolic challenges such as those associated with pregnancy or high-fat diet. It is still unclear whether serotonin is relevant for regular islet physiology and hormone secretion. Here, we show that human beta cells produce and secrete serotonin when stimulated with increases in glucose concentration. Serotonin secretion from beta cells decreases cyclic AMP (cAMP) levels in neighboring alpha cells via 5-HT 1F receptors and inhibits glucagon secretion. Without serotonergic input, alpha cells lose their ability to regulate glucagon secretion in response to changes in glucose concentration, suggesting that diminished serotonergic control of alpha cells can cause glucose blindness and the uncontrolled glucagon secretion associated with diabetes. Supporting this model, pharmacological activation of 5-HT 1F receptors reduces glucagon secretion and has hypoglycemic effects in diabetic mice. Thus, modulation of serotonin signaling in the islet represents a drug intervention opportunity. Published by Elsevier Inc.

Serotonin Transporter Knockout Rats Show Improved Strategy Set-Shifting and Reduced Latent Inhibition

ERIC Educational Resources Information Center

Nonkes, Lourens J. P.; van de Vondervoort, Ilse I. G. M.; de Leeuw, Mark J. C.; Wijlaars, Linda P.; Maes, Joseph H. R.; Homberg, Judith R.

2012-01-01

Behavioral flexibility is a cognitive process depending on prefrontal areas allowing adaptive responses to environmental changes. Serotonin transporter knockout (5-HTT[superscript -/-]) rodents show improved reversal learning in addition to orbitofrontal cortex changes. Another form of behavioral flexibility, extradimensional strategy set-shifting…

Gene-environment interactions and the neurobiology of social conflict.

PubMed

Suomi, Stephen J

2003-12-01

Recent research has disclosed marked individual differences in biobehavioral responses to social conflicts exhibited by rhesus monkeys across the life span. For example, approximately 5-10% of rhesus monkeys growing up in the wild consistently exhibit impulsive and/or inappropriately aggressive responses to mildly stressful situations throughout development; those same individuals also show chronic deficits in their central serotonin metabolism. These characteristic patterns of biobehavioral response emerge early in life and remain remarkably stable from infancy to adulthood. Laboratory studies have demonstrated that although these characteristics are highly heritable, they are also subject to major modification by specific early experiences, particularly those involving early social attachment relationships. Moreover, genetic and early experience factors can interact, often in dramatic fashion. For example, a specific polymorphism in the serotonin transporter gene is associated with deficits in early neurobehavioral functioning and serotonin metabolism, extreme aggression, and excessive alcohol consumption among monkeys who experienced insecure early attachment relationships, but not in monkeys who developed secure attachment relationships with their mothers during infancy. Because daughters tend to develop the same type of attachment relationships with their own offspring that they experienced with their mothers early in life, such early experiences provide a possible nongenetic mechanism for transmitting these patterns to subsequent generations.

Thalamic synaptic transmission of sensory information modulated by synergistic interaction of adenosine and serotonin.

PubMed

Yang, Ya-Chin; Hu, Chun-Chang; Huang, Chen-Syuan; Chou, Pei-Yu

2014-03-01

The thalamic synapses relay peripheral sensory information to the cortex, and constitute an important part of the thalamocortical network that generates oscillatory activities responsible for different vigilance (sleep and wakefulness) states. However, the modulation of thalamic synaptic transmission by potential sleep regulators, especially by combination of regulators in physiological scenarios, is not fully characterized. We found that somnogen adenosine itself acts similar to wake-promoting serotonin, both decreasing synaptic strength as well as short-term depression, at the retinothalamic synapse. We then combined the two modulators considering the coexistence of them in the hypnagogic (sleep-onset) state. Adenosine plus serotonin results in robust synergistic inhibition of synaptic strength and dramatic transformation of short-term synaptic depression to facilitation. These synaptic effects are not achievable with a single modulator, and are consistent with a high signal-to-noise ratio but a low level of signal transmission through the thalamus appropriate for slow-wave sleep. This study for the first time demonstrates that the sleep-regulatory modulators may work differently when present in combination than present singly in terms of shaping information flow in the thalamocortical network. The major synaptic characters such as the strength and short-term plasticity can be profoundly altered by combination of modulators based on physiological considerations. © 2013 International Society for Neurochemistry.

Citalopram Intervention for Hostility: Results of a Randomized Clinical Trial

ERIC Educational Resources Information Center

Kamarck, Thomas W.; Haskett, Roger F.; Muldoon, Matthew; Flory, Janine D.; Anderson, Barbara; Bies, Robert; Pollock, Bruce; Manuck, Stephen B.

2009-01-01

Hostility is associated with an increased risk for cardiovascular disease (CVD). Because central serotonin may modulate aggression, we might expect selective serotonin reuptake inhibitors (SSRIs) to be effective in reducing hostility. Such effects have never been examined in individuals scoring high on hostility who are otherwise free from major…

The effects of glycogen synthase kinase-3beta in serotonin neurons.

PubMed

Zhou, Wenjun; Chen, Ligong; Paul, Jodi; Yang, Sufen; Li, Fuzeng; Sampson, Karen; Woodgett, Jim R; Beaulieu, Jean Martin; Gamble, Karen L; Li, Xiaohua

2012-01-01

Glycogen synthase kinase-3 (GSK3) is a constitutively active protein kinase in brain. Increasing evidence has shown that GSK3 acts as a modulator in the serotonin neurotransmission system, including direct interaction with serotonin 1B (5-HT1B) receptors in a highly selective manner and prominent modulating effect on 5-HT1B receptor activity. In this study, we utilized the serotonin neuron-selective GSK3β knockout (snGSK3β-KO) mice to test if GSK3β in serotonin neurons selectively modulates 5-HT1B autoreceptor activity and function. The snGSK3β-KO mice were generated by crossbreeding GSK3β-floxed mice and ePet1-Cre mice. These mice had normal growth and physiological characteristics, similar numbers of tryptophan hydroxylase-2 (TpH2)-expressing serotonin neurons, and the same brain serotonin content as in littermate wild type mice. However, the expression of GSK3β in snGSK3β-KO mice was diminished in TpH2-expressing serotonin neurons. Compared to littermate wild type mice, snGSK3β-KO mice had a reduced response to the 5-HT1B receptor agonist anpirtoline in the regulation of serotonergic neuron firing, cAMP production, and serotonin release, whereas these animals displayed a normal response to the 5-HT1A receptor agonist 8-OH-DPAT. The effect of anpirtoline on the horizontal, center, and vertical activities in the open field test was differentially affected by GSK3β depletion in serotonin neurons, wherein vertical activity, but not horizontal activity, was significantly altered in snGSK3β-KO mice. In addition, there was an enhanced anti-immobility response to anpirtoline in the tail suspension test in snGSK3β-KO mice. Therefore, results of this study demonstrated a serotonin neuron-targeting function of GSK3β by regulating 5-HT1B autoreceptors, which impacts serotonergic neuron firing, serotonin release, and serotonin-regulated behaviors.

Effects of sugar rich diet on brain serotonin, hyperphagia and anxiety in animal model of both genders.

PubMed

Inam, Qurrat-ul-Aen; Ikram, Huma; Shireen, Erum; Haleem, Darakhshan Jabeen

2016-05-01

Lower levels of 5-hydroxytryptamine (5-HT; serotonin) in the brain elicit sugar craving, while ingestion of sugar rich diet improves mood and alleviates anxiety. Gender differences occur not only in brain serotonin metabolism but also in a serotonin mediated functional responses. The present study was therefore designed to investigate gender related differences on the effects of long term consumption of sugar rich diet on the metabolism of serotonin in the hypothalamus and whole brain which may be relevant with the hyperphagic and anxiety reducing effects of sugar rich diet. Male and female rats were fed freely on a sugar rich diet for five weeks. Hyperphagic effects were monitored by measuring total food intake and body weights changes during the intervention. Anxiolytic effects of sugar rich diet was monitored in light-dark transition test. The results show that ingestion of sugar rich diet decreased serotonin metabolism more in female than male rats. Anxiolytic effects were elicited only in male rats. Hyperphagia was comparable in both male and female rats. Finings would help in understanding the role of sugar rich diet-induced greater decreases of serotonin in sweet craving in women during stress.

Serotonin blockade delays learning performance in a cooperative fish.

PubMed

Soares, Marta C; Paula, José R; Bshary, Redouan

2016-09-01

Animals use learning and memorizing to gather information that will help them to make ecologically relevant decisions. Neuro-modulatory adjustments enable them to make associations between stimuli and appropriate behavior. A key candidate for the modulation of cooperative behavior is serotonin. Previous research has shown that modulation of the serotonergic system spontaneously affects the behavior of the cleaner wrasse Labroides dimidiatus during interactions with so-called 'client' reef fish. Here, we asked whether shifts in serotonin function affect the cleaners' associative learning abilities when faced with the task to distinguish two artificial clients that differ in their value as a food source. We found that the administration of serotonin 1A receptor antagonist significantly slowed learning speed in comparison with saline treated fish. As reduced serotonergic signaling typically enhances fear, we discuss the possibility that serotonin may affect how cleaners appraise, acquire information and respond to client-derived stimuli via manipulation of the perception of danger.

Promoting effects of serotonin on hematopoiesis: ex vivo expansion of cord blood CD34+ stem/progenitor cells, proliferation of bone marrow stromal cells, and antiapoptosis.

PubMed

Yang, Mo; Li, Karen; Ng, Pak Cheung; Chuen, Carmen Ka Yee; Lau, Tze Kin; Cheng, Yuan Shan; Liu, Yuan Sheng; Li, Chi Kong; Yuen, Patrick Man Pan; James, Anthony Edward; Lee, Shuk Man; Fok, Tai Fai

2007-07-01

Serotonin is a monoamine neurotransmitter that has multiple extraneuronal functions. We previously reported that serotonin exerted mitogenic stimulation on megakaryocytopoiesis mediated by 5-hydroxytryptamine (5-HT)2 receptors. In this study, we investigated effects of serotonin on ex vivo expansion of human cord blood CD34+ cells, bone marrow (BM) stromal cell colony-forming unit-fibroblast (CFU-F) formation, and antiapoptosis of megakaryoblastic M-07e cells. Our results showed that serotonin at 200 nM significantly enhanced the expansion of CD34+ cells to early stem/progenitors (CD34+ cells, colony-forming unit-mixed [CFU-GEMM]) and multilineage committed progenitors (burst-forming unit/colony-forming unit-erythroid [BFU/CFU-E], colony-forming unit-granulocyte macrophage, colony-forming unit-megakaryocyte, CD61+ CD41+ cells). Serotonin also increased nonobese diabetic/severe combined immunodeficient repopulating cells in the expansion culture in terms of human CD45+, CD33+, CD14+ cells, BFU/CFU-E, and CFU-GEMM engraftment in BM of animals 6 weeks post-transplantation. Serotonin alone or in addition to fibroblast growth factor, platelet-derived growth factor, or vascular endothelial growth factor stimulated BM CFU-F formation. In M-07e cells, serotonin exerted antiapoptotic effects (annexin V, caspase-3, and propidium iodide staining) and reduced mitochondria membrane potential damage. The addition of ketanserin, a competitive antagonist of 5-HT2 receptor, nullified the antiapoptotic effects of serotonin. Our data suggest the involvement of serotonin in promoting hematopoietic stem cells and the BM microenvironment. Serotonin could be developed for clinical ex vivo expansion of hematopoietic stem cells for transplantation. Disclosure of potential conflicts of interest is found at the end of this article.

Low density and high affinity of platelet [3H]paroxetine binding in women with bulimia nervosa.

PubMed

Ekman, Agneta; Sundblad-Elverfors, Charlotta; Landén, Mikael; Eriksson, Tomas; Eriksson, Elias

2006-06-15

Impaired serotonin transmission has been suggested to be implicated in the pathophysiology of bulimia nervosa. As an indirect measure of brain serotonergic activity, the binding of tritiated ligands to platelet serotonin transporters has been studied in bulimia nervosa as well as in other putatively serotonin-related psychiatric disorders. In this study, the density and affinity of platelet serotonin transporters were assessed in 20 women meeting the DSM-IV criteria for bulimia nervosa and in 14 controls without previous or ongoing eating disorder using [(3)H]paroxetine as a ligand. In comparison to controls, women with bulimia nervosa had a significantly reduced number of platelet binding sites (B(max) = 721 +/- 313 vs. 1145 +/- 293 fmol/mg protein) and an increase in the affinity for the ligand demonstrated by a lower dissociaton constant (K(d) = 33 +/- 10 vs. 44 +/- 10 pM). A significant correlation between B(max) and K(d) values was found in patients but not in controls. Our results support the notion that bulimia nervosa is associated with a reduction in platelet serotonin transporter density. In addition, our study is the first to report that this reduced transporter density in women with bulimia nervosa is accompanied by an increase in the affinity of the transporter for the ligand.

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

PubMed

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

2014-09-08

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. Copyright © 2014 Elsevier Ltd. All rights reserved.

ADSA Foundation Scholar Award: A role for serotonin in lactation physiology-Where do we go from here?

PubMed

Hernandez, L L

2018-04-25

Lactation is a physiological event that is exclusive to mammals. Lactation evolved as a strategy to improve the survival of the young by providing them with the complete nutrition that is required for survival upon birth as well as maternal-offspring bonding. Typically, milk production by the dam matches the demand of the young. The dairy cow is a unique exception in which the discoveries and genetic selection related to lactation physiology have been applied and resulted in a dramatic increase in milk yield of dairy cows. Studies on the role of mammary-derived serotonin and the coordination of various aspects of milk production and maternal metabolism have revealed novel mechanisms by which milk production and maternal metabolism can be improved. Furthermore, the investigation into molecular and cellular mechanisms regulating mammary gland function has revealed the importance of epigenetics on mammary gland function. Understanding mammary gland function at the cellular and physiological levels will be important for improving mammary gland control of maternal metabolism during early lactation. The early lactation period is a critical time for a dairy cow as that is when she is most susceptible to disease and metabolic disorders that can lead to negative effects on her productive capacity and overall health. Our research in the area of serotonin physiology has illustrated the importance of serotonin on the regulation of lactation and maternal homeostasis. Future research in the area of lactation physiology should be targeted at improving maternal health and longevity in the herd through manipulation of the signals the mammary gland sends to coordinate maternal metabolism and synthesize milk. Specifically, we believe that serotonin will play a central role in understanding the communication between the mammary gland and the maternal physiology during lactation. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Elevated brain serotonin turnover in patients with depression: effect of genotype and therapy.

PubMed

Barton, David A; Esler, Murray D; Dawood, Tye; Lambert, Elisabeth A; Haikerwal, Deepak; Brenchley, Celia; Socratous, Florentia; Hastings, Jacqueline; Guo, Ling; Wiesner, Glen; Kaye, David M; Bayles, Richard; Schlaich, Markus P; Lambert, Gavin W

2008-01-01

The biological basis for the development of major depressive disorder (MDD) remains incompletely understood. To quantify brain serotonin (5-hydroxytryptamine [5-HT]) turnover in patients with MDD. Patients with depression were studied both untreated and during administration of a selective serotonin reuptake inhibitor (SSRI) in an unblinded study of sequential design. Healthy volunteers were examined on only 1 occasion. Direct internal jugular venous blood sampling was used to directly quantify brain serotonin turnover. The effect of serotonin transporter (5-HTT) genotype on brain serotonin turnover was evaluated and the influence of SSRI therapy on serotonin turnover was investigated. Participants were recruited from the general community following media advertisement. Experimental procedures were performed in the research catheterization laboratory of a major training hospital and medical research institute. Studies were performed in 21 patients fulfilling the DSM-IV and International Statistical Classification of Diseases, 10th Revision diagnostic criteria for MDD and in 40 healthy volunteers. Treatment for patients consisted of SSRI administration for approximately 12 weeks. Brain serotonin turnover before and after SSRI therapy. Brain serotonin turnover was significantly elevated in unmedicated patients with MDD compared with healthy subjects (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 4.4 [4.3] vs 1.6 [2.4] nmol/L, respectively; P = .003). Analysis of the influence of the 5-HTT genotype in MDD indicated that carriage of the s allele compared with the l allele was associated with greater than a 2-fold increase in brain serotonin turnover (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 6.5 [4.7] vs 2.7 [2.9] nmol/L, respectively; P = .04). Following SSRI therapy, brain serotonin turnover was substantially reduced (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 6.0 [4.0] nmol/L prior to treatment vs 2.0 [3.3] nmol/L following therapy; P = .008). Brain serotonin turnover is elevated in unmedicated patients with MDD and is influenced by the 5-HTT genotype. The marked reduction in serotonin turnover following SSRI treatment and the accompanying improvement in symptoms suggest that high brain serotonin turnover may be a biological substrate of MDD.

Reconciling the role of serotonin in behavioral inhibition and aversion: acute tryptophan depletion abolishes punishment-induced inhibition in humans

PubMed Central

Crockett, Molly J.; Clark, Luke; Robbins, Trevor W.

2009-01-01

The neuromodulator serotonin has been implicated in a large number of affective and executive functions, but its precise contribution to motivation remains unclear. One influential hypothesis has implicated serotonin in aversive processing; another has proposed a more general role for serotonin in behavioral inhibition. Since behavioral inhibition is a pre-potent reaction to aversive outcomes, it has been a challenge to reconcile these two accounts. Here, we show that serotonin is critical for punishment-induced inhibition, but not overall motor response inhibition or reporting aversive outcomes. We used acute tryptophan depletion to temporarily lower brain serotonin in healthy human volunteers as they completed a novel task designed to obtain separate measures of motor response inhibition, punishment-induced inhibition, and sensitivity to aversive outcomes. Following a placebo treatment, participants were slower to respond under punishment conditions, compared to reward conditions. Tryptophan depletion abolished this punishment-induced inhibition, without affecting overall motor response inhibition or the ability to adjust response bias in line with punishment contingencies. The magnitude of reduction in punishment-induced inhibition depended on the degree to which tryptophan depletion reduced plasma tryptophan levels. These findings extend and clarify previous research on the role of serotonin in aversive processing and behavioral inhibition, and fit with current theorizing on serotonin's involvement in predicting aversive outcomes. PMID:19776285

Targeting Oxidative Stress, Cytokines and Serotonin Interactions Via Indoleamine 2, 3 Dioxygenase by Coenzyme Q10: Role in Suppressing Depressive Like Behavior in Rats.

PubMed

Abuelezz, Sally A; Hendawy, Nevien; Magdy, Yosra

2017-06-01

Depression is a major health problem in which oxidative stress and inflammation are inextricably connected in its pathophysiology. Coenzyme Q10 (CoQ10) is an important anti-oxidant compound with anti-inflammatory and neuro-protective properties. This study was designed to investigate the hypothesis that CoQ10 by its anti-oxidant and anti-inflammatory potentials can alleviate depressive- like behavior by restoring the balance of the tryptophan catabolites kynurenine/serotonin toward the serotonin pathway by down-regulation of hippocampal indoleamine 2,3-dioxygenase 1 (IDO-1). Depressive-like behavior was induced by chronic unpredictable mild stress (CUMS) protocol including food or water deprivation, cage tilting, reversed light cycle etc. Male Wistar rats were randomly divided into five groups; Control, CUMS, CUMS and CoQ10 (50,100 and 200 mg/kg/day i.p. respectively) groups. CoQ10 effects on different behavioral and biochemical tests were analyzed. CoQ10 showed significant antidepressant efficacy, as evidenced by significantly decreased stress induced changes to forced swimming challenge and open field test, as well as attenuating raised corticosterone level and adrenal glands weight. The anti-oxidant effect of CoQ10 was exhibited by its ability to significantly reduce hippocampal elevated malondialdehyde and 4-hydroxynonenal levels and elevate the reduced glutathione and catalase levels. CoQ10 significantly reduced different pro-inflammatory cytokines levels including interleukin (IL)-1β, IL-2, IL-6 and tumor necrosis factor-α. It suppressed hippocampal IDO-1 and subsequent production of kynurenine and enhanced the hippocampal contents of tryptophan and serotonin. Immunohistochemical analysis revealed that CoQ10 was able to attenuate the elevated microglial CD68 and elevate the astrocyte glial fibrillary acidic protein compared to CUMS group. CoQ10 exhibited antidepressant-like effects on rats exposed to CUMS. This could be attributed to its ability to reduce IDO-1 leading to shift the balance of the Kynurenine/ serotonin toward the serotonin pathway.

Serotonin, pregnancy and increased autism prevalence: is there a link?

PubMed

Hadjikhani, Nouchine

2010-05-01

The prevalence of autism, a neurodevelopmental condition resulting from genetic and environmental causes, has increased dramatically during the last decade. Among the potential environmental factors, hyperserotonemia during pregnancy and its effect on brain development could be playing a role in this prevalence raise. In the rodent model developed by Whitaker-Azmitia and colleagues, hyperserotonemia during fetal development results in a dysfunction of the hypothalamo-pituitary axis, affecting the amygdala as well as pro-social hormone oxytocin regulation. Dysfunction of the amygdala and abnormal oxytocin levels may underlie many clinical features of ASD. Selective serotonin reuptake inhibitors (SSRI) are the most widely used class of antidepressants drugs, and they are not contraindicated during pregnancy. In this paper, we hypothesize that increased serotonemia during pregnancy, including due to SSRI intake, could be one of the causes of the raising prevalence in autism. If our hypothesis is confirmed, it will not only shed light on one of the possible reason for autism prevalence, but also offer new preventive and treatment options.

Pharmacological depletion of serotonin in the basolateral amygdala complex reduces anxiety and disrupts fear conditioning.

PubMed

Johnson, Philip L; Molosh, Andrei; Fitz, Stephanie D; Arendt, Dave; Deehan, Gerald A; Federici, Lauren M; Bernabe, Cristian; Engleman, Eric A; Rodd, Zachary A; Lowry, Christopher A; Shekhar, Anantha

2015-11-01

The basolateral and lateral amygdala nuclei complex (BLC) is implicated in a number of emotional responses including conditioned fear and social anxiety. Based on previous studies demonstrating that enhanced serotonin release in the BLC leads to increased anxiety and fear responses, we hypothesized that pharmacologically depleting serotonin in the BLC using 5,7-dihydroxytryptamine (5,7-DHT) injections would lead to diminished anxiety and disrupted fear conditioning. To test this hypothesis, 5,7-DHT(a serotonin-depleting agent) was bilaterally injected into the BLC. Desipramine (a norepinephrine reuptake inhibitor) was systemically administered to prevent non-selective effects on norepinephrine. After 5days, 5-7-DHT-treated rats showed increases in the duration of social interaction (SI) time, suggestive of reduced anxiety-like behavior. We then used a cue-induced fear conditioning protocol with shock as the unconditioned stimulus and tone as the conditioned stimulus for rats pretreated with bilateral 5,7-DHT, or vehicle, injections into the BLC. Compared to vehicle-treated rats, 5,7-DHT rats had reduced acquisition of fear during conditioning (measured by freezing time during tone), also had reduced fear retrieval/recall on subsequent testing days. Ex vivo analyses revealed that 5,7-DHT reduced local 5-HT concentrations in the BLC by ~40% without altering local norepinephrine or dopamine concentrations. These data provide additional support for 5-HT playing a critical role in modulating anxiety-like behavior and fear-associated memories through its actions within the BLC. Copyright © 2015 Elsevier Inc. All rights reserved.

Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability.

PubMed

Anikster, Yair; Haack, Tobias B; Vilboux, Thierry; Pode-Shakked, Ben; Thöny, Beat; Shen, Nan; Guarani, Virginia; Meissner, Thomas; Mayatepek, Ertan; Trefz, Friedrich K; Marek-Yagel, Dina; Martinez, Aurora; Huttlin, Edward L; Paulo, Joao A; Berutti, Riccardo; Benoist, Jean-François; Imbard, Apolline; Dorboz, Imen; Heimer, Gali; Landau, Yuval; Ziv-Strasser, Limor; Malicdan, May Christine V; Gemperle-Britschgi, Corinne; Cremer, Kirsten; Engels, Hartmut; Meili, David; Keller, Irene; Bruggmann, Rémy; Strom, Tim M; Meitinger, Thomas; Mullikin, James C; Schwartz, Gerard; Ben-Zeev, Bruria; Gahl, William A; Harper, J Wade; Blau, Nenad; Hoffmann, Georg F; Prokisch, Holger; Opladen, Thomas; Schiff, Manuel

2017-02-02

Phenylketonuria (PKU, phenylalanine hydroxylase deficiency), an inborn error of metabolism, can be detected through newborn screening for hyperphenylalaninemia (HPA). Most individuals with HPA harbor mutations in the gene encoding phenylalanine hydroxylase (PAH), and a small proportion (2%) exhibit tetrahydrobiopterin (BH 4 ) deficiency with additional neurotransmitter (dopamine and serotonin) deficiency. Here we report six individuals from four unrelated families with HPA who exhibited progressive neurodevelopmental delay, dystonia, and a unique profile of neurotransmitter deficiencies without mutations in PAH or BH 4 metabolism disorder-related genes. In these six affected individuals, whole-exome sequencing (WES) identified biallelic mutations in DNAJC12, which encodes a heat shock co-chaperone family member that interacts with phenylalanine, tyrosine, and tryptophan hydroxylases catalyzing the BH 4 -activated conversion of phenylalanine into tyrosine, tyrosine into L-dopa (the precursor of dopamine), and tryptophan into 5-hydroxytryptophan (the precursor of serotonin), respectively. DNAJC12 was undetectable in fibroblasts from the individuals with null mutations. PAH enzyme activity was reduced in the presence of DNAJC12 mutations. Early treatment with BH 4 and/or neurotransmitter precursors had dramatic beneficial effects and resulted in the prevention of neurodevelopmental delay in the one individual treated before symptom onset. Thus, DNAJC12 deficiency is a preventable and treatable cause of intellectual disability that should be considered in the early differential diagnosis when screening results are positive for HPA. Sequencing of DNAJC12 may resolve any uncertainty and should be considered in all children with unresolved HPA. Copyright © 2017 American Society of Human Genetics. All rights reserved.

A pharmacological evidence of positive association between mouse intermale aggression and brain serotonin metabolism.

PubMed

Kulikov, A V; Osipova, D V; Naumenko, V S; Terenina, E; Mormède, P; Popova, N K

2012-07-15

The neurotransmitter serotonin (5-HT) is involved in the regulation of mouse intermale aggression. Previously, it was shown that intensity of mouse intermale aggression was positively associated with activity of the key enzyme of 5-HT synthesis - tryptophan hydroxylase 2 (TPH2) in mouse brain. The aim of the present study was to investigate the effect of pharmacological activation or inhibition of 5-HT synthesis in the brain on intermale aggression in two mouse strains differing in the TPH2 activity: C57BL/6J (B6, high TPH2 activity, high aggressiveness) and CC57BR/Mv (BR, low TPH2 activity, low aggressiveness). Administration of 5-HT precursor L-tryptophan (300 mg/kg, i.p.) to BR mice significantly increased the 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in the midbrain as well as the number of attacks and their duration in the resident-intruder test. And vice versa, administration of TPH2 inhibitor p-chlorophenylalanine (pCPA) (300 mg/kg, i.p., for 3 consecutive days) to B6 mice dramatically reduced the 5-HT and 5-HIAA contents in brain structures and attenuated the frequency and the duration of aggressive attacks. At the same time, L-tryptophan or pCPA did not influence the percentage of aggressive mice and the attack latency reflecting the threshold of aggressive reaction. This result indicated that the intensity of intermale aggression, but not the threshold of aggressive reaction is positively dependent on 5-HT metabolism in mouse brain. Copyright © 2012 Elsevier B.V. All rights reserved.

Molecular imaging of serotonin degeneration in mild cognitive impairment.

PubMed

Smith, Gwenn S; Barrett, Frederick S; Joo, Jin Hui; Nassery, Najlla; Savonenko, Alena; Sodums, Devin J; Marano, Christopher M; Munro, Cynthia A; Brandt, Jason; Kraut, Michael A; Zhou, Yun; Wong, Dean F; Workman, Clifford I

2017-09-01

Neuropathological and neuroimaging studies have consistently demonstrated degeneration of monoamine systems, especially the serotonin system, in normal aging and Alzheimer's disease. The evidence for degeneration of the serotonin system in mild cognitive impairment is limited. Thus, the goal of the present study was to measure the serotonin transporter in vivo in mild cognitive impairment and healthy controls. The serotonin transporter is a selective marker of serotonin terminals and of the integrity of serotonin projections to cortical, subcortical and limbic regions and is found in high concentrations in the serotonergic cell bodies of origin of these projections (raphe nuclei). Twenty-eight participants with mild cognitive impairment (age 66.6±6.9, 16 males) and 28 healthy, cognitively normal, demographically matched controls (age 66.2±7.1, 15 males) underwent magnetic resonance imaging for measurement of grey matter volumes and high-resolution positron emission tomography with well-established radiotracers for the serotonin transporter and regional cerebral blood flow. Beta-amyloid imaging was performed to evaluate, in combination with the neuropsychological testing, the likelihood of subsequent cognitive decline in the participants with mild cognitive impairment. The following hypotheses were tested: 1) the serotonin transporter would be lower in mild cognitive impairment compared to controls in cortical and limbic regions, 2) in mild cognitive impairment relative to controls, the serotonin transporter would be lower to a greater extent and observed in a more widespread pattern than lower grey matter volumes or lower regional cerebral blood flow and 3) lower cortical and limbic serotonin transporters would be correlated with greater deficits in auditory-verbal and visual-spatial memory in mild cognitive impairment, not in controls. Reduced serotonin transporter availability was observed in mild cognitive impairment compared to controls in cortical and limbic areas typically affected by Alzheimer's disease pathology, as well as in sensory and motor areas, striatum and thalamus that are relatively spared in Alzheimer's disease. The reduction of the serotonin transporter in mild cognitive impairment was greater than grey matter atrophy or reductions in regional cerebral blood flow compared to controls. Lower cortical serotonin transporters were associated with worse performance on tests of auditory-verbal and visual-spatial memory in mild cognitive impairment, not in controls. The serotonin system may represent an important target for prevention and treatment of MCI, particularly the post-synaptic receptors (5-HT4 and 5-HT6), which may not be as severely affected as presynaptic aspects of the serotonin system, as indicated by the observation of lower serotonin transporters in MCI relative to healthy controls. Copyright © 2017 Elsevier Inc. All rights reserved.

Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior.

PubMed

Patrick, Rhonda P; Ames, Bruce N

2015-06-01

Serotonin regulates a wide variety of brain functions and behaviors. Here, we synthesize previous findings that serotonin regulates executive function, sensory gating, and social behavior and that attention deficit hyperactivity disorder, bipolar disorder, schizophrenia, and impulsive behavior all share in common defects in these functions. It has remained unclear why supplementation with omega-3 fatty acids and vitamin D improve cognitive function and behavior in these brain disorders. Here, we propose mechanisms by which serotonin synthesis, release, and function in the brain are modulated by vitamin D and the 2 marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Brain serotonin is synthesized from tryptophan by tryptophan hydroxylase 2, which is transcriptionally activated by vitamin D hormone. Inadequate levels of vitamin D (∼70% of the population) and omega-3 fatty acids are common, suggesting that brain serotonin synthesis is not optimal. We propose mechanisms by which EPA increases serotonin release from presynaptic neurons by reducing E2 series prostaglandins and DHA influences serotonin receptor action by increasing cell membrane fluidity in postsynaptic neurons. We propose a model whereby insufficient levels of vitamin D, EPA, or DHA, in combination with genetic factors and at key periods during development, would lead to dysfunctional serotonin activation and function and may be one underlying mechanism that contributes to neuropsychiatric disorders and depression. This model suggests that optimizing vitamin D and marine omega-3 fatty acid intake may help prevent and modulate the severity of brain dysfunction. © FASEB.

Neonatal methamphetamine-induced corticosterone release in rats is inhibited by adrenal autotransplantation without altering the effect of the drug on hippocampal serotonin

PubMed Central

Grace, Curtis E.; Schaefer, Tori L.; Gudelsky, Gary A.; Williams, Michael T.; Vorhees, Charles V.

2010-01-01

Rat neonatal methamphetamine exposure results in corticosterone release and learning and memory impairments in later life; effects also observed after neonatal stress. Previous attempts to test the role of corticosterone release after methamphetamine using corticosterone inhibitors were unsuccessful and adrenalectomy caused reductions in hippocampal serotonin greater than those caused by methamphetamine alone. Here we tested whether adrenal autotransplantation could be used to attenuate methamphetamine-induced corticosterone release without also altering the effects of the drug on serotonin. Adrenal autotransplantation surgery occurred on postnatal day 9 followed by methamphetamine or saline treatment from postnatal day 11–20 (10 mg/kg/dose x 4/day). Plasma corticosterone and hippocampal serotonin and 5-hydroxyindoleacetic acid were determined 30 min following the first treatment on each day between postnatal days 11–20. Adrenal autotransplantation attenuated neonatal methamphetamine-induced corticosterone release by ~70% initially, ~55% midway through treatment, and ~25% by the end of treatment. Methamphetamine reduced serotonin and 5-hydroxyindoleacetic acid in the hippocampus to the same degree as in sham-surgery rats. The data show that neonatal adrenal autotransplantation is an effective method for partially reducing treatment-induce corticosterone release while providing sufficient corticosterone to sustain normal growth and development. The method should is applicable to other models of developmental stress/corticosterone release. PMID:20153424

Antidepressant medications and osteoporosis.

PubMed

Rizzoli, R; Cooper, C; Reginster, J-Y; Abrahamsen, B; Adachi, J D; Brandi, M L; Bruyère, O; Compston, J; Ducy, P; Ferrari, S; Harvey, N C; Kanis, J A; Karsenty, G; Laslop, A; Rabenda, V; Vestergaard, P

2012-09-01

Use of antidepressant medications that act on the serotonin system has been linked to detrimental impacts on bone mineral density (BMD), and to osteoporosis. This article reviews current evidence for such effects, and identifies themes for future research. Serotonin receptors are found in all major types of bone cell (osteoblasts, osteocytes, and osteoclasts), indicating an important role of the neuroendocrine system in bone. Observational studies indicate a complex relationship between depression, antidepressants, and fracture. First, the presence of depression itself increases fracture risk, in relation with decreased BMD and an increase in falls. A range of aspects of depression may operate, including behavioral factors (e.g., smoking and nutrition), biological changes, and confounders (e.g., comorbidities and concomitant medications). A substantial proportion of depressed patients receive antidepressants, mostly selective serotonin reuptake inhibitors (SSRIs). Some of these have been linked to decreased BMD (SSRIs) and increased fracture risk (SSRIs and tricyclic agents). Current use of SSRIs and tricyclics increases fracture risk by as much as twofold versus nonusers, even after adjustment for potential confounders. While there is a dose-response relationship for SSRIs, the effect does not appear to be homogeneous across the whole class of drugs and may be linked to affinity for the serotonin transporter system. The increase in risk is the greatest in the early stages of treatment, with a dramatic increase after initiation, reaching a peak within 1 month for tricyclics and 8 months for SSRIs. Treatment-associated increased risk diminishes towards baseline in the year following discontinuation. The body of evidence suggests that SSRIs should be considered in the list of medications that are risk factors for osteoporotic fractures. Copyright © 2012 Elsevier Inc. All rights reserved.

Gastric pentadecapeptide BPC 157 effective against serotonin syndrome in rats.

PubMed

Boban Blagaic, Alenka; Blagaic, Vladimir; Mirt, Mirela; Jelovac, Nikola; Dodig, Goran; Rucman, Rudolf; Petek, Marijan; Turkovic, Branko; Anic, Tomislav; Dubovecak, Miroslav; Staresinic, Mario; Seiwerth, Sven; Sikiric, Predrag

2005-04-11

Serotonin syndrome commonly follows irreversible monoamine oxidase (MAO)-inhibition and subsequent serotonin (5-HT) substrate (in rats with fore paw treading, hind limbs abduction, wet dog shake, hypothermia followed by hyperthermia). A stable gastric pentadecapeptide BPC 157 with very safe profile (inflammatory bowel disease clinical phase II, PL-10, PLD-116, PL-14736, Pliva) reduced the duration of immobility to a greater extent than imipramine, and, given peripherally, has region specific influence on brain 5-HT synthesis (alpha-[14C]methyl-L-tryptophan autoradiographic measurements) in rats, different from any other serotonergic drug. Thereby, we investigate this peptide (10 microg, 10 ng, 10 pg/kg i.p.) in (i) full serotonin syndrome in rat combining pargyline (irreversible MAO-inhibition; 75 mg/kg i.p.) and subsequent L-tryptophan (5-HT precursor; 100 mg/kg i.p.; BPC 157 as a co-treatment), or (ii, iii) using pargyline or L-tryptophan given separately, as a serotonin-substrate with (ii) pargyline (BPC 157 as a 15-min posttreatment) or as a potential serotonin syndrome inductor with (iii) L-tryptophan (BPC 157 as a 15 min-pretreatment). In all experiments, gastric pentadecapeptide BPC 157 contrasts with serotonin-syndrome either (i) presentation (i.e., particularly counteracted) or (ii) initiation (i.e., neither a serotonin substrate (counteraction of pargyline), nor an inductor for serotonin syndrome (no influence on L-tryptophan challenge)). Indicatively, severe serotonin syndrome in pargyline + L-tryptophan rats is considerably inhibited even by lower pentadecapeptide BPC 157 doses regimens (particularly disturbances such as hyperthermia and wet dog shake thought to be related to stimulation of 5-HT2A receptors), while the highest pentadecapeptide dose counteracts mild disturbances present in pargyline rats (mild hypothermia, feeble hind limbs abduction). Thereby, in severe serotonin syndrome, gastric pentadecapeptide BPC 157 (alone, no behavioral or temperature effect) has a beneficial activity, which is likely, particular, and mostly related to a rather specific counteraction of 5-HT2A receptors phenomena.

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

PubMed Central

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

2016-01-01

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

Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test.

PubMed

Page, M E; Detke, M J; Dalvi, A; Kirby, L G; Lucki, I

1999-11-01

The forced swimming test (FST) is a behavioral test in rodents that predicts the clinical efficacy of many types of antidepressant treatments. Recently, a behavior sampling technique was developed that scores individual response categories, including swimming, climbing and immobility. Although all antidepressant drugs reduce immobility in the FST, at least two distinct active behavioral patterns are produced by pharmacologically selective antidepressant drugs. Serotonin-selective reuptake inhibitors increase swimming behavior, while drugs acting primarily to increase extracellular levels of norepinephrine or dopamine increase climbing behavior. Distinct patterns of active behaviors in the FST may be mediated by distinct neurotransmitters, but this has not been shown directly. The present study examined the role of serotonin in mediating active behaviors in the forced swimming test after treatment with two antidepressant drugs, the selective serotonin reuptake inhibitor, fluoxetine and the selective norepinephrine reuptake inhibitor, desipramine. Endogenous serotonin was depleted by administering para-cholorophenylalanine (PCPA, 150 mg/kg, IP.) to rats 72 h and 48 h prior to the swim test. Fluoxetine (10 mg/kg, SC) or desipramine (10 mg/kg, SC) was given three times over a 24-h period prior to the FST. Behavioral responses, including immobility, swimming and climbing, were counted during the 5-min test. Pretreatment with PCPA blocked fluoxetine-induced reduction in immobility and increase in swimming behavior during the FST. In contrast, PCPA pretreatment did not interfere with the ability of desipramine to reduce immobility and increase climbing behavior. Depletion of serotonin prevented the behavioral effects of the selective serotonin reuptake inhibitor fluoxetine in the rat FST. Furthermore, depletion of serotonin had no impact on the behavioral effects induced by the selective norepinephrine reuptake inhibitor, desipramine. The effects of antidepressant drugs on FST-induced immobility may be exerted by distinguishable contributions from different neurotransmitter systems.

Genetic determinants of aggression and impulsivity in humans.

PubMed

Pavlov, Konstantin A; Chistiakov, Dimitry A; Chekhonin, Vladimir P

2012-02-01

Human aggression/impulsivity-related traits have a complex background that is greatly influenced by genetic and non-genetic factors. The relationship between aggression and anxiety is regulated by highly conserved brain regions including amygdala, which controls neural circuits triggering defensive, aggressive, or avoidant behavioral models. The dysfunction of neural circuits responsible for emotional control was shown to represent an etiological factor of violent behavior. In addition to the amygdala, these circuits also involve the anterior cingulated cortex and regions of the prefrontal cortex. Excessive reactivity in the amygdala coupled with inadequate prefrontal regulation serves to increase the likelihood of aggressive behavior. Developmental alterations in prefrontal-subcortical circuitry as well as neuromodulatory and hormonal abnormality appear to play a role. Imbalance in testosterone/serotonin and testosterone/cortisol ratios (e.g., increased testosterone levels and reduced cortisol levels) increases the propensity toward aggression because of reduced activation of the neural circuitry of impulse control and self-regulation. Serotonin facilitates prefrontal inhibition, and thus insufficient serotonergic activity can enhance aggression. Genetic predisposition to aggression appears to be deeply affected by the polymorphic genetic variants of the serotoninergic system that influences serotonin levels in the central and peripheral nervous system, biological effects of this hormone, and rate of serotonin production, synaptic release and degradation. Among these variants, functional polymorphisms in the monoamine oxidase A (MAOA) and serotonin transporter (5-HTT) may be of particular importance due to the relationship between these polymorphic variants and anatomical changes in the limbic system of aggressive people. Furthermore, functional variants of MAOA and 5-HTT are capable of mediating the influence of environmental factors on aggression-related traits. In this review, we consider genetic determinants of human aggression, with special emphasis on genes involved in serotonin and dopamine metabolism and function.

Exercise, Stress Resistance, and Central Serotonergic Systems

PubMed Central

Greenwood, Benjamin N.; Fleshner, Monika

2015-01-01

Voluntary exercise reduces the incidence of stress-related psychiatric disorders in humans and prevents serotonin-dependent behavioral consequences of stress in rodents. Evidence reviewed herein is consistent with the hypothesis that exercise increases stress resistance by producing neuroplasticity at multiple sites of the central serotonergic system, which all help to limit the behavioral impact of acute increases in serotonin during stressor exposure. PMID:21508844

Serotonin and Social Norms

PubMed Central

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

2014-01-01

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

Oxytocin-Induced Changes in Monoamine Level in Symmetric Brain Structures of Isolated Aggressive C57Bl/6 Mice.

PubMed

Karpova, I V; Mikheev, V V; Marysheva, V V; Bychkov, E R; Proshin, S N

2016-03-01

Changes in activity of monoaminergic systems of the left and right brain hemispheres after administration of saline and oxytocin were studied in male C57Bl/6 mice subjected to social isolation. The concentrations of dopamine, norepinephrine, serotonin, and their metabolites dihydroxyphenylacetic, homovanillic, and 5-hydroxyindoleacetic acids were measured in the cerebral cortex, hippocampus, olfactory tubercle, and striatum of the left and right brain hemispheres by HPLC. In isolated aggressive males treated intranasally with saline, the content of serotonin and 5-hydroxyindoleacetic acid was significantly higher in the right hippocampus. Oxytocin reduces aggression caused by long-term social isolation, but has no absolute ability to suppress this type of behavior. Oxytocin reduced dopamine content in the left cortex and serotonin content in the right hippocampus and left striatum. Furthermore, oxytocin evened the revealed asymmetry in serotonin and 5-hydroxyindoleacetic acid concentrations in the hippocampus. At the same time, asymmetry in dopamine concentration appeared in the cortex with predominance of this transmitter in the right hemisphere. The data are discussed in the context of lateralization of neurotransmitter systems responsible for intraspecific aggression caused by long-term social isolation.

Serotonin-producing enterochromaffin (EC) cells of gastrointestinal mucosa in dexamethasone-treated rats.

PubMed

Glisić, Radmila; Koko, Vesna; Todorović, Vera; Drndarević, Neda; Cvijić, Gordana

2006-09-11

The aim of our study was to investigate the morphological, immunohistochemical and ultrastructural changes of rat serotonin-producing enterochromaffin (EC) cells of gastrointestinal mucosa in dexamethasone-treated rats (D). After 12-daily intraperitoneal administration of 2 mg/kg dexamethasone, rats developed diabetes similar to human diabetes type 2. Stomach, small and large intestines were examined. Large serotonin positive EC cells appeared in the corpus mucosa epithelium of D group of rats, although these cells were not present in control (C) rats. Both volume fraction and the number of EC cells per mm(2) of mucosa were significantly increased only in the duodenum. However, the number of EC cells per circular sections of both antrum and small intestine was increased, but reduced both in the ascending and descending colon in D group. The dexamethasone treatment caused a strong reduction in number of granules in the antral EC cells, while it was gradually increased beginning from the jejunum to descending colon. The mean granular content was reduced in the antral EC cells but increased in the jejunal EC cells in D group. In conclusion, the present study showed that morphological changes in gut serotonin-producing EC cells occurred in diabetic rats.

Brain serotonin transporter density and aggression in abstinent methamphetamine abusers.

PubMed

Sekine, Yoshimoto; Ouchi, Yasuomi; Takei, Nori; Yoshikawa, Etsuji; Nakamura, Kazuhiko; Futatsubashi, Masami; Okada, Hiroyuki; Minabe, Yoshio; Suzuki, Katsuaki; Iwata, Yasuhide; Tsuchiya, Kenji J; Tsukada, Hideo; Iyo, Masaomi; Mori, Norio

2006-01-01

In animals, methamphetamine is known to have a neurotoxic effect on serotonin neurons, which have been implicated in the regulation of mood, anxiety, and aggression. It remains unknown whether methamphetamine damages serotonin neurons in humans. To investigate the status of brain serotonin neurons and their possible relationship with clinical characteristics in currently abstinent methamphetamine abusers. Case-control analysis. A hospital research center. Twelve currently abstinent former methamphetamine abusers (5 women and 7 men) and 12 age-, sex-, and education-matched control subjects recruited from the community. The brain regional density of the serotonin transporter, a structural component of serotonin neurons, was estimated using positron emission tomography and trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([(11)C](+)McN-5652). Estimates were derived from region-of-interest and statistical parametric mapping methods, followed by within-case analysis using the measures of clinical variables. The duration of methamphetamine use, the magnitude of aggression and depressive symptoms, and changes in serotonin transporter density represented by the [(11)C](+)McN-5652 distribution volume. Methamphetamine abusers showed increased levels of aggression compared with controls. Region-of-interest and statistical parametric mapping analyses revealed that the serotonin transporter density in global brain regions (eg, the midbrain, thalamus, caudate, putamen, cerebral cortex, and cerebellum) was significantly lower in methamphetamine abusers than in control subjects, and this reduction was significantly inversely correlated with the duration of methamphetamine use. Furthermore, statistical parametric mapping analyses indicated that the density in the orbitofrontal, temporal, and anterior cingulate areas was closely associated with the magnitude of aggression in methamphetamine abusers. Protracted abuse of methamphetamine may reduce the density of the serotonin transporter in the brain, leading to elevated aggression, even in currently abstinent abusers.

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

PubMed Central

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

2010-01-01

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

Neuroendocrine disruption in the shore crab Carcinus maenas: Effects of serotonin and fluoxetine on chh- and mih-gene expression, glycaemia and ecdysteroid levels.

PubMed

Robert, Alexandrine; Monsinjon, Tiphaine; Delbecque, Jean-Paul; Olivier, Stéphanie; Poret, Agnès; Foll, Frank Le; Durand, Fabrice; Knigge, Thomas

2016-06-01

Serotonin, a highly conserved neurotransmitter, controls many biological functions in vertebrates, but also in invertebrates. Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, are commonly used in human medication to ease depression by affecting serotonin levels. Their residues and metabolites can be detected in the aquatic environment and its biota. They may also alter serotonin levels in aquatic invertebrates, thereby perturbing physiological functions. To investigate whether such perturbations can indeed be expected, shore crabs (Carcinus maenas) were injected either with serotonin, fluoxetine or a combination of both. Dose-dependent effects of fluoxetine ranging from 250 to 750nM were investigated. Gene expression of crustacean hyperglycemic hormone (chh) as well as moult inhibiting hormone (mih) was assessed by RT-qPCR at 2h and 12h after injection. Glucose and ecdysteroid levels in the haemolymph were monitored in regular intervals until 12h. Serotonin led to a rapid increase of chh and mih expression. On the contrary, fluoxetine only affected chh and mih expression after several hours, but kept expression levels significantly elevated. Correspondingly, serotonin rapidly increased glycaemia, which returned to normal or below normal levels after 12h. Fluoxetine, however, resulted in a persistent low-level increase of glycaemia, notably during the period when negative feedback regulation reduced glycaemia in the serotonin treated animals. Ecdysteroid levels were significantly decreased by serotonin and fluoxetine, with the latter showing less pronounced and less rapid, but longer lasting effects. Impacts of fluoxetine on glycaemia and ecdysteroids were mostly observed at higher doses (500 and 750nM) and affected principally the response dynamics, but not the amplitude of glycaemia and ecdysteroid-levels. These results suggest that psychoactive drugs are able to disrupt neuroendocrine control in decapod crustaceans, as they interfere with the normal regulation of the serotonergic system. Copyright © 2016 Elsevier B.V. All rights reserved.

The STRONG STAR Multidisciplinary PTSD Research Consortium

DTIC Science & Technology

2009-09-01

superior A.5 Role of the Serotonin Transporter and Serotonergic Hypotheses related to Alcoholism Vulnerability Due to Low Serotonin. Strong...evidence shows that the biological vulnerability of EOA patients may be related to a serotonergic dysfunction (Johnson, 2000; Johnson and Ait-Daoud...transporter (Johnson et al., 2008). These findings of reduced serotonergic functioning in L-carriers is contrary to previous data indicating that the L

Serotonin 1B Receptors Regulate Prefrontal Function by Gating Callosal and Hippocampal Inputs.

PubMed

Kjaerby, Celia; Athilingam, Jegath; Robinson, Sarah E; Iafrati, Jillian; Sohal, Vikaas S

2016-12-13

Both medial prefrontal cortex (mPFC) and serotonin play key roles in anxiety; however, specific mechanisms through which serotonin might act on the mPFC to modulate anxiety-related behavior remain unknown. Here, we use a combination of optogenetics and synaptic physiology to show that serotonin acts presynaptically via 5-HT1B receptors to selectively suppress inputs from the contralateral mPFC and ventral hippocampus (vHPC), while sparing those from mediodorsal thalamus. To elucidate how these actions could potentially regulate prefrontal circuit function, we infused a 5-HT1B agonist into the mPFC of freely behaving mice. Consistent with previous studies that have optogenetically inhibited vHPC-mPFC projections, activating prefrontal 5-HT1B receptors suppressed theta-frequency mPFC activity (4-12 Hz), and reduced avoidance of anxiogenic regions in the elevated plus maze. These findings suggest a potential mechanism, linking specific receptors, synapses, patterns of circuit activity, and behavior, through which serotonin may regulate prefrontal circuit function, including anxiety-related behaviors. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Serotonin inhibits low-threshold spike interneurons in the striatum

PubMed Central

Cains, Sarah; Blomeley, Craig P; Bracci, Enrico

2012-01-01

Low-threshold spike interneurons (LTSIs) are important elements of the striatal architecture and the only known source of nitric oxide in this nucleus, but their rarity has so far prevented systematic studies. Here, we used transgenic mice in which green fluorescent protein is expressed under control of the neuropeptide Y (NPY) promoter and striatal NPY-expressing LTSIs can be easily identified, to investigate the effects of serotonin on these neurons. In sharp contrast with its excitatory action on other striatal interneurons, serotonin (30 μm) strongly inhibited LTSIs, reducing or abolishing their spontaneous firing activity and causing membrane hyperpolarisations. These hyperpolarisations persisted in the presence of tetrodotoxin, were mimicked by 5-HT2C receptor agonists and reversed by 5-HT2C antagonists. Voltage-clamp slow-ramp experiments showed that serotonin caused a strong increase in an outward current activated by depolarisations that was blocked by the specific M current blocker XE 991. In current-clamp experiments, XE 991 per se caused membrane depolarisations in LTSIs and subsequent application of serotonin (in the presence of XE 991) failed to affect these neurons. We concluded that serotonin strongly inhibits striatal LTSIs acting through postsynaptic 5-HT2C receptors and increasing an M type current. PMID:22495583

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

PubMed

Cataldo, L R; Mizgier, M L; Busso, D; Olmos, P; Galgani, J E; Valenzuela, R; Mezzano, D; Aranda, E; Cortés, V A; Santos, J L

2016-01-01

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

The effect of polymorphism at the serotonin transporter gene on decision-making, memory and executive function in ecstasy users and controls

PubMed Central

Roiser, Jonathan P.; Rogers, Robert D.; Cook, Lynnette J.; Sahakian, Barbara J.

2008-01-01

Rationale 3, 4-Methylenedioxymethamphetamine (MDMA or “ecstasy”) is a popular drug of abuse known to result in depletions of the serotonin (5-HT) system. A number of studies have reported that ecstasy users differ from controls on a variety of measures of cognitive function. However, the literature is not consistent and many negative findings were also reported. One reason for such inconsistency might be interindividual variance in vulnerability to the deleterious effects of ecstasy due to a number of factors, both genetic and environmental. Objectives To investigate the hypothesis that carriers of the s allele at the 5-HT transporter gene-linked polymorphic region (5-HTTLPR), which was associated with reduced serotonergic neurotransmission relative to the l allele, would be most vulnerable to the effects of ecstasy on cognitive function. Methods We assessed memory, decision-making, and executive function in ecstasy users and controls, stratifying by genotype at the 5-HTTLPR. Results We observed that the 5-HTTLPR genotype groups differed on a number of measures in both the ecstasy users and the controls. While performing a risky decision-making task, ss and ls controls attended to differences in the probability of winning chosen gambles to a greater extent than the ll controls. However, this difference was dramatically attenuated in the ss ecstasy users. Furthermore, independent of ecstasy use, volunteers of the ss genotype outperformed the ll genotype on a visual planning task. Conclusions The results are consistent with the hypothesis that cognitive impairment in ecstasy users may depend on genetic variation at the 5-HTTLPR. PMID:16941121

Regulation of Corticoid and Serotonin Receptor Brain System following Early Life Exposure of Glucocorticoids: Long Term Implications for the Neurobiology of Mood

PubMed Central

Vázquez, Delia M.; Neal, Charles R.; Patel, Paresh D.; Kaciroti, Niko; López, Juan F.

2011-01-01

Potent glucocorticoids (GC) administered early in life has improved premature infant survival dramatically. However, these agents may increase the risk for physical, neurological and behavior alterations. Anxiety, depression and attention difficulties are commonly described in adolescent and young adult survivors of prematurity. In the present study we administered vehicle, dexamethasone, or hydrocortisone to Sprague-Dawley rat pups on postnatal days 5 and 6, mimicking a short term clinical protocol commonly used in human infants. Two systems that are implicated in the regulation of stress and behavior were assessed: the limbic-hypothalamic-pituitary-adrenal axis [LHPA, glucocorticoid and mineralocorticoid receptors within] and the Serotonin (5-HT) system. We found that as adults, male Sprague-Dawley pups treated with GC showed agent specific altered growth, anxiety-related behavior, changes in corticoid response to novelty and gene expression changes within LHPA and 5-HT–related circuitry. The data suggest that prolonged GC-receptor stimulation during the early neonatal period can contribute to the development of individual differences in stress response and anxiety-related behavior later in life. PMID:21855221

Characterization and validation of fluorescent receptor ligands: a case study of the ionotropic serotonin receptor.

PubMed

Hovius, Ruud

2013-01-01

The application of fluorescent receptor ligands has become widespread, incited by two important reasons. "Seeing is believing"-it is possible to visualize in real time in live cells ligand-receptor interactions, and to locate the receptors with subcellular precision allowing one to follow, e.g., internalization of the ligand-receptor complex. The high sensitivity of photon detection permits observation of on the one hand receptor-ligand interactions on cells with low, native receptor abundance, and on the other of individual fluorophores unveiling the stochastic properties of single ligand-receptor complexes.The major bottlenecks that impede extensive use of fluorescent ligands are due to possible dramatic changes of the pharmacological properties of a ligand upon chemical modification and fluorophore conjugation, aggravated by the observation that different fluorophores can provoke very dissimilar effects. This makes it virtually impossible to predict beforehand which labelling strategy to use to produce a fluorescent ligand with the desired qualities.Here, we focus on the design, synthesis, and evaluation of a high-affinity fluorescent antagonist for the ionotropic serotonin type-3 receptor.

Neurochemical development of brain stem nuclei involved in the control of respiration.

PubMed

Wong-Riley, Margaret T T; Liu, Qiuli

2005-11-15

The first two postnatal weeks are the most dynamic in the development of brain stem respiratory nuclei in the rat, the primary model for this review. Several neurochemicals (glutamate, glycine receptors, choline acetyltransferase, serotonin, norepinephrine, and thyrotropin-releasing hormone) increase expression with age, while others (GABA, serotonin receptor 1A, substance P, neurokinin 1 receptor, and somatostatin) decrease their expression. Surprisingly, a dramatic shift occurs at postnatal day (P) 12 in the rat. Excitatory neurotransmitter glutamate and its NMDA receptors fall precipitously, whereas inhibitory neurotransmitter GABA, GABA(B), and glycine receptors rise sharply. A concomitant drop in cytochrome oxidase activity occurs in respiratory neurons. Several receptor types undergo subunit switches during development. Notably, GABA(A) receptors switch prevalence from alpha3- to an alpha1-dominant form at P12 in the pre-Bötzinger complex of the rat. The transient dominance of inhibitory over excitatory neurotransmission around P12 may render the respiratory system sensitive to failure when stressed. Relating these neurochemical changes to physiological responses in animals and to sudden infant death syndrome in humans will be a challenge for future research.

Up-regulation of melanin synthesis by the antidepressant fluoxetine.

PubMed

Liao, Sha; Shang, Jing; Tian, Xiaoli; Fan, Xueqi; Shi, Xiupu; Pei, Siran; Wang, Qian; Yu, Boyang

2012-08-01

Fluoxetine, a member of the class of selective serotonin reuptake inhibitors, is a potent antidepressant commonly used in clinical practice. Here, we report that fluoxetine increases cellular tyrosinase (TYR) activity, enhances the protein levels of microphthalmia-associated transcription factor (MITF), TYR and tyrosinase-related protein-1 (TRP-1) and eventually leads to a dramatic increase in melanin production in both murine B16F10 melanoma cells and normal human melanocytes (NHMCs). In well-characterized C57BL/6 mouse models, systemic application of fluoxetine increased hair pigmentation by up-regulating hair follicular MITF, TYR, TRP-1 and tyrosinase-related protein-2 (TRP-2) protein levels. Using a serotonin 1A receptor (SR1A) antagonist and RNA interference (RNAi) technique, we revealed that SR1A appears to be one of the involved pathways in the fluoxetine-induced melanogenesis in B16F10 cells. These results suggest that fluoxetine may hold a significant therapeutic potential for treating skin hypopigmentation disorders, and SR1A may serve as a novel target in modulating melanogenesis. © 2012 John Wiley & Sons A/S.

Immunohistochemical localization of serotonin in the brain during natural sex change in the hermaphroditic goby Lythrypnus dalli.

PubMed

Lorenzi, Varenka; Grober, Matthew S

2012-02-01

The neurotransmitter serotonin (5-HT) may play a central role in the inhibition of socially regulated sex change in fish because of its known modulation of both aggressive and reproductive behavior. This is the first study to use immunohistochemical techniques to examine the morphometry of serotonergic neurons at different times during sex change. Using a model species wherein sex change is socially regulated via agonistic social interactions (the bluebanded goby, Lythrypnus dalli), we sampled brains of males and females with different social status, and of females at different times during sex change. Consistent with previous studies on other teleosts, immunoreactive neurons were found in the posterior periventricular nucleus (NPPv), the nucleus of the lateral recess (NRL), the nucleus of the posterior recess (NRP) and in the raphe nucleus. We measured the total area of NPPv, NRL, NRP, and the number and mean cell area of serotonergic neurons in the raphe nucleus. There was no significant difference in any of the brain regions between males, females or sex changing fish, but there was a slight increase in the number of dorsal raphe neurons in the brain of sex changers 2h after male removal. The results show that in L. dalli the serotonergic system does not present any morphological sex and status differences, nor any dramatic modifications during sex change. These data, together with previous results, do not support the hypothesis that serotonin inhibits socially regulated sex change. Copyright © 2011 Elsevier Inc. All rights reserved.

Serotonin is an endogenous regulator of intestinal CYP1A1 via AhR.

PubMed

Manzella, Christopher; Singhal, Megha; Alrefai, Waddah A; Saksena, Seema; Dudeja, Pradeep K; Gill, Ravinder K

2018-04-17

Aryl hydrocarbon receptor (AhR) is a nuclear receptor that controls xenobiotic detoxification via induction of cytochrome P450 1A1 (CYP1A1) and regulates immune responses in the intestine. Metabolites of L-tryptophan activate AhR, which confers protection against intestinal inflammation. We tested the hypothesis that serotonin (5-HT) is an endogenous activator of AhR in intestinal epithelial cells. Treatment of Caco-2 monolayers with 5-HT induced CYP1A1 mRNA in a time- and concentration-dependent manner and also stimulated CYP1A1 activity. CYP1A1 induction by 5-HT was dependent upon uptake via serotonin transporter (SERT). Antagonism of AhR and knockdown of AhR and its binding partner aryl hydrocarbon receptor nuclear translocator (ARNT) attenuated CYP1A1 induction by 5-HT. Activation of AhR was evident by its nuclear translocation after 5-HT treatment and by induction of an AhR-responsive luciferase reporter. In vivo studies showed a dramatic decrease in CYP1A1 expression and other AhR target genes in SERT KO ileal mucosa by microarray analysis. These results suggest that intracellular accumulation of 5-HT via SERT induces CYP1A1 expression via AhR in intestinal epithelial cells, and SERT deficiency in vivo impairs activation of AhR. Our studies provide a novel link between the serotonergic and AhR pathways which has implications in xenobiotic metabolism and intestinal inflammation.

Simple and rapid determination of serotonin and catecholamines in biological tissue using high-performance liquid chromatography with electrochemical detection.

PubMed

Patel, Bhavik Anil; Arundell, Martin; Parker, Kim H; Yeoman, Mark S; O'Hare, Danny

2005-04-25

Using the CNS of Lymnaea stagnalis a method is described for the rapid analysis of neurotransmitters and their metabolites using high performance liquid chromatography coupled with electrochemical detection. Tissue samples were homogenised in ice-cold 0.1 M perchloric acid and centrifuged. Using a C(18) microbore column the mobile phase was maintained at a flow rate of 100 microl/min and consisted of sodium citrate buffer (pH 3.2)-acetonitrile (82.5:17.5, v/v) with 2 mM decane-sulfonic acid sodium salt. The potential was set at +750 mV versus Ag|AgCl reference electrode at a sensitivity of 50 nA full scale deflection. The detection limit for serotonin was 11.86 ng ml(-1) for a 5 microl injection. Preparation of tissue samples in mobile phase reduced the response to dopamine and serotonin compared with perchloric acid. In addition it was found that the storage of tissue samples at -20 degrees C caused losses of dopamine and serotonin. As a result of optimising the sample preparation and mobile phase the total time of analysis was substantially reduced resulting in a sample preparation and assay time of 15-20 min.

Myenteric denervation differentially reduces enteroendocrine serotonin cell population in rats during postnatal development.

PubMed

Hernandes, Luzmarina; Fernandes, Marilda da Cruz; Pereira, Lucieni Cristina Marques da Silva; Freitas, Priscila de; Gama, Patrícia; Alvares, Eliana Parisi

2006-05-01

The enteric nervous and enteroendocrine systems regulate different processes in the small intestine. Ablation of myenteric plexus with benzalkonium chloride (BAC) stimulates epithelial cell proliferation, whereas endocrine serotonin cells may inhibit the process. To evaluate the connection between the systems and the influence of myenteric plexus on serotoninergic cells in rats during postnatal development, the ileal plexus was partially removed with BAC. Rats were treated at 13 or 21 days and sacrificed after 15 days. The cell bodies of myenteric neurons were stained by beta NADH-diaphorase to detect the extension of denervation. The number of enteroendocrine cells in the ileum was estimated in crypts and villi in paraffin sections immunostained for serotonin. The number of neurons was reduced by 27.6 and 45% in rats treated on the 13th and 21st days, respectively. We tried to establish a correlation of denervation and the serotonin population according to the age of treatment. We observed a reduction of immunolabelled cells in the crypts of rats treated at 13 days, whereas this effect was seen in the villi of rats denervated at 21 days. These results suggest that the enteric nervous system might control the enteroendocrine cell population and this complex mechanism could be correlated to changes in cell proliferation.

Serotonin 1B Receptor Gene (HTR1B) Methylation as a Risk Factor for Callous-Unemotional Traits in Antisocial Boys.

PubMed

Moul, Caroline; Dobson-Stone, Carol; Brennan, John; Hawes, David J; Dadds, Mark R

2015-01-01

The serotonin system is thought to play a role in the aetiology of callous-unemotional (CU) traits in children. Previous research identified a functional single nucleotide polymorphism (SNP) from the promoter region of the serotonin 1B receptor gene as being associated with CU traits in boys with antisocial behaviour problems. This research tested the hypothesis that CU traits are associated with reduced methylation of the promoter region of the serotonin 1B receptor gene due to the influence of methylation on gene expression. Participants (N = 117) were boys with antisocial behaviour problems aged 3-16 years referred to University of New South Wales Child Behaviour Research Clinics. Participants volunteered a saliva sample from which the genotype of a SNP from the promoter region of the serotonin 1B receptor gene and the methylation levels of 30 CpG sites from 3 CpG regions surrounding the location of this polymorphism were assayed. Lower levels of serotonin 1B receptor gene methylation were associated with higher levels of CU traits. This relationship, however, was found to be moderated by genotype and carried exclusively by two CpG sites for which levels of methylation were negatively associated with overall methylation levels in this region of the gene. Results provide support to the emerging literature that argues for a genetically-driven system-wide alteration in serotonin function in the aetiology of CU traits. Furthermore, the results suggest that there may be two pathways to CU traits that involve methylation of the serotonin 1B receptor gene; one that is driven by a genotypic risk and another that is associated with risk for generally increased levels of methylation. Future research that aims to replicate and further investigate these results is required.

The behavioral pharmacology and therapeutic potential of lorcaserin for substance use disorders.

PubMed

Collins, Gregory T; Gerak, Lisa R; France, Charles P

2017-12-12

Substance abuse is serious public health problem for which there are few effective pharmacotherapies. Traditional strategies for drug development have focused on antagonists to block the abuse-related effects of a drug at its site of action, and agonists to replace/mimic the effects of the abused substance. However, recent efforts have targeted receptors, such as serotonin (5-HT) 2 receptors, that can indirectly modulate dopamine neurotransmission with the goal of developing a pharmacotherapy that might be effective at reducing the abuse-related effects of drugs more generally. Lorcaserin is a 5-HT 2C receptor-preferring agonist that is approved by the US Food and Drug Administration for the treatment of obesity. Mounting evidence from preclinical and clinical studies suggests that lorcaserin might also be effective at reducing the abuse-related effects of drugs with different pharmacological mechanisms (e.g., cocaine, heroin, ethanol, and nicotine). Lorcaserin represents a promising and important first step towards the development a new class of pharmacotherapies that have the potential to dramatically improve the treatment of substance abuse. This article will review the behavioral pharmacology of 5-HT 2C receptor-preferring agonists, with a focus on lorcaserin, and evaluate the preclinical evidence supporting the development of lorcaserin for treating substance abuse. Copyright © 2017 Elsevier Ltd. All rights reserved.

Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease

PubMed Central

Teixeira-Castro, Andreia; Kang, Soosung; da Silva Santos, Liliana; Silva-Fernandes, Anabela; Neto, Mário F.; Brielmann, Renée M.; Bessa, Carlos; Duarte-Silva, Sara; Miranda, Adriana; Oliveira, Stéphanie; Neves-Carvalho, Andreia; Bessa, João; Summavielle, Teresa; Silverman, Richard B.; Oliveira, Pedro; Morimoto, Richard I.

2015-01-01

Polyglutamine diseases are a class of dominantly inherited neurodegenerative disorders for which there is no effective treatment. Here we provide evidence that activation of serotonergic signalling is beneficial in animal models of Machado-Joseph disease. We identified citalopram, a selective serotonin reuptake inhibitor, in a small molecule screen of FDA-approved drugs that rescued neuronal dysfunction and reduced aggregation using a Caenorhabditis elegans model of mutant ataxin 3-induced neurotoxicity. MOD-5, the C. elegans orthologue of the serotonin transporter and cellular target of citalopram, and the serotonin receptors SER-1 and SER-4 were strong genetic modifiers of ataxin 3 neurotoxicity and necessary for therapeutic efficacy. Moreover, chronic treatment of CMVMJD135 mice with citalopram significantly reduced ataxin 3 neuronal inclusions and astrogliosis, rescued diminished body weight and strikingly ameliorated motor symptoms. These results suggest that small molecule modulation of serotonergic signalling represents a promising therapeutic target for Machado-Joseph disease. PMID:26373603

Is domestication driven by reduced fear of humans? Boldness, metabolism and serotonin levels in divergently selected red junglefowl (Gallus gallus).

PubMed

Agnvall, Beatrix; Katajamaa, Rebecca; Altimiras, Jordi; Jensen, Per

2015-09-01

Domesticated animals tend to develop a coherent set of phenotypic traits. Tameness could be a central underlying factor driving this, and we therefore selected red junglefowl, ancestors of all domestic chickens, for high or low fear of humans during six generations. We measured basal metabolic rate (BMR), feed efficiency, boldness in a novel object (NO) test, corticosterone reactivity and basal serotonin levels (related to fearfulness) in birds from the fifth and sixth generation of the high- and low-fear lines, respectively (44-48 individuals). Corticosterone response to physical restraint did not differ between selection lines. However, BMR was higher in low-fear birds, as was feed efficiency. Low-fear males had higher plasma levels of serotonin and both low-fear males and females were bolder in an NO test. The results show that many aspects of the domesticated phenotype may have developed as correlated responses to reduced fear of humans, an essential trait for successful domestication. © 2015 The Author(s).

Repeated MDMA ("Ecstasy") exposure in adolescent male rats alters temperature regulation, spontaneous motor activity, attention, and serotonin transporter binding.

PubMed

Piper, Brian J; Fraiman, Joseph B; Meyer, Jerrold S

2005-09-01

Previous research in our laboratory found that repeated exposure of adolescent rats to 3,4-methylenedioxymethamphetamine (MDMA) impaired working memory and reduced anxiety. The present experiment extended these findings by investigating the physiological, behavioral, and neurotoxic effects of a modified MDMA treatment regimen. Male Sprague-Dawley rats received 5 mg/kg of MDMA hourly for a period of 4 hr on every fifth day from postnatal day 35-60. Acute effects of the MDMA treatment included hypothermia, serotonin syndrome behavior, and ejaculation. Body weight gain was attenuated by repeated drug administration. The animals completed anxiety and working memory tests beginning 4 days after the final MDMA dose. MDMA altered habituation to the open-field, increased locomotor activity in the elevated plus-maze, decreased attention in the novel object-recognition test, and reduced serotonin transporter binding in the neocortex. These results indicate that repeated exposure to a relatively moderate MDMA dose during adolescence produces later changes in behavior and neurochemistry. Copyright 2005 Wiley Periodicals, Inc

Serotonin modulates a depression-like state in Drosophila responsive to lithium treatment

PubMed Central

Ries, Ariane-Saskia; Hermanns, Tim; Poeck, Burkhard; Strauss, Roland

2017-01-01

Major depressive disorder (MDD) affects millions of patients; however, the pathophysiology is poorly understood. Rodent models have been developed using chronic mild stress or unavoidable punishment (learned helplessness) to induce features of depression, like general inactivity and anhedonia. Here we report a three-day vibration-stress protocol for Drosophila that reduces voluntary behavioural activity. As in many MDD patients, lithium-chloride treatment can suppress this depression-like state in flies. The behavioural changes correlate with reduced serotonin (5-HT) release at the mushroom body (MB) and can be relieved by feeding the antidepressant 5-hydroxy-L-tryptophan or sucrose, which results in elevated 5-HT levels in the brain. This relief is mediated by 5-HT-1A receptors in the α-/β-lobes of the MB, whereas 5-HT-1B receptors in the γ-lobes control behavioural inactivity. The central role of serotonin in modulating stress responses in flies and mammals indicates evolutionary conserved pathways that can provide targets for treatment and strategies to induce resilience. PMID:28585544

Serotonin 5-HT2C receptor-mediated inhibition of the M-current in hypothalamic POMC neurons.

PubMed

Roepke, T A; Smith, A W; Rønnekleiv, O K; Kelly, M J

2012-06-01

Hypothalamic proopiomelanocortin (POMC) neurons are controlled by many central signals, including serotonin. Serotonin increases POMC activity and reduces feeding behavior via serotonion [5-hydroxytryptamine (5-HT)] receptors by modulating K(+) currents. A potential K(+) current is the M-current, a noninactivating, subthreshold outward K(+) current. Previously, we found that M-current activity was highly reduced in fasted vs. fed states in neuropeptide Y neurons. Because POMC neurons also respond to energy states, we hypothesized that fasting may alter the M-current and/or its modulation by serotonergic input to POMC neurons. Using visualized-patch recording in neurons from fed male enhanced green fluorescent protein-POMC transgenic mice, we established that POMC neurons expressed a robust M-current (102.1 ± 6.7 pA) that was antagonized by the selective KCNQ channel blocker XE-991 (40 μM). However, the XE-991-sensitive current in POMC neurons did not differ between fed and fasted states. To determine if serotonin suppresses the M-current via the 5-HT(2C) receptor, we examined the effects of the 5-HT(2A)/5-HT(2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) on the M-current. Indeed, DOI attenuated the M-current by 34.5 ± 6.9% and 42.0 ± 5.3% in POMC neurons from fed and fasted male mice, respectively. In addition, the 5-HT(1B)/5-HT(2C) receptor agonist m-chlorophenylpiperazine attenuated the M-current by 42.4 ± 5.4% in POMC neurons from fed male mice. Moreover, the selective 5-HT(2C) receptor antagonist RS-102221 abrogated the actions of DOI in suppressing the M-current. Collectively, these data suggest that although M-current expression does not differ between fed and fasted states in POMC neurons, serotonin inhibits the M-current via activation of 5-HT(2C) receptors to increase POMC neuronal excitability and, subsequently, reduce food intake.

Effects of gonadectomy and serotonin depletion on inter-individual differences in anxiety-like behaviour in male Wistar rats.

PubMed

Näslund, Jakob; Studer, Erik; Johansson, Elin; Eriksson, Elias

2016-07-15

Previous studies in Wistar rats suggest inter-individual differences in anxiety-like behaviour as assessed using the elevated plus maze (EPM), both between sexes and among males, to be abolished by serotonin depletion. To shed further light on the influence of sex steroids and serotonin - and on the interplay between the two - on proneness for EPM-assessed anxiety in males, outbred Wistar rats were divided into those with high and low anxiety, respectively, and exposed to gonadectomy or sham operation followed by administration of a serotonin synthesis inhibitor, para-chlorophenylalanine, or saline. Whereas gonadectomy enhanced anxiety-like behaviour in low anxiety rats so that these no longer differed in this regard from the high anxiety group, serotonin depletion reversed this effect, and also reduced anxiety in the low anxiety group regardless of gonadal state. A previously observed association between high anxiety-like behaviour and high expression of the serotonin-synthesizing enzyme tryptophan hydroxylase 2 (Tph2) in the raphe was confirmed in sham-operated animals but absent in gonadectomised rats, an ANCOVA revealing a significant interactive effect of baseline anxiety and gonadal state on Tph2 expression. It is suggested that androgens may contribute to upholding inter-individual differences in anxiety-like behaviour in male rats by interacting with serotonergic neurotransmission. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Hypolocomotion, anxiety and serotonin syndrome-like behavior contribute to the complex phenotype of serotonin transporter knockout mice.

PubMed

Kalueff, A V; Fox, M A; Gallagher, P S; Murphy, D L

2007-06-01

Although mice with a targeted disruption of the serotonin transporter (SERT) have been studied extensively using various tests, their complex behavioral phenotype is not yet fully understood. Here we assess in detail the behavior of adult female SERT wild type (+/+), heterozygous (+/-) and knockout (-/-) mice on an isogenic C57BL/6J background subjected to a battery of behavioral paradigms. Overall, there were no differences in the ability to find food or a novel object, nest-building, self-grooming and its sequencing, and horizontal rod balancing, indicating unimpaired sensory functions, motor co-ordination and behavioral sequencing. In contrast, there were striking reductions in exploration and activity in novelty-based tests (novel object, sticky label and open field tests), accompanied by pronounced thigmotaxis, suggesting that combined hypolocomotion and anxiety (rather than purely anxiety) influence the SERT -/- behavioral phenotype. Social interaction behaviors were also markedly reduced. In addition, SERT -/- mice tended to move close to the ground, frequently displayed spontaneous Straub tail, tics, tremor and backward gait - a phenotype generally consistent with 'serotonin syndrome'-like behavior. In line with replicated evidence of much enhanced serotonin availability in SERT -/- mice, this serotonin syndrome-like state may represent a third factor contributing to their behavioral profile. An understanding of the emerging complexity of SERT -/- mouse behavior is crucial for a detailed dissection of their phenotype and for developing further neurobehavioral models using these mice.

The evolution of violence in men: the function of central cholesterol and serotonin.

PubMed

Wallner, Bernard; Machatschke, Ivo H

2009-04-30

Numerous studies point to central serotonin as an important modulator of maladaptive behaviors. In men, for instance, low concentrations of this neurotransmitter are related to hostile aggression. A key player in serotonin metabolism seems to be central cholesterol. It plays a fundamental role in maintaining the soundness of neuron membranes, especially in the exocytosis transport of serotonin vesicles into the synaptic cleft. In this review, we attempt an evolutionary approach to the neurobiological basis of human male violence. Hominid evolution was shaped by periods of starvation but also by energy demands of an increasingly complex brain. A lack of food resources reduces uptake of glucose and results in a decreased energy-supply for autonomous brain cholesterol synthesis. Consequently, concentrations of neuromembrane cholesterol decrease, which lead to a failure of the presynaptic re-uptake mechanism of serotonin and ultimately to low central serotonin. We propose that starvation might have affected the larger male brains earlier than those of females. Furthermore, this neurophysiological process diminished the threshold for hostile aggression, which in effect represented a prerequisite for being a successful hunter or scavenger. In a Darwinian sense, the odds to acquire reliable energetic resources made those males to attractive spouses in terms of paternal care and mate support. To underpin these mechanisms, a hypothetical four-stage model of synaptic membrane destabilization effected by a prolonged shortage of high-energy, cholesterol-containing food is illustrated.

Acute Fluoxetine Treatment Induces Slow Rolling of Leukocytes on Endothelium in Mice

PubMed Central

Herr, Nadine; Mauler, Maximilian; Witsch, Thilo; Stallmann, Daniela; Schmitt, Stefanie; Mezger, Julius; Bode, Christoph; Duerschmied, Daniel

2014-01-01

Objective Activated platelets release serotonin at sites of inflammation where it acts as inflammatory mediator and enhances recruitment of neutrophils. Chronic treatment with selective serotonin reuptake inhibitors (SSRI) depletes the serotonin storage pool in platelets, leading to reduced leukocyte recruitment in murine experiments. Here, we examined the direct and acute effects of SSRI on leukocyte recruitment in murine peritonitis. Methods C57Bl/6 and Tph1−/− (Tryptophan hydroxylase1) mice underwent acute treatment with the SSRI fluoxetine or vehicle. Serotonin concentrations were measured by ELISA. Leukocyte rolling and adhesion on endothelium was analyzed by intravital microscopy in mesentery venules with and without lipopolysaccharide challenge. Leukocyte extravasation in sterile peritonitis was measured by flow cytometry of abdominal lavage fluid. Results Plasma serotonin levels were elevated 2 hours after fluoxetine treatment (0.70±0.1 µg/ml versus 0.27±0.1, p = 0.03, n = 14), while serum serotonin did not change. Without further stimulation, acute fluoxetine treatment increased the number of rolling leukocytes (63±8 versus 165±17/0.04 mm2min−1) and decreased their velocity (61±6 versus 28±1 µm/s, both p<0.0001, n = 10). In Tph1−/− mice leukocyte rolling was not significantly influenced by acute fluoxetine treatment. Stimulation with lipopolysaccharide decreased rolling velocity and induced leukocyte adhesion, which was enhanced after fluoxetine pretreatment (27±3 versus 36±2/0.04 mm2, p = 0.008, n = 10). Leukocyte extravasation in sterile peritonitis, however, was not affected by acute fluoxetine treatment. Conclusions Acute fluoxetine treatment increased plasma serotonin concentrations and promoted leukocyte-endothelial interactions in-vivo, suggesting that serotonin is a promoter of acute inflammation. E-selectin was upregulated on endothelial cells in the presence of serotonin, possibly explaining the observed increase in leukocyte-endothelial interactions. However transmigration of neutrophils in sterile peritonitis was not affected by higher serotonin concentrations, indicating that the effect of fluoxetine was restricted to early steps in the leukocyte recruitment. Whether SSRI use in humans alters leukocyte recruitment remains to be investigated. PMID:24520366

Convergence of the Insulin and Serotonin Programs in the Pancreatic β-Cell

PubMed Central

Ohta, Yasuharu; Kosaka, Yasuhiro; Kishimoto, Nina; Wang, Juehu; Smith, Stuart B.; Honig, Gerard; Kim, Hail; Gasa, Rosa M.; Neubauer, Nicole; Liou, Angela; Tecott, Laurence H.; Deneris, Evan S.; German, Michael S.

2011-01-01

OBJECTIVE Despite their origins in different germ layers, pancreatic islet cells share many common developmental features with neurons, especially serotonin-producing neurons in the hindbrain. Therefore, we tested whether these developmental parallels have functional consequences. RESEARCH DESIGN AND METHODS We used transcriptional profiling, immunohistochemistry, DNA-binding analyses, and mouse genetic models to assess the expression and function of key serotonergic genes in the pancreas. RESULTS We found that islet cells expressed the genes encoding all of the products necessary for synthesizing, packaging, and secreting serotonin, including both isoforms of the serotonin synthetic enzyme tryptophan hydroxylase and the archetypal serotonergic transcription factor Pet1. As in serotonergic neurons, Pet1 expression in islets required homeodomain transcription factor Nkx2.2 but not Nkx6.1. In β-cells, Pet1 bound to the serotonergic genes but also to a conserved insulin gene regulatory element. Mice lacking Pet1 displayed reduced insulin production and secretion and impaired glucose tolerance. CONCLUSIONS These studies demonstrate that a common transcriptional cascade drives the differentiation of β-cells and serotonergic neurons and imparts the shared ability to produce serotonin. The interrelated biology of these two cell types has important implications for the pathology and treatment of diabetes. PMID:22013016

Convergence of the insulin and serotonin programs in the pancreatic β-cell.

PubMed

Ohta, Yasuharu; Kosaka, Yasuhiro; Kishimoto, Nina; Wang, Juehu; Smith, Stuart B; Honig, Gerard; Kim, Hail; Gasa, Rosa M; Neubauer, Nicole; Liou, Angela; Tecott, Laurence H; Deneris, Evan S; German, Michael S

2011-12-01

Despite their origins in different germ layers, pancreatic islet cells share many common developmental features with neurons, especially serotonin-producing neurons in the hindbrain. Therefore, we tested whether these developmental parallels have functional consequences. We used transcriptional profiling, immunohistochemistry, DNA-binding analyses, and mouse genetic models to assess the expression and function of key serotonergic genes in the pancreas. We found that islet cells expressed the genes encoding all of the products necessary for synthesizing, packaging, and secreting serotonin, including both isoforms of the serotonin synthetic enzyme tryptophan hydroxylase and the archetypal serotonergic transcription factor Pet1. As in serotonergic neurons, Pet1 expression in islets required homeodomain transcription factor Nkx2.2 but not Nkx6.1. In β-cells, Pet1 bound to the serotonergic genes but also to a conserved insulin gene regulatory element. Mice lacking Pet1 displayed reduced insulin production and secretion and impaired glucose tolerance. These studies demonstrate that a common transcriptional cascade drives the differentiation of β-cells and serotonergic neurons and imparts the shared ability to produce serotonin. The interrelated biology of these two cell types has important implications for the pathology and treatment of diabetes.

The nuclear receptor PPARγ individually responds to serotonin- and fatty acid-metabolites

PubMed Central

Waku, Tsuyoshi; Shiraki, Takuma; Oyama, Takuji; Maebara, Kanako; Nakamori, Rinna; Morikawa, Kosuke

2010-01-01

The nuclear receptor, peroxisome proliferator-activated receptor γ (PPARγ), recognizes various synthetic and endogenous ligands by the ligand-binding domain. Fatty-acid metabolites reportedly activate PPARγ through conformational changes of the Ω loop. Here, we report that serotonin metabolites act as endogenous agonists for PPARγ to regulate macrophage function and adipogenesis by directly binding to helix H12. A cyclooxygenase inhibitor, indomethacin, is a mimetic agonist of these metabolites. Crystallographic analyses revealed that an indole acetate functions as a common moiety for the recognition by the sub-pocket near helix H12. Intriguingly, a serotonin metabolite and a fatty-acid metabolite each bind to distinct sub-pockets, and the PPARγ antagonist, T0070907, blocked the fatty-acid agonism, but not that of the serotonin metabolites. Mutational analyses on receptor-mediated transcription and coactivator binding revealed that each metabolite individually uses coregulator and/or heterodimer interfaces in a ligand-type-specific manner. Furthermore, the inhibition of the serotonin metabolism reduced the expression of the endogenous PPARγ-target gene. Collectively, these results suggest a novel agonism, in which PPARγ functions as a multiple sensor in response to distinct metabolites. PMID:20717101

Serotonin Depletion Induces ‘Waiting Impulsivity' on the Human Four-Choice Serial Reaction Time Task: Cross-Species Translational Significance

PubMed Central

Worbe, Yulia; Savulich, George; Voon, Valerie; Fernandez-Egea, Emilio; Robbins, Trevor W

2014-01-01

Convergent results from animal and human studies suggest that reducing serotonin neurotransmission promotes impulsive behavior. Here, serotonin depletion was induced by the dietary tryptophan depletion procedure (TD) in healthy volunteers to examine the role of serotonin in impulsive action and impulsive choice. We used a novel translational analog of a rodent 5-choice serial reaction time task (5-CSRTT)— the human 4-CSRTT—and a reward delay-discounting questionnaire to measure effects on these different forms of ‘waiting impulsivity'. There was no effect of TD on impulsive choice as indexed by the reward delay-discounting questionnaire. However, TD significantly increased 4-CSRTT premature responses (or impulsive action), which is remarkably similar to the previous findings of effect of serotonin depletion on rodent 5-CSRTT performance. Moreover, the increased premature responding in TD correlated significantly with individual differences on the motor impulsivity subscale of the Barratt Impulsivity Scale. TD also improved the accuracy of performance and speeded responding, possibly indicating enhanced attention and reward processing. The results suggest: (i) the 4-CSRTT will be a valuable addition to the tests already available to measure impulsivity in humans in a direct translational analog of a test extensively used in rodents; (ii) TD in humans produces a qualitatively similar profile of effects to those in rodents (ie, enhancing premature responding), hence supporting the conclusion that TD in humans exerts at least some of its effects on central serotonin; and (iii) this manipulation of serotonin produces dissociable effects on different measures of impulsivity, suggesting considerable specificity in its modulatory role. PMID:24385133

Estrous cycle affects the neurochemical and neurobehavioral profile of carvacrol-treated female rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trabace, L., E-mail: trabace@unifg.it; Zotti, M.; Morgese, M.G.

2011-09-01

Carvacrol is the major constituent of essential oils from aromatic plants. It showed antimicrobial, anticancer and antioxidant properties. Although it was approved for food use and included in the chemical flavorings list, no indication on its safety has been estimated. Since the use of plant extracts is relatively high among women, aim of this study was to evaluate carvacrol effects on female physiology and endocrine profiles by using female rats in proestrus and diestrus phases. Serotonin and metabolite tissue content in prefrontal cortex and nucleus accumbens, after carvacrol administration (0.15 and 0.45 g/kg p.o.), was measured. Drug effects in behavioralmore » tests for alterations in motor activity, depression, anxiety-related behaviors and endocrine alterations were also investigated. While in proestrus carvacrol reduced serotonin and metabolite levels in both brain areas, no effects were observed in diestrus phase. Only in proestrus phase, carvacrol induced a depressive-like behavior in forced swimming test, without accompanying changes in ambulation. The improvement of performance in FST after subchronic treatment with fluoxetine (20 mg/kg) suggested a specific involvement of serotonergic system. No differences were found across the groups with regard to self-grooming behavior. Moreover, in proestrus phase, carvacrol reduced only estradiol levels without binding hypothalamic estradiol receptors. Our study showed an estrous-stage specific effect of carvacrol on depressive behaviors and endocrine parameters, involving serotonergic system. Given the wide carvacrol use not only as feed additive, but also as cosmetic essence and herbal remedy, our results suggest that an accurate investigation on the effects of its chronic exposure is warranted. - Highlights: > Carvacrol induced a depressive-like phenotype in rats, depending on ovarian cyclicity. > Carvacrol selectively reduced serotonin content in female rats in proestrus phase. > Carvacrol reduced serotonin levels in areas belonging to the emotional circuit. > Carvacrol reduced plasma estradiol levels only during the proestrus phase.« less

Chronic blockade or constitutive deletion of the serotonin transporter reduces operant responding for food reward.

PubMed

Sanders, Amy Cecilia; Hussain, Ali J; Hen, René; Zhuang, Xiaoxi

2007-11-01

The therapeutic effects of chronic selective serotonin reuptake inhibitors (SSRIs) are well documented, yet the elementary behavioral processes that are affected by such treatment have not been fully investigated. We report here the effects of chronic fluoxetine treatment and genetic deletion of the serotonin transporter (SERT) on food reinforced behavior in three paradigms: the progressive ratio operant task, the concurrent choice operant task, and the Pavlovian-to-Instrumental transfer task. We consistently find that chronic pharmacological blockade or genetic deletion of SERT result in similar behavioral consequences: reduced operant responding for natural reward. This is in line with previous studies reporting declines in operant responding for drugs and intracranial self-stimulation with fluoxetine treatment, suggesting that the effect of SERT blockade can be generalized to different reward types. Detailed analyses of behavioral parameters indicate that this reduction in operant responding affect both goal-directed and non-goal-directed behaviors without affecting the Pavlovian cue-triggered excessive operant responding. In addition, both pharmacological and genetic manipulations reduce locomotor activity in the open field novel environment. Our data contrast with the effect of dopamine in increasing operant responding for natural reward specifically in goal-directed behaviors and in increasing Pavlovian cue-triggered excessive operant responding. Serotonin and dopamine have been proposed to serve opposing functions in motivational processes. Our data suggest that their interactions do not result in simple opponency. The fact that pharmacological blockade and genetic deletion of SERT have similar behavioral consequences reinforces the utility of the SERT null mice for investigation of the mechanisms underlying chronic SSRIs treatment.

Effect of treatment at weaning with the serotonin antagonist mianserin on the brain serotonin and cerebrospinal fluid nocistatin level of adult female rats: a case of late imprinting.

PubMed

Csaba, G; Knippel, Barbara; Karabélyos, Cs; Inczefi-Gonda, Agnes; Hantos, Mónika; Tóthfalusi, L; Tekes, Kornélia

2004-07-09

Four weeks old (weanling) female rats were treated with the tricyclic antidepressant and histamine/serotonin receptor blocker mianserin for studying its faulty hormonal imprinting effect. Measurements were done four months later. Brain serotonin levels significantly decreased in four regions (hippocampus, hypothalamus, striatum and brainstem), without any change in the cortex. Sexual activity of the treated and control rats was similar. Cerebrospinal fluid nocistatin level was one magnitude higher in the treated rats, than in the controls. The density of uterine estrogen receptors was significantly reduced, while binding capacity of glucocorticoid receptors of liver and thymus remained at control level. The results call attention to the possibility of 1. a broad spectrum imprinting at the time of weaning by a receptor level acting non-hormone molecule 2. imprinting of the brain in a non-neonatal period of life and 3. a very durable (lifelong?) effect of the late imprinting with an antidepressant.

Physiologically Relevant Changes in Serotonin Resolved by Fast Microdialysis

PubMed Central

2013-01-01

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

Tryptophan hydroxylase 2 aggregates through disulfide cross-linking upon oxidation: Possible link to serotonin deficits and non-motor symptoms in Parkinson's disease

PubMed Central

Kuhn, Donald M.; Sykes, Catherine E.; Geddes, Timothy J.; Jaunarajs, Karen L. Eskow; Bishop, Christopher

2010-01-01

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopamine neurons of the nigrostriatal system, resulting in severe motor disturbances. Although much less appreciated, non-motor symptoms are also very common in PD and many can be traced to serotonin neuronal deficits. Tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme in the serotonin biosynthesis, is a phenotypic marker for serotonin neurons and is known to be extremely labile to oxidation. Therefore, the oxidative processes that prevail in PD could cause TPH2 misfolding and modify 5HT neuronal function much as is seen in dopamine neurons. Oxidation of TPH2 inhibits enzyme activity and leads to the formation of high molecular weight aggregates in a dithiothreitol-reversible manner. Cysteine-scanning mutagenesis shows that as long as a single cysteine residue (out of a total of 13 per monomer) remains in TPH2, it cross-links upon oxidation and only cysteine-less mutants are resistant to this effect. The effects of oxidants on TPH2 catalytic function and cross-linking are also observed in intact TPH2-expressing HEK293 cells. Oxidation shifts TPH2 from the soluble compartment into membrane fractions and large inclusion bodies. Sequential non-reducing/reducing two-dimensional SDS-PAGE and immunoblotting confirmed that TPH2 was one of a small number of cytosolic proteins that form disulfide-bonded aggregates. The propensity of TPH2 to misfold upon oxidation of its cysteine residues is responsible for its catalytic lability and may be related to loss of serotonin neuronal function in PD and the emergence of non-motor (psychiatric) symptoms. PMID:21105877

Differences in the dynamics of serotonin reuptake transporter occupancy may explain superior clinical efficacy of escitalopram versus citalopram.

PubMed

Kasper, Siegfried; Sacher, Julia; Klein, Nikolas; Mossaheb, Nilufar; Attarbaschi-Steiner, Trawat; Lanzenberger, Rupert; Spindelegger, Christoph; Asenbaum, Susanne; Holik, Alexander; Dudczak, Robert

2009-05-01

Escitalopram the S-enantiomer of the racemate citalopram, is clinically more effective than citalopram in the treatment of major depressive disorder. However, the precise mechanism by which escitalopram achieves superiority over citalopram is yet to be determined. It has been hypothesized that the therapeutically inactive R-enantiomer competes with the serotonin-enhancing S-enantiomer at a low-affinity allosteric site on serotonin reuptake transporters (SERTs), and reduces the effectiveness of the S-enantiomer at the primary, high-affinity serotonin-binding site. This study summarizes the results of two recent single-photon emission computerized tomography studies measuring SERT occupancy in citalopram-treated and escitalopram-treated healthy volunteers, after a single dose and multiple doses (i.e. under steady-state conditions). The single-dose study showed no attenuating effect of R-citalopram. After multiple dosing, however, SERT occupancy was significantly reduced in the presence of R-citalopram. Under steady-state conditions, R-enantiomer concentrations were greater than for the S-enantiomer because of slower clearance of R-citalopram. A pooled analysis suggests that build-up of the R-enantiomer after repeated citalopram dosing may lead to increased inhibition of S-enantiomer occupancy of SERT. This review adds to the growing body of evidence regarding differences in the dynamics of SERT occupancy, that is, molecular mechanisms underlying the often-observed superior clinical efficacy of escitalopram compared with citalopram in major depressive disorder.

Serotonin and the Brain's Rich Club-Association Between Molecular Genetic Variation on the TPH2 Gene and the Structural Connectome.

PubMed

Markett, Sebastian; de Reus, Marcel A; Reuter, Martin; Montag, Christian; Weber, Bernd; Schoene-Bake, Jan-Christoph; van den Heuvel, Martijn P

2017-03-01

The rich club comprises a densely mutually connected set of hub regions in the brain, thought to serve as a processing and integration core. We assessed the impact of normal variation of the tryptophane hydroxylase 2 gene's promotor region (TPH2 rs4570625) on structural connectivity of the rich club pathways by means of a candidate gene association design. Tryptophane hydroxylase 2 (TPH2) is a rate-limiting enzyme in the biosynthesis of serotonin and is known to inhibit, in addition to its role as a trans-synaptic messenger, axonal and dendritic growth. The TPH2 T-variant has been associated with reduced mRNA expression and reduced serotonin levels, which may particularly influence the development of macroscale anatomical connectivity. Here, we show larger mean connectivity in the rich club in carriers of the T-variant, suggesting potential effects of upregulation of neural connectivity growth in this central core system. In addition, by edge-removal statistics, we show that the TPH2-associated higher levels of rich club connectivity are of importance for the functioning of the total structural network. The observed association is speculated to result from an effect of serotonin levels on brain development, potentially leading to stronger structural connectivity in heavily interconnected hubs. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The role of hypothalamic inflammation, the hypothalamic-pituitary-adrenal axis and serotonin in the cancer anorexia-cachexia syndrome.

PubMed

van Norren, Klaske; Dwarkasing, Jvalini T; Witkamp, Renger F

2017-09-01

In cancer patients, the development of cachexia (muscle wasting) is frequently aggravated by anorexia (loss of appetite). Their concurrence is often referred to as anorexia-cachexia syndrome. This review focusses on the recent evidence underlining hypothalamic inflammation as key driver of these processes. Special attention is given to the involvement of hypothalamic serotonin. The anorexia-cachexia syndrome is directly associated with higher mortality in cancer patients. Recent reports confirm its severe impact on the quality of life of patients and their families.Hypothalamic inflammation has been shown to contribute to muscle and adipose tissue loss in cancer via central hypothalamic interleukine (IL)1β-induced activation of the hypothalamic-pituitary-adrenal axis. The resulting release of glucocorticoids directly stimulates catabolic processes in these tissues via activation of the ubiquitin-proteosome pathway. Next to this, hypothalamic inflammation has been shown to reduce food intake in cancer by triggering changes in orexigenic and anorexigenic responses via upregulation of serotonin availability and stimulation of its signalling pathways in hypothalamic tissues. This combination of reduced food intake and stimulation of tissue catabolism represents a dual mechanism by which hypothalamic inflammation contributes to the development and maintenance of anorexia and cachexia in cancer. Hypothalamic inflammation is a driving force in the development of the anorexia-cachexia syndrome via hypothalamic-pituitary-adrenal axis and serotonin pathway activation.

Intrinsic neuromodulation in the Tritonia swim CPG: serotonin mediates both neuromodulation and neurotransmission by the dorsal swim interneurons.

PubMed

Katz, P S; Frost, W N

1995-12-01

1. Neuromodulation has previously been shown to be intrinsic to the central pattern generator (CPG) circuit that generates the escape swim of the nudibranch mollusk Tritonia diomedea; the dorsal swim interneurons (DSIs) make conventional monosynaptic connections and evoke neuromodulatory effects within the swim motor circuit. The conventional synaptic potentials evoked by a DSI onto cerebral neuron 2 (C2) and onto the dorsal flexion neurons (DFNs) consist of a fast excitatory postsynaptic potential (EPSP) followed by a prolonged slow EPSP. In their neuromodulatory role, the DSIs produce an enhancement of the monosynaptic connections made by C2 onto other CPG circuit interneurons and onto efferent flexion neurons. Previous work showed that the DSIs are immunoreactive for serotonin. Here we provide evidence that both the neurotransmission and the neuromodulation evoked by the DSIs are produced by serotonin, and that these effects may be pharmacologically separable. 2. Previously it was shown that bath-applied serotonin both mimics and occludes the modulation of the C2 synapses by the DSIs. Here we find that pressure-applied puffs of serotonin mimic both the fast and slow EPSPs evoked by a DSI onto a DFN, whereas high concentrations of bath-applied serotonin occlude both of these synaptic components. 3. Consistent with the hypothesis that serotonin mediates the actions of the DSIs, the serotonin reuptake inhibitor imipramine prolongs the duration of the fast DSI-DFN EPSP, increases the amplitude of the slow DSI-DFN EPSP, and increases both the amplitude and duration of the modulation of the C2-DFN synapse by the DSIs. 4. Two serotonergic antagonists were found that block the actions of the DSIs. Gramine blocks the fast DSI-DFN EPSP, and has far less of an effect on the slow EPSP and the modulation. Gramine also diminishes the depolarization evoked by pressure-applied serotonin, showing that it is a serotonin antagonist in this system. In contrast, methysergide greatly reduces both the slow EPSP and the modulation evoked by the DSIs, but has mixed effects on the fast EPSP. Methysergide also blocks the ability of exogenous serotonin to enhance the C2-DFN EPSP, demonstrating that it antagonizes the serotonin receptors responsible for this modulation. 5. Taken together with previous work, these results indicate that serotonin is likely to be responsible for all three actions of the DSIs that were examined: the fast and slow DSI-DFN EPSPs and the neuromodulation of the C2-DFN synapse. These results also indicate that the conventional and neuromodulatory effects of the DSIs may be pharmacologically separable. In future work it may be possible to determine the functional role of each in the swim circuit.

Sertraline alleviated osmophobia caused by partial hypopituitarism with isolated ACTH deficiency.

PubMed

Kuo, Yu-Heng; Chang, Yun; Chen, Hsi-Chung; Liao, Shih-Cheng

2013-01-01

Hyperosmia may be an early manifestation of hypocortisolism and may be mistakenly diagnosed as osmophobia. However, sertraline therapy incidentally alleviated the phobic symptoms and hindered accurate diagnosis. A 41-year-old man was diagnosed as having osmophobia. Initial sertraline treatment relieved the symptoms, but its cessation resulted in recurrence of osmophobia. Endocrinological examinations revealed severe hypocortisolism and partial hypopituitarism with isolated adrenocorticotropic hormone deficiency. After prednisolone supplementation, his condition dramatically improved. We recommend that, before intervention with selective serotonin reuptake inhibitors is performed, the hypothalamic-pituitary-adrenal axis be evaluated in psychiatric patients presenting with co-occurring olfactory change. Copyright © 2013 Elsevier Inc. All rights reserved.

Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD).

PubMed

Nichols, David E

2018-03-01

Lysergic acid diethylamide (LSD) is one of the most potent psychoactive agents known, producing dramatic alterations of consciousness after submilligram (≥20 μg) oral doses. Following the accidental discovery of its potent psychoactive effects in 1943, it was supplied by Sandoz Laboratories as an experimental drug that might be useful as an adjunct for psychotherapy, or to give psychiatrists insight into the mental processes in their patients. The finding of serotonin in the mammalian brain in 1953, and its structural resemblance to LSD, quickly led to ideas that serotonin in the brain might be involved in mental disorders, initiating rapid research interest in the neurochemistry of serotonin. LSD proved to be physiologically very safe and nonaddictive, with a very low incidence of adverse events when used in controlled experiments. Widely hailed by psychiatry as a breakthrough in the 1950s and early 1960s, clinical research with LSD ended by about 1970, when it was formally placed into Schedule 1 of the Controlled Substances Act of 1970 following its growing popularity as a recreational drug. Within the past 5 years, clinical research with LSD has begun in Europe, but there has been none in the United States. LSD is proving to be a powerful tool to help understand brain dynamics when combined with modern brain imaging methods. It remains to be seen whether therapeutic value for LSD can be confirmed in controlled clinical trials, but promising results have been obtained in small pilot trials of depression, anxiety, and addictions using psilocybin, a related psychedelic molecule.

Psychoactive “bath salts”: not so soothing

PubMed Central

Baumann, Michael H.; Partilla, John S.; Lehner, Kurt R.

2012-01-01

Recently there has been a dramatic rise in the abuse of so-called “bath salts” products that are purchased as legal alternatives to illicit drugs like cocaine and 3,4-methylenedioxymethamphetamine (MDMA). Baths salts contain one or more synthetic derivatives of the naturally-occurring stimulant cathinone. Low doses of bath salts produce euphoria and increase alertness, but high doses or chronic use can cause serious adverse effects such as hallucinations, delirium, hyperthermia and tachycardia. Owing to the risks posed by bath salts, the governments of many countries have made certain cathinones illegal, namely: 4-methylmethcathinone (mephedrone), 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV). Similar to other psychomotor stimulants, synthetic cathinones target plasma membrane transporters for dopamine (i.e., DAT), norepinephrine (i.e., NET) and serotonin (i.e, SERT). Mephedrone and methylone act as non-selective transporter substrates, thereby stimulating non-exocytotic release of dopamine, norepinephrine and serotonin. By contrast, MDPV acts as a potent blocker at DAT and NET, with little effect at SERT. Administration of mephedrone or methylone to rats increases extracellular concentrations of dopamine and serotonin in the brain, analogous to the effects of MDMA. Not surprisingly, synthetic cathinones elicit locomotor activation in rodents. Stimulation of dopamine transmission by synthetic cathinones predicts a high potential for addiction and may underlie clinical adverse effects. As popular synthetic cathinones are rendered illegal, new replacement cathinones are appearing in the marketplace. More research on the pharmacology and toxicology of abused cathinones is needed to inform public health policy and develop strategies for treating medical consequence of bath salts abuse. PMID:23178799

Acute tryptophan depletion attenuates conscious appraisal of social emotional signals in healthy female volunteers.

PubMed

Beacher, Felix D C C; Gray, Marcus A; Minati, Ludovico; Whale, Richard; Harrison, Neil A; Critchley, Hugo D

2011-02-01

Acute tryptophan depletion (ATD) decreases levels of central serotonin. ATD thus enables the cognitive effects of serotonin to be studied, with implications for the understanding of psychiatric conditions, including depression. To determine the role of serotonin in conscious (explicit) and unconscious/incidental processing of emotional information. A randomized, double-blind, cross-over design was used with 15 healthy female participants. Subjective mood was recorded at baseline and after 4 h, when participants performed an explicit emotional face processing task, and a task eliciting unconscious processing of emotionally aversive and neutral images presented subliminally using backward masking. ATD was associated with a robust reduction in plasma tryptophan at 4 h but had no effect on mood or autonomic physiology. ATD was associated with significantly lower attractiveness ratings for happy faces and attenuation of intensity/arousal ratings of angry faces. ATD also reduced overall reaction times on the unconscious perception task, but there was no interaction with emotional content of masked stimuli. ATD did not affect breakthrough perception (accuracy in identification) of masked images. ATD attenuates the attractiveness of positive faces and the negative intensity of threatening faces, suggesting that serotonin contributes specifically to the appraisal of the social salience of both positive and negative salient social emotional cues. We found no evidence that serotonin affects unconscious processing of negative emotional stimuli. These novel findings implicate serotonin in conscious aspects of active social and behavioural engagement and extend knowledge regarding the effects of ATD on emotional perception.

Mechanisms of tramadol-related neurotoxicity in the rat: Does diazepam/tramadol combination play a worsening role in overdose?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lagard, Camille, E-mail: camille.lagard@gmail.com

Poisoning with opioid analgesics including tramadol represents a challenge. Tramadol may induce respiratory depression, seizures and serotonin syndrome, possibly worsened when in combination to benzodiazepines. Our objectives were to investigate tramadol-related neurotoxicity, consequences of diazepam/tramadol combination, and mechanisms of drug-drug interactions in rats. Median lethal-doses were determined using Dixon–Bruce's up-and-down method. Sedation, seizures, electroencephalography and plethysmography parameters were studied. Concentrations of tramadol and its metabolites were measured using liquid-chromatography-high-resolution-mass-spectrometry. Plasma, platelet and brain monoamines were measured using liquid-chromatography coupled to fluorimetry. Median lethal-doses of tramadol and diazepam/tramadol combination did not significantly differ, although time-to-death was longer with combination (P =more » 0.04). Tramadol induced dose-dependent sedation (P < 0.05), early-onset seizures (P < 0.001) and increase in inspiratory (P < 0.01) and expiratory times (P < 0.05). The diazepam/tramadol combination abolished seizures but significantly enhanced sedation (P < 0.01) and respiratory depression (P < 0.05) by reducing tidal volume (P < 0.05) in addition to tramadol-related increase in respiratory times, suggesting a pharmacodynamic mechanism of interaction. Plasma M1 and M5 metabolites were mildly increased, contributing additionally to tramadol-related respiratory depression. Tramadol-induced early-onset increase in brain concentrations of serotonin and norepinephrine was not significantly altered by the diazepam/tramadol combination. Interestingly neither pretreatment with cyproheptadine (a serotonin-receptor antagonist) nor a benserazide/5-hydroxytryptophane combination (enhancing brain serotonin) reduced tramadol-induced seizures. Our study shows that diazepam/tramadol combination does not worsen tramadol-induced fatality risk but alters its toxicity pattern with enhanced respiratory depression but abolished seizures. Drug-drug interaction is mainly pharmacodynamic but increased plasma M1 and M5 metabolites may also contribute to enhancing respiratory depression. Tramadol-induced seizures are independent of brain serotonin. - Highlights: • Diazepam does not alter tramadol-induced median lethal dose but delays death onset. • Diazepam/tramadol combination worsens respiratory depression but prevents seizures. • Diazepam/tramadol-induced respiratory effects results from a pharmacodynamic drug-drug interaction. • Tramadol increases brain serotonin and norepinephrine that is not altered by diazepam. • Tramadol-induced seizures are independent of brain serotonin.« less

Serotonin Signaling Through the 5-HT1B Receptor and NADPH Oxidase 1 in Pulmonary Arterial Hypertension.

PubMed

Hood, Katie Y; Mair, Kirsty M; Harvey, Adam P; Montezano, Augusto C; Touyz, Rhian M; MacLean, Margaret R

2017-07-01

Serotonin can induce human pulmonary artery smooth muscle cell (hPASMC) proliferation through reactive oxygen species (ROS), influencing the development of pulmonary arterial hypertension (PAH). We hypothesize that in PASMCs, serotonin induces oxidative stress through NADPH-oxidase-derived ROS generation and reduced Nrf-2 (nuclear factor [erythroid-derived 2]-like 2) antioxidant systems, promoting vascular injury. HPASMCs from controls and PAH patients, and PASMCs from Nox1 -/- mice, were stimulated with serotonin in the absence/presence of inhibitors of Src kinase, the 5-HT 1B receptor, and NADPH oxidase 1 (Nox1). Markers of fibrosis were also determined. The pathophysiological significance of our findings was examined in vivo in serotonin transporter overexpressing female mice, a model of pulmonary hypertension. We confirmed thatserotonin increased superoxide and hydrogen peroxide production in these cells. For the first time, we show that serotonin increased oxidized protein tyrosine phosphatases and hyperoxidized peroxiredoxin and decreased Nrf-2 and catalase activity in hPASMCs. ROS generation was exaggerated and dependent on cellular Src-related kinase, 5-HT 1B receptor, and the serotonin transporter in human pulmonary artery smooth muscle cells from PAH subjects. Proliferation and extracellular matrix remodeling were exaggerated in human pulmonary artery smooth muscle cells from PAH subjects and dependent on 5-HT 1B receptor signaling and Nox1, confirmed in PASMCs from Nox1 -/- mice. In serotonin transporter overexpressing mice, SB216641, a 5-HT 1B receptor antagonist, prevented development of pulmonary hypertension in a ROS-dependent manner. Serotonin can induce cellular Src-related kinase-regulated Nox1-induced ROS and Nrf-2 dysregulation, contributing to increased post-translational oxidative modification of proteins and activation of redox-sensitive signaling pathways in hPASMCs, associated with mitogenic responses. 5-HT 1B receptors contribute to experimental pulmonary hypertension by inducing lung ROS production. Our results suggest that 5-HT 1B receptor-dependent cellular Src-related kinase-Nox1-pathways contribute to vascular remodeling in PAH. © 2017 The Authors.

Serotonin Signaling Through the 5-HT1B Receptor and NADPH Oxidase 1 in Pulmonary Arterial Hypertension

PubMed Central

Hood, Katie Y.; Mair, Kirsty M.; Harvey, Adam P.; Montezano, Augusto C.; Touyz, Rhian M.

2017-01-01

Objective— Serotonin can induce human pulmonary artery smooth muscle cell (hPASMC) proliferation through reactive oxygen species (ROS), influencing the development of pulmonary arterial hypertension (PAH). We hypothesize that in PASMCs, serotonin induces oxidative stress through NADPH-oxidase–derived ROS generation and reduced Nrf-2 (nuclear factor [erythroid-derived 2]-like 2) antioxidant systems, promoting vascular injury. Approach and Results— HPASMCs from controls and PAH patients, and PASMCs from Nox1−/− mice, were stimulated with serotonin in the absence/presence of inhibitors of Src kinase, the 5-HT1B receptor, and NADPH oxidase 1 (Nox1). Markers of fibrosis were also determined. The pathophysiological significance of our findings was examined in vivo in serotonin transporter overexpressing female mice, a model of pulmonary hypertension. We confirmed thatserotonin increased superoxide and hydrogen peroxide production in these cells. For the first time, we show that serotonin increased oxidized protein tyrosine phosphatases and hyperoxidized peroxiredoxin and decreased Nrf-2 and catalase activity in hPASMCs. ROS generation was exaggerated and dependent on cellular Src-related kinase, 5-HT1B receptor, and the serotonin transporter in human pulmonary artery smooth muscle cells from PAH subjects. Proliferation and extracellular matrix remodeling were exaggerated in human pulmonary artery smooth muscle cells from PAH subjects and dependent on 5-HT1B receptor signaling and Nox1, confirmed in PASMCs from Nox1−/− mice. In serotonin transporter overexpressing mice, SB216641, a 5-HT1B receptor antagonist, prevented development of pulmonary hypertension in a ROS-dependent manner. Conclusions— Serotonin can induce cellular Src-related kinase–regulated Nox1-induced ROS and Nrf-2 dysregulation, contributing to increased post-translational oxidative modification of proteins and activation of redox-sensitive signaling pathways in hPASMCs, associated with mitogenic responses. 5-HT1B receptors contribute to experimental pulmonary hypertension by inducing lung ROS production. Our results suggest that 5-HT1B receptor–dependent cellular Src-related kinase-Nox1-pathways contribute to vascular remodeling in PAH. PMID:28473438

Differential effect of the 5-HTT gene-linked polymorphic region on emotional eating during stress exposure following tryptophan challenge.

PubMed

Markus, C Rob; Verschoor, Ellen; Smeets, Tom

2012-04-01

Stress and negative moods, which are thought to be partly mediated by reduced brain serotonin function, often increase emotional eating in dieting women (restrainers). Because the short (S) allele polymorphism in the serotonin transporter gene (5-HTTLPR) is associated with serotonin dysfunction, S allele compared to long (L) allele 5-HTTLPR genotypes may be more susceptible to stress-induced emotional eating. Consequently, serotonin challenge via tryptophan (TRP)-rich protein hydrolysate (TPH) may alleviate stress-induced emotional eating particularly in S/S allele carriers. We tested whether acute stress affects emotional eating in women with high or low dietary restraints depending on their 5-HTTLPR genotype and TPH intake. Nineteen female subjects who were homozygous for the short-allele 5-HTTLPR genotype (S'/S'=S/L(G), L(G)/L(G): restrainers vs. nonrestrainers) and 23 female subjects who were homozygous for the long-allele 5-HTTLPR genotype (L'/L'=L(A)/L(A): restrainers vs. nonrestrainers) were tested in a double-blind, placebo-controlled crossover study of stress-induced emotional eating following intake of TPH or a placebo. TPH intake significantly increased the plasma TRP/large neutral amino acid ratio (P<.0001) in the L'/L' group (70%) compared to the S'/S' group (30%). TPH reduced food intake in both groups, but in the L'/L' group, it also reduced stress-induced negative mood (P=.037) and the desire for sweet, high-fat foods (P=.011) regardless of dietary restraint. Since TPH caused a greater increase in the plasma TRP/large neutral amino acid ratio in the L'/L' group compared to S'/S' group, the exclusive beneficial effects of L'/L' genotype may be due to enhanced brain 5-HT function. Copyright © 2012 Elsevier Inc. All rights reserved.

Effects of selective serotonin reuptake inhibition on neural activity related to risky decisions and monetary rewards in healthy males.

PubMed

Macoveanu, Julian; Fisher, Patrick M; Haahr, Mette E; Frokjaer, Vibe G; Knudsen, Gitte M; Siebner, Hartwig R

2014-10-01

Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are commonly prescribed antidepressant drugs targeting the dysfunctional serotonin (5-HT) system, yet little is known about the functional effects of prolonged serotonin reuptake inhibition in healthy individuals. Here we used functional MRI (fMRI) to investigate how a three-week fluoxetine intervention influences neural activity related to risk taking and reward processing. Employing a double-blinded parallel-group design, 29 healthy young males were randomly assigned to receive 3 weeks of a daily dose of 40 mg fluoxetine or placebo. Participants underwent task-related fMRI prior to and after the three-week intervention while performing a card gambling task. The task required participants to choose between two decks of cards. Choices were associated with different risk levels and potential reward magnitudes. Relative to placebo, the SSRI intervention did not alter individual risk-choice preferences, but modified neural activity during decision-making and reward processing: During the choice phase, SSRI reduced the neural response to increasing risk in lateral orbitofrontal cortex, a key structure for value-based decision-making. During the outcome phase, a midbrain region showed an independent decrease in the responsiveness to rewarding outcomes. This midbrain cluster included the raphe nuclei from which serotonergic modulatory projections originate to both cortical and subcortical regions. The findings corroborate the involvement of the normally functioning 5HT-system in decision-making under risk and processing of monetary rewards. The data suggest that prolonged SSRI treatment might reduce emotional engagement by reducing the impact of risk during decision-making or the impact of reward during outcome evaluation. Copyright © 2014 Elsevier Inc. All rights reserved.

SSRI-reduced platelet reactivity in non-responding patients with life-long Recurrent Depressive Disorder: Detection and involved mechanisms.

PubMed

Aleksovski, Boris; Neceva, Violeta; Vujović, Viktorija; Manusheva, Nensi; Rendevski, Vladimir; Novotni, Antoni; Filipce, Ana; Spasovska, Anastazija; Sofijanova, Aspazija; Aleksovski, Vasko; Gjorgoski, Icko

2018-05-01

Adverse effects with bleeding disorders are often associated with the administration of SSRI in depression, although the exact mechanisms remain contradicting. This study is aimed at detecting and exploring the mechanisms of SSRI-induced changes in platelet reactivity in non-responding patients with Recurrent Depressive Disorder (RDD) and life-long exposure to antidepressants. Thirty-one patients and thirty-one healthy controls were included in the study. A comprehensive approach which includes evaluation of peripheral markers and microscopic analyses of platelet morphology changes has been used. RDD SSRI patients have shown blunted aggregatory responses towards collagen and epinephrine. Evident differences in the microscopic evaluation of platelet morphology were observed between the groups, with inherent absence of micro-aggregates and platelet shape changes within the patients; after quantification, the sensitivity and specificity of this method were assessed as high. The abnormalities were found in association with lower platelet serotonin content and high fluctuations of free plasma serotonin levels. Changes in the levels of CRP, fibrinogen and nitric oxide were not observed. Macroplatelets were also detected within RDD SSRI patients via increased MPV, PDW and P-LCR, which were associated with discoid shape and without procoagulant activity. The microscopic evaluation might be useful as a simple method for detection of SSRI-reduced platelet function for research purposes or systematic correlations with other biochemical parameters. The mechanisms involved in SSRI-reduced platelet function in non-responding RDD patients are complex, including combined effects of lower platelet serotonin content, high fluctuations in plasma serotonin concentration and abnormal α-AR function. Copyright © 2018 Elsevier Ltd. All rights reserved.

Regulation of corticoid and serotonin receptor brain system following early life exposure of glucocorticoids: long term implications for the neurobiology of mood.

PubMed

Vázquez, Delia M; Neal, Charles R; Patel, Paresh D; Kaciroti, Niko; López, Juan F

2012-03-01

Potent glucocorticoids (GC) administered early in life have improved premature infant survival dramatically. However, these agents may increase the risk for physical, neurological and behavior alterations. Anxiety, depression and attention difficulties are commonly described in adolescent and young adult survivors of prematurity. In the present study we administered vehicle, dexamethasone, or hydrocortisone to Sprague-Dawley rat pups on postnatal days 5 and 6, mimicking a short term clinical protocol commonly used in human infants. Two systems that are implicated in the regulation of stress and behavior were assessed: the limbic-hypothalamic-pituitary-adrenal axis [LHPA; glucocorticoid and mineralocorticoid receptors within] and the Serotonin (5-HT) system. We found that as adults, male Sprague-Dawley pups treated with GC showed agent specific altered growth, anxiety-related behavior, changes in corticoid response to novelty and gene expression changes within LHPA and 5-HT-related circuitry. The data suggest that prolonged GC-receptor stimulation during the early neonatal period can contribute to the development of individual differences in stress response and anxiety-related behavior later in life. Copyright © 2011 Elsevier Ltd. All rights reserved.

A patient with a metastatic gastroenteropancreatic endocrine carcinoma causing hyperinsulinaemic hypoglycaemia and the carcinoid syndrome.

PubMed

Hinchliffe, E; Allcock, R L; Mansoor, W; Myers, M A

2011-11-01

We present the case of a 57-year-old patient who initially presented with a constellation of symptoms including intense pruritis, flushing and diarrhoea. Following several months clinical deterioration, the patient was investigated radiologically, where multiple hepatic tumours were identified. Liver biopsy confirmed the presence of a well-differentiated metastatic gastroenteropancreatic endocrine carcinoma with biochemical evidence of serotonin secretion. Over a period of six months, the clinical course of the patient's disease progressed whereby severe hypoglycaemia became the major manifestation. Subsequent biochemical investigations confirmed the diagnosis of an insulinoma. Extensive radiological investigation revealed a solitary primary pancreatic tumour, indicating the presence of a metastatic pancreatic endocrine tumour (PET) secreting both insulin and serotonin. The patient was treated with a chemotherapy regimen consisting of 12 cycles of 5-fluorouracil/oxaliplatin, responding clinically - improved World Health Organization performance score from 3 to 1, biochemically - significantly reduced plasma chromogranin A and cancer antigen 19-9 concentrations and improved liver function tests, and radiologically - reduced pancreatic and hepatic tumour size. This is the first report of a primary PET secreting insulin and serotonin. Due to the association of serotonin-secreting gastroenteropancreatic endocrine tumours (GEP-ETs) with multiple endocrine neoplasia type-1 (MEN1) and biochemical evidence of an insulinoma, MEN1 should also be considered in such cases. The case provides further evidence for the biological heterogeneity of GEP-ETs and the myriad secretory humoral products and resultant clinical syndromes arising from such tumours.

Uptake of (/sup 3/H)serotonin into plasma membrane vesicles from mouse cerebral cortex

DOE Office of Scientific and Technical Information (OSTI.GOV)

O'Reilly, C.A.; Reith, M.E.A.

1988-05-05

Preparations of plasma membrane vesicles were used as a tool to study the properties of the serotonin transporter in the central nervous system. The vesicles were obtained after hypotonic shock of synaptosomes purified from mouse cerebral cortex. Uptake of (/sup 3/H)serotonin had a Na/sup +/-dependent and Na/sup +/-independent component. The Na/sup +/-dependent uptake was inhibited by classical blockers of serotonin uptake and had a K/sub m/ of 63-180 nM, and a V/sub max/ of 0.1-0.3 pmol mg/sup -1/ s/sup -1/ at 77 mM Na/sup +/. The uptake required the presence of external Na/sup +/ and internal K/sup +/. Replacement ofmore » Cl/sup -/ by other anions (NO/sub 2//sup -/, S/sub 2/O/sub 3//sup 2 -/) reduced uptake appreciably. Gramicidin prevented uptake. Although valinomycin increased uptake somewhat, the membrane potential per se could not drive uptake because no uptake was observed when a membrane potential was generated by the SCN/sup -/ ion in the absence of internal K/sup +/ and with equal (Na/sup +/) inside and outside. The increase of uptake as a function of (Na/sup +/) indicated a K/sub m/ for Na/sup +/ of 118 mM and a Hill number of 2.0, suggesting a requirement of two sodium ions for serotonin transport. The present results are accommodated very well by the model developed for porcine platelet serotonin transport except for the number of sodium ions that are required for transport.« less

Monoamine Oxidases Regulate Telencephalic Neural Progenitors in Late Embryonic and Early Postnatal Development

PubMed Central

Cheng, Aiwu; Scott, Anna L.; Ladenheim, Bruce; Chen, Kevin; Ouyang, Xin; Lathia, Justin D.; Mughal, Mohamed; Cadet, Jean Lud; Mattson, Mark P.; Shih, Jean C.

2010-01-01

Monoamine neurotransmitters play major roles in regulating a range of brain functions in adults and increasing evidence suggests roles for monoamines in brain development. Here we show that mice lacking the monoamine metabolic enzymes MAO A and MAO B (MAO AB-deficient mice) exhibit diminished proliferation of neural stem cells (NSC) in the developing telencephalon beginning in late gestation [embryonic day (E) 17.5], a deficit that persists in neonatal and adult mice. These mice showed significantly increased monoamine levels and anxiety-like behaviors as adults. Assessments of markers of intermediate progenitor cells (IPC) and mitosis showed that NSC in the subventricular zone (SVZ), but not in the ventricular zone, are reduced in MAO AB-deficient mice. A developmental time course of monoamines in frontal cortical tissues revealed increased serotonin levels as early as E14.5, and a further large increase was found between E17.5 and postnatal day 2. Administration of an inhibitor of serotonin synthesis (parachlorophenylalanine) between E14.5 and E19.5 restored the IPC numbers and SVZ thickness, suggesting the role of serotonin in the suppression of IPC proliferation. Studies of neurosphere cultures prepared from the telencephalon at different embryonic and postnatal ages showed that serotonin stimulates proliferation in wild-type, but not in MAO AB-deficient, NSC. Together, these results suggest that a MAO-dependent long-lasting alteration in the proliferation capacity of NSC occurs late in embryonic development and is mediated by serotonin. Our findings reveal novel roles for MAOs and serotonin in the regulation of IPC proliferation in the developing brain. PMID:20702706

Selective decrease in central nervous system serotonin turnover in children with dopa-nonresponsive dystonia.

PubMed

Assmann, Birgit; Köhler, Martin; Hoffmann, Georg F; Heales, Simon; Surtees, Robert

2002-07-01

Childhood dystonia that does not respond to treatment with levodopa (dopa-nonresponsive dystonia, DND) has an unclear pathogenesis and is notoriously difficult to treat. To test the hypothesis that there may be abnormalities in serotonin turnover in DND we measured cerebrospinal fluid (CSF) concentrations of homovanillic (HVA) and 5-hydroxyindoleacetic (HIAA) acids, metabolites of dopamine and serotonin, respectively, in 18 children with dystonia not responsive to levodopa. These were combined with a reference population of 85 children with neurologic or metabolic disease known not to affect dopamine or serotonin metabolism. Because of the known natural age-related decrement in HVA and HIAA concentrations, the results were analyzed using multiple regression using age and DND as predictors of CSF HIAA and HVA concentrations. DND was a highly significant predictor of CSF HIAA concentration (p < 0.001) but not of CSF HVA concentration (p = 0.59). After fitting a regression model, the geometric mean ratio of CSF HIAA in DND compared with the reference range was 0.53 whereas that for CSF HVA was 0.95. We also analyzed CSF HIAA/HVA ratios. After fitting a regression model, we found no dependence on age, and the mean of CSF HIAA/HVA in DND was 0.28 whereas that for the reference range was 0.49 (p < 0.001). We conclude that a significant number of children with DND have reduced CNS serotonin turnover. Treatment with drugs that increase serotonin concentration in the synaptic cleft should be considered in this group of patients.

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

PubMed

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

2015-01-15

The brain-gut axis is a bidirectional communication system between the central nervous system and the gastrointestinal tract. Serotonin functions as a key neurotransmitter at both terminals of this network. Accumulating evidence points to a critical role for the gut microbiome in regulating normal functioning of this axis. In particular, it is becoming clear that the microbial influence on tryptophan metabolism and the serotonergic system may be an important node in such regulation. There is also substantial overlap between behaviours influenced by the gut microbiota and those which rely on intact serotonergic neurotransmission. The developing serotonergic system may be vulnerable to differential microbial colonisation patterns prior to the emergence of a stable adult-like gut microbiota. At the other extreme of life, the decreased diversity and stability of the gut microbiota may dictate serotonin-related health problems in the elderly. The mechanisms underpinning this crosstalk require further elaboration but may be related to the ability of the gut microbiota to control host tryptophan metabolism along the kynurenine pathway, thereby simultaneously reducing the fraction available for serotonin synthesis and increasing the production of neuroactive metabolites. The enzymes of this pathway are immune and stress-responsive, both systems which buttress the brain-gut axis. In addition, there are neural processes in the gastrointestinal tract which can be influenced by local alterations in serotonin concentrations with subsequent relay of signals along the scaffolding of the brain-gut axis to influence CNS neurotransmission. Therapeutic targeting of the gut microbiota might be a viable treatment strategy for serotonin-related brain-gut axis disorders. Copyright © 2014 Elsevier B.V. All rights reserved.

Acute tryptophan depletion attenuates conscious appraisal of social emotional signals in healthy female volunteers

PubMed Central

Gray, Marcus A.; Minati, Ludovico; Whale, Richard; Harrison, Neil A.; Critchley, Hugo D.

2010-01-01

Rationale Acute tryptophan depletion (ATD) decreases levels of central serotonin. ATD thus enables the cognitive effects of serotonin to be studied, with implications for the understanding of psychiatric conditions, including depression. Objective To determine the role of serotonin in conscious (explicit) and unconscious/incidental processing of emotional information. Materials and methods A randomized, double-blind, cross-over design was used with 15 healthy female participants. Subjective mood was recorded at baseline and after 4 h, when participants performed an explicit emotional face processing task, and a task eliciting unconscious processing of emotionally aversive and neutral images presented subliminally using backward masking. Results ATD was associated with a robust reduction in plasma tryptophan at 4 h but had no effect on mood or autonomic physiology. ATD was associated with significantly lower attractiveness ratings for happy faces and attenuation of intensity/arousal ratings of angry faces. ATD also reduced overall reaction times on the unconscious perception task, but there was no interaction with emotional content of masked stimuli. ATD did not affect breakthrough perception (accuracy in identification) of masked images. Conclusions ATD attenuates the attractiveness of positive faces and the negative intensity of threatening faces, suggesting that serotonin contributes specifically to the appraisal of the social salience of both positive and negative salient social emotional cues. We found no evidence that serotonin affects unconscious processing of negative emotional stimuli. These novel findings implicate serotonin in conscious aspects of active social and behavioural engagement and extend knowledge regarding the effects of ATD on emotional perception. PMID:20596858

Afraid to help: social anxiety partially mediates the association between 5-HTTLPR triallelic genotype and prosocial behavior.

PubMed

Stoltenberg, Scott F; Christ, Christa C; Carlo, Gustavo

2013-01-01

There is growing evidence that the serotonin system influences prosocial behavior. We examined whether anxiety mediated the association between variation in the serotonin transporter gene regulatory region (5-HTTLPR) and prosocial behavior. We collected self-reported tendencies to avoid certain situations and history of helping others using standard instruments and buccal cells for standard 5-HTTLPR genotyping from 398 undergraduate students. Triallelic 5-HTTLPR genotype was significantly associated with prosocial behavior and the effect was partially mediated by social anxiety, such that those carrying the S' allele reported higher levels of social avoidance and lower rates of helping others. These results are consistent with accounts of the role of serotonin on anxiety and prosocial behavior and suggest that targeted efforts to reduce social anxiety in S' allele carriers may enhance prosocial behavior.

Effect of beta-endorphin imprinting during late pregnancy on the brain serotonin and plasma nocistatin levels of adult male rats.

PubMed

Tekes, K; Gyenge, M; Hantos, M; Csaba, G

2007-07-01

Female rats were treated with 10 microg of beta-endorphin on the 19th day of pregnancy. Offspring were studied when five months old. Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) content in four brain regions were determined by HPLC-EC and the nocistatin levels of blood plasma using RIA methods. In each brain region studied, the 5-HT levels were highly significantly reduced and that of 5-HIAA in three regions was highly significantly increased. When 5HIAA/5HT ratios, as a measure of serotonin turnover, were calculated, imprinted animals showed extremely high values. Plasma nocistatin level was also significantly elevated. The results call attention to the effect of perinatal endorphin imprinting and its long-term consequences (e.g., setting of aggressiveness, pain tolerance).

Effects of a short-term reduction in brain serotonin synthesis on the availability of the soluble leptin receptor in healthy women.

PubMed

Zepf, F D; Dingerkus, V L S; Helmbold, K; Bubenzer-Busch, S; Biskup, C S; Herpertz-Dahlmann, B; Schaab, M; Kratzsch, J; Eisert, A; Rink, L; Hagenah, U; Gaber, T J

2015-03-01

Serotonin (5-HT) and the hormone leptin have been linked to the underlying neurobiology of appetite regulation with evidence coming from animal and cellular research, but direct evidence linking these two pathways in humans is lacking. We examined the effects of reduced brain 5-HT synthesis due to acute tryptophan depletion (ATD) on levels of soluble leptin receptor (sOb-R), the main high-affinity leptin binding protein, in healthy adults using an exploratory approach. Women, but not men, showed reduced sOb-R concentrations after ATD administration. With females showing reduced baseline levels of central 5-HT synthesis compared to males diminished brain 5-HT synthesis affected the leptin axis through the sOb-R in females, thereby potentially influencing their vulnerability to dysfunctional appetite regulation and co-morbid mood symptoms.

Differential effects of serotonin-specific and excitotoxic lesions of OFC on conditioned reinforcer devaluation and extinction in rats

PubMed Central

West, Elizabeth A.; Forcelli, Patrick A.; McCue, David L.; Malkova, Ludise

2013-01-01

The orbitofrontal cortex (OFC) is critical for behavioral adaptation in response to changes in reward value. Here we investigated, in rats, the role of OFC and, specifically, serotonergic neurotransmission within OFC in a reinforcer devaluation task (which measures behavioral flexibility). This task used two visual cues, each predicting one of two foods, with the spatial position (left-right) of the cues above two levers pseudorandomized across trials. An instrumental action (lever press) was required for reinforcer delivery. After training, rats received either excitotoxic OFC lesions made by NMDA (N-methyl-D-aspartic acid), serotonin-specific OFC lesions made by 5,7-DHT (5,7-dihydroxytryptamine), or sham lesions. In sham-lesioned rats, devaluation of one food (by feeding to satiety) significantly decreased responding to the cue associated with that food, when both cues were presented simultaneously during extinction. Both types of OFC lesions disrupted the devaluation effect. In contrast, extinction learning was not affected by serotonin-specific lesions and was only mildly retarded in rats with excitotoxic lesions. Thus, serotonin within OFC is necessary for appropriately adjusting behavior towards cues that predict reward but not for reducing responses in the absence of reward. Our results are the first to demonstrate that serotonin in OFC is necessary for reinforcer devaluation, but not extinction. PMID:23458741

Differential effects of serotonin-specific and excitotoxic lesions of OFC on conditioned reinforcer devaluation and extinction in rats.

PubMed

West, Elizabeth A; Forcelli, Patrick A; McCue, David L; Malkova, Ludise

2013-06-01

The orbitofrontal cortex (OFC) is critical for behavioral adaptation in response to changes in reward value. Here we investigated, in rats, the role of OFC and, specifically, serotonergic neurotransmission within OFC in a reinforcer devaluation task (which measures behavioral flexibility). This task used two visual cues, each predicting one of two foods, with the spatial position (left-right) of the cues above two levers pseudorandomized across trials. An instrumental action (lever press) was required for reinforcer delivery. After training, rats received either excitotoxic OFC lesions made by NMDA (N-methyl-d-aspartic acid), serotonin-specific OFC lesions made by 5,7-DHT (5,7-dihydroxytryptamine), or sham lesions. In sham-lesioned rats, devaluation of one food (by feeding to satiety) significantly decreased responding to the cue associated with that food, when both cues were presented simultaneously during extinction. Both types of OFC lesions disrupted the devaluation effect. In contrast, extinction learning was not affected by serotonin-specific lesions and was only mildly retarded in rats with excitotoxic lesions. Thus, serotonin within OFC is necessary for appropriately adjusting behavior toward cues that predict reward but not for reducing responses in the absence of reward. Our results are the first to demonstrate that serotonin in OFC is necessary for reinforcer devaluation, but not extinction. Copyright © 2013 Elsevier B.V. All rights reserved.

Monoaminc and metabolite levels in the cerebrospinal fluid of hibernating and euthermic marmots.

PubMed

Reid; Kilduff; Romero; Florant; Dement; Heller

1992-03-01

Cerebrospinal fluid from yellow-bellied marmots, Marmota flaviventris, was analysed for monoamine and monoamine metabolite content during euthermia and deep hibernation. Dopamine (DA) levels were decreased, while DA metabolite levels, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were dramatically increased in hibernating marmots. Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5HIAA) levels were also greatly enhanced during hibernation while norepinephrine (NE) levels were only moderately increased. These findings demonstrate that cerebrospinal monoamine levels are dynamically altered during hibernation, such that DA versus 5-HT and NE levels undergo opposite changes. Therefore, these data indicate that DA, 5-HT and NE neuronal systems are differentially altered during hibernation in mammals.

Identification of oxalic acid and tartaric acid as major persistent pain-inducing toxins in the stinging hairs of the nettle, Urtica thunbergiana.

PubMed

Fu, Han Yi; Chen, Shiang Jiuun; Chen, Ruei Feng; Ding, Wang Hsien; Kuo-Huang, Ling Long; Huang, Rong Nan

2006-07-01

Once human skin contacts stinging hairs of Urtica spp. (stinging nettles), the irritant is released and produces pain, wheals or a stinging sensation which may last for >12 h. However, the existence of pain-inducing toxins in the stinging hairs of Urtica thunbergiana has never been systematically demonstrated. Experiments were therefore conducted to identify the persistent pain-inducing agents in the stinging hairs of U. thunbergiana. The stinging hairs of U. thunbergiana were removed and immersed in deionized water. After centrifugation, the clear supernatants were then subjected to high-performance liquid chromatography (HPLC), enzymatic analysis and/or behavioural bioassays. The HPLC results showed that the major constituents in the stinging hairs of U. thunbergiana were histamine, oxalic acid and tartaric acid. However, the well-recognized pain-inducing agents, serotonin and formic acid, existed at a low concentration as estimated by HPLC and/or enzymatic analyses. The behavioural tests showed that 2% oxalic acid and 10% tartaric acid dramatically elicited persistent pain sensations in rats. In contrast, 10% formic acid and 2% serotonin only elicited moderate pain sensation in the first 10 min. Moreover, no significant pain-related behavioural response was observed after injecting 10% acetylcholine and histamine in rats. Oxalic acid and tartaric acid were identified, for the first time, as major long-lasting pain-inducing toxins in the stinging hairs of U. thunbergiana. The general view that formic acid, histamine and serotonin are the pain-inducing agents in the stinging hairs of U. dioica may require updating, since their concentrations in U. thunbergiana were too low to induce significant pain sensation in behavioural bioassays.

Mechanisms of tramadol-related neurotoxicity in the rat: Does diazepam/tramadol combination play a worsening role in overdose?

PubMed

Lagard, Camille; Chevillard, Lucie; Malissin, Isabelle; Risède, Patricia; Callebert, Jacques; Labat, Laurence; Launay, Jean-Marie; Laplanche, Jean-Louis; Mégarbane, Bruno

2016-11-01

Poisoning with opioid analgesics including tramadol represents a challenge. Tramadol may induce respiratory depression, seizures and serotonin syndrome, possibly worsened when in combination to benzodiazepines. Our objectives were to investigate tramadol-related neurotoxicity, consequences of diazepam/tramadol combination, and mechanisms of drug-drug interactions in rats. Median lethal-doses were determined using Dixon-Bruce's up-and-down method. Sedation, seizures, electroencephalography and plethysmography parameters were studied. Concentrations of tramadol and its metabolites were measured using liquid-chromatography-high-resolution-mass-spectrometry. Plasma, platelet and brain monoamines were measured using liquid-chromatography coupled to fluorimetry. Median lethal-doses of tramadol and diazepam/tramadol combination did not significantly differ, although time-to-death was longer with combination (P=0.04). Tramadol induced dose-dependent sedation (P<0.05), early-onset seizures (P<0.001) and increase in inspiratory (P<0.01) and expiratory times (P<0.05). The diazepam/tramadol combination abolished seizures but significantly enhanced sedation (P<0.01) and respiratory depression (P<0.05) by reducing tidal volume (P<0.05) in addition to tramadol-related increase in respiratory times, suggesting a pharmacodynamic mechanism of interaction. Plasma M1 and M5 metabolites were mildly increased, contributing additionally to tramadol-related respiratory depression. Tramadol-induced early-onset increase in brain concentrations of serotonin and norepinephrine was not significantly altered by the diazepam/tramadol combination. Interestingly neither pretreatment with cyproheptadine (a serotonin-receptor antagonist) nor a benserazide/5-hydroxytryptophane combination (enhancing brain serotonin) reduced tramadol-induced seizures. Our study shows that diazepam/tramadol combination does not worsen tramadol-induced fatality risk but alters its toxicity pattern with enhanced respiratory depression but abolished seizures. Drug-drug interaction is mainly pharmacodynamic but increased plasma M1 and M5 metabolites may also contribute to enhancing respiratory depression. Tramadol-induced seizures are independent of brain serotonin. Copyright © 2016 Elsevier Inc. All rights reserved.

The short (S) allele of the serotonin transporter polymorphism and acute tryptophan depletion both increase impulsivity in men.

PubMed

Walderhaug, Espen; Herman, Aryeh Isaac; Magnusson, Andres; Morgan, Michael John; Landrø, Nils Inge

2010-04-12

Reduced serotonergic neurotransmission is implicated in impulsive behavior. We studied the triallelic system of the serotonin transporter gene linked polymorphic region (5-HTTLPR) and acute manipulation of serotonin together to further delineate the mechanisms by which serotonergic neurotransmission affects impulsivity. Fifty-two healthy participants (38 men and 14 women) underwent acute tryptophan depletion (ATD) or placebo in a randomized, double-blind, parallel group experiment. Impulsive response style was measured on two versions of the Continuous Performance Task (CPT), and calculated using signal detection theory. We observed a dose-dependent effect for the short (S') allele of the 5-HTTLPR on impulsive response style. Individuals who had the S'/S' genotype were more impulsive than individuals with the L/S' genotype. Participants with the L/S' genotype were more impulsive than those with the L/L genotype. ATD increased impulsivity in men, and decreased impulsivity in women. These data demonstrate for the first time that reduced serotonergic tone as a result of either 5-HTTLPR genotype, or experimental ATD, are both independently and additively, associated with elevated impulsive response style in Caucasian men. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Association between tryptophan hydroxylase-2 genotype and the antidepressant effect of citalopram and paroxetine on immobility time in the forced swim test in mice.

PubMed

Kulikov, Alexander V; Tikhonova, Maria A; Osipova, Daria V; Kulikov, Victor A; Popova, Nina K

2011-10-01

Tryptophan hydroxylase-2 (TPH2) is the rate limiting enzyme of serotonin synthesis in the brain. The 1473G allele of the C1473G polymorphism in mTPH2 gene is associated with reduced enzyme activity and serotonin synthesis rate in the mouse brain. Here, the influence of the 1473G allele on the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs), citalopram (2.5 or 5.0mg/kg) and paroxetine (5.0 or 10.0mg/kg), in the forced swim test was studied using B6-1473G and B6-1473C congenic mouse lines with the 1473G (decreased TPH2 activity) or 1473C (normal TPH2 activity) alleles, respectively, transferred to the genome of C57BL/6 mouse strain. Paroxetine (5.0 or 10.0mg/kg) and citalopram (2.5 or 5.0mg/kg) decreased immobility time in B6-1473C mice, while both doses of paroxetine and 2.5mg/kg of citaloprame did not alter immobility time in B6-1473G mice. However, 5.0mg/kg of citalopram reduced immobility in B6-1473G mice. The results provided genetic evidence of moderate association between 1473G allele and reduced sensitivity to SSRIs in mice. Copyright © 2011 Elsevier Inc. All rights reserved.

Codeine

MedlinePlus

... with other medications, to reduce coughing. Codeine will help relieve symptoms but will not treat the cause ... granisetron (Kytril), ondansetron (Zofran, Zuplenz), or palonosetron (Aloxi); selective serotonin-reuptake inhibitors such as citalopram (Celexa), escitalopram ( ...

Lower serotonin level and higher rate of fibromyalgia syndrome with advancing pregnancy.

PubMed

Atasever, Melahat; Namlı Kalem, Muberra; Sönmez, Çiğdem; Seval, Mehmet Murat; Yüce, Tuncay; Sahin Aker, Seda; Koç, Acar; Genc, Hakan

2017-09-01

The aim of the study is to investigate the relationship between changes in serotonin levels during pregnancy and fibromyalgia syndrome (FS) and the relationships between FS and the physical/psychological state, biochemical and hormonal parameters, which may be related to the musculoskeletal system. This study is a prospective case-control study conducted with 277 pregnant women at the obstetric unit of Ankara University Faculty of Medicine, in the period between January and June 2015. FS was determined based on the presence or absence of the 2010 ACR diagnostic criteria and all the volunteers were asked to answer the questionnaires as Fibromyalgia Impact Criteria (FIQ), Widespread Pain Index (WPI), Symptom Severity Scale (SS), Beck Depression Inventory and Visual Analog Scale (VAS). Biochemical and hormonal markers (glucose, TSH, T4, Ca (calcium), P (phosphate), PTH (parathyroid hormone) and serotonin levels) relating to muscle and bone metabolism were measured. In the presence of fibromyalgia, the physical and psychological parameters are negatively affected (p < 0.001). There was no significant difference between the fibromyalgia and control groups in terms of glucose, Ca (calcium), P (phosphorus), PTH (parathyroid hormone), TSH (thyroid stimulant hormone), fT4 (free T4) levels (p = 0.060, 0.799, 0.074, 0.104, 0.797, 0.929, respectively). A reduction in serotonin levels may contribute to the development of fibromyalgia but this was not statistically significant. The Beck Depression Inventory scale statistically showed that increasing scores also increase the risk of fibromyalgia (p <0.001). Our study has shown that serotonin levels in women with FS are lower than the control group and that serotonin levels reduce as pregnancy progresses. Anxiety and depression in pregnant women with FS are higher than the control group. The presence of depression increases the likelihood of developing FS at a statistically significant level. Serotonin impairment also increases the chance of developing FS, but this correlation has not been shown to be statistically significant.

Monoaminylation of Fibrinogen and Glia-Derived Proteins: Indication for Similar Mechanisms in Posttranslational Protein Modification in Blood and Brain.

PubMed

Hummerich, René; Costina, Victor; Findeisen, Peter; Schloss, Patrick

2015-07-15

Distinct proteins have been demonstrated to be posttranslationally modified by covalent transamidation of serotonin (5-hydropxytryptamin) to glutamine residues of the target proteins. This process is mediated by transglutaminase (TGase) and has been termed "serotonylation." It has also been shown that other biogenic amines, including the neurotransmitters dopamine and norepinephrine, can substitute for serotonin, implying a more general mechanism of "monoaminylation" for this kind of protein modification. Here we transamidated the autofluorescent monoamine monodansylcadaverine (MDC) to purified plasma fibrinogen and to proteins from a primary glia cell culture. Electrophoretic separation of MDC-conjugated proteins followed by mass spectrometry identified three fibrinogen subunits (Aα, Bβ, γ), a homomeric Aα2 dimer, and adducts of >250 kDa molecular weight, as well as several glial proteins. TGase-mediated MDC incorporation was strongly reduced by serotonin, underlining the general mechanism of monoaminylation.

Serotonin Augmentation Reduces Response to Attack in Aggressive Individuals

PubMed Central

Berman, Mitchell E.; McCloskey, Michael S.; Fanning, Jennifer R.; Schumacher, Julie A.; Coccaro, Emil F.

2009-01-01

We tested the theory that central serotonin (5- hydroxytryptamine, or 5-HT) activity regulates aggression by modulating response to provocation. Eighty men and women (40 with and 40 without a history of aggression) were randomly assigned to receive either 40 mg of paroxetine (to acutely augment serotonergic activity) or a placebo, administered using double-blind procedures. Aggression was assessed during a competitive reaction time game with a fictitious opponent. Shocks were selected by the participant and opponent before each trial, with the loser on each trial receiving the shock set by the other player. Provocation was manipulated by having the opponent select increasingly intense shocks for the participant and eventually an ostensibly severe shock toward the end of the trials. Aggression was measured by the number of severe shocks set by the participant for the opponent. As predicted, aggressive responding after provocation was attenuated by augmentation of serotonin in individuals with a pronounced history of aggression. PMID:19422623

Origins of serotonin innervation of forebrain structures

NASA Technical Reports Server (NTRS)

Kellar, K. J.; Brown, P. A.; Madrid, J.; Bernstein, M.; Vernikos-Danellis, J.; Mehler, W. R.

1977-01-01

The tryptophan hydroxylase activity and high-affinity uptake of (3H) serotonin ((3H)5-HT) were measured in five discrete brain regions of rats following lesions of the dorsal or median raphe nuclei. Dorsal raphe lesions reduced enzyme and uptake activity in the striatum only. Median raphe lesions reduced activities in the hippocampus, septal area, frontal cortex, and, to a lesser extent, in the hypothalamus. These data are consistent with the suggestion that the dorsal and median raphe nuclei are the origins of two separate ascending serotonergic systems - one innervating striatal structures and the other mesolimbic structures, predominantly. In addition, the data suggest that measurements of high-affinity uptake of (3H)5-HT may be a more reliable index of innervation than either 5-HT content or tryptophan hydroxylase activity.

Serotonin modulates insect hemocyte phagocytosis via two different serotonin receptors

PubMed Central

Qi, Yi-xiang; Huang, Jia; Li, Meng-qi; Wu, Ya-su; Xia, Ren-ying; Ye, Gong-yin

2016-01-01

Serotonin (5-HT) modulates both neural and immune responses in vertebrates, but its role in insect immunity remains uncertain. We report that hemocytes in the caterpillar, Pieris rapae are able to synthesize 5-HT following activation by lipopolysaccharide. The inhibition of a serotonin-generating enzyme with either pharmacological blockade or RNAi knock-down impaired hemocyte phagocytosis. Biochemical and functional experiments showed that naive hemocytes primarily express 5-HT1B and 5-HT2B receptors. The blockade of 5-HT1B significantly reduced phagocytic ability; however, the blockade of 5-HT2B increased hemocyte phagocytosis. The 5-HT1B-null Drosophila melanogaster mutants showed higher mortality than controls when infected with bacteria, due to their decreased phagocytotic ability. Flies expressing 5-HT1B or 5-HT2B RNAi in hemocytes also showed similar sensitivity to infection. Combined, these data demonstrate that 5-HT mediates hemocyte phagocytosis through 5-HT1B and 5-HT2B receptors and serotonergic signaling performs critical modulatory functions in immune systems of animals separated by 500 million years of evolution. DOI: http://dx.doi.org/10.7554/eLife.12241.001 PMID:26974346

Serotonin and dopamine transporter binding in children with autism determined by SPECT.

PubMed

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

2008-08-01

Disturbances in the serotonergic system have been recognized in autism. To investigate the association between serotonin and dopamine transporters and autism, we studied 15 children (14 males, one female; mean age 8 y 8 mo [SD 3 y 10 mo]) with autism and 10 non-autistic comparison children (five males, five females; mean age 9 y 10 mo [SD 2 y 8 mo]) using single-photon emission computed tomography (SPECT) with [123 I] nor-beta-CIT. The children, with autism were studied during light sedation. They showed reduced serotonin transporter (SERT) binding capacity in the medial frontal cortex, midbrain, and temporal lobe areas. However, after correction due to the estimated effect of sedation, the difference remained significant only in the medial frontal cortex area (p=0.002). In the individuals with autism dopamine transporter (DAT) binding did not differ from that of the comparison group. The results indicate that SERT binding capacity is disturbed in autism. The reduction is more evident in adolescence than in earlier childhood. The low SERT binding reported here and the low serotonin synthesis capacity shown elsewhere may indicate maturation of a lesser number of serotonergic nerve terminals in individuals with autism.

The effects of acute tryptophan depletion on speech and behavioural mimicry in individuals at familial risk for depression.

PubMed

Hogenelst, Koen; Sarampalis, Anastasios; Leander, N Pontus; Müller, Barbara C N; Schoevers, Robert A; aan het Rot, Marije

2016-03-01

Major depressive disorder (MDD) has been associated with abnormalities in speech and behavioural mimicry. These abnormalities may contribute to the impairments in interpersonal functioning that are often seen in MDD patients. MDD has also been associated with disturbances in the brain serotonin system, but the extent to which serotonin regulates speech and behavioural mimicry remains unclear. In a randomized, double-blind, crossover study, we induced acute tryptophan depletion (ATD) in individuals with or without a family history of MDD. Five hours afterwards, participants engaged in two behavioural-mimicry experiments in which speech and behaviour were recorded. ATD reduced the time participants waited before speaking, which might indicate increased impulsivity. However, ATD did not significantly alter speech otherwise, nor did it affect mimicry. This suggests that a brief lowering of brain serotonin has limited effects on verbal and non-verbal social behaviour. The null findings may be due to low test sensitivity, but they otherwise suggest that low serotonin has little effect on social interaction quality in never-depressed individuals. It remains possible that recovered MDD patients are more strongly affected. © The Author(s) 2016.

The effect of Psilocybe cubensis extract on hippocampal neurons in vitro.

PubMed

Moldavan, M G; Grodzinskaya, A A; Solomko, E F; Lomberh, M L; Wasser, S P; Storozhuk, V M

2001-01-01

The action of P. cubensis mushroom extract, containing psilocybin (PCB) and psilocin, on spike activity of hippocampal CA1 pyramidal neurons was studied in in vitro rat brain slices. In 38 (76%) out of 50 investigated neurons spike activity was decreased, in 2 (4%) cells it increased. There was no response 10 (20%) neurons. Application of the extract caused short burst firing in 12 (24%) neurons. All neurons showing inhibition during PCB-containing extract application, were also inhibited by serotonin (5-HT). Usually inhibitory reaction did not last over 4-5 min upon 3 min extract application and could be prolonged up to 10-43 min up on serotonin application. Part of neurons were inhibited by serotonin and did not react to extract application. Inhibitory reactions induced by extract application were blocked by ritanserin in half of the tested units and were induced due to activation of 5-HT2 serotonin receptors. The extract suppressed excitative spike reactions caused by application of L-glutamic acid. It is concluded, that application of PCB-containing extract in most cases reduced spike activity in hippocampal CA1 pyramidal neurons and suppressed glutamate transmission.

Analysis of Serotonin Molecules on Silver Nanocolloids—A Raman Computational and Experimental Study

PubMed Central

Manciu, Felicia S.; Ciubuc, John D.; Sundin, Emma M.; Qiu, Chao; Bennet, Kevin E.

2017-01-01

Combined theoretical and experimental analysis of serotonin by quantum chemical density functional calculations and surface-enhanced Raman spectroscopy, respectively, is presented in this work to better understand phenomena related to this neurotransmitter’s detection and monitoring at very low concentrations specific to physiological levels. In addition to the successful ultrasensitive analyte detection on silver nanoparticles for concentrations as low as 10−11 molar, the relatively good agreement between the simulated and experimentally determined results indicates the presence of all serotonin molecular forms, such as neutral, ionic, and those oxidized through redox reactions. Obvious structural molecular deformations such as bending of lateral amino chains are observed for both ionic and oxidized forms. Not only does this combined approach reveal more probable adsorption of serotonin into the silver surface through hydroxyl/oxygen sites than through NH/nitrogen sites, but also that it does so predominantly in its neutral (reduced) form, somewhat less so in its ionic forms, and much less in its oxidized forms. If the development of opto-voltammetric biosensors and their effective implementation is envisioned for the future, this study provides some needed scientific background for comprehending changes in the vibrational signatures of this important neurotransmitter. PMID:28640186

Influence of serotonin and melatonin on some parameters of gastrointestinal activity.

PubMed

Bubenik, G A; Dhanvantari, S

1989-01-01

In vitro melatonin (M) reduced the tone of gut muscles and counteracted the tonic effect of serotonin (5-HT). In vivo 0.1 to 4 mg of 5-HT (contained in beeswax implants) decreased the food transit time (FTT) in a dose-dependent manner, but higher doses (5 and 6 mg) increased the FTT. Melatonin injected intraperitoneally into mice bearing 5-HT implants (2 mg per animal) blocked partly the serotonin effect and increased FTT by 50%; however, no dose-dependent effect was observed when doses between 0.01 and 1 mg were used. Surprisingly, M injected into intact mice decreased FTT to levels comparable to those observed in 5-HT implanted, M-treated mice. Again, this significant decrease was not dose-dependent between 0.02 and 1 mg. Although in vitro the maximal inhibition of serotonin-induced spasm was achieved when the M:5-HT ratio was 50-100:1, in vivo the effective ratio was about 1:1. This may indicate that part of M action on the gut movement is mediated by extraintestinal mechanisms. A hypothetical, counterbalancing system of M and 5-HT regulation of gut activity (similar to adrenaline-acetylcholine system) is proposed.

Duloxetine reduces morphine requirements after knee replacement surgery.

PubMed

Ho, K-Y; Tay, W; Yeo, M-C; Liu, H; Yeo, S-J; Chia, S-L; Lo, N-N

2010-09-01

Multimodal analgesia is advocated for perioperative pain management to reduce opioid use and its associated adverse effects. Serotonin and norepinephrine are involved in the modulation of endogenous analgesic mechanisms via descending inhibitory pain pathways in the brain and spinal cord. An increase in serotonin and norepinephrine may increase inhibition of nociceptive input and improve pain relief. Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, has demonstrated efficacy in chronic pain conditions such as painful diabetic neuropathy and post-herpetic neuralgia. The objective of the study was to evaluate the efficacy of duloxetine in reducing morphine requirements in patients after knee replacement surgery. Fifty patients received either two doses of oral duloxetine 60 mg (2 h before surgery and on first postoperative day) or placebo. All patients received patient-controlled analgesia with morphine for 48 h after operation. Pain and adverse effects were assessed at 0.5, 1, 2, 6, 12, 24, and 48 h after surgery on an 11-point numeric rating scale. Twenty-three patients in the duloxetine group and 24 patients in the placebo group completed the study. Morphine requirements during the 48 h after surgery were significantly lower in the duloxetine group [19.5 mg, standard deviation (sd) 14.5 mg] compared with the placebo group (30.3 mg, sd 18.1 mg) (P=0.017). There were no statistically significant differences between the groups in pain scores (at rest and on movement) or in adverse effects. Perioperative administration of duloxetine reduced postoperative morphine requirements during the first 48 h after knee replacement surgery, without significant adverse effects.

DOPA Decarboxylase Modulates Tau Toxicity.

PubMed

Kow, Rebecca L; Sikkema, Carl; Wheeler, Jeanna M; Wilkinson, Charles W; Kraemer, Brian C

2018-03-01

The microtubule-associated protein tau accumulates into toxic aggregates in multiple neurodegenerative diseases. We found previously that loss of D 2 -family dopamine receptors ameliorated tauopathy in multiple models including a Caenorhabditis elegans model of tauopathy. To better understand how loss of D 2 -family dopamine receptors can ameliorate tau toxicity, we screened a collection of C. elegans mutations in dopamine-related genes (n = 45) for changes in tau transgene-induced behavioral defects. These included many genes responsible for dopamine synthesis, metabolism, and signaling downstream of the D 2 receptors. We identified one dopamine synthesis gene, DOPA decarboxylase (DDC), as a suppressor of tau toxicity in tau transgenic worms. Loss of the C. elegans DDC gene, bas-1, ameliorated the behavioral deficits of tau transgenic worms, reduced phosphorylated and detergent-insoluble tau accumulation, and reduced tau-mediated neuron loss. Loss of function in other genes in the dopamine and serotonin synthesis pathways did not alter tau-induced toxicity; however, their function is required for the suppression of tau toxicity by bas-1. Additional loss of D 2 -family dopamine receptors did not synergize with bas-1 suppression of tauopathy phenotypes. Loss of the DDC bas-1 reduced tau-induced toxicity in a C. elegans model of tauopathy, while loss of no other dopamine or serotonin synthesis genes tested had this effect. Because loss of activity upstream of DDC could reduce suppression of tau by DDC, this suggests the possibility that loss of DDC suppresses tau via the combined accumulation of dopamine precursor levodopa and serotonin precursor 5-hydroxytryptophan. Published by Elsevier Inc.

Brain aging phenomena in migrating sockeye salmon Oncorhynchus nerka nerka.

PubMed

Götz, M E; Malz, C R; Dirr, A; Blum, D; Gsell, W; Schmidt, S; Burger, R; Pohli, S; Riederer, P

2005-09-01

Aging, a process occurring in all vertebrates, is closely related to a loss in physical and functional abilities. There is widespread interest in clarifying the relevance of environmental, metabolic, and genetic factors for vertebrate aging. In the Pacific salmon a dramatic example of aging is known. Looking for changes in the salmon brain, perhaps even in the role of initiating the aging processes, we investigated several biochemical parameters that should reflect brain functional activity and stress response such as the neurotransmitters dopamine, and serotonin, and two of their respective metabolites 3,4-dihydroxyphenylacetic acid, and 5-hydroxyindole acetic acid, as well as glutathione, glutathione disulfide, and the extent of terminal deoxynucleotidyltransferase-mediated dUTP nick end-labelling. The aging of migrating sockeye salmon (Oncorhynchus nerka nerka) is accompanied by gradual increase in dopamine and serotonin turnover and a gradual decrease of brain total protein and glutathione levels. There appears to be an increased need for detoxification of reactive biological intermediates since activities of superoxide dismutase and catalase increase with age. However, our data do not support a major increase in apoptotic cell death during late aging but rather implicate an age related downward regulation of protein and glutathione synthesis and proteolysis increasing the need for autophagocytosis or heterophagocytosis in the course of cell death.

Variant at serotonin transporter gene predicts increased imitation in toddlers: relevance to the human capacity for cumulative culture.

PubMed

Schroeder, Kari Britt; Asherson, Philip; Blake, Peter R; Fenstermacher, Susan K; Saudino, Kimberly J

2016-04-01

Cumulative culture ostensibly arises from a set of sociocognitive processes which includes high-fidelity production imitation, prosociality and group identification. The latter processes are facilitated by unconscious imitation or social mimicry. The proximate mechanisms of individual variation in imitation may thus shed light on the evolutionary history of the human capacity for cumulative culture. In humans, a genetic component to variation in the propensity for imitation is likely. A functional length polymorphism in the serotonin transporter gene, the short allele at 5HTTLPR, is associated with heightened responsiveness to the social environment as well as anatomical and activational differences in the brain's imitation circuity. Here, we evaluate whether this polymorphism contributes to variation in production imitation and social mimicry. Toddlers with the short allele at 5HTTLPR exhibit increased social mimicry and increased fidelity of demonstrated novel object manipulations. Thus, the short allele is associated with two forms of imitation that may underlie the human capacity for cumulative culture. The short allele spread relatively recently, possibly due to selection, and its frequency varies dramatically on a global scale. Diverse observations can be unified via conceptualization of 5HTTLPR as influencing the propensity to experience others' emotions, actions and sensations, potentially through the mirror mechanism. © 2016 The Author(s).

Altered dopamine levels induced by the parasite Profilicollis antarcticus on its intermediate host, the crab Hemigrapsus crenulatus.

PubMed

Rojas, José Miguel; Ojeda, F Patricio

2005-01-01

A serotonergic pathway is apparently involved in parasite-host interactions. Previous studies conducted in our laboratory showed increased rates in oxygen consumption and alterations in body posture in the crab Hemigrapsus crenulatus parasitized by the acanthocephalan, Profilicollis antarcticus. Such changes may be related to the functions described for biogenic amines in crustaceans. During the infective stage the acanthocephalans live freely in the hemocelomic cavity, suggesting that the possible alteration induced by biogenic amines may be related to their neurohormonal function in crustaceans. To test whether the presence of P. antarcticus produced neurohormonal changes in its intermediate host, H. crenulatus, we analyzed serotonin and dopamine levels in the host using HPLC with electrochemical detection. Two groups of 11 female crabs were studied; one group was artificially inoculated with two cystacanths while the other was used as the control. Our results show a dramatic increase in hemolymph dopamine, but not serotonin in H. crenulatus parasitized by the acanthocephalan P. antarcticus. Our results, along with those reported by Maynard (1996), suggest a parasite-specific strategy involved in the behavior alteration caused by the acanthocephalans on their intermediate host. The use of a biogenic amine as a mechanism of interaction by the parasites gives them an endless number of alternative potential actions on their intermediate hosts.

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

PubMed

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

2014-06-01

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. © 2013 Elsevier Inc. All rights reserved.

Serotonin and dopamine differentially affect appetitive and aversive general Pavlovian-to-instrumental transfer.

PubMed

Hebart, Martin N; Gläscher, Jan

2015-01-01

Human motivation and decision-making is influenced by the interaction of Pavlovian and instrumental systems. The neurotransmitters dopamine and serotonin have been suggested to play a major role in motivation and decision-making, but how they affect this interaction in humans is largely unknown. We investigated the effect of these neurotransmitters in a general Pavlovian-to-instrumental transfer (PIT) task which measured the nonspecific effect of appetitive and aversive Pavlovian cues on instrumental responses. For that purpose, we used selective dietary depletion of the amino acid precursors of serotonin and dopamine: tryptophan (n = 34) and tyrosine/phenylalanine (n = 35), respectively, and compared the performance of these groups to a control group (n = 34) receiving a nondepleted (balanced) amino acid drink. We found that PIT differed between groups: Relative to the control group that exhibited only appetitive PIT, we found reduced appetitive PIT in the tyrosine/phenylalanine-depleted group and enhanced aversive PIT in the tryptophan-depleted group. These results demonstrate a differential involvement of serotonin and dopamine in motivated behavior. They suggest that reductions in serotonin enhance the motivational influence of aversive stimuli on instrumental behavior and do not affect the influence of appetitive stimuli, while reductions in dopamine diminish the influence of appetitive stimuli. No conclusions could be drawn about how dopamine affects the influence of aversive stimuli. The interplay of both neurotransmitter systems allows for flexible and adaptive responses depending on the behavioral context.

Quantitative PET studies of the serotonin transporter in MDMA users and controls using [11C]McN5652 and [11C]DASB.

PubMed

McCann, Una D; Szabo, Zsolt; Seckin, Esen; Rosenblatt, Peter; Mathews, William B; Ravert, Hayden T; Dannals, Robert F; Ricaurte, George A

2005-09-01

(+/-)3,4-Methylenedioxymethamphetamine (MDMA, 'Ecstasy') is a widely used illicit drug that produces toxic effects on brain serotonin axons and axon terminals in animals. The results of clinical studies addressing MDMA's serotonin neurotoxic potential in humans have been inconclusive. In the present study, 23 abstinent MDMA users and 19 non-MDMA controls underwent quantitative positron emission tomography (PET) studies using [11C]McN5652 and [11C]DASB, first- and second-generation serotonin transporter (SERT) ligands previously validated in baboons for detecting MDMA-induced brain serotonin neurotoxicity. Global and regional distribution volumes (DVs) and two additional SERT-binding parameters (DV(spec) and DVR) were compared in the two subject populations using parametric statistical analyses. Data from PET studies revealed excellent correlations between the various binding parameters of [11C]McN5652 and [11C]DASB, both in individual brain regions and individual subjects. Global SERT reductions were found in MDMA users with both PET ligands, using all three of the above-mentioned SERT-binding parameters. Preplanned comparisons in 15 regions of interest demonstrated reductions in selected cortical and subcortical structures. Exploratory correlational analyses suggested that SERT measures recover with time, and that loss of the SERT is directly associated with MDMA use intensity. These quantitative PET data, obtained using validated first- and second-generation SERT PET ligands, provide strong evidence of reduced SERT density in some recreational MDMA users.

Action potential-independent and pharmacologically unique vesicular serotonin release from dendrites

PubMed Central

Colgan, Lesley A.; Cavolo, Samantha L.; Commons, Kathryn G.; Levitan, Edwin S.

2012-01-01

Serotonin released within the dorsal raphe nucleus (DR) induces feedback inhibition of serotonin neuron activity and consequently regulates mood-controlling serotonin release throughout the forebrain. Serotonin packaged in vesicles is released in response to action potentials by the serotonin neuron soma and terminals, but the potential for release by dendrites is unknown. Here three-photon (3P) microscopy imaging of endogenous serotonin in living rat brain slice, immunofluorescence and immuno-gold electron microscopy detection of VMAT2 (vesicular monoamine transporter 2) establish the presence of vesicular serotonin within DR dendrites. Furthermore, activation of glutamate receptors is shown to induce vesicular serotonin release from dendrites. However, unlike release from the soma and terminals, dendritic serotonin release is independent of action potentials, relies on L-type Ca2+ channels, is induced preferentially by NMDA, and displays distinct sensitivity to the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine. The unique control of dendritic serotonin release has important implications for DR physiology and the antidepressant action of SSRIs, dihydropyridines and NMDA receptor antagonists. PMID:23136413

The capsaicin analog nonivamide decreases total energy intake from a standardized breakfast and enhances plasma serotonin levels in moderately overweight men after administered in an oral glucose tolerance test: a randomized, crossover trial.

PubMed

Hochkogler, Christina M; Rohm, Barbara; Hojdar, Karin; Pignitter, Marc; Widder, Sabine; Ley, Jakob P; Krammer, Gerhard E; Somoza, Veronika

2014-06-01

Since bolus administration of capsaicin has been shown to reduce appetite and ad libitum energy intake, this study elucidated the satiating effect of the less pungent capsaicin analog, nonivamide, on subjective feelings of hunger, ad libitum food intake, and satiating hormones in moderately overweight male subjects. Following a randomized, crossover design, 24 male subjects (BMI 27.5 ± 1.53 kg/m(2) ) received either 75 g glucose in 300 mL water (control treatment, CT) or the same glucose solution supplemented with 0.15 mg nonivamide (nonivamide treatment, NT). Ratings of hunger were assessed before and 2 h after each intervention by means of visual analog scales. Ad libitum energy and macronutrient intakes from a standardized breakfast 2 h postintervention were calculated. Plasma glucose, insulin, peptide YY (3-36), glucagon-like peptide 1, and serotonin were quantified in blood samples drawn before and 15, 30, 60, 90, and 120 min after each intervention. NT reduced subjective feelings of hunger and ad libitum energy and carbohydrate intakes from a standardized breakfast compared to CT. Plasma analysis revealed higher mean plasma glucagon-like peptide 1 and serotonin concentrations after NT versus CT. Addition of 0.15 mg nonivamide to a glucose solution reduced ad libitum energy intake from a standardized breakfast in moderately overweight men. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Plasma serotonin in autism.

PubMed

Connors, Susan L; Matteson, Karla J; Sega, Gary A; Lozzio, Carmen B; Carroll, Roger C; Zimmerman, Andrew W

2006-09-01

Serotonin is necessary for normal fetal brain development. Administration of serotonin inhibitors to pregnant rats results in offspring with abnormal behaviors, brain morphology, and serotonin receptor numbers. Low maternal plasma serotonin may contribute to abnormal brain development in autism. In this study, plasma serotonin levels in autism mothers and control mothers of typically developing children were compared, and plasma serotonin levels in children with autism (n = 17) and their family members were measured. Plasma serotonin levels in autism mothers were significantly lower than in mothers of normal children (P = 0.002). Plasma serotonin levels correlated between autism mothers and their children, but differed between autistic children and their fathers (P = 0.028) and siblings (P = 0.063). Low maternal plasma serotonin may be a risk factor for autism through effects on fetal brain development.

Voltammetric and Mathematical Evidence for Dual Transport Mediation of Serotonin Clearance In Vivo

PubMed Central

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

2014-01-01

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 (SERTs) and have variable clinical effects. Adjunctive therapies, targeting other systems including serotonin autoreceptors, also vary clinically and carry adverse consequences. Fast scan cyclic voltammetry (FSCV) 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 (MFB) to provoke and detect terminal serotonin in the substantia nigra reticulata (SNr). In response to MFB 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

Preliminary evidence that sub-chronic citalopram triggers the re-evaluation of value in intimate partnerships

PubMed Central

Bilderbeck, Amy C.; Wakeley, Judi; Godlewska, Beata R.; McGlone, Francis; Harris, Tirril; Cowen, Phillip J.

2014-01-01

Depression frequently involves disrupted inter-personal relationships, while treatment with serotonergic anti-depressants can interfere with libido and sexual function. However, little is known about how serotonin activity influences appraisals of intimate partnerships. Learning more could help to specify how serotonergic mechanisms mediate social isolation in psychiatric illness. Forty-four healthy heterosexual adults, currently in romantic relationships, received 8 days treatment with the selective serotonin re-uptake inhibitor citalopram (N = 21; 10 male) or placebo (N = 23; 12 male). Participants viewed photographs of unknown, heterosexual couples and made a series of judgements about their relationships. Participants also indicated the importance of relationship features in their own close partnerships, and close partnerships generally. Citalopram reduced the rated quality of couples’ physical relationships and the importance attributed to physical and intimate aspects of participants’ own relationships. In contrast, citalopram also enhanced the evaluated worth of mutual trust in relationships. Amongst males, citalopram was associated with judgements of reduced turbulence and bickering in others’ relationships, and increased male dominance. These data constitute preliminary evidence that enhancing serotonin activity modulates cognitions about sexual activity as part of a re-appraisal of sources of value within close intimate relationships, enhancing the judged importance of longer-term benefits of trust and shared experiences. PMID:23996287

Correction to Smith et al. (2013).

PubMed

Smith, Carl D; Piasecki, Christopher C; Weera, Marcus; Olszewicz, Joshua; Lonstein, Joseph S

2015-08-01

Reports an error in "Noradrenergic alpha-2 receptor modulators in the ventral bed nucleus of the stria terminalis: Effects on anxiety behavior in postpartum and virgin female rats" by Carl D. Smith, Christopher C. Piasecki, Marcus Weera, Joshua Olszewicz and Joseph S. Lonstein (Behavioral Neuroscience, 2013[Aug], Vol 127[4], 582-597). Table 2 should have used the ratio of 5HIAA/serotonin - rather than the inverse - as the indicator of serotonin turnover. Using the correct ratio, differences in serotonin turnover between the postpartum and virgin females are: BSTv - 1.11 0.06 vs 0.79 0.11 (t 2.57, p 0.05); BSTd - 1.01 0.07 vs 0.68 0.11 (t 2.58, p 0.05). That is, contrary to what was originally reported, postpartum females had higher serotonin turnover in both subregions of the BST compared to virgins. The penultimate sentence in the abstract noting serotonin turnover in mothers has been corrected in the online version of this article. (The following abstract of the original article appeared in record 2013-22430-001.) Emotional hyperreactivity can inhibit maternal responsiveness in female rats and other animals. Maternal behavior in postpartum rats is disrupted by increasing norepinephrine release in the ventral bed nucleus of the stria terminalis (BSTv) with the α2-autoreceptor antagonist, yohimbine, or the more selective α2-autoreceptor antagonist, idazoxan (Smith et al., 2012). Because high noradrenergic activity in the BSTv can also increase anxiety-related behaviors, increased anxiety may underlie the disrupted mothering of dams given yohimbine or idazoxan. To assess this possibility, anxiety-related behaviors in an elevated plus maze were assessed in postpartum rats after administration of yohimbine or idazoxan. It was further assessed if the α2-autoreceptor agonist clonidine (which decreases norepinephrine release) would, conversely, reduce dams' anxiety. Groups of diestrous virgins were also examined. It was found that peripheral or intra-BSTv yohimbine did increase anxiety-related behavior in postpartum females. However, BSTv infusion of idazoxan did not reproduce yohimbine's anxiogenic effects and anxiety was not reduced by peripheral or intra-BSTv clonidine. Because yohimbine is a weak 5HT1A receptor agonist, other groups of females received BSTv infusion of the 5HT1A receptor agonist 8OH-DPAT, but it did not alter their anxiety-related behavior. Lastly, levels of norepinephrine and serotonin in tissue punches from the BSTv did not differ between postpartum and diestrous rats, but serotonin turnover was higher in mothers. These results suggest that the impaired maternal behavior after BSTv infusion of yohimbine or idazoxan cannot both be readily explained by an increase in dams' anxiety, and that BSTv α2-autoreceptor modulation alone has little influence on anxiety-related behaviors in postpartum or diestrous rats. (c) 2015 APA, all rights reserved).

Serum serotonin concentration associated with bone mineral density in Chinese postmenopausal women.

PubMed

Wei, Qiu-Shi; Chen, Zhen-Qiu; Tan, Xin; Kang, Lu-Chen; Jiang, Xiao-Bing; Liang, Jiang; He, Wei; Deng, Wei-Min

2017-02-01

Recent studies have shown that circulating serotonin plays a potential role in bone metabolism. However, conflicting results have been reported for the relationship between serum serotonin concentrations and bone mineral density (BMD). We investigated whether the serum serotonin concentrations related to BMD in Chinese postmenopausal women. Serum serotonin and bone turnover concentrations of 117 premenopausal women and 262 asymptomatic postmenopausal women were analyzed by enzyme-linked immunosorbent assay. BMD at the lumbar spine and femoral neck was measured by dual energy X-ray absorptiometry. The relationship between serotonin and BMD was investigated. The postmenopausal women had lower mean serum serotonin concentrations compared to the premenopausal women. Serotonin concentrations were negatively associated with age, weight, BMI, fat mass, and β-CTX concentrations in postmenopausal women. No significant correlations were found between serotonin and these parameters in premenopausal women. In postmenopausal women, age- and BMI-adjusted serotonin concentrations were positively correlated with BMD of the lumbar spine and femoral neck. Multiple regression analyses showed serum serotonin and β-CTX were the predictors for lumbar spine BMD. Only serum serotonin was the determinant for femoral neck BMD. In conclusion, lower serum serotonin concentrations are linked to low lumbar spine and femoral neck BMD in postmenopausal women.

(3H)WB4101 labels the 5-HT1A serotonin receptor subtype in rat brain. Guanine nucleotide and divalent cation sensitivity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Norman, A.B.; Battaglia, G.; Creese, I.

1985-12-01

In the presence of a 30 nM prazosin mask, (/sup 3/H)-2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane ((/sup 3/H)WB4101) can selectively label 5-HT1 serotonin receptors. Serotonin exhibits high affinity (Ki = 2.5 nM) and monophasic competition for (/sup 3/H) WB4101 binding in cerebral cortex. We have found a significant correlation (r = 0.96) between the affinities of a number of serotonergic and nonserotonergic compounds at (/sup 3/H)WB4101-binding sites in the presence of 30 nM prazosin and (/sup 3/H) lysergic acid diethylamide ((/sup 3/H)LSD)-labeled 5-HT1 serotonin receptors in homogenates of rat cerebral cortex. Despite similar pharmacological profiles, distribution studies indicate that, in the presence of 5more » mM MgSO4, the Bmax of (/sup 3/H)WB4101 is significantly lower than the Bmax of (/sup 3/H)LSD in various brain regions. WB4101 competition for (/sup 3/H) LSD-labeled 5-HT1 receptors fits best to a computer-derived model assuming two binding sites, with the KH for WB4101 being similar to the KD of (/sup 3/H)WB4101 binding derived from saturation experiments. This suggests that (/sup 3/H)WB4101 labels only one of the subtypes of the 5-HT1 serotonin receptors labeled by (/sup 3/H)LSD. The selective 5-HT1A serotonin receptor antagonist, spiperone, and the selective 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetraline, exhibit high affinity and monophasic competition for (/sup 3/H)WB4101 but compete for multiple (/sup 3/H)LSD 5-HT1 binding sites. These data indicate that (/sup 3/H)WB4101 selectively labels the 5-HT1A serotonin receptor, whereas (/sup 3/H) LSD appears to label both the 5-HT1A and the 5-HT1B serotonin receptor subtypes. The divalent cations, Mn2+, Mg2+, and Ca2+ were found to markedly increase the affinity and Bmax of (/sup 3/H)WB4101 binding in cerebral cortex. Conversely, the guanine nucleotides guanylylimidodiphosphate and GTP, but not the adenosine nucleotide ATP, markedly reduce the Bmax of (/sup 3/H)WB4101 binding.« less

Severe Serotonin Depletion after Conditional Deletion of the Vesicular Monoamine Transporter 2 Gene in Serotonin Neurons: Neural and Behavioral Consequences

PubMed Central

Narboux-Nême, Nicolas; Sagné, Corinne; Doly, Stephane; Diaz, Silvina L; Martin, Cédric B P; Angenard, Gaelle; Martres, Marie-Pascale; Giros, Bruno; Hamon, Michel; Lanfumey, Laurence; Gaspar, Patricia; Mongeau, Raymond

2011-01-01

The vesicular monoamine transporter type 2 gene (VMAT2) has a crucial role in the storage and synaptic release of all monoamines, including serotonin (5-HT). To evaluate the specific role of VMAT2 in 5-HT neurons, we produced a conditional ablation of VMAT2 under control of the serotonin transporter (slc6a4) promoter. VMAT2sert−cre mice showed a major (−95%) depletion of 5-HT levels in the brain with no major alterations in other monoamines. Raphe neurons contained no 5-HT immunoreactivity in VMAT2sert−cre mice but developed normal innervations, as assessed by both tryptophan hydroxylase 2 and 5-HT transporter labeling. Increased 5-HT1A autoreceptor coupling to G protein, as assessed with agonist-stimulated [35S]GTP-γ-S binding, was observed in the raphe area, indicating an adaptive change to reduced 5-HT transmission. Behavioral evaluation in adult VMAT2sert−cre mice showed an increase in escape-like reactions in response to tail suspension and anxiolytic-like response in the novelty-suppressed feeding test. In an aversive ultrasound-induced defense paradigm, VMAT2sert−cre mice displayed a major increase in escape-like behaviors. Wild-type-like defense phenotype could be rescued by replenishing intracellular 5-HT stores with chronic pargyline (a monoamine oxidase inhibitor) treatment. Pargyline also allowed some form of 5-HT release, although in reduced amounts, in synaptosomes from VMAT2sert−cre mouse brain. These findings are coherent with the notion that 5-HT has an important role in anxiety, and provide new insights into the role of endogenous 5-HT in defense behaviors. PMID:21814181

The Effects of Response Interruption and Redirection and Sertraline on Vocal Stereotypy

ERIC Educational Resources Information Center

Miguel, Caio F.; Clark, Kathy; Tereshko, Lisa; Ahearn, William H.

2009-01-01

Although response interruption and redirection (RIRD) has been shown to be successful in reducing vocal stereotypy, recent reports have suggested that selective serotonin reuptake inhibitors (SSRIs) may also reduce these behaviors. The purpose of the current investigation was to examine the effects of RIRD with and without sertraline on…

Regulation of serotonin release from enterochromaffin cells of rat cecum mucosa

DOE Office of Scientific and Technical Information (OSTI.GOV)

Simon, C.; Ternaux, J.P.

1990-05-01

The release of endogenous serotonin or previously taken up tritiated serotonin from isolated strips of rat cecum mucosa containing enterochromaffin cells was studied in vitro. Release of tritiated serotonin was increased by potassium depolarization and was decreased by tetrodotoxin, veratridine and the absence of calcium. Endogenous serotonin was released at a lower rate than tritiated serotonin; endogenous serotonin release was stimulated by potassium depolarization but was unaffected by tetrodotoxin, veratridine or the absence of calcium. Carbachol, norepinephrine, clonidine and isoproterenol decreased release of tritiated serotonin but had less or reverse effect on release of endogenous serotonin. The results suggest twomore » different serotoninergic pools within the enterochromaffin cell population.« less

Serotonin syndrome: a complex but easily avoidable condition.

PubMed

Dvir, Yael; Smallwood, Patrick

2008-01-01

Serotonin syndrome is a potentially life-threatening adverse drug reaction caused by excessive serotonergic agonism in central and peripheral nervous system serotonergic receptors (Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-1120). Symptoms are characterized by a triad of neuron-excitatory features, which include (a) neuromuscular hyperactivity -- tremor, clonus, myoclonus, hyperreflexia and, in advanced stages, pyramidal rigidity; (b) autonomic hyperactivity -- diaphoresis, fever, tachycardia and tachypnea; (c) altered mental status -- agitation, excitement and, in advanced stages, confusion (Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth 2005;95:434-441). It arises when pharmacological agents increase serotonin neurotransmission at postsynaptic 5-hydroxytryptamine 1A and 5-hydroxytryptamine 2A receptors through increased serotonin synthesis, decreased serotonin metabolism, increased serotonin release, inhibition of serotonin reuptake or direct agonism of the serotonin receptors (Houlihan D. Serotonin syndrome resulting from coadministration of tramodol, venlafaxine, and mirtazapine. Ann Pharmacother 2004;38:411-413). The etiology is often the result of therapeutic drug use, intentional overdosing of serotonergic agents or complex interactions between drugs that directly or indirectly modulate the serotonin system (Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-1120). Due to the increasing availability of agents with serotonergic activity, physicians need to more aware of serotonin syndrome. The following case highlights the complex nature in which serotonin syndrome can arise, as well as the proper recognition and treatment of a potentially life-threatening yet easily avoidable condition.

Serotonin-induced hypophagia is mediated via α2 and β2 adrenergic receptors in neonatal layer-type chickens.

PubMed

Zendehdel, M; Sardari, F; Hassanpour, S; Rahnema, M; Adeli, A; Ghashghayi, E

2017-06-01

1. Serotoninergic and adrenergic systems play crucial roles in feed intake regulation in avians but there is no report on possible interactions among them. So, in this study, 5 experiments were designed to evaluate the interaction of central serotonergic and adrenergic systems on food intake regulation in 3 h food deprived (FD 3 ) neonatal layer-type chickens. 2. In Experiment 1, chickens received intracerebroventricular (ICV) injection of control solution, serotonin (56.74 nmol), prazosin (α 1 receptor antagonist, 10 nmol) and co-injection of serotonin plus prazosin. In Experiment 2, control solution, serotonin (56.74 nmol), yohimbine (α 2 receptor antagonist, 13 nmol) and co-injection of serotonin plus yohimbine were used. In Experiment 3, the birds received control solution, serotonin (56.74 nmol), metoprolol (β 1 receptor antagonist, 24 nmol) and co-injection of serotonin plus metoprolol. In Experiment 4, injections were control solution, serotonin (56.74 nmol), ICI 118.551 (β 2 receptor antagonist, 5 nmol) and serotonin plus ICI 118.551. In Experiment 5, control solution, serotonin (56.74 nmol), SR59230R (β 3 receptor antagonist, 20 nmol) and co-administration of serotonin and SR59230R were injected. In all experiments the cumulative food intake was measured until 120 min post injection. 3. The results showed that ICV injection of serotonin alone decreased food intake in chickens. A combined injection of serotonin plus ICI 118.551 significantly attenuated serotonin-induced hypophagia. Also, co-administration of serotonin and yohimbine significantly amplified the hypophagic effect of serotonin. However, prazosin, metoprolol and SR59230R had no effect on serotonin-induced hypophagia in chickens. 4. These results suggest that serotonin-induced feeding behaviour is probably mediated via α 2 and β 2 adrenergic receptors in neonatal layer-type chicken.

Indoleamines and calcium channels influence morphogenesis in in vitro cultures of Mimosa pudica L.

PubMed

Ramakrishna, Akula; Giridhar, Parvatam; Ravishankar, G A

2009-12-01

The present article reports the interplay of indoleamine neurohormones viz. serotonin, melatonin and calcium channels on shoot organogenesis in Mimosa pudica L. In vitro grown nodal segments were cultured on MS medium with B5 vitamins containing Serotonin (SER) and Melatonin (MEL) at 100 microM and indoleamine inhibitors viz. serotonin to melatonin conversion inhibitor p-chlorophenylalanine (p-CPA) at 40 microM, serotonin reuptake inhibitor (Prozac) 20 microM. In another set of experiment, calcium at 5 mM, calcium ionophore (A23187) 100 microM, and calcium channel blocker varapamil hydrochloride (1 mM) a calcium chelator EGTA (100 microM) were administered to the culture medium. The percentage of shoot multiplication, endogenous MEL and SER were monitored during shoot organogenesis. At 100 microM SER and MEL treatment 60% and 70% explants responded for shoot multiplication respectively. Medium supplemented with either SER or MEL along with calcium (5 mM) 75%-80% explants responded for organogenesis. SER or MEL along with calcium ionophore (A23187) at 100 microM 70% explants responded for shoot multiplication. p-CPA, prozac, verapamil and EGTA, shoot multiplication was reduced and endogenous pools of SER, MEL decreased by 40-70%. The results clearly demonstrated that indoleamines and calcium channels positively influenced shoot organogenesis in M. pudica L.

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

PubMed

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

2016-10-01

Dopamine and serotonin have opponent interactions on aspects of impulsivity. Therefore we wanted to test the hypothesis that dopamine and serotonin would have opposing effects on speed-accuracy trade offs in a perceptual decision making task. Unlike other behavioral measures of impulsivity, perceptual decision making allows us to determine whether decreasing premature responses, often interpreted as decreased impulsivity, corresponds to increased behavioral performance. We administered GBR-12909 (a dopamine transporter blocker), escitalopram (a serotonin transporter blocker), or saline in separate sessions to 3 rhesus macaques. We found that animals had slower reaction times (RTs) on escitalopram than on GBR-12909 or saline. However, they were also least accurate on escitalopram. Animals were faster, although nonsignificantly, on GBR than saline and had equivalent accuracy. Administration of GBR-12909 did cause animals to be faster in error trials than correct trials. Therefore, from the point of view of RTs the animals were less impulsive on escitalopram. However, the decreased accuracy of the monkeys shows that they were not able to make use of their slower response times to make more accurate decisions. Therefore, impulsivity was reduced on escitalopram, but at the expense of a slower information-processing rate in the perceptual inference task. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Long term effects of neonatal exposure to fluoxetine on energy balance: A systematic review of experimental studies.

PubMed

da L D Barros, Manuella; Manhães-de-Castro, Raul; Alves, Daniele T; Quevedo, Omar Guzmán; Toscano, Ana Elisa; Bonnin, Alexandre; Galindo, Ligia

2018-06-08

Serotonin exerts a modulating function on the development of the central nervous system, including hypothalamic circuits controlling feeding behavior and energy expenditure. Based on the developmental plasticity theory, early disturbances of synaptic availability of serotonin may promote phenotypic adaptations and late disorders of energy balance regulation leading to obesity and associated diseases. The aim of this systematic review is to determine the effects of pharmacological neonatal inhibition of serotonin reuptake by fluoxetine, on parameters related to feeding behavior and energy balance. Literature searches were performed in Medline/PubMed and Lilacs databases, out of which 9726 studies were found. Using predefined protocol and registered on CAMARADES website, 23 studies were included for qualitative synthesis. The internal validity was assessed using the SYRCLE's risk of bias toll. Kappa index was also measured for analyzing the concordance between the reviewers. In addition, the PRISMA statement was used for reporting this systematic review. Most of the included studies demonstrated that neonatal serotonin reuptake inhibition is associated with long term reduced body weight, lower fat mass and higher thermogenic capacity and mitochondrial oxygen consumption in key metabolic tissues. Therefore, experimental fluoxetine exposure during neonatal development may promote long-term changes related to energy balance associated with a lean phenotype. Copyright © 2018 Elsevier B.V. All rights reserved.

Bright ambient light conditions reduce the effect of tryptophan depletion in healthy females.

PubMed

Defrancesco, Michaela; Niederstätter, Harald; Parson, Walther; Kemmler, Georg; Hinterhuber, Hartmann; Marksteiner, Josef; Deisenhammer, Eberhard A

2013-11-30

Tryptophan depletion (TD) is an established method to influence the serotonergic system and mood. The purpose of this study was to examine the effect of TD under different ambient light conditions, measured through serotonin-associated plasma levels and a visual analog scale (VAS), on healthy females. Thirty-eight healthy female s-allele carriers of the serotonin transporter promoter gene (5-HTTLPR) were administered a TD under dim light conditions (75 lx). A sub-group of 8 participants repeated the procedure randomized in two additional light conditions (585 lx and 1530 lx respectively). Prior to, and 5h following administration of TD, various variables (serotonin-associated plasma levels, VAS) were measured. Due to not normal distributed data, non-parametric statistical tests were used. Overall analysis showed a significant mood lowering effect of TD. Moreover, TD decreased all measured serotonin-associated plasma levels significantly. Significant differences in varying light conditions were found for the VAS and plasma tryptophan, with the greatest effect of TD in the 75 lx condition. Results of our study showed an influence of even slight differences in ambient light intensity on the effect of TD concerning mood as well as on the serotonergic system. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Sleep, serotonin, and suicide in Japan.

PubMed

Kohyama, Jun

2011-01-01

This article reviews evidence supporting the hypothesis that suicide rates in Japan could be reduced by elevating serotonin levels via increasing the average duration of sleep. Seven major relevant findings were apparent in the literature: 1) Sleep loss is associated with suicide, but the direction of causality is equivocal. 2) Decreased serotonergic activity may be involved in suicidal behavior. 3) Sleep debt may decrease serotonergic activity. 4) The suicide rate in Japan has remained at a heightened level for the past 12 years. 5) The average sleep duration in Japan has decreased over the past 40 years. 6) The average sleep duration in Japan is among the lowest in the world. 7) The average sleep duration in Japan plateaued in 1995 and has been relatively stable since. From the research reviewed, two major problematic issues were apparent: 1) Most people in Japan receive inadequate sleep. 2) Individuals whose sleep is inadequate are unlikely to be sufficiently physically active to stimulate serotonergic systems to a desirable level. I propose that public health initiatives encouraging a longer duration of sleep may provide a relatively simple way of addressing the disturbing current trend in Japan. The combination of actigraph and brain serotonin level measurement could allow large population-based cohort studies to be designed, to elucidate the causal links between sleep duration, serotonin levels, and suicide rates.

The serotonin transporter: Examination of the changes in transporter affinity induced by ligand binding

DOE Office of Scientific and Technical Information (OSTI.GOV)

Humphreys, C.J.

1989-01-01

The plasmalemmal serotonin transporter uses transmembrane gradients of Na{sup +}, Cl{sup {minus}} and K{sup +} to accumulate serotonin within blood platelets. Transport is competitively inhibited by the antidepressant imipramine. Like serotonin transport, imipramine binding requires Na{sup +}. Unlike serotonin, however, imipramine does not appear to be transported. To gain insight into the mechanism of serotonin transport the author have analyzed the influences of Na{sup +} and Cl{sup {minus}}, the two ions cotransported with serotonin, on both serotonin transport and the interaction of imipramine and other antidepressant drugs with the plasmalemmal serotonin transporter of human platelets. Additionally, the author have synthesized,more » purified and characterized the binding of 2-iodoimipramine to the serotonin transporter. Finally, the author have conducted a preliminary study of the inhibition of serotonin transport and imipramine binding produced by dicyclohexylcarbodiimide. My results reveal many instances of positive heterotropic cooperativity in ligand binding to the serotonin transporter. Na{sup +} binding enhances the transporters affinity for imipramine and several other antidepressant drugs, and also increases the affinity for Cl{sup {minus}}. Cl{sup {minus}} enhances the transporters affinity for imipramine, as well as for Na{sup +}. At concentrations in the range of its K{sub M} for transport serotonin is a competitive inhibitor of imipramine binding. At much higher concentrations, however, serotonin also inhibits imipramines dissociation rate constant. This latter effect which is Na{sup +}-independent and species specific, is apparently produced by serotonin binding at a second, low affinity site on, or near, the transporter complex. Iodoimipramine competitively inhibit both ({sup 3}H)imipramine binding and ({sup 3}H)serotonin transport.« less

Presynaptic Partners of Dorsal Raphe Serotonergic and GABAergic Neurons

PubMed Central

Weissbourd, Brandon; Ren, Jing; DeLoach, Katherine E.; Guenthner, Casey J.; Miyamichi, Kazunari; Luo, Liqun

2016-01-01

SUMMARY The serotonin system powerfully modulates physiology and behavior in health and disease, yet the circuit mechanisms underlying serotonin neuron activity are poorly understood. The major source of forebrain serotonergic innervation is from the dorsal raphe nucleus (DR), which contains both serotonin and GABA neurons. Using viral tracing combined with electrophysiology, we found that GABA and serotonin neurons in the DR receive excitatory, inhibitory, and peptidergic inputs from the same specific brain regions. Embedded in this overall similarity are important differences. Serotonin neurons are more likely to receive synaptic inputs from anterior neocortex while GABA neurons receive disproportionally higher input from the central amygdala. Local input mapping revealed extensive serotonin-serotonin as well as GABA-serotonin connectivity with a distinct spatial organization. Covariance analysis suggests heterogeneity of both serotonin and GABA neurons with respect to the inputs they receive. These analyses provide a foundation for further functional dissection of the serotonin system. PMID:25102560

A-FABP and oxidative stress underlie the impairment of endothelium-dependent relaxations to serotonin and the intima-medial thickening in the porcine coronary artery with regenerated endothelium.

PubMed

Chan, Calvin K; Zhao, Yingzi; Liao, Song Yan; Zhang, Yue Lin; Lee, Mary Y K; Xu, Aimin; Tse, Hung Fat; Vanhoutte, Paul M

2013-01-16

Experiments were designed to determine the cause of the selective dysfunction of G(i) proteins, characterized by a reduced endothelium-dependent relaxation to serotonin (5-hydroxytryptamine), in coronary arteries lined with regenerated endothelial cells. Part of the endothelium of the left anterior descending coronary artery of female pigs was removed in vivo to induce regeneration. The animals were treated chronically with vehicle (control), apocynin (antioxidant), or BMS309403 (A-FABP inhibitor) for 28 days before functional examination and histological analysis of segments of coronary arteries with native or regenerated endothelium of the same hearts. Isometric tension was recorded in organ chambers and cumulative concentration-relaxation curves obtained in response to endothelium-dependent [serotonin (G(i) protein mediated activation of eNOS) and bradykinin (G(q) protein mediated activation of eNOS)] and independent [detaNONOate (cGMP-mediated), isoproterenol (cAMP-mediated)] vasodilators. The two inhibitors tested did not acutely affect relaxations of preparations with either native or regenerated endothelium. In the chronically treated groups, however, both apocynin and BMS309403 abolished the reduction in relaxation to serotonin in segments covered with regenerated endothelium and prevented the intima-medial thickening caused by endothelial regeneration, without affecting responses to bradykinin or endothelium-independent agonists (detaNONOate and isoproterenol). Thus, inhibition of either oxidative stress or A-FABP likely prevents both the selective dysfunction of G(i) protein mediated relaxation to serotonin and the neointimal thickening resulting from endothelial regeneration.

Comparison of the neurobiological effects of attribution retraining group therapy with those of selective serotonin reuptake inhibitors

PubMed Central

Wang, C.; Zhang, N.; Zhang, Y.L.; Zhang, J.; Yang, H.; Timothy, T.C.

2013-01-01

The aim of this study was to compare the effectiveness of attribution retraining group therapy (ARGT) with selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), and obsessive-compulsive disorder (OCD). Subjects were sequentially recruited and randomized into two groups, one receiving ARGT (n = 63) and the other SSRIs (n = 66) for 8 weeks. Fifty-four ARGT outpatients with MDD (n = 19), GAD (n = 19), and OCD (n = 16) and 55 SSRI outpatients with MDD (n = 19), GAD (n = 19), and OCD (n = 17) completed the study. All subjects were assessed using the Hamilton Depression Scale and Hamilton Anxiety Scale before and after treatment. The 10-item Yale-Brown Obsessive Compulsive Scale was employed only for OCD subjects. Plasma levels of serotonin, norepinephrine, cortisol, and adrenocorticotropic hormone were also measured at baseline and 8 weeks after completion of treatment. Symptom scores were significantly reduced (P < 0.001) in both the ARGT and SSRI groups at the end of treatment. However, MDD, GAD and OCD patients in the ARGT group had significantly lower plasma cortisol concentrations compared to baseline (P < 0.05), whereas MDD and OCD patients receiving SSRIs showed significantly increased plasma levels of serotonin (P < 0.05). These findings suggest that ARGT may modulate plasma cortisol levels and affect the hypothalamus-pituitary-adrenal axis as opposed to SSRIs, which may up-regulate plasma serotonin levels via a different pathway to produce an overall improvement in the clinical condition of the patients. PMID:23558857

Cortical serotonin-S2 receptor binding in Lewy body dementia, Alzheimer's and Parkinson's diseases.

PubMed

Cheng, A V; Ferrier, I N; Morris, C M; Jabeen, S; Sahgal, A; McKeith, I G; Edwardson, J A; Perry, R H; Perry, E K

1991-11-01

The binding of the selective 5-HT2 antagonist [3H]ketanserin has been investigated in the temporal cortex of patients with Alzheimer's disease (SDAT), Parkinson's disease (PD), senile dementia of Lewy body type (SDLT) and neuropathologically normal subjects (control). 5-HT2 binding was reduced in SDAT, PD with dementia and SDLT. SDAT showed a 5-HT2 receptor deficit across most of the cortical layers. A significant decrease in 5-HT2 binding in the deep cortical layers was found in those SDLT cases without hallucinations. SDLT cases with hallucinations only showed a deficit in one upper layer. There was a significant difference in cortical layers III and V between SDLT without hallucinations and SDLT with hallucinations. The results confirm an abnormality of serotonin binding in various forms of dementia and suggest that preservation of 5-HT2 receptor in the temporal cortex may differentiate hallucinating from non-hallucinating cases of SDLT.

Single bright light exposure decreases sweet taste threshold in healthy volunteers.

PubMed

Srivastava, Shrikant; Donaldson, Lucy F; Rai, Dheeraj; Melichar, Jan K; Potokar, John

2013-10-01

Bright light exposure can alter circulating serotonin levels, and alteration of available serotonin by acute selective serotonin reuptake inhibition significantly lowers sweet but not salt taste recognition thresholds. We tested the hypothesis that bright light exposure would increase sweet but not salt taste sensitivity in healthy adults. Fourteen healthy volunteers were exposed to bright (10,000 lux) and dim (<20 lux) light for 30 min each, in counterbalanced order. Measures of taste perception (salt and sweet) and mood were determined at baseline, and before and after each light exposure period. Recognition thresholds for sucrose were significantly lower after bright but not dim light exposure. Thresholds for salt were unaffected by either condition. There were no significant changes in taste acuity, intensity or pleasantness for both the taste modalities and on visual analogue scales (VASs) for mood, anxiety, sleepiness and alertness, under either light condition. Brief bright light exposure reduces sweet but not salt taste recognition thresholds in healthy humans.

Correction of respiratory disorders in a mouse model of Rett syndrome

PubMed Central

Abdala, Ana P. L.; Dutschmann, Mathias; Bissonnette, John M.; Paton, Julian F. R.

2010-01-01

Rett syndrome (RTT) is an autism spectrum disorder caused by mutations in the X-linked gene that encodes the transcription factor methyl-CpG-binding protein 2 (MeCP2). A major debilitating phenotype in affected females is frequent apneas, and heterozygous Mecp2-deficient female mice mimic the human respiratory disorder. GABA defects have been demonstrated in the brainstem of Mecp2-deficient mice. Here, using an intact respiratory network, we show that apnea in RTT mice is characterized by excessive excitatory activity in expiratory cranial and spinal nerves. Augmenting GABA markedly improves the respiratory phenotype. In addition, a serotonin 1a receptor agonist that depresses expiratory neuron activity also reduces apnea, corrects the irregular breathing pattern, and prolongs survival in MeCP2 null males. Combining a GABA reuptake blocker with a serotonin 1a agonist in heterozygous females completely corrects their respiratory defects. The results indicate that GABA and serotonin 1a receptor activity are candidates for treatment of the respiratory disorders in Rett syndrome. PMID:20921395

Urinary serotonin level is associated with serotonin syndrome after moclobemide, sertraline, and citalopram overdose.

PubMed

Brvar, Miran; Stajer, Dusan; Kozelj, Gordana; Osredkar, Josko; Mozina, Martin; Bunc, Matjaz

2007-01-01

Altered mental status, autonomic dysfunction, and neuromuscular abnormalities are a characteristic triad of serotonin syndrome. No laboratory tests confirm the diagnosis of serotonin syndrome. A 35-year-old woman took moclobemide, sertraline, and citalopram in a suicide attempt. She was conscious with mild tachycardia, hypertension, and tachypnea one hour after ingestion. In the second hour after ingestion diaphoresis, mydriasis, horizontal nystagmus, trismus, hyperreflexia, clonus, and tremor appeared. She became agitated and unresponsive. In the third hour after ingestion she became comatose and hyperthermic. She was anesthetized, paralyzed, intubated, and ventilated for 24 hours. Serum moclobemide, sertraline, and citalopram levels were above therapeutic levels. The serum serotonin level was within normal limits and the urinary 5-hydroxyindoleacetic acid:creatinine ratio was below the average daily value. The urinary serotonin:creatinine ratio was increased on arrival (1 mg/g). The urinary serotonin level is increased in serotonin syndrome due to a monoamine oxidase inhibitor and selective serotonin-reuptake inhibitors overdose. It is possible that urinary serotonin concentration could be used as a biochemical marker of serotonin syndrome.

Development and aminergic neuromodulation of a spinal locomotor network controlling swimming in Xenopus larvae.

PubMed

Sillar, K T; Reith, C A; McDearmid, J R

1998-11-16

In this article we review our research on the development and intrinsic neuromodulation of a spinal network controlling locomotion in a simple vertebrate. Swimming in hatchling Xenopus embryos is generated by a restricted network of well-characterized spinal neurons. This network produces a stereotyped motor pattern which, like real swimming, involves rhythmic activity that alternates across the body and progresses rostrocaudally with a brief delay between muscle segments. The stereotypy results from motoneurons discharging a single impulse in each cycle; because all motoneurons appear to behave similarly there is little scope for altering the output to the myotomes from one cycle to the next. Just one day later, however, Xenopus larvae generate a more complex and flexible motor pattern in which motoneurons can discharge a variable number of impulses which contribute to ventral root bursts in each cycle. This maturation of swimming is due, in part, to the influence of serotonin released from brain-stem raphespinal interneurons whose axonal projections innervate the cord early in larval life. Larval swimming is differentially modulated by both serotonin and by noradrenaline: serotonin leads to relatively fast, intense swimming whereas noradrenaline favors slower, weaker activity. Thus, these two biogenic amines select opposite extremes from the spectrum of possible output patterns that the swimming network can produce. Our studies on the cellular and synaptic effects of the amines indicate that they can control the strength of reciprocal glycinergic inhibition in the spinal cord. Serotonin and noradrenaline act presynaptically on the terminals of glycinergic commissural interneurons to weaken and strengthen, respectively, crossed glycinergic inhibition during swimming. As a result, serotonin reduces and noradrenaline increases interburst intervals. The membrane properties of spinal neurons are also affected by the amines. In particular, serotonin can induce intrinsic oscillatory membrane properties in the presence of NMDA. These depolarizations are slow compared to the cycle periods during swimming and so may contribute to enhancement of swimming over several consecutive cycles of activity.

Serotonin-Labeled CdSe Nanocrystals: Applications for Neuroscience

NASA Astrophysics Data System (ADS)

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

2000-03-01

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

Massage Therapy for Reducing Stress Hormones and Enhancing Immune Function in Breast Cancer Survivors

DTIC Science & Technology

2001-08-01

massage therapy (n=20), a relaxation therapy (n=20) or a control group (n=20). Women in the massage and relaxation therapies will receive 3 sessions a...women reveal for the massage therapy group 1) reduced anxiety, 2) improved mood, 3) increased serotonin and dopamine levels and 4) increased Natural

Toll-like receptors 2 and 4 exert opposite effects on the contractile response induced by serotonin in mouse colon: role of serotonin receptors.

PubMed

Forcén, R; Latorre, E; Pardo, J; Alcalde, A I; Murillo, M D; Grasa, L

2016-08-01

What is the central question of this study? The action of Toll-like receptors (TLRs) 2 and 4 on the motor response to serotonin in mouse colon has not previously been reported. What is the main finding and its importance? Toll-like receptors 2 and 4 modulate the serotonin-induced contractile response in mouse colon by modifying the expression of serotonin (5-HT) receptors. Alterations in 5-HT2A and 5-HT2C receptors explain the increase of the response to serotonin in TLR2(-/-) mice. Alterations in 5-HT2C and 5-HT4 receptors explain the suppression of the response to serotonin in TLR4(-/-) mice. The microbiota, through Toll-like receptors (TLRs), may regulate gastrointestinal motility by activating neuroendocrine mechanisms. We evaluated the influence of TLR2 and TLR4 in spontaneous contractions and in the serotonin (5-HT)-induced motor response in mouse colon, and assessed the 5-HT receptors involved. Muscle contractility studies to evaluate the intestinal spontaneous motility and the response to 5-HT were performed in the colon from wild-type (WT), TLR2(-/-) , TLR4(-/-) and TLR2/4 double knockout (DKO) mice. The 5-HT receptor mRNA expression was determined by real-time PCR. The amplitude and frequency of the spontaneous contractions of the colon were smaller in TLR4(-/-) and TLR2/4 DKO mice with respect to WT mice. In WT, TLR2(-/-) and TLR2/4 DKO mice, 100 μm 5-HT evoked a contractile response. The contractile response induced by 5-HT was significantly higher in TLR2(-/-) than in WT mice. In TLR4(-/-) mice, 5-HT did not evoke any contractile response. The mRNA expression of 5-HT2A was increased in TLR2(-/-) and TLR2/4 DKO mice. The 5-HT2C and 5-HT4 mRNA expressions were increased in TLR4(-/-) and TLR2/4 DKO mice. The 5-HT2C mRNA expression was diminished in TLR2(-/-) mice. The 5-HT3 mRNA expression was increased in TLR2(-/-) , TLR4(-/-) and TLR2/4 DKO mice. The 5-HT7 mRNA expression was diminished in TLR2/4 DKO mice. In WT, TLR2(-/-) and TLR2/4 DKO mice, 5-HT2 , 5-HT3 , 5-HT4 and 5-HT7 receptor antagonists reduced or blocked the contractile response evoked by 5-HT. We postulate that TLR2 and TLR4 modulate the serotonin contractile motor response in mouse colon in an opposing manner by modifying the expression of several serotonin receptors. © 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.

Serotonin-Sensitive Adenylate Cyclase in Neural Tissue and Its Similarity to the Serotonin Receptor: A Possible Site of Action of Lysergic Acid Diethylamide

PubMed Central

Nathanson, James A.; Greengard, Paul

1974-01-01

An adenylate cyclase (EC 4.6.1.1) that is activated specifically by low concentrations of serotonin has been identified in homogenates of the thoracic ganglia of an insect nervous system. The activation of this enzyme by serotonin was selectively inhibited by extremely low concentrations of D-lysergic acid diethylamide (LSD), 2-bromo-LSD, and cyproheptadine, agents which are known to block certain serotonin receptors in vivo. The inhibition was competitive with respect to serotonin, and the calculated inhibitory constant of LSD for this serotonin-sensitive adenylate cyclase was 5 nM. The data are consistent with a model in which the serotonin receptor of neural tissue is intimately associated with a serotonin-sensitive adenylate cyclase which mediates serotonergic neurotransmission. The results are also compatible with the possibility that some of the physiological effects of LSD may be mediated through interaction with serotonin-sensitive adenylate cyclase. PMID:4595572

Non-conventional features of peripheral serotonin signalling - the gut and beyond.

PubMed

Spohn, Stephanie N; Mawe, Gary M

2017-07-01

Serotonin was first discovered in the gut, and its conventional actions as an intercellular signalling molecule in the intrinsic and extrinsic enteric reflexes are well recognized, as are a number of serotonin signalling pharmacotherapeutic targets for treatment of nausea, diarrhoea or constipation. The latest discoveries have greatly broadened our understanding of non-conventional actions of peripheral serotonin within the gastrointestinal tract and in a number of other tissues. For example, it is now clear that bacteria within the lumen of the bowel influence serotonin synthesis and release by enterochromaffin cells. Also, serotonin can act both as a pro-inflammatory and anti-inflammatory signalling molecule in the intestinal mucosa via activation of serotonin receptors (5-HT 7 or 5-HT 4 receptors, respectively). For decades, serotonin receptors have been known to exist in a variety of tissues other than the gut, but studies have now provided strong evidence for physiological roles of serotonin in several important processes, including haematopoiesis, metabolic homeostasis and bone metabolism. Furthermore, evidence for serotonin synthesis in peripheral tissues outside of the gut is emerging. In this Review, we expand the discussion beyond gastrointestinal functions to highlight the roles of peripheral serotonin in colitis, haematopoiesis, energy and bone metabolism, and how serotonin is influenced by the gut microbiota.

Modulation of defensive reflex conditioning in snails by serotonin

PubMed Central

Andrianov, Vyatcheslav V.; Bogodvid, Tatiana K.; Deryabina, Irina B.; Golovchenko, Aleksandra N.; Muranova, Lyudmila N.; Tagirova, Roza R.; Vinarskaya, Aliya K.; Gainutdinov, Khalil L.

2015-01-01

Highlights Daily injection of serotonin before a training session accelerated defensive reflex conditioning in snails.Daily injection of 5-hydroxytryptophan before a training session in snails with a deficiency of serotonin induced by the “neurotoxic” analog of serotonin 5,7-dihydroxytryptamine, restored the ability of snails to learn.After injection of the “neurotoxic” analogs of serotonin 5,6- and 5,7-dihydroxytryptamine as well as serotonin, depolarization of the membrane and decrease of the threshold potential of premotor interneurons was observed. We studied the role of serotonin in the mechanisms of learning in terrestrial snails. To produce a serotonin deficit, the “neurotoxic” analogs of serotonin, 5,6- or 5,7-dihydroxytryptamine (5,6/5,7-DHT) were used. Injection of 5,6/5,7-DHT was found to disrupt defensive reflex conditioning. Within 2 weeks of neurotoxin application, the ability to learn had recovered. Daily injection of serotonin before a training session accelerated defensive reflex conditioning and daily injections of 5-HTP in snails with a deficiency of serotonin induced by 5,7-DHT restored the snail's ability to learn. We discovered that injections of the neurotoxins 5,6/5,7-DHT as well as serotonin, caused a decrease in the resting and threshold potentials of the premotor interneurons LPa3 and RPa3. PMID:26557063

Alterations to global but not local motion processing in long-term ecstasy (MDMA) users.

PubMed

White, Claire; Brown, John; Edwards, Mark

2014-07-01

Growing evidence indicates that the main psychoactive ingredient in the illegal drug "ecstasy" (methylendioxymethamphetamine) causes reduced activity in the serotonin and gamma-aminobutyric acid (GABA) systems in humans. On the basis of substantial serotonin input to the occipital lobe, recent research investigated visual processing in long-term users and found a larger magnitude of the tilt aftereffect, interpreted to reflect broadened orientation tuning bandwidths. Further research found higher orientation discrimination thresholds and reduced long-range interactions in the primary visual area of ecstasy users. The aim of the present research was to investigate whether serotonin-mediated V1 visual processing deficits in ecstasy users extend to motion processing mechanisms. Forty-five participants (21 controls, 24 drug users) completed two psychophysical studies: A direction discrimination study directly measured local motion processing in V1, while a motion coherence task tested global motion processing in area V5/MT. "Primary" ecstasy users (n = 18), those without substantial polydrug use, had significantly lower global motion thresholds than controls [p = 0.027, Cohen's d = 0.78 (large)], indicating increased sensitivity to global motion stimuli, but no difference in local motion processing (p = 0.365). These results extend on previous research investigating the long-term effects of illicit drugs on visual processing. Two possible explanations are explored: defuse attentional processes may be facilitating spatial pooling of motion signals in users. Alternatively, it may be that a GABA-mediated disruption to V5/MT processing is reducing spatial suppression and therefore improving global motion perception in ecstasy users.

Serotonin decreases the production of Th1/Th17 cytokines and elevates the frequency of regulatory CD4+ T cell subsets in multiple sclerosis patients.

PubMed

Sacramento, Priscila M; Monteiro, Clarice; Dias, Aleida S O; Kasahara, Taissa M; Ferreira, Thaís B; Hygino, Joana; Wing, Ana Cristina; Andrade, Regis M; Rueda, Fernanda; Sales, Marisa C; Vasconcelos, Claudia Cristina; Bento, Cleonice A M

2018-05-02

Excessive levels of pro-inflammatory cytokines in the central nervous system (CNS) are associated with reduced serotonin (5-HT) synthesis, a neurotransmitter with diverse immune effects. In this study, we evaluated the ability of exogenous 5-HT to modulate the T-cell behavior of patients with multiple sclerosis (MS), a demyelinating autoimmune disease mediated by Th1 and Th17 cytokines. Here, 5-HT attenuated, in vitro, T-cell proliferation and Th1 and Th17 cytokines production in cell cultures from MS patients. Additionally, 5-HT reduced IFN-γ and IL-17 release by CD8 + T-cells. By contrast, 5-HT increased IL-10 production by CD4 + T-cells from MS patients. A more accurate analysis of these IL-10-secreting CD4 + T-cells revealed that 5-HT favors the expansion of FoxP3 + CD39 + regulatory T cells (Tregs) and type 1 regulatory T cells. Notably, this neurotransmitter also elevated the frequency of Treg17 cells, a novel regulatory T-cell subset. The effect of 5-HT in up-regulating CD39 + Treg and Treg17 cells was inversely correlated with the number of active brain lesions. Finally, in addition to directly reducing cytokine production by purified Th1 and Th17 cells, 5-HT enhanced in vitro Treg function. In summary, our data suggest that serotonin may play a protective role in the pathogenesis of MS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Fluoxetine prevents the development of depressive-like behavior in a mouse model of cancer related fatigue.

PubMed

Norden, Diana M; Devine, Raymond; Bicer, Sabahattin; Jing, Runfeng; Reiser, Peter J; Wold, Loren E; Godbout, Jonathan P; McCarthy, Donna O

2015-03-01

Cancer patients frequently suffer from fatigue, a complex syndrome associated with tiredness and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, escalates during treatment, and can persist for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. We have previously shown that increased pro-inflammatory cytokine expression in the brain contributes to depressive- and fatigue-like behaviors in a mouse model of CRF. Inflammatory cytokines increase the activity of indoleamine 2,3-dioxygenase (IDO) and kynurenine 3-monooxygenase (KMO), which competitively reduce serotonin synthesis. Reduced serotonin availability in the brain and increased production of alternative neuroactive metabolites of tryptophan are thought to contribute to the development of depression and fatigue. The purpose of this study was to determine the effects of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on brain cytokines and behavioral measures of fatigue and depression in tumor-bearing mice. Here we show that tumor growth increased brain expression of pro-inflammatory cytokines and KMO. Treatment with fluoxetine had no effect on tumor growth, muscle wasting, fatigue behavior, or cytokine expression in the brain. Fluoxetine, however, reduced depressive-like behaviors in tumor bearing mice. In conclusion, our data confirm that increased brain expression of pro-inflammatory cytokines is associated with tumor-induced fatigue- and depressive-like behaviors. However, it is possible to separate the effects of tumor growth on mood and fatigue-like behaviors using SSRIs such as fluoxetine. Copyright © 2014 Elsevier Inc. All rights reserved.

Behavioural, neurochemical and neuroendocrine effects of the endogenous β-carboline harmane in fear-conditioned rats.

PubMed

Smith, Karen L; Ford, Gemma K; Jessop, David S; Finn, David P

2013-02-01

The putative endogenous imidazoline binding site ligand harmane enhances neuronal activation in response to psychological stress and alters behaviour in animal models of anxiety and antidepressant efficacy. However, the neurobiological mechanisms underlying harmane's psychotropic effects are poorly understood. We investigated the effects of intraperitoneal injection of harmane (2.5 and 10 mg/kg) on fear-conditioned behaviour, hypothalamo-pituitary-adrenal axis activity, and monoaminergic activity within specific fear-associated areas of the rat brain. Harmane had no significant effect on the duration of contextually induced freezing or 22 kHz ultrasonic vocalisations and did not alter the contextually induced suppression of motor activity, including rearing. Harmane reduced the duration of rearing and tended to increase freezing in non-fear-conditioned controls, suggesting potential sedative effects. Harmane increased plasma ACTH and corticosterone concentrations, and serotonin (in hypothalamus, amygdaloid cortex, prefrontal cortex and hippocampus) and noradrenaline (prefrontal cortex) content, irrespective of fear-conditioning. Furthermore, harmane reduced dopamine and serotonin turnover in the PFC and hypothalamus, and serotonin turnover in the amygdaloid cortex in both fear-conditioned and non-fear-conditioned rats. In contrast, harmane increased dopamine and noradrenaline content and reduced dopamine turnover in the amygdala of fear-conditioned rats only, suggesting differential effects on catecholaminergic transmission in the presence and absence of fear. The precise mechanism(s) mediating these effects of harmane remain to be determined but may involve its inhibitory action on monoamine oxidases. These findings support a role for harmane as a neuromodulator, altering behaviour, brain neurochemistry and neuroendocrine function.

Effects of a short-course MDMA binge on dopamine transporter binding and on levels of dopamine and its metabolites in adult male rats

PubMed Central

Biezonski, Dominik K.; Piper, Brian J.; Shinday, Nina M.; Kim, Peter J.; Ali, Syed F.; Meyer, Jerrold S.

2013-01-01

Although the recreational drug 3,4-methylenedioxymethamphetamine (MDMA) is often described as a selective serotonergic neurotoxin, some research has challenged this view. The objective of this study was to determine the influence of MDMA on subsequent levels of two different markers of dopaminergic function, the dopamine transporter (DAT) as well as dopamine and its major metabolites. In experiment I, adult male Sprague–Dawley rats were administered either a low or moderate dose MDMA binge (2.5 or 5.0 mg/kg × 4 with an inter-dose interval of 1 h) or saline, and were killed 1 week later. The moderate dose dramatically reduced [3H]WIN 35,428 binding to striatal DAT by 73.7% (P ≤ 0.001). In experiment II, animals were binged with a higher dose of MDMA (10 mg/kg × 4) to determine the drug’s effects on concentrations of serotonin (5-HT), dopamine, and their respective major metabolites 5-hydroxyindoleacetic acid (5-HIAA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in the striatum and frontal cortex 1 week later. As expected, MDMA significantly reduced 5-HT and 5-HIAA (≥ 50%) in these structures, while only a marginal decrease in dopamine was noted in the striatum. In contrast, levels of DOPAC (34.3%, P < 0.01) and HVA (33.5%, P < 0.001) were reduced by MDMA treatment, suggesting a decrease in dopamine turnover. Overall, these findings indicate that while serotonergic markers are particularly vulnerable to MDMA-induced depletion, significant dopaminergic deficits may also occur under some conditions. Importantly, DAT expression may be more vulnerable to perturbation by MDMA than dopamine itself. PMID:23276666

Serotonin 2c receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis

USDA-ARS?s Scientific Manuscript database

Energy and glucose homeostasis are regulated by central serotonin 2C receptors. These receptors are attractive pharmacological targets for the treatment of obesity; however, the identity of the serotonin 2C receptor-expressing neurons that mediate the effects of serotonin and serotonin 2C receptor a...

An analysis of psychotropic drug sales. Increasing sales of selective serotonin reuptake inhibitors are closely related to number of products.

PubMed

Nielsen, Margrethe; Gøtzsche, Peter

2011-01-01

Prescribing of selective serotonin reuptake inhibitors (SSRIs) has increased dramatically. To compare the sales of benzodiazepines and SSRIs within the primary care sector in Denmark and relate changes in usage to number of indications and products on the market. We used data from various sources to establish the sales curves of psychotropic drugs in the period 1970 to 2007, based on the Anatomic Therapeutic Classification system and Defined Daily Doses. Fluctuations in sales of psychotropic drugs that cannot be explained by disease prevalence were caused by changes in sales of the benzodiazepines and SSRIs. We found a decline in the sales of benzodiazepines after a peak in 1986, likely due to the recognition that they cause dependence. From a low level in 1992, we found that the sales of SSRIs increased almost linearly by a factor of 18, up to 44 DDD per 1000 inhabitants, which was closely related to the number of products on the market that increased by a factor of 16. Sales of antidepressant drugs are mainly determined by market availability of products indicating that marketing pressures are playing an important role. Thus the current level of use of SSRIs may not be evidence-based, which is supported by studies showing that the effect of SSRIs has been overestimated.

Serotonin Improves High Fat Diet Induced Obesity in Mice.

PubMed

Watanabe, Hitoshi; Nakano, Tatsuya; Saito, Ryo; Akasaka, Daisuke; Saito, Kazuki; Ogasawara, Hideki; Minashima, Takeshi; Miyazawa, Kohtaro; Kanaya, Takashi; Takakura, Ikuro; Inoue, Nao; Ikeda, Ikuo; Chen, Xiangning; Miyake, Masato; Kitazawa, Haruki; Shirakawa, Hitoshi; Sato, Kan; Tahara, Kohji; Nagasawa, Yuya; Rose, Michael T; Ohwada, Shyuichi; Watanabe, Kouichi; Aso, Hisashi

2016-01-01

There are two independent serotonin (5-HT) systems of organization: one in the central nervous system and the other in the periphery. 5-HT affects feeding behavior and obesity in the central nervous system. On the other hand, peripheral 5-HT also may play an important role in obesity, as it has been reported that 5-HT regulates glucose and lipid metabolism. Here we show that the intraperitoneal injection of 5-HT to mice inhibits weight gain, hyperglycemia and insulin resistance and completely prevented the enlargement of intra-abdominal adipocytes without having any effect on food intake when on a high fat diet, but not on a chow diet. 5-HT increased energy expenditure, O2 consumption and CO2 production. This novel metabolic effect of peripheral 5-HT is critically related to a shift in the profile of muscle fiber type from fast/glycolytic to slow/oxidative in soleus muscle. Additionally, 5-HT dramatically induced an increase in the mRNA expression of peroxisome proliferator-activated receptor coactivator 1α (PGC-1α)-b and PGC-1α-c in soleus muscle. The elevation of these gene mRNA expressions by 5-HT injection was inhibited by treatment with 5-HT receptor (5HTR) 2A or 7 antagonists. Our results demonstrate that peripheral 5-HT may play an important role in the relief of obesity and other metabolic disorders by accelerating energy consumption in skeletal muscle.

Serotonin Receptors in the Medulla Oblongata of the Human Fetus and Infant: The Analytic Approach of the International Safe Passage Study

PubMed Central

Folkerth, Rebecca D.; Paterson, David S.; Broadbelt, Kevin G.; Dan Zaharie, S.; Hewlett, Richard H.; Dempers, Johan J.; Burger, Elsie; Wadee, Shabbir; Schubert, Pawel; Wright, Colleen; Sens, Mary Ann; Nelsen, Laura; Randall, Bradley B.; Tran, Hoa; Geldenhuys, Elaine; Elliott, Amy J.; Odendaal, Hein J.; Kinney, Hannah C.

2016-01-01

The Safe Passage Study is an international, prospective study of approximately 12 000 pregnancies to determine the effects of prenatal alcohol exposure (PAE) upon stillbirth and the sudden infant death syndrome (SIDS). A key objective of the study is to elucidate adverse effects of PAE upon binding to serotonin (5-HT) 1A receptors in brainstem homeostatic networks postulated to be abnormal in unexplained stillbirth and/or SIDS. We undertook a feasibility assessment of 5-HT1A receptor binding using autoradiography in the medulla oblongata (6 nuclei in 27 cases). 5-HT1A binding was compared to a reference dataset from the San Diego medical examiner’s system. There was no adverse effect of postmortem interval ≤100 h. The distribution and quantitated values of 5-HT1A binding in Safe Passage Study cases were essentially identical to those in the reference dataset, and virtually identical between stillbirths and live born fetal cases in grossly non-macerated tissues. The pattern of binding was present at mid-gestation with dramatic changes in binding levels in the medullary 5-HT nuclei over the second half of gestation; there was a plateau at lower levels in the neonatal period and into infancy. This study demonstrates feasibility of 5-HT1A binding analysis in the medulla in the Safe Passage Study. PMID:27634962

What Gene Mutations Affect Serotonin in Mice?

PubMed

Tenpenny, Richard C; Commons, Kathryn G

2017-05-17

Although serotonin neurotransmission has been implicated in several neurodevelopmental and psychological disorders, the factors that drive dysfunction of the serotonin system are poorly understood. Current research regarding the serotonin system revolves around its dysfunction in neuropsychiatric disorders, but there is no database collating genetic mutations that result in serotonin abnormalities. To bridge this gap, we developed a list of genes in mice that, when perturbed, result in altered levels of serotonin either in brain or blood. Due to the intrinsic limitations of search, the current list should be considered a preliminary subset of all relevant cases. Nevertheless, it offered an opportunity to gain insight into what types of genes have the potential to impact serotonin by using gene ontology (GO). This analysis found that genes associated with monoamine metabolism were more often associated with increases in brain serotonin than decreases. Speculatively, this could be because several pathways (and therefore many genes) are responsible for the clearance and metabolism of serotonin whereas only one pathway (and therefore fewer genes) is directly involved in the synthesis of serotonin. Another contributor could be cross talk between monoamine systems such as dopamine. In contrast, genes that were associated with decreases in brain serotonin were more likely linked to a developmental process. Sensitivity of serotonin neurons to developmental perturbations could be due to their complicated neuroanatomy or possibly they may be negatively regulated by dysfunction of their innervation targets. Thus, these observations suggest hypotheses regarding the mechanisms underlying the vulnerability of brain serotonin neurotransmission.

Serotonergic modulation of the rat pup ultrasonic isolation call: studies with 5HT1 and 5HT2 subtype-selective agonists and antagonists.

PubMed

Winslow, J T; Insel, T R

1991-01-01

A modulatory role for serotonin has been described for the development and expression of the ultrasonic call of infant rat pups during brief maternal separations. In previous studies, serotonin reuptake inhibitors selectively reduced the rate of calling following acute administration to 9-11-day-old pups and a serotonin neurotoxin (MDMA) systematically disrupted the development of ultrasonic vocalizations but not other measures of motor development. In the current studies, we extended our investigations to include drugs with purported receptor subtype selectivities. Consistent with previous reports, acute administration of 5HT1A agonists buspirone and 8-OH-DPAT [+/-)-8-hydroxy-2-(di-N-propylamino)tetralin) reduced the rate of calling at doses which did not affect motor activity or core body temperature. The rate reducing effects of buspirone persisted up to 1 but not 2 h after injection. Administration of purported 5HT1B receptor agonists, CGS12066B (7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a] quinoxaline) and TFMPP (1-[3-fluoromethyl)phenyl]-piperazine) increased the rate of calling depending on the specificity of the drug for the 5HT1B receptor. d,l-Propranolol, a 5HT1 receptor antagonist, blocked the effects of both 8-OH-DPAT and TFMPP. m-CPP (1-(3-chlorophenyl)piperazine) and DOI [+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), drugs with putative actions at 5HT1C and 5HT2 receptor sites both decreased calling but differed according to their effects on motor activity. Ritanserin, a 5HT2 and 5HT1C antagonist, produced a dose-related increase in call rate. A dose of ritanserin with no apparent intrinsic effects effectively antagonized DOI rate reducing effects but potentiated the rate reducing effects of m-CPP.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced Vesicular Acetylcholine Transporter favors antidepressant behaviors and modulates serotonin and dopamine in female mouse brain.

PubMed

Pádua-Reis, Marina; Aquino, Nayara S; Oliveira, Vinícius E M; Szawka, Raphael E; Prado, Marco A M; Prado, Vânia F; Pereira, Grace S

2017-07-14

Depression is extremely harmful to modern society. Despite its complex spectrum of symptoms, previous studies have mostly focused on the monaminergic system in search of pharmacological targets. However, other neurotransmitter systems have also been linked to the pathophysiology of depression. In this study, we provide evidence for a role of the cholinergic system in depressive-like behavior of female mice. We evaluated mice knockdown for the vesicular acetylcholine transporter (VAChT KD mice), which have been previously shown to exhibit reduced cholinergic transmission. Animals were subjected to the tail suspension and marble burying tests, classical paradigms to assess depressive-like behaviors and to screen for novel antidepressant drugs. In addition, brain levels of serotonin and dopamine were measured by high performance liquid chromatography. We found that female homozygous VAChT KD mice spent less time immobile during tail suspension and buried less marbles, indicating a less depressive phenotype. These differences in behavior were reverted by central, but not peripheral, acetylcholinesterase inhibition. Moreover, female homozygous VAChT KD mice exhibited higher levels of dopamine and serotonin in the striatum, and increased dopamine in the hippocampus. Our study thus shows a connection between depressive-like behaviors and the cholinergic system, and that the latter interacts with the monoaminergic system. Copyright © 2017 Elsevier B.V. All rights reserved.

Preliminary evidence that sub-chronic citalopram triggers the re-evaluation of value in intimate partnerships.

PubMed

Bilderbeck, Amy C; Wakeley, Judi; Godlewska, Beata R; McGlone, Francis; Harris, Tirril; Cowen, Phillip J; Rogers, Robert D

2014-09-01

Depression frequently involves disrupted inter-personal relationships, while treatment with serotonergic anti-depressants can interfere with libido and sexual function. However, little is known about how serotonin activity influences appraisals of intimate partnerships. Learning more could help to specify how serotonergic mechanisms mediate social isolation in psychiatric illness. Forty-four healthy heterosexual adults, currently in romantic relationships, received 8 days treatment with the selective serotonin re-uptake inhibitor citalopram (N = 21; 10 male) or placebo (N = 23; 12 male). Participants viewed photographs of unknown, heterosexual couples and made a series of judgements about their relationships. Participants also indicated the importance of relationship features in their own close partnerships, and close partnerships generally. Citalopram reduced the rated quality of couples' physical relationships and the importance attributed to physical and intimate aspects of participants' own relationships. In contrast, citalopram also enhanced the evaluated worth of mutual trust in relationships. Amongst males, citalopram was associated with judgements of reduced turbulence and bickering in others' relationships, and increased male dominance. These data constitute preliminary evidence that enhancing serotonin activity modulates cognitions about sexual activity as part of a re-appraisal of sources of value within close intimate relationships, enhancing the judged importance of longer-term benefits of trust and shared experiences. © The Author (2013). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

The serotonin system in autism spectrum disorder: from biomarker to animal models

PubMed Central

Muller, Christopher L.; Anacker, Allison M.J.; Veenstra-VanderWeele, Jeremy

2015-01-01

Elevated whole blood serotonin, or hyperserotonemia, was the first biomarker identified in autism spectrum disorder (ASD) and is present in more than 25% of affected children. The serotonin system is a logical candidate for involvement in ASD due to its pleiotropic role across multiple brain systems both dynamically and across development. Tantalizing clues connect this peripheral biomarker with changes in brain and behavior in ASD, but the contribution of the serotonin system to ASD pathophysiology remains incompletely understood. Studies of whole blood serotonin levels in ASD and in a large founder population indicate greater heritability than for the disorder itself and suggest an association with recurrence risk. Emerging data from both neuroimaging and postmortem samples also indicate changes in the brain serotonin system in ASD. Genetic linkage and association studies of both whole blood serotonin levels and of ASD risk point to the chromosomal region containing the serotonin transporter (SERT) gene in males but not in females. In ASD families with evidence of linkage to this region, multiple rare SERT amino acid variants lead to a convergent increase in serotonin uptake in cell models. A knock-in mouse model of one of these variants, SERT Gly56Ala, recapitulates the hyperserotonemia biomarker and shows increased brain serotonin clearance, increased serotonin receptor sensitivity, and altered social, communication, and repetitive behaviors. Data from other rodent models also suggest an important role for the serotonin system in social behavior, in cognitive flexibility, and in sensory development. Recent work indicates that reciprocal interactions between serotonin and other systems, such as oxytocin, may be particularly important for social behavior. Collectively, these data point to the serotonin system as a prime candidate for treatment development in a subgroup of children defined by a robust, heritable biomarker. PMID:26577932

A gene-environment investigation on personality traits in two independent clinical sets of adult patients with personality disorder and attention deficit/hyperactive disorder.

PubMed

Jacob, Christian P; Nguyen, Thuy Trang; Dempfle, Astrid; Heine, Monika; Windemuth-Kieselbach, Christine; Baumann, Katarina; Jacob, Florian; Prechtl, Julian; Wittlich, Maike; Herrmann, Martin J; Gross-Lesch, Silke; Lesch, Klaus-Peter; Reif, Andreas

2010-06-01

While an interactive effect of genes with adverse life events is increasingly appreciated in current concepts of depression etiology, no data are presently available on interactions between genetic and environmental (G x E) factors with respect to personality and related disorders. The present study therefore aimed to detect main effects as well as interactions of serotonergic candidate genes (coding for the serotonin transporter, 5-HTT; the serotonin autoreceptor, HTR1A; and the enzyme which synthesizes serotonin in the brain, TPH2) with the burden of life events (#LE) in two independent samples consisting of 183 patients suffering from personality disorders and 123 patients suffering from adult attention deficit/hyperactivity disorder (aADHD). Simple analyses ignoring possible G x E interactions revealed no evidence for associations of either #LE or of the considered polymorphisms in 5-HTT and TPH2. Only the G allele of HTR1A rs6295 seemed to increase the risk of emotional-dramatic cluster B personality disorders (p = 0.019, in the personality disorder sample) and to decrease the risk of anxious-fearful cluster C personality disorders (p = 0.016, in the aADHD sample). We extended the initial simple model by taking a G x E interaction term into account, since this approach may better fit the data indicating that the effect of a gene is modified by stressful life events or, vice versa, that stressful life events only have an effect in the presence of a susceptibility genotype. By doing so, we observed nominal evidence for G x E effects as well as main effects of 5-HTT-LPR and the TPH2 SNP rs4570625 on the occurrence of personality disorders. Further replication studies, however, are necessary to validate the apparent complexity of G x E interactions in disorders of human personality.

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

PubMed Central

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

2012-01-01

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

Increase in expression of brain serotonin transporter and monoamine oxidase a genes induced by repeated experience of social defeats in male mice.

PubMed

Filipenko, M L; Beilina, A G; Alekseyenko, O V; Dolgov, V V; Kudryavtseva, N N

2002-04-01

Serotonin transporter and monoamine oxidase (MAO) A are involved in the inactivation of serotonin. The former is responsible for serotonin re-uptake from the synapse, whereas the latter catalyzes serotonin deamination in presynaptic terminals. Expression of serotonin transporter and MAO A genes was investigated in raphe nuclei of midbrain of CBA/Lac male mice with repeated experience of social victories or defeats in 10 daily aggressive confrontations. The amount of cDNA of these genes was evaluated using multiplex RT-PCR. Two independent experiments revealed that the defeated mice were characterized by significantly higher levels of serotonin transporter and MAO A mRNAs than the control and aggressive animals. Increased expression of MAO A and serotonin transporter genes is suggested to reflect the accelerated serotonin degradation in response to activation of the serotonergic system functioning induced by social stress. Significant positive correlation between MAO A and serotonin transporter mRNA levels suggests common pathways of regulation of transcriptional activity of these genes.

Oxytocin and Serotonin Brain Mechanisms in the Nonhuman Primate.

PubMed

Lefevre, Arthur; Richard, Nathalie; Jazayeri, Mina; Beuriat, Pierre-Aurélien; Fieux, Sylvain; Zimmer, Luc; Duhamel, Jean-René; Sirigu, Angela

2017-07-12

Oxytocin (OT) is increasingly studied for its therapeutic potential in psychiatric disorders, which are associated with the deregulation of several neurotransmission systems. Studies in rodents demonstrated that the interaction between OT and serotonin (5-HT) is critical for several aspects of social behavior. Using PET scan in humans, we have recently found that 5-HT 1A receptor (5-HT 1A R) function is modified after intranasal oxytocin intake. However, the underlying mechanism between OT and 5-HT remains unclear. To understand this interaction, we tested 3 male macaque monkeys using both [ 11 C]DASB and [ 18 F]MPPF, two PET radiotracers, marking the serotonin transporter and the 5-HT 1A R, respectively. Oxytocin (1 IU in 20 μl of ACSF) or placebo was injected into the brain lateral ventricle 45 min before scans. Additionally, we performed postmortem autoradiography. Compared with placebo, OT significantly reduced [ 11 C]DASB binding potential in right amygdala, insula, and hippocampus, whereas [ 18 F]MPPF binding potential increased in right amygdala and insula. Autoradiography revealed that [ 11 C]DASB was sensitive to physiological levels of 5-HT modification, and that OT does not act directly on the 5-HT 1A R. Our results show that oxytocin administration in nonhuman primates influences serotoninergic neurotransmission via at least two ways: (1) by provoking a release of serotonin in key limbic regions; and (2) by increasing the availability of 5-HT 1A R receptors in the same limbic areas. Because these two molecules are important for social behavior, our study sheds light on the specific nature of their interaction, therefore helping to develop new mechanisms-based therapies for psychiatric disorders. SIGNIFICANCE STATEMENT Social behavior is largely controlled by brain neuromodulators, such as oxytocin and serotonin. While these are currently targeted in the context of psychiatric disorders such as autism and schizophrenia, a new promising pharmaceutical strategy is to study the interaction between these systems. Here we depict the interplay between oxytocin and serotonin in the nonhuman primate brain. We found that oxytocin provokes the release of serotonin, which in turn impacts on the serotonin 1A receptor system, by modulating its availability. This happens in several key brain regions for social behavior, such as the amygdala and insula. This novel finding can open ways to advance treatments where drugs are combined to influence several neurotransmission networks. Copyright © 2017 the authors 0270-6474/17/376741-10$15.00/0.

[The serotonin syndrome. Fatal course of intoxication with citalopram and moclobemide].

PubMed

Cassens, S; Nickel, E A; Quintel, M; Neumann, P

2006-11-01

The serotonin syndrome is caused by a drug-induced increase of the intrasynaptic serotonin concentration. Milder forms of the syndrome may be difficult to diagnose because of the variability of symptoms. Severe forms often rapidly turn into a life-threatening situation, therefore the serotonin syndrome may be a challenge for physicians. We describe the pathophysiology and therapeutic options of the serotonin syndrome and report about a 42-year-old female patient who ingested large amounts of moclobemide, a monoamine oxidase inhibitor, and citalopram, a selective serotonin reuptake inhibitor, for attempted suicide. Within a few hours the patient developed a lethal serotonin syndrome although ICU therapy was initiated immediately.

The serotonin transporter plays an important role in male sexual behavior: a study in serotonin transporter knockout rats.

PubMed

Chan, Johnny S W; Snoeren, Eelke M S; Cuppen, Edwin; Waldinger, Marcel D; Olivier, Berend; Oosting, Ronald S

2011-01-01

Serotonin (5-HT) is an important neurotransmitter for sexual behaviors. Heterozygous (+/-) serotonin transporter (SERT) rats and SERT knockout rats (-/-) have serotonergic disturbances with significant elevations of basal extracellular 5-HT levels. To investigate the putative role of the SERT in male sexual behavior. After extensive sexual training, the effects of the 5-HT(1A/7) receptor agonist ± 8-OH-DPAT, the 5-HT(1A) receptor antagonist WAY100 635 and a combination of both on sexual behaviors of SERT(-/-) and SERT(+/-) knockout and wildtype (SERT(+/+) ) male Wistar rats were examined. Male rat sexual behaviors of mounts, intromissions, and ejaculations. SERT(-/-) had lower basal ejaculation frequencies than SERT(+/-) and SERT(+/+) animals. ± 8-OH-DPAT enhanced sexual performance in all three genotypes to the same extent. WAY100635 dose-dependently inhibited sexual behavior in all three genotypes with significant dose to genotype interactions. WAY100635 exerted the strongest effects in SERT(-/-) animals. The combination of a dose range of ± 8-OH-DPAT and a selected dose of WAY100635 revealed only partial antagonism by ± 8-OH-DPAT of the sexual inhibitory effects of WAY100635. Absence of the serotonin transporter reduces basal ejaculatory performance in male rats. Pharmacological experiments suggest that separate pools of 5-HT(1A) receptors regulate different aspects of sexual performance in male rats. 5-HT(7) receptors may play a minor role in the partial recovery of sexual behavior after combination of ± 8-OH-DPAT and WAY100635. The SERT(-/-) rat may be a model for chronic SSRI treatment, delayed ejaculation, anorgasmia, and/or low libido. © 2010 International Society for Sexual Medicine.

The pulmonary neuroendocrine system and drainage of the fetal lung: effects of serotonin.

PubMed

Chua, B A; Perks, A M

1999-03-01

The neuroendocrine system of the lungs is maximally developed and activated at birth, but has no clear function. Here, one of its products, serotonin, was tested for an ability to stop lung fluid production or activate reabsorption. Lungs from fetal guinea pigs (61 +/- 2 days of gestation) were supported in vitro for 3 h; lung liquid production was monitored by a dye dilution method. Initial studies on 36 young fetuses (61 +/- 1 days of gestation) showed that untreated controls produced fluid at 1.17 +/- 0.23 ml.kg-1.h-1, with no significant change over 3 h (ANOVA; regression analysis); those given 10(-8) M serotonin during the middle hour showed no significant changes, but those given 5 x 10(-8), 10(-7), 10(-6), or 10(-5) M serotonin reduced production significantly (P < 0.01 to P < 0.0005). Responses were linear up to 10(-7) M (threshold, 10(-9) M) and then become maximal at 50% reduction. However, responses increased with age. Comparison of 40 fetuses divided into groups of 60-61 or 65-67 days of gestation showed a large and significant increase in responses in the older fetuses (P < 0.01), where half the preparations reabsorbed fluid. Serotonin receptors were involved, since 10(-6) M cyproheptadine abolished responses (based on 24 preparations). Amiloride-sensitive Na+ channels were involved, since 10(-6) M amiloride abolished responses (based on 24 preparations). These results, in combination with earlier results from somatostatin and dopamine, together with histochemical and clinical observations, strongly suggest that the neuroendocrine system of the lungs may find a function in clearing fluid from the lungs at time of birth. Copyright 1999 Academic Press.

The Effect of Citalopram on Midbrain CRF Receptors 1 and 2 in a Primate Model of Stress-Induced Amenorrhea

PubMed Central

Senashova, Olga; Reddy, Arubala P.; Cameron, Judy L.; Bethea, Cynthia L.

2012-01-01

We have demonstrated marked differences in the neurobiology of the serotonin system between stress-sensitive (SS) and stress-resilient (SR) cynomolgus macaques characterized in a model of stress-induced amenorrhea, also called functional hypothalamic amenorrhea (FHA). Dysfunction of the serotonin system in SS monkeys suggested that administration of a selective serotonin reuptake inhibitor (SSRI) might correct FHA. This study examines the effect of escitalopram (CIT) administration to SS and SR monkeys on corticotrophin-releasing factor (CRF) receptor 1 (CRF-R1) and CRF receptor 2 (CRF-R2) gene expression in the serotonin cell body region of the midbrain dorsal raphe. CRF-R1 was not significantly different between groups. There was a significant effect of treatment and a significant interaction between treatment and stress sensitivity on the average CRF-R2-positive pixel area (P < .004 and P < .006, respectively) and on the average number of CRF-R2-positive cells (P < .023 and P < .025, respectively). CIT significantly increased CRF-R2-positive pixel area and cell number in the SS group (pixel area P < .001; cell number P < .01; Bonferoni) but not in the SR group. In summary, CIT administration tended to decrease CRF-R1, but the small animal number precluded significance. CIT administration significantly increased CRF-R2 only in SS animals. These data suggest that the administration of CIT reduces anxiogenic components and increases anxiolytic components of the CRF system in the midbrain serotonin network, which in turn leads to improved ovarian function. Moreover, these data raise the possibility that SSRIs may be effective in the treatment of stress-induced infertility. PMID:22412189

Profiling of tryptophan-related plasma indoles in patients with carcinoid tumors by automated, on-line, solid-phase extraction and HPLC with fluorescence detection.

PubMed

Kema, I P; Meijer, W G; Meiborg, G; Ooms, B; Willemse, P H; de Vries, E G

2001-10-01

Profiling of the plasma indoles tryptophan, 5-hydroxytryptophan (5-HTP), serotonin, and 5-hydroxyindoleacetic acid (5-HIAA) is useful in the diagnosis and follow-up of patients with carcinoid tumors. We describe an automated method for the profiling of these indoles in protein-containing matrices as well as the plasma indole concentrations in healthy controls and patients with carcinoid tumors. Plasma, cerebrospinal fluid, and tissue homogenates were prepurified by automated on-line solid-phase extraction (SPE) in Hysphere Resin SH SPE cartridges containing strong hydrophobic polystyrene resin. Analytes were eluted from the SPE cartridge by column switching. Subsequent separation and detection were performed by reversed-phase HPLC combined with fluorometric detection in a total cycle time of 20 min. We obtained samples from 14 healthy controls and 17 patients with metastasized midgut carcinoid tumors for plasma indole analysis. In the patient group, urinary excretion of 5-HIAA and serotonin was compared with concentrations of plasma indoles. Within- and between-series CVs for indoles in platelet-rich plasma were 0.6-6.2% and 3.7-12%, respectively. Results for platelet-rich plasma serotonin compared favorably with those obtained by single-component analysis. Plasma 5-HIAA, but not 5-HTP was detectable in 8 of 17 patients with carcinoid tumors. In the patient group, platelet-rich plasma total tryptophan correlated negatively with platelet-rich plasma serotonin (P = 0.021; r = -0.56), urinary 5-HIAA (P = 0.003; r = -0.68), and urinary serotonin (P <0.0001; r = -0.80). The present chromatographic approach reduces analytical variation and time needed for analysis and gives more detailed information about metabolic deviations in indole metabolism than do manual, single-component analyses.

Traumatic injury induces changes in the expression of the serotonin 1A receptor in the spinal cord of lampreys.

PubMed

Cornide-Petronio, María Eugenia; Fernández-López, Blanca; Barreiro-Iglesias, Antón; Rodicio, María Celina

2014-02-01

After spinal cord injury (SCI) in mammals, the loss of serotonin coming from the brainstem reduces the excitability of motor neurons and leads to a compensatory overexpression of serotonin receptors. Despite the key role of the serotonin receptor 1a in the control of locomotion, little attention has been put in the study of this receptor after SCI. In contrast to mammals, lampreys recover locomotion after a complete SCI, so, studies in this specie could help to understand events that lead to recovery of function. Here, we showed that in lampreys there is an acute increase in the expression of the serotonin 1A receptor transcript (5-ht1a) after SCI and a few weeks later expression levels go back to normal rostrally and caudally to the lesion. Overexpression of the 5-ht1a in rostral levels after SCI has not been reported in mammals, suggesting that this could be part of the plastic events that lead to the recovery of function in lampreys. The analysis of changes in 5-ht1a expression by zones (periventricular region and horizontally extended grey matter) showed that they followed the same pattern of changes detected in the spinal cord as a whole, with the exception of the caudal periventricular layer, where no significant differences were observed between control and experimental animals at any time post lesion. This suggests that different molecular signals act on the periventricular cells of the rostral and caudal regions to injury site and thus affecting their response to the injury in terms of expression of the 5-ht1a.

Effects of Silexan on the Serotonin-1A Receptor and Microstructure of the Human Brain: A Randomized, Placebo-Controlled, Double-Blind, Cross-Over Study with Molecular and Structural Neuroimaging

PubMed Central

Baldinger, Pia; Höflich, Anna S.; Mitterhauser, Markus; Hahn, Andreas; Rami-Mark, Christina; Spies, Marie; Wadsak, Wolfgang; Lanzenberger, Rupert

2015-01-01

Background: Recently, Silexan, a patented active substance comprised of an essential oil produced from Lavandula angustifolia flowers, has been authorized in Germany as a medicinal product for the treatment of states of restlessness related to anxious mood. Its efficacy has been shown in several forms of anxiety disorders. Findings from preclinical and clinical studies attribute a major role to the serotonin-1A receptor in the pathogenesis and treatment of anxiety. Methods: To elucidate the effect of Silexan on serotonin-1A receptor binding, 17 healthy men underwent 2 positron emission tomography measurements using the radioligand [carbonyl-11C]WAY-100635 following the daily intake of 160mg Silexan or placebo for a minimum of 8 weeks (randomized, double-blind, cross-over design). Additionally, structural magnetic resonance imaging and voxel-based morphometry analysis was performed to determine potential effects on gray matter microstructure. Results: Serotonin-1A receptor binding potential was shown to be significantly reduced following the intake of Silexan compared with placebo in 2 large clusters encompassing the temporal gyrus, the fusiform gyrus and the hippocampus on one hand as well as the insula and anterior cingulate cortex on the other hand. No effects of Silexan on gray matter volume could be detected in this investigation. Conclusion: This positron emission tomography study proposes an involvement of the serotonin-1A receptor in the anxiolytic effects of Silexan. The study was registered in the International Standard Randomized Controlled Trial Number Register as ISRCTN30885829 (http://www.controlled-trials.com/isrctn/). PMID:25522403

The effect of early trauma exposure on serotonin type 1B receptor expression revealed by reduced selective radioligand binding.

PubMed

Murrough, James W; Czermak, Christoph; Henry, Shannan; Nabulsi, Nabeel; Gallezot, Jean-Dominique; Gueorguieva, Ralitza; Planeta-Wilson, Beata; Krystal, John H; Neumaier, John F; Huang, Yiyun; Ding, Yu-Shin; Carson, Richard E; Neumeister, Alexander

2011-09-01

Serotonergic dysfunction is implicated in the pathogenesis of posttraumatic stress disorder (PTSD), and recent animal models suggest that disturbances in serotonin type 1B receptor function, in particular, may contribute to chronic anxiety. However, the specific role of the serotonin type 1B receptor has not been studied in patients with PTSD. To investigate in vivo serotonin type 1B receptor expression in individuals with PTSD, trauma-exposed control participants without PTSD (TC), and healthy (non-trauma-exposed) control participants (HC) using positron emission tomography and the recently developed serotonin type 1B receptor selective radiotracer [(11)C]P943. Cross-sectional positron emission tomography study under resting conditions. Academic and Veterans Affairs medical centers. Ninety-six individuals in 3 study groups: PTSD (n = 49), TC (n = 20), and HC (n = 27). Main Outcome Measure  Regional [(11)C]P943 binding potential (BP(ND)) values in an a priori-defined limbic corticostriatal circuit investigated using multivariate analysis of variance and multiple regression analysis. A history of severe trauma exposure in the PTSD and TC groups was associated with marked reductions in [(11)C]P943 BP(ND) in the caudate, the amygdala, and the anterior cingulate cortex. Participant age at first trauma exposure was strongly associated with low [(11)C]P943 BP(ND). Developmentally earlier trauma exposure also was associated with greater PTSD symptom severity and major depression comorbidity. These data suggest an enduring effect of trauma history on brain function and the phenotype of PTSD. The association of early age at first trauma and more pronounced neurobiological and behavioral alterations in PTSD suggests a developmental component in the cause of PTSD.

Indoleamines and calcium channels influence morphogenesis in in vitro cultures of Mimosa pudica L.

PubMed Central

Ramakrishna, Akula; Giridhar, Parvatam

2009-01-01

The present article reports the interplay of indoleamine neurohormones viz. serotonin, melatonin and calcium channels on shoot organogenesis in Mimosa pudica L. In vitro grown nodal segments were cultured on MS medium with B5 vitamins containing Serotonin (SER) and Melatonin (MEL) at 100 µM and indoleamine inhibitors viz. serotonin to melatonin conversion inhibitor p-chlorophenylalanine (p-CPA) at 40 µM, serotonin reuptake inhibitor (Prozac) 20 µM. In another set of experiment, calcium at 5 mM, calcium ionophore (A23187) 100 µM, and calcium channel blocker varapamil hydrochloride (1 mM) a calcium chelator EGTA (100 µM) were administered to the culture medium. The percentage of shoot multiplication, endogenous MEL and SER were monitored during shoot organogenesis. At 100 µM SER and MEL treatment 60% and 70% explants responded for shoot multiplication respectively. Medium supplemented with either SER or MEL along with calcium (5 mM) 75%–80% explants responded for organogenesis. SER or MEL along with calcium ionophore (A23187) at 100 µM 70% explants responded for shoot multiplication. p-CPA, prozac, verapamil and EGTA, shoot multiplication was reduced and endogenous pools of SER, MEL decreased by 40–70%. The results clearly demonstrated that indoleamines and calcium channels positively influenced shoot organogenesis in M. pudica L. PMID:20514228

Serotonin Modulation of Prefronto-Hippocampal Rhythms in Health and Disease.

PubMed

Puig, M Victoria; Gener, Thomas

2015-07-15

There is mounting evidence that most cognitive functions depend upon the coordinated activity of neuronal networks often located far from each other in the brain. Ensembles of neurons synchronize their activity, generating oscillations at different frequencies that may encode behavior by allowing an efficient communication between brain areas. The serotonin system, by virtue of the widespread arborisation of serotonergic neurons, is in an excellent position to exert strong modulatory actions on brain rhythms. These include specific oscillatory activities in the prefrontal cortex and the hippocampus, two brain areas essential for many higher-order cognitive functions. Psychiatric patients show abnormal oscillatory activities in these areas, notably patients with schizophrenia who display psychotic symptoms as well as affective and cognitive impairments. Synchronization of neural activity between the prefrontal cortex and the hippocampus seems to be important for cognition and, in fact, reduced prefronto-hippocampal synchrony has been observed in a genetic mouse model of schizophrenia. Here, we review recent advances in the field of neuromodulation of brain rhythms by serotonin, focusing on the actions of serotonin in the prefrontal cortex and the hippocampus. Considering that the serotonergic system plays a crucial role in cognition and mood and is a target of many psychiatric treatments, it is surprising that this field of research is still in its infancy. In that regard, we point to future investigations that are much needed in this field.

Protective propensity of bacoside A and bromelain on renal cholinesterases, γ-Aminobutyric acid and serotonin level of Mus musculus intoxicated with dichlorvos.

PubMed

Agarwal, Sonam; Chaudhary, Bharti; Bist, Renu

2017-01-05

Current study established a protective action of bacoside A and bromelain against the toxic effects of dichlorvos in kidneys of mice. Experimental design included five groups. The first group was control. Mice of groups II, III and IV were administered doses of dichlorvos, bromelain and bacoside A respectively. In group V, mice were treated with both the antioxidants (bacoside A and bromelain) and dichlorvos. After 21 days of exposure of different doses, levels of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), γ-aminobutyric acid (GABA) and serotonin were measured in renal tissues. Dichlorvos significantly reduced the kidney AChE (p < 0.001), BChE (p < 0.01) and GABA level (p < 0.01) compared to control. A simultaneous significant elevation in the serotonin level (p < 0.01) was recorded after dichlorvos exposure. Concomitant exposure of bacoside A and bromelain followed by dichlorvos treatment in group V not only restored, but increased the renal cholinesterases and GABA level. Meanwhile, a significant decline in serotonin level (p < 0.001) was revealed, compared to dichlorvos exposed mice. Bacoside A and bromelain occupy a tremendous antioxidant action in the mice kidneys and a combination of the same ameliorates the renal toxicity induced by dichlorvos. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Effects of T'ai Chi on Serotonin, Nicotine Dependency, Depression, and Anger in Hospitalized Alcohol-Dependent Patients.

PubMed

Oh, Chung-Uk; Kim, Nam-Cho

2016-12-01

The aim of this study was to investigate the effects of t'ai chi on blood serotonin levels, nicotine dependence, depression, and anger in hospitalized alcohol-dependent patients. This study followed an experimental and nonequivalent control group in a non-synchronized design. It was performed in a hospital located in Young Ju city, Korea, from April to August 2013. Thirty-eight patients who were hospitalized with alcohol dependence were included. They were randomly divided into an experimental and a control group, with 19 patients in each group. Patients in the experimental group practiced the 24-posture yang style t'ai chi for 50 min three times per week for 8 weeks as part of the routine hospital rehabilitation program, and those in the control group followed only the routine hospital rehabilitation program. The effect of treatment was measured using blood serotonin levels and a questionnaire on nicotine dependence, depression, and anger. Both measurements were performed before and after 8 weeks of intervention. Data were analyzed using the t-test, chi-square test, and paired t-tests. The experimental group showed a significantly increased blood serotonin level (p = 0.001) and significantly reduced nicotine dependence, depression, and anger (p = 0.001) than the control group did after 8 weeks of treatment. T'ai chi was shown to be an effective nursing intervention in hospitalized alcohol-dependent patients.

The role of serotonin in nonnormative risky choice: the effects of tryptophan supplements on the "reflection effect" in healthy adult volunteers.

PubMed

Murphy, Susannah E; Longhitano, Carlo; Ayres, Rachael E; Cowen, Philip J; Harmer, Catherine J; Rogers, Robert D

2009-09-01

Risky decision-making involves weighing good and bad outcomes against their probabilities in order to determine the relative values of candidate actions. Although human decision-making sometimes conforms to rational models of how this weighting is achieved, irrational (or nonnormative) patterns of risky choice, including shifts between risk-averse and risk-seeking choices involving equivalent-value gambles (the "reflection effect"), are frequently observed. In the present experiment, we investigated the role of serotonin in decision-making under conditions of uncertainty. Fifteen healthy adult volunteers received a treatment of 3 g per day of the serotonin precursor, tryptophan, in the form of dietary supplements over a 14-day period, whereas 15 age- and IQ-matched control volunteers received a matched placebo substance. At test, all participants completed a risky decision-making task involving a series of choices between two simultaneously presented gambles, differing in the magnitude of their possible gains, the magnitude of their possible losses, and the probabilities with which these outcomes were delivered. Tryptophan supplements were associated with alterations in the weighting of gains and small losses perhaps reflecting reduced loss-aversion, and a marked and significant diminution of the reflection effect. We conclude that serotonin activity plays a significant role in nonnormative risky decision-making under conditions of uncertainty.

Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors.

PubMed

Carter, Olivia L; Burr, David C; Pettigrew, John D; Wallis, Guy M; Hasler, Felix; Vollenweider, Franz X

2005-10-01

Increasing evidence suggests a link between attention, working memory, serotonin (5-HT), and prefrontal cortex activity. In an attempt to tease out the relationship between these elements, this study tested the effects of the hallucinogenic mixed 5-HT1A/2A receptor agonist psilocybin alone and after pretreatment with the 5-HT2A antagonist ketanserin. Eight healthy human volunteers were tested on a multiple-object tracking task and spatial working memory task under the four conditions: placebo, psilocybin (215 microg/kg), ketanserin (50 mg), and psilocybin and ketanserin. Psilocybin significantly reduced attentional tracking ability, but had no significant effect on spatial working memory, suggesting a functional dissociation between the two tasks. Pretreatment with ketanserin did not attenuate the effect of psilocybin on attentional performance, suggesting a primary involvement of the 5-HT1A receptor in the observed deficit. Based on physiological and pharmacological data, we speculate that this impaired attentional performance may reflect a reduced ability to suppress or ignore distracting stimuli rather than reduced attentional capacity. The clinical relevance of these results is also discussed.

Reducing Anxiety in Stutterers through the Association between “Purpose in Life/Ikigai” and Emotions

PubMed Central

Ishida, Riichiro

2012-01-01

The prefrontal lobe is more evolved in humans than in other mammals. The functioning of human prefrontal lobes promotes an innate need to establish a meaningful life, often referred to as “Purpose in life (PIL)/ikigai.” PIL/ikigai and the prefrontal lobe psychologically and physiologically, respectively, shape ambition, regulate the development of emotions and integrate psychological events. PIL/ikigai contributes to both a reduction in the anxiety caused by a need for approval from others and the stimulation of pleasure and comfort, which may be related to the well-balanced secretion of neurotransmitters such as serotonin, dopamine, and β-endorphin. Thus, if a stutterer aware that articulate speech is advantageous in communication feels a need for social desirability (SD) based on a need for approval from others, they may develop stress and anxiety caused by their perceived failure when engaging in conversations. This feeling of failure may be related to an imbalanced secretion of serotonin and dopamine. Therefore, previous work has suggested that PIL/ikigai may reduce anxiety in stutterers who seek SD by reducing the symptoms associated with stuttering. PMID:22980384

Genetics Home Reference: dopa-responsive dystonia

MedlinePlus

... neurotransmitters called dopamine and serotonin. Among their many functions, dopamine transmits signals within the brain to produce smooth ... production of a tyrosine hydroxylase enzyme with reduced function, which leads to a decrease in dopamine production. A reduction in the amount of dopamine ...

FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin

PubMed Central

Kode, Aruna; Mosialou, Ioanna; Silva, Barbara C.; Rached, Marie-Therese; Zhou, Bin; Wang, Ji; Townes, Tim M.; Hen, Rene; DePinho, Ronald A.; Guo, X. Edward; Kousteni, Stavroula

2012-01-01

Serotonin is a critical regulator of bone mass, fulfilling different functions depending on its site of synthesis. Brain-derived serotonin promotes osteoblast proliferation, whereas duodenal-derived serotonin suppresses it. To understand the molecular mechanisms of duodenal-derived serotonin action on osteoblasts, we explored its transcriptional mediation in mice. We found that the transcription factor FOXO1 is a crucial determinant of the effects of duodenum-derived serotonin on bone formation We identified two key FOXO1 complexes in osteoblasts, one with the transcription factor cAMP-responsive element–binding protein 1 (CREB) and another with activating transcription factor 4 (ATF4). Under normal levels of circulating serotonin, the proliferative activity of FOXO1 was promoted by a balance between its interaction with CREB and ATF4. However, high circulating serotonin levels prevented the association of FOXO1 with CREB, resulting in suppressed osteoblast proliferation. These observations identify FOXO1 as the molecular node of an intricate transcriptional machinery that confers the signal of duodenal-derived serotonin to inhibit bone formation. PMID:22945629

Molecular fMRI of Serotonin Transport.

PubMed

Hai, Aviad; Cai, Lili X; Lee, Taekwan; Lelyveld, Victor S; Jasanoff, Alan

2016-11-23

Reuptake of neurotransmitters from the brain interstitium shapes chemical signaling processes and is disrupted in several pathologies. Serotonin reuptake in particular is important for mood regulation and is inhibited by first-line drugs for treatment of depression. Here we introduce a molecular-level fMRI technique for micron-scale mapping of serotonin transport in live animals. Intracranial injection of an MRI-detectable serotonin sensor complexed with serotonin, together with serial imaging and compartmental analysis, permits neurotransmitter transport to be quantified as serotonin dissociates from the probe. Application of this strategy to much of the striatum and surrounding areas reveals widespread nonsaturating serotonin removal with maximal rates in the lateral septum. The serotonin reuptake inhibitor fluoxetine selectively suppresses serotonin removal in septal subregions, whereas both fluoxetine and a dopamine transporter blocker depress reuptake in striatum. These results highlight promiscuous pharmacological influences on the serotonergic system and demonstrate the utility of molecular fMRI for characterization of neurochemical dynamics. Copyright © 2016 Elsevier Inc. All rights reserved.

Plasma serotonin level is a predictor for recurrence and poor prognosis in colorectal cancer patients.

PubMed

Xia, Yan; Wang, Dawei; Zhang, Nan; Wang, Zhihao; Pang, Li

2018-02-01

To investigate the prognostic value of plasma serotonin levels in colorectal cancer (CRC). Preoperative plasma serotonin levels of 150 healthy control (HC) cases, 150 benign colorectal polyp (BCP) cases, and 176 CRC cases were determined using radioimmunoassay assay. Serotonin levels were compared between HC, BCP, and CRC cases, and those in CRC patients were related to 5-year outcome. Plasma serotonin levels were markedly higher in CRC patients than in either HCs or BCP cases. An elevated serotonin level was significantly associated with advanced tumor node metastasis. Receiver operating characteristic curve analysis showed that the level of serotonin had a high predictive value for disease recurrence and mortality. Multivariate analysis revealed that high serotonin level was significantly associated with poor recurrence-free survival and overall survival. Our results suggest that a high peri-operative plasma serotonin level is useful as a prognostic biomarker for CRC recurrence and poor survival. © 2017 Wiley Periodicals, Inc.

Multiple mechanisms of serotonin 5-HT2 receptor desensitization.

PubMed

Rahman, S; Neuman, R S

1993-07-20

Desensitization of serotonin 5-HT2 receptor-mediated enhancement of the N-methyl-D-aspartate (NMDA) depolarization was studied in rat cortical neurons. Serotonin and (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induced long term desensitization. Staurosporine, a nonspecific protein kinase C inhibitor, potentiated the serotonin and DOI facilitation, suggesting acute desensitization was operative. In the case of DOI, long term desensitization was prevented by staurosporine. Activators of protein kinase C abolished the serotonin facilitation, an action prevented by staurosporine. Concanavalin A potentiated the facilitation at 100 microM, but not 30 microM serotonin, suggesting these receptors undergo dose dependent internalization. Calmodulin antagonists prevent long term desensitization induced by serotonin. The depolarization induced by NMDA alone was not altered by staurosporine, protein kinase C activators, concanavalin A or calmodulin antagonists. Serotonin at 100 microM, but not 30 microM, induced heterologous desensitization of phenylephrine and carbachol induced facilitation of the NMDA depolarization. We conclude that serotonin 5-HT2 receptors both induce and undergo several forms of desensitization.

Multiple receptor subtypes mediate the effects of serotonin on rat subfornical organ neurons

NASA Technical Reports Server (NTRS)

Scrogin, K. E.; Johnson, A. K.; Schmid, H. A.

1998-01-01

The subfornical organ (SFO) receives significant serotonergic innervation. However, few reports have examined the functional effects of serotonin on SFO neurons. This study characterized the effects of serotonin on spontaneously firing SFO neurons in the rat brain slice. Of 31 neurons tested, 80% responded to serotonin (1-100 microM) with either an increase (n = 15) or decrease (n = 10) in spontaneous activity. Responses to serotonin were dose dependent and persisted after synaptic blockade. Excitatory responses could also be mimicked by the 5-hydroxytryptamine (5-HT)2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI; 1-10 microM) and could be blocked by the 5-HT2A/2C-receptor antagonist LY-53,857 (10 microM). LY-53,857 unmasked inhibitory responses to serotonin in 56% of serotonin-excited cells tested. Serotonin-inhibited cells were also inhibited by the 5-HT1A-receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT; 1-10 microM; n = 7). The data indicate that SFO neurons are responsive to serotonin via postsynaptic activation of multiple receptor subtypes. The results suggest that excitatory responses to serotonin are mediated by 5-HT2A or 5-HT2C receptors and that inhibitory responses may be mediated by 5-HT1A receptors. In addition, similar percentages of serotonin-excited and -inhibited cells were also sensitive to ANG II. As such the functional relationship between serotonin and ANG II in the SFO remains unclear.

Multiple receptor subtypes mediate the effects of serotonin on rat subfornical organ neurons.

PubMed

Scrogin, K E; Johnson, A K; Schmid, H A

1998-12-01

The subfornical organ (SFO) receives significant serotonergic innervation. However, few reports have examined the functional effects of serotonin on SFO neurons. This study characterized the effects of serotonin on spontaneously firing SFO neurons in the rat brain slice. Of 31 neurons tested, 80% responded to serotonin (1-100 microM) with either an increase (n = 15) or decrease (n = 10) in spontaneous activity. Responses to serotonin were dose dependent and persisted after synaptic blockade. Excitatory responses could also be mimicked by the 5-hydroxytryptamine (5-HT)2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI; 1-10 microM) and could be blocked by the 5-HT2A/2C-receptor antagonist LY-53,857 (10 microM). LY-53,857 unmasked inhibitory responses to serotonin in 56% of serotonin-excited cells tested. Serotonin-inhibited cells were also inhibited by the 5-HT1A-receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT; 1-10 microM; n = 7). The data indicate that SFO neurons are responsive to serotonin via postsynaptic activation of multiple receptor subtypes. The results suggest that excitatory responses to serotonin are mediated by 5-HT2A or 5-HT2C receptors and that inhibitory responses may be mediated by 5-HT1A receptors. In addition, similar percentages of serotonin-excited and -inhibited cells were also sensitive to ANG II. As such the functional relationship between serotonin and ANG II in the SFO remains unclear.

Lorcaserin in Obese and Overweight Patients Taking Prohibited Serotonergic Agents: A Retrospective Analysis.

PubMed

Nguyen, Charles T; Zhou, Sharon; Shanahan, William; Fain, Randi

2016-06-01

Lorcaserin is a selective serotonin 2C receptor (5-HT2C) agonist approved in the United States for use in chronic weight management as an adjunct to a reduced-calorie diet and increased physical activity. Its pharmacologic activity is limited to 5-HT subtype 2 receptors. The potency of lorcaserin for the 5-HT2C receptor is 14-fold greater than its potency for the 5-HT2A receptor and 61-fold greater than its potency for the 5-HT2B receptor. Although 5-HT receptors have been implicated in serotonin syndrome, the precise pathogenesis is unknown. Given a theoretic risk for this syndrome in patients administered lorcaserin either alone or in combination with certain serotonergic agents (eg, selective serotonin reuptake inhibitors [SSRIs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]), patients taking prohibited serotonergic agents were excluded from the Phase III clinical trials. This retrospective analysis evaluated the tolerability of lorcaserin in patients who took protocol-allowed or proscribed serotonergic agents for varying durations of up to 1 year during the BLOOM, BLOSSOM, and BLOOM-DM studies. Patients randomly assigned to receive either lorcaserin 10 mg QD, lorcaserin 10 mg BID, or placebo and who took a spectrum of serotonergic agents were evaluated at week 52 of treatment (814 and 624 patients receiving lorcaserin and placebo, respectively, were found to have taken allowed or prohibited serotonergic agents during these trials). After the use of a proscribed serotonergic agent was discovered, these patients were discontinued from the trial and followed. None of the patients in the serotonergic agent subpopulation or in the overall safety population met the clinical criteria of serotonin syndrome. The proportions of patients experiencing any adverse event (AE) were balanced in the lorcaserin and placebo groups in the prohibited serotonergic agent subpopulation. The prevalences of the most common AEs were similar between the serotonergic agent subpopulation and the overall safety population. The concurrent use of lorcaserin and prohibited or allowed serotonergic agents did not appear to have increased the spectrum or intensity of AEs potentially associated with serotonin excess in this limited dataset. However, the sample population was too small to rule out an effect on a rare event such as serotonin syndrome. ClinicalTrials.gov identifiers: NCT00395135, NCT00603902, and NCT00603291. Published by Elsevier Inc.

Stimulation of aortic smooth muscle cell mitogenesis by serotonin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nemecek, G.M.; Coughlin, S.R.; Handley, D.A.

1986-02-01

Bovine aortic smooth muscle cells in vitro responded to 1 nM to 10 ..mu..M serotonin with increased incorporation of (/sup 3/H)thymidine into DNA. The mitogenic effect of serotonin was half-maximal at 80 nM and maximal above 1 ..mu..M. At a concentration of 1 ..mu..M, serotonin stimulated smooth muscle cell mitogenesis to the same extent as human platelet-derived growth factor (PDGF) at 12 ng/ml. Tryptamine was approx. = 1/10th as potent as serotonin as a mitogen for smooth muscle cells. Other indoles that are structurally related to serotonin (D- and L-tryptophan, 5-hydroxy-L-tryptophan, N-acetyl-5-hydroxytryptamine, melatonin, 5-hydroxyindoleacetic acid, and 5-hydroxytryptophol) and quipazine weremore » inactive. The stimulatory effect of serotonin on smooth muscle cell DNA synthesis required prolonged (20-24 hr) exposure to the agonist and was attenuated in the presence of serotonin D receptor antagonists. When smooth muscle cells were incubated with submaximal concentrations of serotonin and PDGF, synergistic rather than additive mitogenic responses were observed. These data indicate that serotonin has a significant mitogenic effect on smooth muscle cells in vitro, which appears to be mediated by specific plasma membrane receptors.« less

How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systems.

PubMed

Murphy, Dennis L; Fox, Meredith A; Timpano, Kiara R; Moya, Pablo R; Ren-Patterson, Renee; Andrews, Anne M; Holmes, Andrew; Lesch, Klaus-Peter; Wendland, Jens R

2008-11-01

Discovered and crystallized over sixty years ago, serotonin's important functions in the brain and body were identified over the ensuing years by neurochemical, physiological and pharmacological investigations. This 2008 M. Rapport Memorial Serotonin Review focuses on some of the most recent discoveries involving serotonin that are based on genetic methodologies. These include examples of the consequences that result from direct serotonergic gene manipulation (gene deletion or overexpression) in mice and other species; an evaluation of some phenotypes related to functional human serotonergic gene variants, particularly in SLC6A4, the serotonin transporter gene; and finally, a consideration of the pharmacogenomics of serotonergic drugs with respect to both their therapeutic actions and side effects. The serotonin transporter (SERT) has been the most comprehensively studied of the serotonin system molecular components, and will be the primary focus of this review. We provide in-depth examples of gene-based discoveries primarily related to SLC6A4 that have clarified serotonin's many important homeostatic functions in humans, non-human primates, mice and other species.

Mutations in monoamine oxidase (MAO) genes in mice lead to hypersensitivity to serotonin-enhancing drugs: implications for drug side effects in humans.

PubMed

Fox, M A; Panessiti, M G; Moya, P R; Tolliver, T J; Chen, K; Shih, J C; Murphy, D L

2013-12-01

A possible side effect of serotonin-enhancing drugs is the serotonin syndrome, which can be lethal. Here we examined possible hypersensitivity to two such drugs, the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) and the atypical opioid tramadol, in mice lacking the genes for both monoamine oxidase A (MAOA) and MAOB. MAOA/B-knockout (KO) mice displayed baseline serotonin syndrome behaviors, and these behavioral responses were highly exaggerated following 5-HTP or tramadol versus baseline and wild-type (WT) littermates. Compared with MAOA/B-WT mice, baseline tissue serotonin levels were increased ∼2.6-3.9-fold in MAOA/B-KO mice. Following 5-HTP, serotonin levels were further increased ∼4.5-6.2-fold in MAOA/B-KO mice. These exaggerated responses are in line with the exaggerated responses following serotonin-enhancing drugs that we previously observed in mice lacking the serotonin transporter (SERT). These findings provide a second genetic mouse model suggestive of possible human vulnerability to the serotonin syndrome in individuals with lesser-expressing MAO or SERT polymorphisms that confer serotonergic system changes.

Mutations in monoamine oxidase (MAO) genes in mice lead to hypersensitivity to serotonin-enhancing drugs: implications for drug side effects in humans

PubMed Central

Fox, MA; Panessiti, MG; Moya, PR; Tolliver, TJ; Chen, K; Shih, JC; Murphy, DL

2012-01-01

A possible side effect of serotonin-enhancing drugs is the serotonin syndrome, which can be lethal. Here we examined possible hypersensitivity to two such drugs, the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) and the atypical opioid tramadol, in mice lacking the genes for both monoamine oxidase A (MAOA) and MAOB. MAOA/B-knockout (KO) mice displayed baseline serotonin syndrome behaviors, and these behavioral responses were highly exaggerated following 5-HTP or tramadol versus baseline and wild-type (WT) littermates. Compared with MAOA/B-WT mice, baseline tissue serotonin levels were increased ~2.6–3.9-fold in MAOA/B-KO mice. Following 5-HTP, serotonin levels were further increased ~4.5–6.2-fold in MAOA/B-KO mice. These exaggerated responses are in line with the exaggerated responses following serotonin-enhancing drugs that we previously observed in mice lacking the serotonin transporter (SERT). These findings provide a second genetic mouse model suggestive of possible human vulnerability to the serotonin syndrome in individuals with lesser-expressing MAO or SERT polymorphisms that confer serotonergic system changes. PMID:22964922

Nutrient-induced glucagon like peptide-1 release is modulated by serotonin.

PubMed

Ripken, Dina; van der Wielen, Nikkie; Wortelboer, Heleen M; Meijerink, Jocelijn; Witkamp, Renger F; Hendriks, Henk F J

2016-06-01

Glucagon like peptide-1 (GLP-1) and serotonin are both involved in food intake regulation. GLP-1 release is stimulated upon nutrient interaction with G-protein coupled receptors by enteroendocrine cells (EEC), whereas serotonin is released from enterochromaffin cells (ECC). The central hypothesis for the current study was that nutrient-induced GLP-1 release from EECs is modulated by serotonin through a process involving serotonin receptor interaction. This was studied by assessing the effects of serotonin reuptake inhibition by fluoxetine on nutrient-induced GLP-1, PYY and CCK release from isolated pig intestinal segments. Next, serotonin-induced GLP-1 release was studied in enteroendocrine STC-1 cells, where effects of serotonin receptor inhibition were studied using specific and non-specific antagonists. Casein (1% w/v), safflower oil (3.35% w/v), sucrose (50mM) and rebaudioside A (12.5mM) stimulated GLP-1 release from intestinal segments, whereas casein only stimulated PYY and CCK release. Combining nutrients with fluoxetine further increased nutrient-induced GLP-1, PYY and CCK release. Serotonin release from intestinal tissue segments was stimulated by casein and safflower oil while sucrose and rebaudioside A had no effect. The combination with fluoxetine (0.155μM) further enhanced casein and safflower oil induced-serotonin release. Exposure of ileal tissue segments to serotonin (30μM) stimulated GLP-1 release whereas it did not induce PYY and CCK release. Serotonin (30 and 100μM) also stimulated GLP-1 release from STC-1 cells, which was inhibited by the non-specific 5HT receptor antagonist asenapine (1 and 10μM). These data suggest that nutrient-induced GLP-1 release is modulated by serotonin through a receptor mediated process. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Plasma and serum serotonin concentrations and surface-bound platelet serotonin expression in Cavalier King Charles Spaniels with myxomatous mitral valve disease.

PubMed

Cremer, Signe E; Kristensen, Annemarie T; Reimann, Maria J; Eriksen, Nynne B; Petersen, Stine F; Marschner, Clara B; Tarnow, Inge; Oyama, Mark A; Olsen, Lisbeth H

2015-06-01

To investigate serum and plasma serotonin concentrations, percentage of serotonin-positive platelets, level of surface-bound platelet serotonin expression (mean fluorescence intensity [MFI]), and platelet activation (CD62 expression) in platelet-rich plasma from Cavalier King Charles Spaniels with myxomatous mitral valve disease (MMVD). Healthy dogs (n = 15) and dogs with mild MMVD (18), moderate-severe MMVD (19), or severe MMVD with congestive heart failure (CHF; 10). Blood samples were collected from each dog. Serum and plasma serotonin concentrations were measured with an ELISA, and surface-bound platelet serotonin expression and platelet activation were determined by flow cytometry. Dogs with mild MMVD had higher median serum (746 ng/mL) and plasma (33.3 ng/mL) serotonin concentrations, compared with MMVD-affected dogs with CHF (388 ng/mL and 9.9 ng/mL, respectively), but no other group differences were found. Among disease groups, no differences in surface-bound serotonin expression or platelet activation were found. Thrombocytopenic dogs had lower serum serotonin concentration (482 ng/mL) than nonthrombocytopenic dogs (731 ng/mL). In 26 dogs, a flow cytometry scatterplot subpopulation (FSSP) of platelets was identified; dogs with an FSSP had a higher percentage of serotonin-positive platelets (11.0%), higher level of surface-bound serotonin expression (MFI, 32,068), and higher platelet activation (MFI, 2,363) than did dogs without an FSSP (5.7%, 1,230, and 1,165, respectively). An FSSP was present in 93.8% of thrombocytopenic dogs and in 29.5% of nonthrombocytopenic dogs. A substantive influence of circulating serotonin on MMVD stages prior to CHF development in Cavalier King Charles Spaniels was not supported by the study findings. An FSSP of highly activated platelets with pronounced serotonin binding was strongly associated with thrombocytopenia but not MMVD.

A serum and platelet-rich plasma serotonin assay using liquid chromatography tandem mass spectrometry for monitoring of neuroendocrine tumor patients.

PubMed

Korse, Catharina M; Buning-Kager, Johanna C G M; Linders, Theodora C; Heijboer, Annemieke C; van den Broek, Daan; Tesselaar, Margot E T; van Tellingen, Olaf; van Rossum, Huub H

2017-06-01

Serotonin is used for the diagnosis and follow-up of neuroendocrine tumors (NET). We describe the analytical and clinical validation of a liquid chromatography tandem mass spectrometry (LC-MS/MS) based serotonin assay for serum and platelet-rich plasma (PRP). An LC-MS/MS based method for serum and PRP serotonin was validated by determination of assay imprecision, carry-over, linearity, interference, recovery, sample stability and a matrix/method comparison of serum and PRP serotonin was made with whole blood serotonin. Furthermore, upper limits of normal were determined and serotonin concentrations of healthy individuals, 14 NET patients without evidence of disease and 51 NET patients with evidence of disease were compared. For serum and PRP fractions, total assay imprecision was <5%. All correlation coefficients were 0.98 and the serum and platelet-rich serotonin upper limit of normal were 5.5nmol/10 9 platelet and 5.1nmol/10 9 platelet, respectively. NET patients with confirmed evidence of disease had significantly higher serum and PRP serotonin levels when compared to NET patients without evidence of disease and healthy volunteers. LC-MS/MS based serum and PRP serotonin assays were developed with suitable analytical characteristics. Furthermore, serum and PRP serotonin was found to be useful for monitoring NET patients. Copyright © 2017 Elsevier B.V. All rights reserved.

MDMA, serotonergic neurotoxicity, and the diverse functional deficits of recreational 'Ecstasy' users.

PubMed

Parrott, Andrew C

2013-09-01

Serotonergic neurotoxicity following MDMA is well-established in laboratory animals, and neuroimaging studies have found lower serotonin transporter (SERT) binding in abstinent Ecstasy/MDMA users. Serotonin is a modulator for many different psychobiological functions, and this review will summarize the evidence for equivalent functional deficits in recreational users. Declarative memory, prospective memory, and higher cognitive skills are often impaired. Neurocognitive deficits are associated with reduced SERT in the hippocampus, parietal cortex, and prefrontal cortex. EEG and ERP studies have shown localised reductions in brain activity during neurocognitive performance. Deficits in sleep, mood, vision, pain, psychomotor skill, tremor, neurohormonal activity, and psychiatric status, have also been demonstrated. The children of mothers who take Ecstasy/MDMA during pregnancy have developmental problems. These psychobiological deficits are wide-ranging, and occur in functions known to be modulated by serotonin. They are often related to lifetime dosage, with light users showing slight changes, and heavy users displaying more pronounced problems. In summary, abstinent Ecstasy/MDMA users can show deficits in a wide range of biobehavioral functions with a serotonergic component. Copyright © 2013 Elsevier Ltd. All rights reserved.

Low serum concentrations of vitamin B6 and iron are related to panic attack and hyperventilation attack.

PubMed

Mikawa, Yasuhito; Mizobuchi, Satoshi; Egi, Moritoki; Morita, Kiyoshi

2013-01-01

Patients undergoing a panic attack (PA) or a hyperventilation attack (HVA) are sometimes admitted to emergency departments (EDs). Reduced serotonin level is known as one of the causes of PA and HVA. Serotonin is synthesized from tryptophan. For the synthesis of serotonin, vitamin B6 (Vit B6) and iron play important roles as cofactors. To clarify the pathophysiology of PA and HVA, we investigated the serum levels of vitamins B2, B6, and B12 and iron in patients with PA or HVA attending an ED. We measured each parameter in 21 PA or HVA patients and compared the values with those from 20 volunteers. We found that both Vit B6 and iron levels were significantly lower in the PA/HVA group than in the volunteer group. There was no significant difference in the serum levels of vitamins B2 or B12. These results suggest that low serum concentrations of Vit B6 and iron are involved in PA and HVA. Further studies are needed to clarify the mechanisms involved in such differences.

Antidepressant Specificity of Serotonin Transporter Suggested by Three LeuT-SSRI Structures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Z.; Zhen, J; Karpowich, N

2009-01-01

Sertraline and fluoxetine are selective serotonin re-uptake inhibitors (SSRIs) that are widely prescribed to treat depression. They exert their effects by inhibiting the presynaptic plasma membrane serotonin transporter (SERT). All SSRIs possess halogen atoms at specific positions, which are key determinants for the drugs' specificity for SERT. For the SERT protein, however, the structural basis of its specificity for SSRIs is poorly understood. Here we report the crystal structures of LeuT, a bacterial SERT homolog, in complex with sertraline, R-fluoxetine or S-fluoxetine. The SSRI halogens all bind to exactly the same pocket within LeuT. Mutation at this halogen-binding pocket (HBP)more » in SERT markedly reduces the transporter's affinity for SSRIs but not for tricyclic antidepressants. Conversely, when the only nonconserved HBP residue in both norepinephrine and dopamine transporters is mutated into that found in SERT, their affinities for all the three SSRIs increase uniformly. Thus, the specificity of SERT for SSRIs is dependent largely on interaction of the drug halogens with the protein's HBP.« less

Drug pharmacokinetics and pharmacodynamics: PET and microdial studies of SR 46349B, a selective 5HT2 antagonist

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tan, P.; Dewey, S.L.; Gatley, S.J.

1994-05-01

The brain serotonin system is an important molecular target in drug development. SR 46349B is a propenone oxime ether derivative with a high affinity and selectivity for the serotonin 5HT2 receptor (Kd=1.2 nM). We have labeled SR 46349B with carbon-11 via N-methylation of a nor-precursor (supplied by Sanofi Recherche) with C-11 methyl iodide. Purification by HPLC gave [11C]SR 46349B in 98% radiochemical purity with a specific activity of 1.5 Ci/{mu}mol. Serial PET studies were carried out in a baboon for a 60 minute study period with a two hour time interval between studies. The first study was at baseline andmore » the second after pretreatment with altanserin (0.5 mg/kg iv, 30 min prior to [11C]SR 46349B). Carbon-11 peaked at ca. 20 minutes in the frontal, parietal, temporal and occipital cortices where it plateaued for the rest of the study. Cerebellum, thalamus and striatum peaked at ca. 10 minutes and cleared to 62%, 72% and 80% of peak by 60 min. At 60 minutes, the frontal cortex to cerebellum ratio was 1.5. Treatment with altanserin reduced the frontal cortex to cerebellum ratio to 1.0. HPLC of mouse brain homogenate after [11C]SR 46349B showed >94% of the C-11 was parent compound. Microdialysis in freely moving rats after injection of SR 46349B (n=6; 10 mg/kg, ip) showed an average peak increase in extracellular dopamine of 375% which is higher than the 150% effect of altanserin. Spontaneous movements were markedly reduced. The pharmacokinetics of [11C] SR 46349B in cortical areas is consistent with the long term effects of SR 46349B on 5HT2 receptors and the elevations in extracellular dopamine without increased locomotor activity are consistent with serotonin mediated disinhibition of striatal dopamine release via blockade of serotonin receptors.« less

GLP-1 is both anxiogenic and antidepressant; divergent effects of acute and chronic GLP-1 on emotionality.

PubMed

Anderberg, Rozita H; Richard, Jennifer E; Hansson, Caroline; Nissbrandt, Hans; Bergquist, Filip; Skibicka, Karolina P

2016-03-01

Glucagon-like peptide 1 (GLP-1), produced in the intestine and hindbrain, is known for its glucoregulatory and appetite suppressing effects. GLP-1 agonists are in clinical use for treatment of type 2 diabetes and obesity. GLP-1, however, may also affect brain areas associated with emotionality regulation. Here we aimed to characterize acute and chronic impact of GLP-1 on anxiety and depression-like behavior. Rats were subjected to anxiety and depression behavior tests following acute or chronic intracerebroventricular or intra-dorsal raphe (DR) application of GLP-1 receptor agonists. Serotonin or serotonin-related genes were also measured in the amygdala, DR and the hippocampus. We demonstrate that both GLP-1 and its long lasting analog, Exendin-4, induce anxiety-like behavior in three rodent tests of this behavior: black and white box, elevated plus maze and open field test when acutely administered intraperitoneally, into the lateral ventricle, or directly into the DR. Acute central GLP-1 receptor stimulation also altered serotonin signaling in the amygdala. In contrast, chronic central administration of Exendin-4 did not alter anxiety-like behavior but significantly reduced depression-like behavior in the forced swim test. Importantly, this positive effect of Exendin-4 was not due to significant body weight loss and reduced food intake, since rats pair-fed to Exendin-4 rats did not show altered mood. Collectively we show a striking impact of central GLP-1 on emotionality and the amygdala serotonin signaling that is divergent under acute versus chronic GLP-1 activation conditions. We also find a novel role for the DR GLP-1 receptors in regulation of behavior. These results may have direct relevance to the clinic, and indicate that Exendin-4 may be especially useful for obese patients manifesting with comorbid depression. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Expression changes of serotonin receptor gene subtype 5HT3a in peripheral blood mononuclear cells from schizophrenic patients treated with haloperidol and Olanzapin.

PubMed

Shariati, Gholam Reza; Ahangari, Ghasem; Hossein-nezhad, Arash; Asadi, Seyed Mohammad; Pooyafard, Farzaneh; Ahmadkhaniha, Hamid Reza

2009-09-01

Serotonin receptors are involved in pathophysiology of schizophrenia and may mediate other neurotransmitter effects. We investigated serotonin receptors gene expression in peripheral blood mononuclear cells (PBMC) of naïve schizophrenic patients, before and after treatment. Also serotonin receptor gene expression was compared in two treatment groups including Haloperidol and Olanzapine. The PBMC was separated from whole blood by Ficoll-hypaque. The total cellular RNA was extracted and the cDNA was synthesized. This process was followed by real-time PCR using primer pairs specific for 5HT(3a) serotonin receptor mRNA and beta-actin as internal control. The results showed the presence of subtype of serotonin receptor in lymphocytes. Serotonin gene expression showed significant changes in Olanzapine treatment group which correlated with Clinical Global Impression (CGI) score improvement. In conclusion, the present study has shown that human PBMC express serotonin receptors 5HT(3a). Moreover, clinical symptom improvement of Olanzapin may be demonstrated by a change in serotonin receptor gene expression.

Sucrose preload reduces snacking after mild mental stress in healthy participants as a function of 5-hydroxytryptamine transporter gene promoter polymorphism.

PubMed

Markus, C Rob; Jonkman, Lisa M; Capello, Aimee; Leinders, Sacha; Hüsch, Fabian

2015-01-01

Brain serotonin (5-hydroxytryptamine, 5-HT) dysfunction is considered to promote food intake and eating-related disturbances, especially under stress or negative mood. Vulnerability for 5-HT disturbances is considered to be genetically determined, including a short (S) allele polymorphism in the serotonin transporter gene (5-HTTLPR) that is associated with lower serotonin function. Since 5-HT function may be slightly increased by carbohydrate consumption, S-allele 5-HTTLPR carriers in particular may benefit from a sugar-preload due to their enhanced 5-HT vulnerability. The aim of the current study was to investigate whether a sugar-containing preload may reduce appetite and energy intake after exposure to stress to induce negative mood, depending on genetic 5-HT vulnerability. From a population of 771 healthy young male and female genotyped college students 31 S/S carriers (8 males, 23 females) and 26 long allele (L/L) carriers (9 males, 17 females) (mean ± S.D. 22 ± 1.6 years; body mass index, BMI, 18-33 kg/m(2)) were monitored for changes in appetite and snacking behavior after stress exposure. Results revealed an increased energy intake after mild mental stress (negative mood) mainly for high-fat sweet foods, which was significantly greater in S/S carriers, and only in these genotypes this intake was significantly reduced by a sucrose-containing preload. Although alternative explanations are possible, it is suggested that S/S participants may have enhanced brain (hypothalamic) 5-HT responsiveness to food that makes them more susceptible to the beneficial satiation effects of a sucrose-preload as well as to the negative effects of mild mental stress on weight gain.

Serotonin abnormalities in Engrailed-2 knockout mice: New insight relevant for a model of Autism Spectrum Disorder.

PubMed

Viaggi, Cristina; Gerace, Claudio; Pardini, Carla; Corsini, Giovanni U; Vaglini, Francesca

2015-08-01

Autism spectrum disorder (ASD) is a congenital neurodevelopmental behavioral disorder that appears in early childhood. Recent human genetic studies identified the homeobox transcription factor, Engrailed 2 (EN2), as a possible ASD susceptibility gene. En2 knockout mice (En2-/-) display subtle cerebellar neuropathological changes and reduced levels of tyrosine hydroxylase, noradrenaline and serotonin in the hippocampus and cerebral cortex similar to those ones which have been observed in the ASD brain. Furthermore other similarities link En2 knockout mice to ASD patients. Several lines of evidence suggest that serotonin may play an important role in the pathophysiology of the disease. In the present study we measured, by using an HPLC, the 5-HT levels in different brain areas and at different ages in En2-/- mice. In the frontal and occipital cortex, the content of 5HT was reduced in En2-/- 1 and 3 months old mice; in 6 month old mice, the difference was still present, but it was not statistically significant. The 5-HT content of cerebellar cortex was significantly reduced at 1 month old but significantly high when the KO mice reached 3 months of age. The increase was present even at 6 months of age. A similar trend was highlighted by SERT immunolabeling in En2-/- mice compared to control in the same areas and age analyzed. Our findings, in agreement with the current knowledge on the 5-HT system alterations in ASD, confirm the early neurotransmitter deficit with a late compensatory recovery in En2 KO-mice further suggesting that this experimental animal may be considered a good predictive model for the human disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

The immunomodulatory tellurium compound ammonium trichloro (dioxoethylene-O,O') tellurate reduces anxiety-like behavior and corticosterone levels of submissive mice.

PubMed

Gross, Moshe; Stanciu, Emanuel; Kenigsbuch-Sredni, Dvora; Sredni, Benjamin; Pinhasov, Albert

2017-09-01

Ammonium trichloro (dioxoethylene-O,O') tellurate (AS101) is a synthetic organotellurium compound with potent immunomodulatory and neuroprotective properties shown to inhibit the function of integrin αvβ3, a presynaptic cell-surface-adhesion receptor. As partial deletion of αvβ3 downregulated reuptake of serotonin by the serotonin transporter, we hypothesized that AS101 may influence pathways regulating anxiety. AS101 was tested in the modulation of anxiety-like behavior using the selectively bred Submissive (Sub) mouse strain that develop anxiety-like behavior in response to an i.p. injection. Mice were treated daily with AS101 (i.p., 125 or 200 μg/kg) or vehicle for 3 weeks, after which their anxiety-like behavior was measured in the elevated plus maze. Animals were then culled for the measurement of serum corticosterone levels by ELISA and hippocampal expression of brain-derived neurotrophic factor (BDNF) by RT-PCR. Chronic administration of AS101 significantly reduced anxiety-like behavior of Sub mice in the elevated plus maze, according to both time spent and entries to open arms, relative to vehicle-treated controls. AS101 also markedly reduced serum corticosterone levels of the treated mice and increased their hippocampal BDNF expression. Anxiolytic-like effects of AS101 may be attributed to the modulation of the regulatory influence integrin of αvβ3 upon the serotonin transporter, suggesting a multifaceted mechanism by which AS101 buffers the hypothalamic-pituitary-adrenal axis response to injection stress, enabling recovery of hippocampal BDNF expression and anxiety-like behavior in Sub mice. Further studies should advance the potential of AS101 in the context of anxiety-related disorders.

Serotonin neurones have anti-convulsant effects and reduce seizure-induced mortality

PubMed Central

Buchanan, Gordon F; Murray, Nicholas M; Hajek, Michael A; Richerson, George B

2014-01-01

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. Defects in central control of breathing are important contributors to the pathophysiology of SUDEP, and serotonin (5-HT) system dysfunction may be involved. Here we examined the effect of 5-HT neurone elimination or 5-HT reduction on seizure risk and seizure-induced mortality. Adult Lmx1bf/f/p mice, which lack >99% of 5-HT neurones in the CNS, and littermate controls (Lmx1bf/f) were subjected to acute seizure induction by maximal electroshock (MES) or pilocarpine, variably including electroencephalography, electrocardiography, plethysmography, mechanical ventilation or pharmacological therapy. Lmx1bf/f/p mice had a lower seizure threshold and increased seizure-induced mortality. Breathing ceased during most seizures without recovery, whereas cardiac activity persisted for up to 9 min before terminal arrest. The mortality rate of mice of both genotypes was reduced by mechanical ventilation during the seizure or 5-HT2A receptor agonist pretreatment. The selective serotonin reuptake inhibitor citalopram reduced mortality of Lmx1bf/f but not of Lmx1bf/f/p mice. In C57BL/6N mice, reduction of 5-HT synthesis with para-chlorophenylalanine increased MES-induced seizure severity but not mortality. We conclude that 5-HT neurones raise seizure threshold and decrease seizure-related mortality. Death ensued from respiratory failure, followed by terminal asystole. Given that SUDEP often occurs in association with generalised seizures, some mechanisms causing death in our model might be shared with those leading to SUDEP. This model may help determine the relationship between seizures, 5-HT system dysfunction, breathing and death, which may lead to novel ways to prevent SUDEP. PMID:25107926

Decreased Incentive Motivation Following Knockout or Acute Blockade of the Serotonin Transporter: Role of the 5-HT2C Receptor.

PubMed

Browne, Caleb J; Fletcher, Paul J

2016-09-01

Acute pharmacological elevation of serotonin (5-hydroxytryptamine; 5-HT) activity decreases operant responding for primary reinforcers, suggesting that 5-HT reduces incentive motivation. The mechanism by which 5-HT alters incentive motivation is unknown, but parallel evidence that 5-HT2C receptor agonists also reduce responding for primary reinforcers implicates this receptor as a potential candidate. These experiments examined whether chronic and acute disruptions of serotonin transporter (SERT) activity altered incentive motivation, and whether the 5-HT2C receptor mediated the effects of elevated 5-HT on behavior. To assess incentive motivation, we measured responding for three different reinforcers: a primary reinforcer (saccharin), a conditioned reinforcer (CRf), and an unconditioned sensory reinforcer (USRf). In the chronic condition, responding was compared between SERT knockout (SERT-KO) mice and their wild-type littermates. In the acute condition, responding was examined in wild-type mice following treatment with 10 or 20 mg/kg citalopram, or its vehicle. The ability of the selective 5-HT2C antagonist SB 242084 to prevent the effects of SERT-KO and citalopram on responding was subsequently examined. Both SERT-KO and citalopram reduced responding for saccharin, a CRf, and a USRf. Treatment with SB 242084 enhanced responding for a CRf and a USRf in SERT-KO mice and blocked the effects of citalopram on CRf and USRf responding. However, SB 242084 was unable to prevent the effects of SERT-KO or citalopram on responding for saccharin. These results support a powerful inhibitory function for 5-HT in the control of incentive motivation, and indicate that the 5-HT2C receptor mediates these effects of 5-HT in a reinforcer-dependent manner.

Serotonin delays habituation of leech swim response to touch.

PubMed

Alkatout, Bilal A; Marvin, Nicole M; Crisp, Kevin M

2007-08-22

Serotonin, acting through a cAMP-signaling pathway, delayed habituation to criterion of the leech's swim response to touch. This delay was reversed by crushing the connective between serotonin-exposed and serotonin-naive ganglia, and correlated with an increase in spontaneous impulse activity in this connective. We suggest that increased activity in intersegmental interneurons may play a role in maintaining swim responsiveness when concentrations of serotonin are elevated.

β-cell serotonin production is associated with female sex, old age, and diabetes-free condition.

PubMed

Kim, Yeong Gi; Moon, Joon Ho; Kim, Kyuho; Kim, Hyeongseok; Kim, Juok; Jeong, Ji-Seon; Lee, Junguee; Kang, Shinae; Park, Joon Seong; Kim, Hail

2017-11-25

Serotonin is known to be present in pancreatic β-cells and to play several physiological roles, including insulin secretion, β-cell proliferation, and paracrine inhibition of α-cells. However, the serotonin production of different cell lines and islets has not been compared based on age, sex, and diabetes related conditions. Here, we directly compared the serotonin concentrations in βTC and MIN6 cell lines, as well as in islets from mice using ultra-performance liquid chromatography tandem mass spectrometry. The average serotonin concentration was 5-10 ng/mg protein in the islets of male and non-pregnant female mice. The serotonin level was higher in females than males at 8 weeks, although there was no difference at 1 year. Furthermore, we observed serotonin by immunofluorescence staining in the pancreatic tissues of mice and human. Serotonin was detected by immunofluorescence staining in a portion of β-cells from islets of old female mice, but not of male or young female mice. A similar pattern was observed in human pancreas as well. In humans, serotonin production in β-cells was associated with a diabetes-free condition. Thus, serotonin production in β-cells was associated with old age, female sex, and diabetes-free condition. Copyright © 2017 Elsevier Inc. All rights reserved.

Metabolomics Approach Reveals Integrated Metabolic Network Associated with Serotonin Deficiency

PubMed Central

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

2015-01-01

Serotonin is an important neurotransmitter that broadly participates in various biological processes. While serotonin deficiency has been associated with multiple pathological conditions such as depression, schizophrenia, Alzheimer’s disease and Parkinson’s disease, the serotonin-dependent mechanisms remain poorly understood. This study therefore aimed to identify novel biomarkers and metabolic pathways perturbed by serotonin deficiency using metabolomics approach in order to gain new metabolic insights into the serotonin deficiency-related molecular mechanisms. Serotonin deficiency was achieved through pharmacological inhibition of tryptophan hydroxylase (Tph) using p-chlorophenylalanine (pCPA) or genetic knockout of the neuronal specific Tph2 isoform. This dual approach improved specificity for the serotonin deficiency-associated biomarkers while minimizing nonspecific effects of pCPA treatment or Tph2 knockout (Tph2-/-). Non-targeted metabolic profiling and a targeted pCPA dose-response study identified 21 biomarkers in the pCPA-treated mice while 17 metabolites in the Tph2-/- mice were found to be significantly altered compared with the control mice. These newly identified biomarkers were associated with amino acid, energy, purine, lipid and gut microflora metabolisms. Oxidative stress was also found to be significantly increased in the serotonin deficient mice. These new biomarkers and the overall metabolic pathways may provide new understanding for the serotonin deficiency-associated mechanisms under multiple pathological states. PMID:26154191

Metabolomics Approach Reveals Integrated Metabolic Network Associated with Serotonin Deficiency.

PubMed

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

2015-07-08

Serotonin is an important neurotransmitter that broadly participates in various biological processes. While serotonin deficiency has been associated with multiple pathological conditions such as depression, schizophrenia, Alzheimer's disease and Parkinson's disease, the serotonin-dependent mechanisms remain poorly understood. This study therefore aimed to identify novel biomarkers and metabolic pathways perturbed by serotonin deficiency using metabolomics approach in order to gain new metabolic insights into the serotonin deficiency-related molecular mechanisms. Serotonin deficiency was achieved through pharmacological inhibition of tryptophan hydroxylase (Tph) using p-chlorophenylalanine (pCPA) or genetic knockout of the neuronal specific Tph2 isoform. This dual approach improved specificity for the serotonin deficiency-associated biomarkers while minimizing nonspecific effects of pCPA treatment or Tph2 knockout (Tph2-/-). Non-targeted metabolic profiling and a targeted pCPA dose-response study identified 21 biomarkers in the pCPA-treated mice while 17 metabolites in the Tph2-/- mice were found to be significantly altered compared with the control mice. These newly identified biomarkers were associated with amino acid, energy, purine, lipid and gut microflora metabolisms. Oxidative stress was also found to be significantly increased in the serotonin deficient mice. These new biomarkers and the overall metabolic pathways may provide new understanding for the serotonin deficiency-associated mechanisms under multiple pathological states.

Metabolomics Approach Reveals Integrated Metabolic Network Associated with Serotonin Deficiency

NASA Astrophysics Data System (ADS)

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

2015-07-01

Serotonin is an important neurotransmitter that broadly participates in various biological processes. While serotonin deficiency has been associated with multiple pathological conditions such as depression, schizophrenia, Alzheimer’s disease and Parkinson’s disease, the serotonin-dependent mechanisms remain poorly understood. This study therefore aimed to identify novel biomarkers and metabolic pathways perturbed by serotonin deficiency using metabolomics approach in order to gain new metabolic insights into the serotonin deficiency-related molecular mechanisms. Serotonin deficiency was achieved through pharmacological inhibition of tryptophan hydroxylase (Tph) using p-chlorophenylalanine (pCPA) or genetic knockout of the neuronal specific Tph2 isoform. This dual approach improved specificity for the serotonin deficiency-associated biomarkers while minimizing nonspecific effects of pCPA treatment or Tph2 knockout (Tph2-/-). Non-targeted metabolic profiling and a targeted pCPA dose-response study identified 21 biomarkers in the pCPA-treated mice while 17 metabolites in the Tph2-/- mice were found to be significantly altered compared with the control mice. These newly identified biomarkers were associated with amino acid, energy, purine, lipid and gut microflora metabolisms. Oxidative stress was also found to be significantly increased in the serotonin deficient mice. These new biomarkers and the overall metabolic pathways may provide new understanding for the serotonin deficiency-associated mechanisms under multiple pathological states.

Comparison of serum serotonin and serum 5-HIAA LC-MS/MS assays in the diagnosis of serotonin producing neuroendocrine neoplasms: A pilot study.

PubMed

Lindström, Mikael; Tohmola, Niina; Renkonen, Risto; Hämäläinen, Esa; Schalin-Jäntti, Camilla; Itkonen, Outi

2018-07-01

Serotonin (5-hydroxytyramine) is a mediator of gastrointestinal smooth muscle contraction, and is secreted by neuroendocrine neoplasms (NENs). We developed a liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for serum serotonin to be used in NEN diagnostics and follow-up. We used serum samples from healthy volunteers (n = 31) and patients suspected or monitored for NEN (n = 98). Serotonin-D 4 internal standard was added to samples before solid phase extraction (SPE) and quantification by LC-MS/MS. The effects of sample handling and preparation on serotonin stability were studied. Finally, we established a provisional reference range for serum serotonin and compared our assay with serum 5-hydroxyindoleacetic acid (5-HIAA) for detection of NENs. Our assay is sensitive and has a wide linear range (10-10,000 nmol/l). Serum serotonin is stable for 7 days at room temperature and for 3 months at -20 °C. Sampling temperature is not critical. Normal range for serum serotonin was 270-1490 nmol/l. We found that serum serotonin and 5-HIAA performed equally well as diagnostic tests for NENs. Our LC-MS/MS assay for serum serotonin is well suited for clinical research and patient diagnostics. Our results confirm that it can complement 5-HIAA in diagnosis of NENs. Copyright © 2018 Elsevier B.V. All rights reserved.

De novo microdeletion of Xp11.3 exclusively encompassing the monoamine oxidase A and B genes in a male infant with episodic hypotonia: A genomics approach to personalized medicine

PubMed Central

O’Leary, Ryan E.; Shih, Jean C.; Hyland, Keith; Kramer, Nancy; Asher, Y. Jane Tavyev; Graham, John M.

2012-01-01

Monoamine oxidase A and B (MAOA and MAOB) play key roles in deaminating neurotransmitters and various other biogenic amines. Patients deficient in one or both enzymes have distinct metabolic and neurologic profiles. MAOB deficient patients exhibit normal clinical characteristics and behavior, while MAOA deficient patients have borderline intellectual deficiency and impaired impulse control. Patients who lack both MAOA and MAOB have the most extreme laboratory values (urine, blood, and CSF serotonin 4–6 times normal, with elevated O-methylated amine metabolites and reduced deaminated metabolites) in addition to severe intellectual deficiency and behavioral problems. Mice lacking maoa and moab exhibit decreased proliferation of neural stem cells beginning in late gestation and persisting into adulthood These mice show significantly increased monoamine levels, particularly serotonin, as well as anxiety-like behaviors as adults, suggesting that brain maturation in late embryonic development is adversely affected by elevated serotonin levels. We report the case of a male infant with a de novo Xp11.3 microdeletion exclusively encompassing the MAOA and MAOB genes. This newly recognized X-linked disorder is characterized by severe intellectual disability and unusual episodes of hypotonia, which resemble atonic seizures, but have no EEG correlate. A customized low dietary amine diet was implemented in an attempt to prevent the cardiovascular complications that can result from the excessive intake of these compounds. This is the second report of this deletion and the first attempt to maintain the patient’s cardiovascular health through dietary manipulation. Even though a diet low in tyramine, phenylethylamine, and dopa/dopamine is necessary for long-term management, it will not rescue the abnormal monoamine profile seen in combined MAOA and MAOB deficiency. Our patient displays markedly elevated levels of serotonin in blood, serum, urine, and CSF while on this diet. Serotonin biosynthesis inhibitors like para-chlorophenylalanine and p-ethynylphenylalanine may be needed to lower serotonin levels in patients with absent monoamine oxidase enzymes. PMID:22365943

De novo microdeletion of Xp11.3 exclusively encompassing the monoamine oxidase A and B genes in a male infant with episodic hypotonia: a genomics approach to personalized medicine.

PubMed

O'Leary, Ryan E; Shih, Jean C; Hyland, Keith; Kramer, Nancy; Asher, Y Jane Tavyev; Graham, John M

2012-05-01

Monoamine oxidase A and B (MAOA and MAOB) play key roles in deaminating neurotransmitters and various other biogenic amines. Patients deficient in one or both enzymes have distinct metabolic and neurologic profiles. MAOB deficient patients exhibit normal clinical characteristics and behavior, while MAOA deficient patients have borderline intellectual deficiency and impaired impulse control. Patients who lack both MAOA and MAOB have the most extreme laboratory values (urine, blood, and CSF serotonin 4-6 times normal, with elevated O-methylated amine metabolites and reduced deaminated metabolites) in addition to severe intellectual deficiency and behavioral problems. Mice lacking maoa and moab exhibit decreased proliferation of neural stem cells beginning in late gestation and persisting into adulthood. These mice show significantly increased monoamine levels, particularly serotonin, as well as anxiety-like behaviors as adults, suggesting that brain maturation in late embryonic development is adversely affected by elevated serotonin levels. We report the case of a male infant with a de novo Xp11.3 microdeletion exclusively encompassing the MAOA and MAOB genes. This newly recognized X-linked disorder is characterized by severe intellectual disability and unusual episodes of hypotonia, which resemble atonic seizures, but have no EEG correlate. A customized low dietary amine diet was implemented in an attempt to prevent the cardiovascular complications that can result from the excessive intake of these compounds. This is the second report of this deletion and the first attempt to maintain the patient's cardiovascular health through dietary manipulation. Even though a diet low in tyramine, phenylethylamine, and dopa/dopamine is necessary for long-term management, it will not rescue the abnormal monoamine profile seen in combined MAOA and MAOB deficiency. Our patient displays markedly elevated levels of serotonin in blood, serum, urine, and CSF while on this diet. Serotonin biosynthesis inhibitors like para-chlorophenylalanine and p-ethynylphenylalanine may be needed to lower serotonin levels in patients with absent monoamine oxidase enzymes. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Effects of Fluoxetine and Potential Antidepressant 8-Trifluoromethyl 1,2,3,4,5-Benzopentathiepin-6-Amine Hydrochloride (TC-2153) on Behavior of Danio rerio Fish in the Novel Tank Test and Brain Content of Biogenic Amines and Their Metabolites.

PubMed

Sinyakova, N A; Kulikova, E A; Englevskii, N A; Kulikov, A V

2018-03-01

We compared the effect of a new potential antidepressant 8-trifluoromethyl 1,2,3,4,5-benzopentathiepine-6-amine hydrochloride (TC-2153) and classical antidepressant fluoxetine in a dose of 0.25 mg/liter on the behavior of Danio rerio in the "novel tank" test and content of biogenic amines and their metabolites in the brain. Fluoxetine alone and TC-2153 alone significantly increased the time spent in the upper part of the tank and insignificantly reduced motor activity. Combined exposure of fishes in the solution containing potential and classical antidepressants potentiated their effects on both parameters. The compounds did not affect brain contents of serotonin, dopamine, and norepinephrine. At the same time, fluoxetine, but not TC-2153, reduced brain content of the main serotonin metabolite 5-hydroxyindole acetic acid.

Serotonin rebalances cortical tuning and behavior linked to autism symptoms in 15q11-13 CNV mice

PubMed Central

Nakai, Nobuhiro; Nagano, Masatoshi; Saitow, Fumihito; Watanabe, Yasuhito; Kawamura, Yoshinobu; Kawamoto, Akiko; Tamada, Kota; Mizuma, Hiroshi; Onoe, Hirotaka; Watanabe, Yasuyoshi; Monai, Hiromu; Hirase, Hajime; Nakatani, Jin; Inagaki, Hirofumi; Kawada, Tomoyuki; Miyazaki, Taisuke; Watanabe, Masahiko; Sato, Yuka; Okabe, Shigeo; Kitamura, Kazuo; Kano, Masanobu; Hashimoto, Kouichi; Suzuki, Hidenori; Takumi, Toru

2017-01-01

Serotonin is a critical modulator of cortical function, and its metabolism is defective in autism spectrum disorder (ASD) brain. How serotonin metabolism regulates cortical physiology and contributes to the pathological and behavioral symptoms of ASD remains unknown. We show that normal serotonin levels are essential for the maintenance of neocortical excitation/inhibition balance, correct sensory stimulus tuning, and social behavior. Conversely, low serotonin levels in 15q dup mice (a model for ASD with the human 15q11-13 duplication) result in impairment of the same phenotypes. Restoration of normal serotonin levels in 15q dup mice revealed the reversibility of a subset of ASD-related symptoms in the adult. These findings suggest that serotonin may have therapeutic potential for discrete ASD symptoms. PMID:28691086

Maternal 25-hydroxyvitamin D is inversely correlated with foetal serotonin.

PubMed

Murthi, Padma; Davies-Tuck, Miranda; Lappas, Martha; Singh, Harmeet; Mockler, Joanne; Rahman, Rahana; Lim, Rebecca; Leaw, Bryan; Doery, James; Wallace, Euan M; Ebeling, Peter R

2017-03-01

Maternal vitamin D deficiency during pregnancy has been linked to impaired neurocognitive development in childhood. The mechanism by which vitamin D affects childhood neurocognition is unclear but may be via interactions with serotonin, a neurotransmitter involved in foetal brain development. In this study, we aimed to explore associations between maternal and foetal vitamin D concentrations, and foetal serotonin concentrations at term. Serum 25-hydroxyvitamin D (25(OH)D, nmol/l) and serotonin (5-HT, nmol/l) concentrations were measured in maternal and umbilical cord blood from mother-infant pairs (n = 64). Association between maternal 25(OH)D, cord 25(OH)D and cord serotonin was explored using linear regression, before and after adjusting for maternal serotonin levels. We also assessed the effects of siRNA knockdown of the vitamin D receptor (VDR) and administration of 10 nm 1,25-dihydroxyvitamin D 3 on serotonin secretion in human umbilical vein endothelial cells (HUVECs) in vitro. We observed an inverse relationship between both maternal and cord 25(OH)D concentrations with cord serotonin concentrations. The treatment of HUVECs with 1,25-dihydroxyvitamin D 3 in vitro decreased the release of serotonin (193·9 ±14·8 nmol/l vs 458·9 ± 317·5 nmol/l, control, P < 0·05). Conversely, inactivation of VDR increased serotonin release in cultured HUVECs. These observations provide the first evidence of an inverse relationship between maternal 25(OH)D and foetal serotonin concentrations. We propose that maternal vitamin D deficiency increases foetal serotonin concentrations and thereby contributes to longer-term neurocognitive impairment in infants and children. © 2016 John Wiley & Sons Ltd.

[Escitalopram and citalopram: the unexpected role of the R-enantiomer].

PubMed

Jacquot, C; David, D J; Gardier, A M; Sánchez, C

2007-01-01

Citalopram, a selective serotonin reuptake inhibitor, is composed of 2 enantiomers, R-citalopram and S-citalopram, 2 different non-superimposable mirror image forms of the same molecule. Separating these 2 enantiomers has enabled studying their individual properties. Citalopram's pharmacologic activity is centered on the S enantiomer's high affinity for the serotonin transporter which is twice as high as citalopram's and 30 to 40 times higher than R-citalopram. This leads to an inhibition of serotonin reuptake two times higher for escitalopram compared with citalopram and confirms that citalopram's pharmacologic activity is due to the S-enantiomer. Contrary to what might be expected, the effect of escitalopram (DCI of S-citalopram) is not superimposable on an equivalent dose of citalopram but is superior. Several hypotheses could explain this superiority. First, conversions of the S-enantiomer into the R-enantiomer may occur, but there is no reason why this phenomenon would happen more when both enantiomers are present than when escitalopram is alone. Furthermore, pharmacokinetic studies have shown that S or R configurations are stable in vivo. Second, a particular action of R-citalopram may influence the S-enantiomer's kinetic from intestinal absorption to blood-brain barrier. But concentrations of both enantiomers in the frontal cortex are the same. Therefore, R-citalopram does not interfere with escitalopram's kinetic. Finally, interactions may appear at the synaptic level. Results of experimentation, after in situ injection to the cortex level, confirm that an interaction between the 2 enantiomers takes place at that level. A direct negative interaction of R-citalopram on one or several effectors that create the antidepressive effect seems justified. This negative interaction has been studied in depth. Animal models have shown that the R-enantiomer has no antidepressive potential and when associated with escitalopram prohedonic effects disappear. Escitalopram is more powerful than citalopram in reducing anxiety but the presence of R-citalopram reduces the positive effects of escitalopram. We then may conclude that R-citalopram antagonizes the antidepressive effects of escitalopram and that its presence limits the therapeutic effect and reduces the speed of action of citalopram. The antagonism of escitalopram by R-citalopram was not expected and one hypothesis is that a direct interaction between the 2 enantiomers may occur on a particular site of the serotonin transporter. Results have shown that R-citalopram has a significant affinity only for the allosteric site of the transporter, which regulates the affinity of the ligand for the active site at the origin of serotonin reuptake inhibition. Unlike citalopram, escitalopram's pharmacologic action is not blocked by R-citalopram explaining its greater therapeutic efficacy and more rapid mode of action.

Prospective trial of efficacy and safety of ondansetron and fluoxetine in patients with obstructive sleep apnea syndrome.

PubMed

Prasad, Bharati; Radulovacki, Miodrag; Olopade, Christopher; Herdegen, James J; Logan, Thomas; Carley, David W

2010-07-01

Incremental withdrawal of serotonin during wake to sleep transition is postulated as a key mechanism that renders the pharyngeal airway collapsible. While serotonin promotion with reuptake inhibitors have demonstrated modest beneficial effects during NREM sleep on obstructive sleep apnea (OSA), animal studies suggest a potential therapeutic role for selective serotonin receptor antagonists (5-HT3) in REM sleep. We aimed to test the hypothesis that a combination of ondansetron (Ond) and fluoxetine (Fl) may effectively reduce expression of disordered breathing during REM and NREM sleep in patients with OSA. A prospective, parallel-groups, single-center trial in patients with OSA. 35 adults with apnea hypopnea index (AHI) > 10; range 10-98. Subjects were randomized to placebo, n = 7; Ond (24 mg QD), n = 9; Fl (5 mg QD) + Ond (12 mg QD), n = 9; and Fl (10 mg QD) + Ond (24 mg QD), n = 10. AHI was measured by in-lab polysomnography after a 7-day no-treatment period (Baseline) and on days 14 and 28 of treatment. The primary endpoint was AHI reduction at days 14 and 28. OND+FL resulted in approximately 40% reduction of baseline AHI at days 14 and 28 (unadjusted P < 0.03 for each) and improved oximetry trends. This treatment-associated relative reduction in AHI was also observed in REM and supine sleep. Combined treatment with OND+FL is well-tolerated and reduces AHI, yielding a potentially therapeutic response in some subjects with OSA.

Deep serotonergic and dopaminergic structures in fetal alcoholic syndrome: a study with nor-beta-CIT-single-photon emission computed tomography and magnetic resonance imaging volumetry.

PubMed

Riikonen, Raili S; Nokelainen, Pekka; Valkonen, Kirsi; Kolehmainen, Anni I; Kumpulainen, Kirsti I; Könönen, Mervi; Vanninen, Ritva-Liisa S; Kuikka, Jyrki T

2005-06-15

In prenatally alcohol exposed children, the relationship between brain structure and function is highlighted to be important to study. We studied 12 children with fetal alcoholic syndrome (FAS) and fetal alcoholic effects (FAE) by magnetic resonance imaging volumetry and by single-photon emission computed tomography with iodine-123 labeled 2beta-carbomethoxy-3beta-(4-iodophenyl) ([123I]nor-beta-CIT) and related these findings to those from neuropsychological and psychiatric tests. The absolute volumes of studied nuclei, including the brain volume, were significantly smaller in FAS/FAE children than in control patients. After normalization of volumes, significant differences were not found. Left hippocampus was smaller than the right (p<.003) but did not significantly differ from the control subjects. The children with FAS/FAE showed reduced serotonin (p=.02) in the medial frontal cortex and slightly increased striatal dopamine transporter binding. All FAS/FAE children had attention-deficit/hyperkinetic disorder (ADHD). None had depression. The internalization scores correlated with dopamine transporter binding (r=-.65; p=.03). The results indicate that the serotonin (5-HT) system may be vulnerable to the effects of ethanol in utero. The high dopamine transporter levels may correlate with the ADHD findings. Reduced serotonin and increased binding of dopamine transporter are also seen in type 2 alcoholism. Some behavioral problems of FAS/FAE might be preventable by early intervention and treatment.

Selective labeling of serotonin uptake sites in rat brain by (/sup 3/H)citalopram contrasted to labeling of multiple sites by (/sup 3/H)imipramine

DOE Office of Scientific and Technical Information (OSTI.GOV)

D'Amato, R.J.; Largent, B.L.; Snowman, A.M.

1987-07-01

Citalopram is a potent and selective inhibitor of neuronal serotonin uptake. In rat brain membranes (/sup 3/H)citalopram demonstrates saturable and reversible binding with a KD of 0.8 nM and a maximal number of binding sites (Bmax) of 570 fmol/mg of protein. The drug specificity for (/sup 3/H)citalopram binding and synaptosomal serotonin uptake are closely correlated. Inhibition of (/sup 3/H)citalopram binding by both serotonin and imipramine is consistent with a competitive interaction in both equilibrium and kinetic analyses. The autoradiographic pattern of (/sup 3/H)citalopram binding sites closely resembles the distribution of serotonin. By contrast, detailed equilibrium-saturation analysis of (/sup 3/H)imipramine bindingmore » reveals two binding components, i.e., high affinity (KD = 9 nM, Bmax = 420 fmol/mg of protein) and low affinity (KD = 553 nM, Bmax = 8560 fmol/mg of protein) sites. Specific (/sup 3/H)imipramine binding, defined as the binding inhibited by 100 microM desipramine, is displaced only partially by serotonin. Various studies reveal that the serotonin-sensitive portion of binding corresponds to the high affinity sites of (/sup 3/H)imipramine binding whereas the serotonin-insensitive binding corresponds to the low affinity sites. Lesioning of serotonin neurons with p-chloroamphetamine causes a large decrease in (/sup 3/H)citalopram and serotonin-sensitive (/sup 3/H)imipramine binding with only a small effect on serotonin-insensitive (/sup 3/H)imipramine binding. The dissociation rate of (/sup 3/H)imipramine or (/sup 3/H)citalopram is not altered by citalopram, imipramine or serotonin up to concentrations of 10 microM. The regional distribution of serotonin sensitive (/sup 3/H)imipramine high affinity binding sites closely resembles that of (/sup 3/H)citalopram binding.« less

Conundrums in neurology: diagnosing serotonin syndrome - a meta-analysis of cases.

PubMed

Werneke, Ursula; Jamshidi, Fariba; Taylor, David M; Ott, Michael

2016-07-12

Serotonin syndrome is a toxic state, caused by serotonin (5HT) excess in the central nervous system. Serotonin syndrome's main feature is neuro-muscular hyperexcitability, which in many cases is mild but in some cases can become life-threatening. The diagnosis of serotonin syndrome remains challenging since it can only be made on clinical grounds. Three diagnostic criteria systems, Sternbach, Radomski and Hunter classifications, are available. Here we test the validity of four assumptions that have become widely accepted: (1) The Hunter classification performs clinically better than the Sternbach and Radomski criteria; (2) in contrast to neuroleptic malignant syndrome, the onset of serotonin syndrome is usually rapid; (3) hyperthermia is a hallmark of severe serotonin syndrome; and (4) serotonin syndrome can readily be distinguished from neuroleptic malignant syndrome on clinical grounds and on the basis of medication history. Systematic review and meta-analysis of all cases of serotonin syndrome and toxicity published between 2004 and 2014, using PubMed and Web of Science. Two of the four assumptions (1 and 2) are based on only one published study each and have not been independently validated. There is little agreement between current criteria systems for the diagnosis of serotonin syndrome. Although frequently thought to be the gold standard for the diagnosis of the serotonin syndrome, the Hunter criteria did not perform better than the Sternbach and Radomski criteria. Not all cases seem to be of rapid onset and only relatively few cases may present with hyperthermia. The 0 differential diagnosis between serotonin syndrome and neuroleptic malignant syndrome is not always clear-cut. Our findings challenge four commonly made assumptions about serotonin syndrome. We propose our meta-analysis of cases (MAC) method as a new way to systematically pool and interpret anecdotal but important clinical information concerning uncommon or emergent phenomena that cannot be captured in any other way but through case reports.

Engineering of Escherichia coli for the synthesis of N-hydroxycinnamoyl tryptamine and serotonin.

PubMed

Lee, Su Jin; Sim, Geun-Young; Lee, Youngshim; Kim, Bong-Gyu; Ahn, Joong-Hoon

2017-11-01

Plants synthesize various phenol amides. Among them, hydroxycinnamoyl (HC) tryptamines and serotonins exhibit antioxidant, anti-inflammatory, and anti-atherogenic activities. We synthesized HC-tryptamines and HC-serotonin from several HCs and either tryptamine or serotonin using Escherichia coli harboring the 4CL (4-coumaroyl CoA ligase) and CaHCTT [hydroxycinnamoyl-coenzyme A:serotonin N-(hydroxycinnamoyl)transferase] genes. E. coli was engineered to synthesize N-cinnamoyl tryptamine from glucose. TDC (tryptophan decarboxylase) and PAL (phenylalanine ammonia lyase) along with 4CL and CaHCTT were introduced into E. coli and the phenylalanine biosynthetic pathway of E. coli was engineered. Using this strategy, approximately 110.6 mg/L of N-cinnamoyl tryptamine was synthesized. By feeding 100 μM serotonin into the E. coli culture, which could induce the synthesis of cinnamic acid or p-coumaric acid, more than 99 μM of N-cinnamoyl serotonin and N-(p-coumaroyl) serotonin were synthesized.

Perturbation of Serotonin Homeostasis during Adulthood Affects Serotonergic Neuronal Circuitry.

PubMed

Pratelli, Marta; Migliarini, Sara; Pelosi, Barbara; Napolitano, Francesco; Usiello, Alessandro; Pasqualetti, Massimo

2017-01-01

Growing evidence shows that the neurotransmitter serotonin (5-HT) modulates the fine-tuning of neuron development and the establishment of wiring patterns in the brain. However, whether serotonin is involved in the maintenance of neuronal circuitry in the adult brain remains elusive. Here, we use a Tph2 fl ° x conditional knockout (cKO) mouse line to assess the impact of serotonin depletion during adulthood on serotonergic system organization. Data show that the density of serotonergic fibers is increased in the hippocampus and decreased in the thalamic paraventricular nucleus (PVN) as a consequence of brain serotonin depletion. Strikingly, these defects are rescued following reestablishment of brain 5-HT signaling via administration of the serotonin precursor 5-hydroxytryptophan (5-HTP). Finally, 3D reconstruction of serotonergic fibers reveals that changes in serotonin homeostasis affect axonal branching complexity. These data demonstrate that maintaining proper serotonin homeostasis in the adult brain is crucial to preserve the correct serotonergic axonal wiring.

Chemical regulation of spawning in the zebra mussel (Dreissena polymorpha)

USGS Publications Warehouse

Ram, Jeffrey L.; Nichols, S. Jerrine; Nalepa, Thomas F.; Schloesser, Donald W.

1992-01-01

Previous literature suggests that spawning in bivalves is chemically regulated, both by environmental chemical cues and by internal chemical mediators. In a model proposed for zebra mussels, chemicals from phytoplankton initially trigger spawning, and chemicals associated with gametes provide further stimulus for spawning. The response to environmental chemicals is internally mediated by a pathway utilizing serotonin (5-hydroxytryptamine, a neurotransmitter), which acts directly on both male and female gonads. The role of serotonin and most other aspects of the model have been tested only on bivalves other than zebra mussels. The effect of serotonin on zebra mussel spawning was tested. Serotonin (10-5 and 10-3 M) injected into ripe males induced spawning, but injection of serotonin into females did not. Gametes were not released by 10-6 serotonin; in most cases, serotonin injection did not release gametes from immature recipients. Serotonin injection provides a reliable means for identifying ripe male zebra mussels and for obtaining zebra mussel sperm without the need for dissection.

Intestinal crosstalk between microbiota and serotonin and its impact on gut motility.

PubMed

Ge, Xiaolong; Pan, Junhai; Liu, Yichang; Wang, Hongkan; Zhou, Wei; Wang, Xianfa

2018-05-27

The gastrointestinal tract harbours a diverse bacterial community that contributes to health and disease. A number of studies have demonstrated that the gut microbiota plays a critical role in the metabolism of serotonin. Microbial-derived metabolites, such as bile acids and short-chain fatty acids, are reported to affect the production of serotonin which, in turn, directly or indirectly regulates gut motility. Enterochromaffin cells are important specialized endocrine cells found in the intestine, which is the major location of serotonin biosynthesis. The relationship between microbiota and gut motility are studied depended on microbial-derived metabolites and serotonin. Both bile acids and short-chain fatty acids can modulate serotonin metabolism in hosts by affecting key intermediates of the serotonin pathway. Thus, gut motility may be regulated through microbial modifications of host serotonin biosynthesis, which continues to be evaluated as a target for functional gastrointestinal disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Understanding the Role of Serotonin in Female Hypoactive Sexual Desire Disorder and Treatment Options.

PubMed

Croft, Harry A

2017-12-01

The neurobiology of sexual response is driven in part by dopamine and serotonin-the former modulating excitatory pathways and the latter regulating inhibitory pathways. Neurobiological underpinnings of hypoactive sexual desire disorder (HSDD) are seemingly related to overactive serotonin activity that results in underactive dopamine activity. As such, pharmacologic agents that decrease serotonin, increase dopamine, or some combination thereof, have therapeutic potential for HSDD. To review the role of serotonin in female sexual function and the effects of pharmacologic interventions that target the serotonin system in the treatment of HSDD. Searches of the Medline database for articles on serotonin and female sexual function. Relevant articles from the peer-reviewed literature were included. Female sexual response is regulated not only by the sex hormones but also by several neurotransmitters. It is postulated that dopamine, norepinephrine, oxytocin, and melanocortins serve as key neuromodulators for the excitatory pathways, whereas serotonin, opioids, and endocannabinoids serve as key neuromodulators for the inhibitory pathways. Serotonin appears to be a key inhibitory modulator of sexual desire, because it decreases the ability of excitatory systems to be activated by sexual cues. Centrally acting drugs that modulate the excitatory and inhibitory pathways involved in sexual desire (eg, bremelanotide, bupropion, buspirone, flibanserin) have been investigated as treatment options for HSDD. However, only flibanserin, a multifunctional serotonin agonist and antagonist (5-hydroxytryptamine [5-HT] 1A receptor agonist and 5-HT 2A receptor antagonist), is currently approved for the treatment of HSDD. The central serotonin system is 1 biochemical target for medications intended to treat HSDD. This narrative review integrates findings from preclinical studies and clinical trials to elucidate neurobiological underpinnings of HSDD but is limited to 1 neurotransmitter system (serotonin). Serotonin overactivity is a putative cause of sexual dysfunction in patients with HSDD. The unique pharmacologic profile of flibanserin tones down inhibitory serotonergic function and restores dopaminergic and noradrenergic function. Croft HA. Understanding the Role of Serotonin in Female Hypoactive Sexual Desire Disorder and Treatment Options. J Sex Med 2017;14:1575-1584. Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Ethanol intake and sup 3 H-serotonin uptake II: A study in alcoholic patients using platelets sup 3 H-paroxetine binding

DOE Office of Scientific and Technical Information (OSTI.GOV)

Daoust, M.; Boucly, P.; Ernouf, D.

1991-01-01

The kinetic parameters of {sup 3}H-paroxetine binding and {sup 3}H-serotonin uptake were studied in platelets of alcoholic patients. There was no difference between alcoholic and non alcoholic subjects in {sup 3}H-paroxetine binding. When binding and {sup 3}H-serotonin uptake were studied, in the same plasma of the same subjects, the Vmax of serotonin uptake was increased in alcoholics. The data confirm the involvement of serotonin uptake system in alcohol dependance and suggest that serotonin uptake and paroxetine binding sites may be regulated independently in this pathology.

Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis.

PubMed

Berglund, Eric D; Liu, Chen; Sohn, Jong-Woo; Liu, Tiemin; Kim, Mi Hwa; Lee, Charlotte E; Vianna, Claudia R; Williams, Kevin W; Xu, Yong; Elmquist, Joel K

2013-12-01

Energy and glucose homeostasis are regulated by central serotonin 2C receptors. These receptors are attractive pharmacological targets for the treatment of obesity; however, the identity of the serotonin 2C receptor-expressing neurons that mediate the effects of serotonin and serotonin 2C receptor agonists on energy and glucose homeostasis are unknown. Here, we show that mice lacking serotonin 2C receptors (Htr2c) specifically in pro-opiomelanocortin (POMC) neurons had normal body weight but developed glucoregulatory defects including hyperinsulinemia, hyperglucagonemia, hyperglycemia, and insulin resistance. Moreover, these mice did not show anorectic responses to serotonergic agents that suppress appetite and developed hyperphagia and obesity when they were fed a high-fat/high-sugar diet. A requirement of serotonin 2C receptors in POMC neurons for the maintenance of normal energy and glucose homeostasis was further demonstrated when Htr2c loss was induced in POMC neurons in adult mice using a tamoxifen-inducible POMC-cre system. These data demonstrate that serotonin 2C receptor-expressing POMC neurons are required to control energy and glucose homeostasis and implicate POMC neurons as the target for the effect of serotonin 2C receptor agonists on weight-loss induction and improved glycemic control.

Genes affecting sensitivity to serotonin in Caenorhabditis elegans.

PubMed

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

1996-07-01

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

Genes Affecting Sensitivity to Serotonin in Caenorhabditis Elegans

PubMed Central

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

1996-01-01

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

Serotonin induces ecdysteroidogenesis and methyl farnesoate synthesis in the mud crab, Scylla serrata.

PubMed

Girish, B P; Swetha, C H; Reddy, P Sreenivasula

2017-09-02

In the current study, we have examined the role of serotonin in regulating the levels of methyl farnesoate and ecdysteroids in the giant mud crab Scylla serrata and validated that serotonin indeed is a reproductive hormone. Administration of serotonin elevated circulatory levels of methyl farnesoate and ecdysteroids in crabs. Since methyl farnesoate and ecdysteroid act through retinoid X receptor (RXR) and ecdysteroid receptor (EcR) respectively and these receptors are involved in the regulation of reproduction in crustaceans, we have determined the mRNA levels of RXR and EcR in hepatopancreas and ovary after serotonin administration. The expression levels of both RXR and EcR increased significantly in the hepatopancreas and ovary of serotonin injected crabs when compared to the controls. In vitro organ culture studies revealed that incubation of Y-orgas and mandibular organ explants in the presence of serotonin resulted in a significant increase in the secretion of ecdysteroids by Y-organs, but without alterations in MF synthesis in mandibular organs. From the above studies it is evident that serotonin stimulates Y organs resulting in increased ecdysteroidogenesis. Though the circulatory levels methyl farnesoate elevated after serotonin administration, organ culture studies revealed serotonin mediated methyl farnesaote synthesis is indirect probably by inhibiting release of mandibular organ inhibiting hormone from eyestalks. Copyright © 2017 Elsevier Inc. All rights reserved.

A Dualistic Conformational Response to Substrate Binding in the Human Serotonin Transporter Reveals a High Affinity State for Serotonin*

PubMed Central

Bjerregaard, Henriette; Severinsen, Kasper; Said, Saida; Wiborg, Ove; Sinning, Steffen

2015-01-01

Serotonergic neurotransmission is modulated by the membrane-embedded serotonin transporter (SERT). SERT mediates the reuptake of serotonin into the presynaptic neurons. Conformational changes in SERT occur upon binding of ions and substrate and are crucial for translocation of serotonin across the membrane. Our understanding of these conformational changes is mainly based on crystal structures of a bacterial homolog in various conformations, derived homology models of eukaryotic neurotransmitter transporters, and substituted cysteine accessibility method of SERT. However, the dynamic changes that occur in the human SERT upon binding of ions, the translocation of substrate, and the role of cholesterol in this interplay are not fully elucidated. Here we show that serotonin induces a dualistic conformational response in SERT. We exploited the substituted cysteine scanning method under conditions that were sensitized to detect a more outward-facing conformation of SERT. We found a novel high affinity outward-facing conformational state of the human SERT induced by serotonin. The ionic requirements for this new conformational response to serotonin mirror the ionic requirements for translocation. Furthermore, we found that membrane cholesterol plays a role in the dualistic conformational response in SERT induced by serotonin. Our results indicate the existence of a subpopulation of SERT responding differently to serotonin binding than hitherto believed and that membrane cholesterol plays a role in this subpopulation of SERT. PMID:25614630

Effects of 60-Hz electric fields on serotonin metabolism in the rat pineal gland

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anderson, L.E.; Hilton, D.I.; Phillips, R.D.

Serotonin and two of its metabolites, melatonin and 5-methoxytryptophol, exhibit circadian rhythmicity in the pineal gland. We recently reported a marked reduction in the normal night-time increase in melatonin concentration in the pineal glands of rats exposed to 60-Hz electric fields. Concomitant with the apparent abolition of melatonin rhythmicity, serotonin-N-acetyl transferase (SNAT) activity was suppressed. We have now conducted studies to determine if abolition of the rhythm in melatonin production in electric-field-exposed rats arises solely from interference in SNAT activity, or if the availability of pineal serotonin is a factor that is affected by exposure. Pineal serotonin concentrations were comparedmore » in rats that were either exposed or sham exposed to 65 kV/m for 30 days. Sham-exposed animals exhibited normal diurnal rhythmicity for pineal concentrations of both melatonin and serotonin; melatonin levels increased markedly during the dark phase with a concurrent decrease in serotonin levels. In the exposed animals, however, normal serotonin rhythmicity was abolished; serotonin levels in these animals did not increase during the light period. The conclusion that electric field exposure results in a biochemical alteration in SNAT enzyme activity can be inferred from the loss of both serotonin and melatonin rhythmicity, as well as by direct measurement of SNAT activity itself. 35 references, 3 figures, 1 table.« less

Serotonin and conditioning: focus on Pavlovian psychostimulant drug conditioning.

PubMed

Carey, Robert J; Damianopoulos, Ernest N

2015-04-01

Serotonin containing neurons are located in nuclei deep in the brainstem and send axons throughout the central nervous system from the spinal cord to the cerebral cortex. The vast scope of these connections and interactions enable serotonin and serotonin analogs to have profound effects upon sensory/motor processes. In that conditioning represents a neuroplastic process that leads to new sensory/motor connections, it is apparent that the serotonin system has the potential for a critical role in conditioning. In this article we review the basics of conditioning as well as the serotonergic system and point up the number of non-associative ways in which manipulations of serotonin neurotransmission have an impact upon conditioning. We focus upon psychostimulant drug conditioning and review the contribution of drug stimuli in the use of serotonin drugs to investigate drug conditioning and the important impact drug stimuli can have on conditioning by introducing new sensory stimuli that can create or mask a CS. We also review the ways in which experimental manipulations of serotonin can disrupt conditioned behavioral effects but not the associative processes in conditioning. In addition, we propose the use of the recently developed memory re-consolidation model of conditioning as an approach to assess the possible role of serotonin in associative processes without the complexities of performance effects related to serotonin treatment induced alterations in sensory/motor systems. Copyright © 2014 Elsevier B.V. All rights reserved.

Organization of monosynaptic inputs to the serotonin and dopamine neuromodulatorysystems

PubMed Central

Ogawa, Sachie K.; Cohen, Jeremiah Y.; Hwang, Dabin; Uchida, Naoshige; Watabe-Uchida, Mitsuko

2014-01-01

SUMMARY Serotonin and dopamine are major neuromodulators. Here we used a modified rabies virus to identify monosynaptic inputs to serotonin neurons in the dorsal and median raphe (DR and MR). We found that inputs to DR and MR serotonin neurons are spatially shiftedin the forebrain, with MRserotonin neurons receiving inputs from more medial structures. We then compared these data with inputs to dopamine neurons in the ventral tegmental area (VTA) and substantianigra pars compacta (SNc). We found that DR serotonin neurons receive inputs from a remarkably similar set of areas as VTA dopamine neurons, apart from the striatum, which preferentially targets dopamine neurons. Ourresults suggest three majorinput streams: amedial stream regulates MR serotonin neurons, anintermediate stream regulatesDR serotonin and VTA dopamine neurons, and alateral stream regulatesSNc dopamine neurons. These results providefundamental organizational principlesofafferent control forserotonin and dopamine. PMID:25108805

Dextromethorphan, chlorphenamine and serotonin toxicity: case report and systematic literature review

PubMed Central

Monte, Andrew A; Chuang, Ryan; Bodmer, Michael

2010-01-01

The aim of this review was to describe a patient with serotonin toxicity after an overdose of dextromethorphan and chlorphenamine and to perform a systematic literature review exploring whether dextromethorphan and chlorphenamine may be equally contributory in the development of serotonin toxicity in overdose. A Medline literature review was undertaken to identify cases of serotonin toxicity due to dextromethorphan and/or chlorphenamine. Case reports were included if they included information on the ingested dose or plasma concentrations of dextromethorphan and/or chlorphenamine, information about co-ingestions and detailed clinical information to evaluate for serotonin toxicity. Cases were reviewed by two toxicologists and serotonin toxicity, defined by the Hunter criteria, was diagnosed when appropriate. The literature was then reviewed to evaluate whether chlorphenamine may be a serotonergic agent. One hundred and fifty-five articles of dextromethorphan or chlorphenamine poisoning were identified. There were 23 case reports of dextromethorphan, of which 18 were excluded for lack of serotonin toxicity. No cases were identified in which serotonin toxicity could be solely attributed to chlorphenamine. This left six cases of dextrometorphane and/or chlorphenamine overdose, including our own, in which serotonin toxicity could be diagnosed based on the presented clinical information. In three of the six eligible cases dextromethorphan and chlorphenamine were the only overdosed drugs. There is substantial evidence from the literature that chlorphenamine is a similarly potent serotonin re-uptake inhibitor when compared with dextrometorphan. Chlorphenamine is a serotonergic medication and combinations of chlorphenamine and dextromethorphan may be dangerous in overdose due to an increased risk of serotonin toxicity. PMID:21175434

The level of serotonin in the superficial masseter muscle in relation to local pain and allodynia.

PubMed

Ernberg, M; Hedenberg-Magnusson, B; Alstergren, P; Kopp, S

1999-01-01

The aim of this study was to investigate if serotonin is present in the human masseter muscle and if so, whether it is involved in the modulation of local muscle pain or allodynia. Thirty-five patients with pain and tenderness of the masseter muscle as well as ten healthy individuals were included in the study. Of the patients, 18 suffered from fibromyalgia and 17 had localized myalgia, e.g. myofascial pain in the temporomandibular system. The participants were examined clinically with special consideration to the masseter muscle and the pressure pain threshold as well as tolerance levels of this muscle were assessed. Intramuscular microdialysis was performed in order to sample serotonin and a venous blood sample was collected for analysis of the serum level of serotonin. Serotonin was present in the masseter muscle and the level was significantly higher in the initial sample than in the sample collected during steady state. The level of serotonin in the masseter muscle in relation to the level of serotonin in the blood serum was calculated. This fraction of serotonin was higher in the patients with fibromyalgia than in healthy individuals and high level of serotonin was associated with pain as well as allodynia of the masseter muscle. In conclusion, the results of this study show that serotonin is present in the human masseter muscle both immediately following puncture and in a subsequent steady state and that it is associated with pain and allodynia. The origin of the serotonin seems partly to be the blood, but our results indicate that peripheral release also occurs.

Hyperserotoninemia and Antiserotonin Antibodies in Autism and Other Disorders.

ERIC Educational Resources Information Center

Yuwiler, Arthur; And Others

1992-01-01

This study examined the linkage between elevated blood serotonin in autism and the presence of circulating autoantibodies against the serotonin 5HT receptor. Results showed elevated blood serotonin was not closely related to inhibition of serotonin binding by antibody-rich blood fractions. Data were insufficient to determine whether people with…

Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-β levels in early-stage Alzheimer's-like disease in mice.

PubMed

von Linstow, Christian Ulrich; Waider, Jonas; Grebing, Manuela; Metaxas, Athanasios; Lesch, Klaus Peter; Finsen, Bente

2017-09-12

Dysfunction of the serotonergic (5-HTergic) system has been implicated in the cognitive and behavioural symptoms of Alzheimer's disease (AD). Accumulation of toxic amyloid-β (Aβ) species is a hallmark of AD and an instigator of pathology. Serotonin (5-HT) augmentation therapy by treatment with selective serotonin reuptake inhibitors (SSRIs) in patients with AD has had mixed success in improving cognitive function, whereas SSRI administration to mice with AD-like disease has been shown to reduce Aβ pathology. The objective of this study was to investigate whether an increase in extracellular levels of 5-HT induced by chronic SSRI treatment reduces Aβ pathology and whether 5-HTergic deafferentation of the cerebral cortex could worsen Aβ pathology in the APP swe /PS1 ΔE9 (APP/PS1) mouse model of AD. We administered a therapeutic dose of the SSRI escitalopram (5 mg/kg/day) in the drinking water of 3-month-old APP/PS1 mice to increase levels of 5-HT, and we performed intracerebroventricular injections of the neurotoxin 5,7-dihydroxytryptamine (DHT) to remove 5-HTergic afferents. We validated the effectiveness of these interventions by serotonin transporter autoradiography (neocortex 79.7 ± 7.6%) and by high-performance liquid chromatography for 5-HT (neocortex 64% reduction). After 6 months of escitalopram treatment or housing after DHT-induced lesion, we evaluated brain tissue by mesoscale multiplex analysis and sections by IHC analysis. Amyloid-β-containing plaques had formed in the neocortex and hippocampus of 9-month-old APP/PS1 mice after 6 months of escitalopram treatment and 5-HTergic deafferentation. Unexpectedly, levels of insoluble Aβ42 were unaffected in the neocortex and hippocampus after both types of interventions. Levels of insoluble Aβ40 increased in the neocortex of SSRI-treated mice compared with those treated with vehicle control, but they were unaffected in the hippocampus. 5-HTergic deafferentation was without effect on the levels of insoluble/soluble Aβ42 and Aβ40 in both the neocortex and hippocampus. However, levels of soluble amyloid precursor protein α were reduced in the neocortex after 5-HTergic deafferentation. Because this study shows that modulation of the 5-HTergic system has either no effect or increases levels of insoluble/soluble Aβ42 and Aβ40 in the cerebral cortex of APP/PS1 mice, our observations do not support 5-HT augmentation therapy as a preventive strategy for reducing Aβ pathology.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gerthoffer, W.T.; Murphey, K.A.; Khoyi, M.A.

Previous studies have shown that muscarinic activation of airway smooth muscle in low Ca++ solutions increases myosin phosphorylation without increasing tension. Blocking Ca++ influx reduced phosphorylation, but not to basal levels. It was proposed that release of intracellular Ca++ contributed to dissociation of phosphorylation and contraction. To test this hypothesis the effects of ryanodine were studied under similar conditions. Ryanodine (10(-7) to 10(-5) M) antagonized caffeine-induced contraction of canine tracheal smooth muscle. Ryanodine also reduced carbachol-induced contractions and carbachol-induced myosin phosphorylation. The effect of ryanodine on potassium and serotonin-induced contractions was also investigated to test for a nonspecific inhibitory effect.more » In contrast to the effect on carbachol responses, ryanodine (10(-5) M) potentiated the contractile response to low concentrations of serotonin and potassium, but had no effect on the maximum response to either stimulant. Carbachol (10(-6) M) and ryanodine (10(-5) M) both significantly decreased /sup 45/Ca++ content of tracheal muscle. The effect of ryanodine and carbachol together on /sup 45/Ca++ content was not greater than either drug alone suggesting that ryanodine reduces the caffeine and carbachol responses by depleting releaseable Ca++ stores. Ryanodine significantly reduced Ca++-induced contraction and myosin phosphorylation in carbachol-stimulated muscle, suggesting that some of the Ca++ responsible for elevated phosphorylation is released from the sarcoplasmic reticulum.« less

Disturbed Neurotransmitter Transporter Expression in Alzheimer Disease Brain

PubMed Central

Chen, Kevin H.; Reese, Edmund A.; Kim, Hyung-Wook; Rapoport, Stanley I.; Rao, Jagadeesh S.

2011-01-01

Alzheimer disease (AD) is a neurodegenerative disorder characterized by memory loss and behavioral and psychological symptoms of dementia. An imbalance of different neurotransmitters – glutamate, acetylcholine, dopamine, and serotonin - has been proposed as the neurobiological basis of behavioral symptoms in AD. The molecular changes associated with neurotransmission imbalance in AD are not clear. We hypothesized that altered reuptake of neurotransmitters by vesicular glutamate transporters (VGLUTs), excitatory amino acid transporters (EAATs), the vesicular acetylcholine transporter (VAChT), the serotonin reuptake transporter (SERT), or the dopamine reuptake transporter (DAT)) are involved in the neurotransmission imbalance in AD. We tested this hypothesis by examining protein and mRNA levels of these transporters in postmortem prefrontal cortex from 10 AD patients and 10 matched non-AD controls. Compared with controls, protein and mRNA levels of VGLUTs, EAAT1–3, VAChT, and SERT were reduced significantly in AD. Expression of DAT and catechol O-methyltransferase (COMT) was unchanged. Reduced VGLUTs and EAATs may contribute to an alteration in glutamatergic recycling, and reduced SERT could exacerbate depressive symptoms in AD. The reduced VAChT expression could contribute to the recognized cholinergic deficit in AD. Altered neurotransmitter transporters could contribute to the pathophysiology of AD and are potential targets for therapy. PMID:21743130

Mice with reduced brain-derived neurotrophic factor expression show decreased choline acetyltransferase activity, but regular brain monoamine levels and unaltered emotional behavior.

PubMed

Chourbaji, Sabine; Hellweg, Rainer; Brandis, Dorothee; Zörner, Björn; Zacher, Christiane; Lang, Undine E; Henn, Fritz A; Hörtnagl, Heide; Gass, Peter

2004-02-05

The "neurotrophin hypothesis" of depression predicts that depressive disorders in humans coincide with a decreased activity and/or expression of brain-derived neurotrophic factor (BDNF) in the brain. Therefore, we investigated whether mice with a reduced BDNF expression due to heterozygous gene disruption demonstrate depression-like neurochemical changes or behavioral symptoms. BNDF protein levels of adult BDNF(+/-) mice were reduced to about 60% in several brain areas investigated, including the hippocampus, frontal cortex, striatum, and hypothalamus. The content of monoamines (serotonin, norepinephrine, and dopamine) as well as of serotonin and dopamine degradation products was unchanged in these brain regions. By contrast, choline acetyltransferase activity was significantly reduced by 19% in the hippocampus of BDNF(+/-) mice, indicating that the cholinergic system of the basal forebrain is critically dependent on sufficient endogenous BDNF levels in adulthood. Moreover, BDNF(+/-) mice exhibited normal corticosterone and adrenocorticotropic hormone (ACTH) serum levels under baseline conditions and following immobilization stress. In a panel of behavioral tests investigating locomotor activity, exploration, anxiety, fear-associated learning, and behavioral despair, BDNF(+/-) mice were indistinguishable from wild-type littermates. Thus, a chronic reduction of BDNF protein content in adult mice is not sufficient to induce neurochemical or behavioral alterations that are reminiscent of depressive symptoms in humans.

Effect of chronic D-fenfluramine administration on rat hypothalamic serotonin levels and release

NASA Technical Reports Server (NTRS)

Schaechter, Judith D.; Wurtman, Richard J.

1989-01-01

The effect of administering to rats (in doses of 1.25, 2.5, 5, or 10 mg/kg/day for 10 days) of an anorectic agent, D-fenfluramine, on the serotonin levels in hypothalamic tissue and on the in vitro release of serotonin by hypothalamic slices was investigated in rats which were sacrificed six days after the end of treatment. It was found that D-fenfuramine had no effect on tissue serotonin in doses from 1.25 to 5 mg/kg. However, given at 10 mg/kg level, serotonin led to a 22 percent decrease. The release of serotonin was found to be not affected by D-fenfluramine.

Peripheral Serotonin: a New Player in Systemic Energy Homeostasis

PubMed Central

Namkung, Jun; Kim, Hail; Park, Sangkyu

2015-01-01

Whole body energy balance is achieved through the coordinated regulation of energy intake and energy expenditure in various tissues including liver, muscle and adipose tissues. A positive energy imbalance by excessive energy intake or insufficient energy expenditure results in obesity and related metabolic diseases. Although there have been many obesity treatment trials aimed at the reduction of energy intake, these strategies have achieved only limited success because of their associated adverse effects. An ancient neurotransmitter, serotonin is among those traditional pharmacological targets for anti-obesity treatment because it exhibits strong anorectic effect in the brain. However, recent studies suggest the new functions of peripheral serotonin in energy homeostasis ranging from the endocrine regulation by gut-derived serotonin to the autocrine/paracrine regulation by adipocyte-derived serotonin. Here, we discuss the role of serotonin in the regulation of energy homeostasis and introduce peripheral serotonin as a possible target for anti-obesity treatment. PMID:26628041

Plasma levels of serotonin, gastrointestinal symptoms,and sleep problems in children with autism.

PubMed

Kheirouri, Sorayya; Kalejahi, Parinaz; Noorazar, Seyyed Gholamreza

2016-12-20

Autism is a neurodevelopmental disorder identified with higher frequency of serotonin abnormalities and gastrointestinal (GI) and sleep problems. This study aimed to evaluate the plasma levels of serotonin, GI symptoms, and sleep problems, and their relationship with autism severity in children with autism. Thirty-five children with autism and 31 healthy subjects were studied. GI problems, sleep disorders, and severity of disorder were assessed. Plasma serotonin was determined using ELISA. There was no significant association between GI problems and autism severity, but a significant positive correlation was seen between different indicators of sleep disorder and severity of autism. Plasma levels of serotonin were significantly higher in autistic children and a significant negative correlation was observed between plasma levels of serotonin and autism severity (r = -0.39, P = 0.02). Elevated plasma serotonin in autistic children and its negative correlation with disease severity may indicate involvement of the neurotransmitter in the neurophysiologic mechanism of autism.

Demonstration of clomipramine and venlafaxine occupation at serotonin reuptake sites in man in vivo.

PubMed

Malizia, A L; Melichar, J M; Brown, D J; Gunn, R N; Reynolds, A; Jones, T; Nutt, D J

1997-01-01

We describe the use of 11CRTI-55 and the Multiple Objects Coincidences Counter (MOCC) to detect in-vivo binding to peripheral serotonin reuptake sites (left chest comprising platelet and lung serotonin reuptake sites) in man. Displacement and preloading experiments with clomipramine and venlafaxine in two healthy volunteers demonstrated that 11CRTI-55 binding is decreased in a dose-dependent fashion by both these drugs which bind to the serotonin transporter. In addition parallel data from the total head curve (representing 11CRTI-55 binding to central serotonin and dopamine (DA) reuptake sites) suggest that prior blockade of the serotonin transporter may be a useful strategy to maximize radioactive counts in the head when measuring the DA transporter. The MOCC is likely to be useful to determine sequential indices of relative serotonin reuptake blockade in patients on treatment.

The Serotonin 2C Receptor Agonist Lorcaserin Attenuates Intracranial Self-Stimulation and Blocks the Reward-Enhancing Effects of Nicotine.

PubMed

Zeeb, Fiona D; Higgins, Guy A; Fletcher, Paul J

2015-07-15

Lorcaserin, a serotonin (5-hydroxytryptamine, 5-HT) 2C receptor agonist, was recently approved for the treatment of obesity. We previously suggested that 5-HT2C receptor agonists affect reward processes and reduce the rewarding effects of drugs of abuse. Here, we determined whether lorcaserin (1) decreases responding for brain stimulation reward (BSR) and (2) prevents nicotine from enhancing the efficacy of BSR. Rats were trained on the intracranial self-stimulation (ICSS) paradigm to nosepoke for BSR of either the dorsal raphé nucleus or left medial forebrain bundle. In Experiment 1, lorcaserin (0.3-1.0 mg/kg) dose-dependently reduced the efficacy of BSR. This effect was blocked by prior administration of the 5-HT2C receptor antagonist SB242084. In Experiment 2, separate groups of rats received saline or nicotine (0.4 mg/kg) for eight sessions prior to testing. Although thresholds were unaltered in saline-treated rats, nicotine reduced reward thresholds. An injection of lorcaserin (0.3 mg/kg) prior to nicotine prevented the reward-enhancing effect of nicotine across multiple test sessions. These results demonstrated that lorcaserin reduces the rewarding value of BSR and also prevents nicotine from facilitating ICSS. Hence, lorcaserin may be effective in treating psychiatric disorders, including obesity and nicotine addiction, by reducing the value of food or drug rewards.

21 CFR 862.1390 - 5-Hydroxyindole acetic acid/serotonin test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false 5-Hydroxyindole acetic acid/serotonin test system... Test Systems § 862.1390 5-Hydroxyindole acetic acid/serotonin test system. (a) Identification. A 5-hydroxyindole acetic acid/serotonin test system is a device intended to measure 5-hydroxyindole acetic acid...

21 CFR 862.1390 - 5-Hydroxyindole acetic acid/serotonin test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false 5-Hydroxyindole acetic acid/serotonin test system... Test Systems § 862.1390 5-Hydroxyindole acetic acid/serotonin test system. (a) Identification. A 5-hydroxyindole acetic acid/serotonin test system is a device intended to measure 5-hydroxyindole acetic acid...

21 CFR 862.1390 - 5-Hydroxyindole acetic acid/serotonin test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false 5-Hydroxyindole acetic acid/serotonin test system... Test Systems § 862.1390 5-Hydroxyindole acetic acid/serotonin test system. (a) Identification. A 5-hydroxyindole acetic acid/serotonin test system is a device intended to measure 5-hydroxyindole acetic acid...

21 CFR 862.1390 - 5-Hydroxyindole acetic acid/serotonin test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false 5-Hydroxyindole acetic acid/serotonin test system... Test Systems § 862.1390 5-Hydroxyindole acetic acid/serotonin test system. (a) Identification. A 5-hydroxyindole acetic acid/serotonin test system is a device intended to measure 5-hydroxyindole acetic acid...

THE RELATIONSHIP BETWEEN WHOLE BLOOD SEROTONIN AND REPETITIVE BEHAVIORS IN AUTISM

PubMed Central

Kolevzon, Alexander; Newcorn, Jeffrey H.; Kryzak, Lauren; Chaplin, William; Watner, Dryden; Hollander, Eric; Smith, Christopher J.; Cook, Edwin H.; Silverman, Jeremy M.

2009-01-01

This study was conducted to examine the relationship between whole blood serotonin level and behavioral symptoms in 78 subjects with autism. No significant associations were found between serotonin level and the primary behavioral outcome measures. However, a significant inverse relationship between serotonin level and self-injury was demonstrated. PMID:20044143

Association of Serotonin Concentration to Behavior and IQ in Autistic Children.

ERIC Educational Resources Information Center

Kuperman, Samuel; And Others

1987-01-01

The IQ and behavior patterns on the Autism Behavior Checklist (ABC) of 25 boys were compared to blood concentrations of platelet rich plasma (PRP) serotonin. Although no correlations were found between serotonin levels and IQ or ABC scales, four individual ABC items did correlate with serotonin concentrations. (Author/DB)

Different components of /sup 3/H-imipramine binding in rat brain membranes: relation to serotonin uptake sites

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gobbi, M.; Taddei, C.; Mennini, T.

1988-01-01

In the present paper, the authors confirm and extend previous studies showing heterogeneous /sup 3/H-imipramine (/sup 3/H-IMI) binding sites. Inhibition curves of various drugs (serotonin, imipramine, desmethyl-imipramine, d-fenfluramine, d-norfenfluramine and indalpine, a potent serotonin uptake inhibitor) obtained using 2 nM /sup 3/H-IMI and in presence of 120 mM NaCl, confirmed the presence of at least three /sup 3/H-IMI binding sites: two of these were serotonin-insensitive while the third one was selectively inhibited by serotonin and indalpine with nanomolar affinities. Moreover this last component was found to be selectively modulated by chronic imipramine treatment thus suggesting a close relation to serontoninmore » uptake mechanism. These data indicate that the use of a more selective inhibitors of the serotonin-sensitive component (like indalpine or serotonin itself) to define non specific /sup 3/H-IMI, may be of help in understanding its relation with serotonin uptake system. 22 references, 2 figures, 2 tables.« less

Serotonin levels in platelet-poor plasma and whole blood in people with type 2 diabetes with chronic kidney disease.

PubMed

Hara, Katsuko; Hirowatari, Yuji; Shimura, Yuko; Takahashi, Hakuo

2011-11-01

Patients with diabetes mellitus (DM) are prone to atherosclerosis. Atherosclerosis activates platelets; activated platelets release serotonin, and therefore, evaluation of serotonin levels in blood could be a valuable biomarker for future risk of cardiovascular events. Plasma serotonin levels obtained from patients with DM complicated with chronic kidney disease were measured using HPLC and were compared to serotonin levels of healthy control subjects. Patients with DM were classified into 2 subgroups of mildly (group 1) and moderately/severely (group 2) impaired renal function. Serotonin concentration in platelet-poor plasma for group 1 was significantly higher than that of healthy control subjects (p < 0.01), and was significantly higher than that of patients from group 2 (p < 0.05). The concentration of serotonin in whole blood for group 2 patients was significantly lower than that measured from healthy control subjects (p < 0.01). The ratio of the plasma to whole blood level was significantly elevated in both groups 1 and 2 compared with healthy controls (p < 0.01). Our results indicate that platelets are activated to release serotonin into plasma in diabetic patients with mildly impaired renal function. When renal damage is advanced, platelets are over-activated to release serotonin. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Anorectic activities of serotonin uptake inhibitors: correlation with their potencies at inhibiting serotonin uptake in vivo and /sup 3/H-mazindol binding in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Angel, I.; Taranger, M.A.; Claustre, Y.

1988-01-01

The mechanism of anorectic action of several serotonin uptake inhibitors was investigated by comparing their anorectic potencies with several biochemical and pharmacological properties and in reference to the novel compound SL 81.0385. The anorectic effect of the potent serotonin uptake inhibitor SL 81.0385 was potentiated by pretreatment with 5-hydroxytryptophan and blocked by the serotonin receptor antagonist metergoline. A good correlation was obtained between the ED/sub 50/ values of anorectic action and the ED/sub 50/ values of serotonin uptake inhibition in vivo (but not in vitro) for several specific serotonin uptake inhibitors. Most of the drugs tested displaced (/sup 3/H)-mazindol frommore » its binding to the anorectic recognition site in the hypothalamus, except the pro-drug zimelidine which was inactive. Excluding zimelidine, a good correlation was obtained between the affinities of these drugs for (/sup 3/H)-mazindol binding and their anorectic action indicating that their anorectic activity may be associated with an effect mediated through this site. Taken together these results suggest that the anorectic action of serotonin uptake inhibitors is directly associated to their ability to inhibit serotonin uptake and thus increasing the synaptic levels of serotonin. The interactions of these drugs with the anorectic recognition site labelled with (/sup 3/H)-mazindol is discussed in connection with the serotonergic regulation of carbohydrate intake.« less

The Role of Serotonin in Ventricular Repolarization in Pregnant Mice

PubMed Central

Park, Hyelim; Mun, Dasom; Lee, Seung-Hyun; Kim, Hyoeun; Yun, Nuri; Kim, Hail; Kim, Michael; Pak, Hui-Nam; Lee, Moon-Hyoung

2018-01-01

Purpose The mechanisms underlying repolarization abnormalities during pregnancy are not fully understood. Although maternal serotonin (5-hydroxytryptamine, 5-HT) production is an important determinant for normal fetal development in mice, its role in mothers remains unclear. We evaluated the role of serotonin in ventricular repolarization in mice hearts via 5Htr3 receptor (Htr3a) and investigated the mechanism of QT-prolongation during pregnancy. Materials and Methods We measured current amplitudes and the expression levels of voltage-gated K+ (Kv) channels in freshly-isolated left ventricular myocytes from wild-type non-pregnant (WT-NP), late-pregnant (WT-LP), and non-pregnant Htr3a homozygous knockout mice (Htr3a−/−-NP). Results During pregnancy, serotonin and tryptophan hydroxylase 1, a rate-limiting enzyme for the synthesis of serotonin, were markedly increased in hearts and serum. Serotonin increased Kv current densities concomitant with the shortening of the QT interval in WT-NP mice, but not in WT-LP and Htr3a−/−-NP mice. Ondansetron, an Htr3 antagonist, decreased Kv currents in WT-LP mice, but not in WT-NP mice. Kv4.3 directly interacted with Htr3a, and this binding was facilitated by serotonin. Serotonin increased the trafficking of Kv4.3 channels to the cellular membrane in WT-NP. Conclusion Serotonin increases repolarizing currents by augmenting Kv currents. Elevated serotonin levels during pregnancy counterbalance pregnancy-related QT prolongation by facilitating Htr3-mediated Kv currents. PMID:29436197

Serotonin-induced contractile responses of esophageal smooth muscle in the house musk shrew (Suncus murinus).

PubMed

Shiina, T; Naitou, K; Nakamori, H; Suzuki, Y; Horii, K; Sano, Y; Shimaoka, H; Shimizu, Y

2016-11-01

Serotonin (5-hydroxytryptamine, 5-HT) is a regulatory factor in motility of the gastrointestinal tract including the esophagus. Although we proposed that vagal cholinergic and mast cell-derived non-cholinergic components including serotonin coordinately shorten the esophagus, the precise mechanism of serotonin-induced contractions in the suncus esophagus is still unclear. Therefore, the aims of this study were to determine characteristics of contractile responses induced by serotonin and to identify 5-HT receptor subtypes responsible for regulating motility in the suncus esophagus. An isolated segment of the suncus esophagus was placed in an organ bath, and longitudinal or circular mechanical responses were recorded using a force transducer. Serotonin evoked contractile responses of the suncus esophagus in the longitudinal direction but not in the circular direction. Tetrodotoxin did not affect the serotonin-induced contractions. Pretreatment with a non-selective 5-HT receptor antagonist or double application of 5-HT 1 and 5-HT 2 receptor antagonists blocked the serotonin-induced contractions. 5-HT 1 and 5-HT 2 receptor agonists, but not a 5-HT 3 receptor agonist, evoked contractile responses in the suncus esophagus. The findings suggest that serotonin induces contractile responses of the longitudinal smooth muscle in the muscularis mucosae of the suncus esophagus that are mediated via 5-HT 1 and 5-HT 2 receptors on muscle cells. The serotonin-induced contractions might contribute to esophageal peristalsis and emetic response. © 2016 John Wiley & Sons Ltd.

Rotavirus and Serotonin Cross-Talk in Diarrhoea

PubMed Central

Nordgren, Johan; Karlsson, Thommie; Sharma, Sumit; Magnusson, Karl-Eric; Svensson, Lennart

2016-01-01

Rotavirus (RV) has been shown to infect and stimulate secretion of serotonin from human enterochromaffin (EC) cells and to infect EC cells in the small intestine of mice. It remains to identify which intracellularly expressed viral protein(s) is responsible for this novel property and to further establish the clinical role of serotonin in RV infection. First, we found that siRNA specifically silencing NSP4 (siRNANSP4) significantly attenuated secretion of serotonin from Rhesus rotavirus (RRV) infected EC tumor cells compared to siRNAVP4, siRNAVP6 and siRNAVP7. Second, intracellular calcium mobilization and diarrhoeal capacity from virulent and avirulent porcine viruses correlated with the capacity to release serotonin from EC tumor cells. Third, following administration of serotonin, all (10/10) infants, but no (0/8) adult mice, responded with diarrhoea. Finally, blocking of serotonin receptors using Ondansetron significantly attenuated murine RV (strain EDIM) diarrhoea in infant mice (2.9 vs 4.5 days). Ondansetron-treated mice (n = 11) had significantly (p < 0.05) less diarrhoea, lower diarrhoea severity score and lower total diarrhoea output as compared to mock-treated mice (n = 9). Similarly, Ondansetron-treated mice had better weight gain than mock-treated animals (p < 0.05). A most surprising finding was that the serotonin receptor antagonist significantly (p < 0.05) also attenuated total viral shedding. In summary, we show that intracellularly expressed NSP4 stimulates release of serotonin from human EC tumor cells and that serotonin participates in RV diarrhoea, which can be attenuated by Ondansetron. PMID:27459372

Regulation of Bone Metabolism by Serotonin.

PubMed

Lavoie, Brigitte; Lian, Jane B; Mawe, Gary M

2017-01-01

The processes of bone growth and turnover are tightly regulated by the actions of various signaling molecules, including hormones, growth factors, and cytokines. Imbalances in these processes can lead to skeletal disorders such as osteoporosis or high bone mass disease. It is becoming increasingly clear that serotonin can act through a number of mechanisms, and at different locations in the body, to influence the balance between bone formation and resorption. Its actions on bone metabolism can vary, based on its site of synthesis (central or peripheral) as well as the cells and subtypes of receptors that are activated. Within the central nervous system, serotonergic neurons act via the hypothalamus to suppress sympathetic input to the bone. Since sympathetic input inhibits bone formation, brain serotonin has a net positive effect on bone growth. Gut-derived serotonin is thought to inhibit bone growth by attenuating osteoblast proliferation via activation of receptors on pre-osteoblasts. There is also evidence that serotonin can be synthesized within the bone and act to modulate bone metabolism. Osteoblasts, osteoclasts, and osteocytes all have the machinery to synthesize serotonin, and they also express the serotonin-reuptake transporter (SERT). Understanding the roles of serotonin in the tightly balanced system of bone modeling and remodeling is a clinically relevant goal. This knowledge can clarify bone-related side effects of drugs that affect serotonin signaling, including serotonin-specific reuptake inhibitors (SSRIs) and receptor agonists and antagonists, and it can potentially lead to therapeutic approaches for alleviating bone pathologies.

The Role of Serotonin in Ventricular Repolarization in Pregnant Mice.

PubMed

Cui, Shanyu; Park, Hyewon; Park, Hyelim; Mun, Dasom; Lee, Seung Hyun; Kim, Hyoeun; Yun, Nuri; Kim, Hail; Kim, Michael; Pak, Hui Nam; Lee, Moon Hyoung; Joung, Boyoung

2018-03-01

The mechanisms underlying repolarization abnormalities during pregnancy are not fully understood. Although maternal serotonin (5-hydroxytryptamine, 5-HT) production is an important determinant for normal fetal development in mice, its role in mothers remains unclear. We evaluated the role of serotonin in ventricular repolarization in mice hearts via 5Htr3 receptor (Htr3a) and investigated the mechanism of QT-prolongation during pregnancy. We measured current amplitudes and the expression levels of voltage-gated K⁺ (Kv) channels in freshly-isolated left ventricular myocytes from wild-type non-pregnant (WT-NP), late-pregnant (WT-LP), and non-pregnant Htr3a homozygous knockout mice (Htr3a(-/-)-NP). During pregnancy, serotonin and tryptophan hydroxylase 1, a rate-limiting enzyme for the synthesis of serotonin, were markedly increased in hearts and serum. Serotonin increased Kv current densities concomitant with the shortening of the QT interval in WT-NP mice, but not in WT-LP and Htr3a(-/-)-NP mice. Ondansetron, an Htr3 antagonist, decreased Kv currents in WT-LP mice, but not in WT-NP mice. Kv4.3 directly interacted with Htr3a, and this binding was facilitated by serotonin. Serotonin increased the trafficking of Kv4.3 channels to the cellular membrane in WT-NP. Serotonin increases repolarizing currents by augmenting Kv currents. Elevated serotonin levels during pregnancy counterbalance pregnancy-related QT prolongation by facilitating Htr3-mediated Kv currents. © Copyright: Yonsei University College of Medicine 2018

Serotonin Control of Thermotaxis Memory Behavior in Nematode Caenorhabditis elegans

PubMed Central

Guo, Yuling; Wang, Daoyong; Li, Chaojun; Wang, Dayong

2013-01-01

Caenorhabditis elegans is as an ideal model system for the study of mechanisms underlying learning and memory. In the present study, we employed C. elegans assay system of thermotaxis memory to investigate the possible role of serotonin neurotransmitter in memory control. Our data showed that both mutations of tph-1, bas-1, and cat-4 genes, required for serotonin synthesis, and mutations of mod-5 gene, encoding a serotonin reuptake transporter, resulted in deficits in thermotaxis memory behavior. Exogenous treatment with serotonin effectively recovered the deficits in thermotaxis memory of tph-1 and bas-1 mutants to the level of wild-type N2. Neuron-specific activity assay of TPH-1 suggests that serotonin might regulate the thermotaxis memory behavior by release from the ADF sensory neurons. Ablation of ADF sensory neurons by expressing a cell-death activator gene egl-1 decreased the thermotaxis memory, whereas activation of ADF neurons by expression of a constitutively active protein kinase C homologue (pkc-1(gf)) increased the thermotaxis memory and rescued the deficits in thermotaxis memory in tph-1 mutants. Moreover, serotonin released from the ADF sensory neurons might act through the G-protein-coupled serotonin receptors of SER-4 and SER-7 to regulate the thermotaxis memory behavior. Genetic analysis implies that serotonin might further target the insulin signaling pathway to regulate the thermotaxis memory behavior. Thus, our results suggest the possible crucial role of serotonin and ADF sensory neurons in thermotaxis memory control in C. elegans. PMID:24223727

Serotonin produces monoamine oxidase-dependent oxidative stress in human heart valves.

PubMed

Peña-Silva, Ricardo A; Miller, Jordan D; Chu, Yi; Heistad, Donald D

2009-10-01

Heart valve disease and pulmonary hypertension, in patients with carcinoid tumors and people who used the fenfluramine-phentermine combination for weight control, have been associated with high levels of serotonin in blood. The mechanism by which serotonin induces valvular changes is not well understood. We recently reported that increased oxidative stress is associated with valvular changes in aortic valve stenosis in humans and mice. In this study, we tested the hypothesis that serotonin induces oxidative stress in human heart valves, and examined mechanisms by which serotonin may increase reactive oxygen species. Superoxide (O2*.-) was measured in heart valves from explanted human hearts that were not used for transplantation. (O2*.-) levels (lucigenin-enhanced chemoluminescence) were increased in homogenates of cardiac valves and blood vessels after incubation with serotonin. A nonspecific inhibitor of flavin-oxidases (diphenyliodonium), or inhibitors of monoamine oxidase [MAO (tranylcypromine and clorgyline)], prevented the serotonin-induced increase in (O2*.-). Dopamine, another MAO substrate that is increased in patients with carcinoid syndrome, also increased (O2*.-) levels in heart valves, and this effect was attenuated by clorgyline. Apocynin [an inhibitor of NAD(P)H oxidase] did not prevent increases in (O2*.-) during serotonin treatment. Addition of serotonin to recombinant human MAO-A generated (O2*.-), and this effect was prevented by an MAO inhibitor. In conclusion, we have identified a novel mechanism whereby MAO-A can contribute to increased oxidative stress in human heart valves and pulmonary artery exposed to serotonin and dopamine.

Altered Cav1.2 function in the Timothy syndrome mouse model produces ascending serotonergic abnormalities.

PubMed

Ehlinger, Daniel G; Commons, Kathryn G

2017-10-01

Polymorphism in the gene CACNA1C, encoding the pore-forming subunit of Cav1.2 L-type calcium channels, has one of the strongest genetic linkages to schizophrenia, bipolar disorder and major depressive disorder: psychopathologies in which serotonin signaling has been implicated. Additionally, a gain-of-function mutation in CACNA1C is responsible for the neurodevelopmental disorder Timothy syndrome that presents with prominent behavioral features on the autism spectrum. Given an emerging role for serotonin in the etiology of autism spectrum disorders (ASD), we investigate the relationship between Cav1.2 and the ascending serotonin system in the Timothy syndrome type 2 (TS2-neo) mouse, which displays behavioral features consistent with the core triad of ASD. We find that TS2-neo mice exhibit enhanced serotonin tissue content and axon innervation of the dorsal striatum, as well as decreased serotonin turnover in the amygdala. These regionally specific alterations are accompanied by an enhanced active coping response during acute stress (forced swim), serotonin neuron Fos activity in the caudal dorsal raphe, and serotonin type 1A receptor-dependent feedback inhibition of the rostral dorsal raphe nuclei. Collectively, these results suggest that the global gain-of-function Cav1.2 mutation associated with Timothy syndrome has pleiotropic effects on the ascending serotonin system including neuroanatomical changes, regional differences in forebrain serotonin metabolism and feedback regulatory control mechanisms within the dorsal raphe. Altered activity of the ascending serotonin system continues to emerge as a common neural signature across several ASD mouse models, and the capacity for Cav1.2 L-type calcium channels to impact both serotonin structure and function has important implications for several neuropsychiatric conditions. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Serotonin transporter occupancy by escitalopram and citalopram in the non-human primate brain: a [(11)C]MADAM PET study.

PubMed

Finnema, Sjoerd J; Halldin, Christer; Bang-Andersen, Benny; Bundgaard, Christoffer; Farde, Lars

2015-11-01

A number of serotonin receptor positron emission tomography (PET) radioligands have been shown to be sensitive to changes in extracellular serotonin concentration, in a generalization of the well-known dopamine competition model. High doses of selective serotonin reuptake inhibitors (SSRIs) decrease serotonin receptor availability in monkey brain, consistent with increased serotonin concentrations. However, two recent studies on healthy human subjects, using a single, lower and clinically relevant SSRI dose, showed increased cortical serotonin receptor radioligand binding, suggesting potential decreases in serotonin concentration in projection regions when initiating treatment. The cross-species differential SSRI effect may be partly explained by serotonin transporter (SERT) occupancy in monkey brain being higher than is clinically relevant. We here determine SERT occupancy after single doses of escitalopram or citalopram by conducting PET measurements with [(11)C]MADAM in monkeys. Relationships between dose, plasma concentration and SERT occupancy were estimated by one-site binding analyses. Binding affinity was expressed as dose (ID50) or plasma concentration (K i) where 50 % SERT occupancy was achieved. Estimated ID50 and K i values were 0.020 mg/kg and 9.6 nmol/L for escitalopram and 0.059 mg/kg and 9.7 nmol/L for citalopram, respectively. Obtained K i values are comparable to values reported in humans. Escitalopram or citalopram doses nearly saturated SERT in previous monkey studies which examined serotonin sensitivity of receptor radioligands. PET-measured cross-species differential effects of SSRI on cortical serotonin concentration may thus be related to SSRI dose. Future monkey studies using SSRI doses inducing clinically relevant SERT occupancy may further illuminate the delayed onset of SSRI therapeutic effects.

Senescence-Induced Serotonin Biosynthesis and Its Role in Delaying Senescence in Rice Leaves1[C][W][OA

PubMed Central

Kang, Kiyoon; Kim, Young-Soon; Park, Sangkyu; Back, Kyoungwhan

2009-01-01

Serotonin, which is well known as a pineal hormone in mammals, plays a key role in conditions such as mood, eating disorders, and alcoholism. In plants, although serotonin has been suggested to be involved in several physiological roles, including flowering, morphogenesis, and adaptation to environmental changes, its regulation and functional roles are as yet not characterized at the molecular level. In this study, we found that serotonin is greatly accumulated in rice (Oryza sativa) leaves undergoing senescence induced by either nutrient deprivation or detachment, and its synthesis is closely coupled with transcriptional and enzymatic induction of the tryptophan biosynthetic genes as well as tryptophan decarboxylase (TDC). Transgenic rice plants that overexpressed TDC accumulated higher levels of serotonin than the wild type and showed delayed senescence of rice leaves. However, transgenic rice plants, in which expression of TDC was suppressed through an RNA interference (RNAi) system, produced less serotonin and senesced faster than the wild type, suggesting that serotonin is involved in attenuating leaf senescence. The senescence-retarding activity of serotonin is associated with its high antioxidant activity compared to either tryptophan or chlorogenic acid. Results of TDC overexpression and TDC RNAi plants suggest that TDC plays a rate-limiting role for serotonin accumulation, but the synthesis of serotonin depends on an absolute amount of tryptophan accumulation by the coordinate induction of the tryptophan biosynthetic genes. In addition, immunolocalization analysis revealed that serotonin was abundant in the vascular parenchyma cells, including companion cells and xylem-parenchyma cells, suggestive of its involvement in maintaining the cellular integrity of these cells for facilitating efficient nutrient recycling from senescing leaves to sink tissues during senescence. PMID:19439571

Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder.

PubMed

Miller, Jeffrey M; Hesselgrave, Natalie; Ogden, R Todd; Sullivan, Gregory M; Oquendo, Maria A; Mann, J John; Parsey, Ramin V

2013-08-15

Several lines of evidence implicate abnormal serotonergic function in suicidal behavior and completed suicide, including low serotonin transporter binding in postmortem studies of completed suicide. We have also reported low in vivo serotonin transporter binding in major depressive disorder (MDD) during a major depressive episode using positron emission tomography (PET) with [(11)C]McN5652. We quantified regional brain serotonin transporter binding in vivo in depressed suicide attempters, depressed nonattempters, and healthy controls using PET and a superior radiotracer, [(11)C]DASB. Fifty-one subjects with DSM-IV current MDD, 15 of whom were past suicide attempters, and 32 healthy control subjects underwent PET scanning with [(11)C]DASB to quantify in vivo regional brain serotonin transporter binding. Metabolite-corrected arterial input functions and plasma free-fraction were acquired to improve quantification. Depressed suicide attempters had lower serotonin transporter binding in midbrain compared with depressed nonattempters (p = .031) and control subjects (p = .0093). There was no difference in serotonin transporter binding comparing all depressed subjects with healthy control subjects considering six a priori regions of interest simultaneously (p = .41). Low midbrain serotonin transporter binding appears to be related to the pathophysiology of suicidal behavior rather than of major depressive disorder. This is consistent with postmortem work showing low midbrain serotonin transporter binding capacity in depressed suicides and may partially explain discrepant in vivo findings quantifying serotonin transporter in depression. Future studies should investigate midbrain serotonin transporter binding as a predictor of suicidal behavior in MDD and determine the cause of low binding. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Decreased contractile response of peripheral arterioles to serotonin after CPB in patients with diabetes.

PubMed

Sabe, Sharif A; Feng, Jun; Liu, Yuhong; Scrimgeour, Laura A; Ehsan, Afshin; Sellke, Frank W

2018-05-11

Regulation of coronary vasomotor tone by serotonin is significantly changed after cardioplegic arrest and reperfusion. The current study investigates whether cardiopulmonary bypass may also affect peripheral arteriolar response to serotonin in patients with or without diabetes. Human peripheral microvessels (90-180 µm diameter) were dissected from harvested skeletal muscle tissues from diabetic and non-diabetic patients before and after cardiopulmonary bypass and cardiac surgery (n = 8/group). In vitro contractile response to serotonin was assessed by videomicroscopy in the presence or absence of serotonin alone (10 -9 -10 -5 M) or combined with the selective serotonin 1B receptor (5-HT1B) antagonist, SB224289 (10 -6 M). 5-HT1A/1B protein expression in the skeletal muscle was measured by Western-blot and immunohistochemistry. There were no significant differences in contractile response of peripheral arterioles to serotonin (10 -5 M) pre-cardiopulmonary bypass between diabetic and non-diabetic patients. After cardiopulmonary bypass, contractile response to serotonin was significantly impaired in both diabetic and non-diabetic patients compared to their pre-cardiopulmonary bypass counterparts (P < .05). This effect was more pronounced in diabetic patients than non-diabetic patients (P < .05 versus non-diabetic). The contractile response to serotonin was significantly inhibited by the 5-HT1B antagonist in both diabetic and non-diabetic vessels (P < .05 versus serotonin alone). There were no significant differences in the expression/distribution of 5-HT1A/1B between non-diabetic and diabetic groups or between pre- versus post- cardiopulmonary bypass vessels. Cardiopulmonary bypass is associated with decreased contractile response of peripheral arterioles to serotonin and this effect was exaggerated in the presence of diabetes. Serotonin-induced contractile response of the peripheral arterioles was via 5-HT1B in both diabetic and non-diabetic patients. Copyright © 2018 Elsevier Inc. All rights reserved.

Estradiol Valerate and Remifemin ameliorate ovariectomy-induced decrease in a serotonin dorsal raphe-preoptic hypothalamus pathway in rats.

PubMed

Wang, Wenjuan; Cui, Guangxia; Jin, Biao; Wang, Ke; Chen, Xing; Sun, Yu; Qin, Lihua; Bai, Wenpei

2016-11-01

Perimenopausal syndromes begin as ovarian function ceases and the most common symptoms are hot flushes. Data indicate that the projections of serotonin to hypothalamus may be involved in the mechanism of hot flushes. Therefore, the aim of this study is to investigate the potential role of the serotonin dorsal raphe-preoptic hypothalamus pathway for hot flushes in an animal model of menopause. We determined the changes in serotonin expression in the dorsal raphe (DR) and preoptic anterior hypothalamus (POAH) in ovariectomized rats. We also explored the therapeutical effects of estradiol valerate and Remifemin in this model. Eighty female Sprague-Dawley rats were randomly assigned to sham-operated (SHAM) group, ovariectomy (OVX) group with vehicle, ovariectomy with estradiol valerate treatment (OVX+E) group and ovariectomy with Remifemin (OVX+ICR) group. Serotonin expression was evaluated in the DR and POAH using immunofluorescence and quantified in the DR using an enzyme-linked immunosorbent assay (ELISA). Apoptosis was analyzed in the DR by TUNEL assay. The number of serotonin immunoreactive neurons and the level of serotonin expression in the DR decreased significantly following OVX compared to the SHAM group. No TUNEL-positive cells were detected in the DR in any group. In addition, following OVX, the number of serotonin-positive fibers decreased significantly in the ventromedial preoptic nucleus (VMPO), especially in the ventrolateral preoptic nucleus (VLPO). Treatment with either estradiol or Remifemin for 4 weeks countered the OVX-induced decreases in serotonin levels in both the DR and the hypothalamus, with levels in the treated rats similar to those in the SHAM group. A fluorescently labeled retrograde tracer was injected into the VLPO at the 4-week time point. A significantly lower percentage of serotonin with CTB double-labeled neurons in CTB-labeled neurons was demonstrated after ovariectomy, and both estradiol and Remifemin countered this OVX-induced decrease. We conclude that serotonin pathway is changed after ovariectomy, including the serotonin synthesis in DR and serotonin fibers in PO/AH, both E and Remifemin have an equivalent therapeutic effect on it. Copyright © 2016 Elsevier GmbH. All rights reserved.

Effect of diet on serotonergic neurotransmission in depression.

PubMed

Shabbir, Faisal; Patel, Akash; Mattison, Charles; Bose, Sumit; Krishnamohan, Raathathulaksi; Sweeney, Emily; Sandhu, Sarina; Nel, Wynand; Rais, Afsha; Sandhu, Ranbir; Ngu, Nguasaah; Sharma, Sushil

2013-02-01

Depression is characterized by sadness, purposelessness, irritability, and impaired body functions. Depression causes severe symptoms for several weeks, and dysthymia, which may cause chronic, low-grade symptoms. Treatment of depression involves psychotherapy, medications, or phototherapy. Clinical and experimental evidence indicates that an appropriate diet can reduce symptoms of depression. The neurotransmitter, serotonin (5-HT), synthesized in the brain, plays an important role in mood alleviation, satiety, and sleep regulation. Although certain fruits and vegetables are rich in 5-HT, it is not easily accessible to the CNS due to blood brain barrier. However the serotonin precursor, tryptophan, can readily pass through the blood brain barrier. Tryptophan is converted to 5-HT by tryptophan hydroxylase and 5-HTP decarboxylase, respectively, in the presence of pyridoxal phosphate, derived from vitamin B(6). Hence diets poor in tryptophan may induce depression as this essential amino acid is not naturally abundant even in protein-rich foods. Tryptophan-rich diet is important in patients susceptible to depression such as certain females during pre and postmenstrual phase, post-traumatic stress disorder, chronic pain, cancer, epilepsy, Parkinson's disease, Alzheimer's disease, schizophrenia, and drug addiction. Carbohydrate-rich diet triggers insulin response to enhance the bioavailability of tryptophan in the CNS which is responsible for increased craving of carbohydrate diets. Although serotonin reuptake inhibitors (SSRIs) are prescribed to obese patients with depressive symptoms, these agents are incapable of precisely regulating the CNS serotonin and may cause life-threatening adverse effects in the presence of monoamine oxidase inhibitors. However, CNS serotonin synthesis can be controlled by proper intake of tryptophan-rich diet. This report highlights the clinical significance of tryptophan-rich diet and vitamin B(6) to boost serotonergic neurotransmission in depression observed in various neurodegenerative diseases. However pharmacological interventions to modulate serotonergic neurotransmission in depression, remains clinically significant. Depression may involve several other molecular mechanisms as discussed briefly in this report. Copyright © 2012 Elsevier Ltd. All rights reserved.

The Antidepressant 5-HT2A Receptor Antagonists Pizotifen and Cyproheptadine Inhibit Serotonin-Enhanced Platelet Function

PubMed Central

Lin, Olivia A.; Karim, Zubair A.; Vemana, Hari Priya; Espinosa, Enma V. P.; Khasawneh, Fadi T.

2014-01-01

There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR) expressed on many cell types, and a known therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, pizotifen, and EMD 281014 inhibited serotonin-enhanced ADP-induced phosphatidylserine (PS) exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EMD 281014, and to clopidogrel, a commonly used antiplatelet drug, again, in a fashion comparable to clopidogrel and EMD 281014. Collectively, our data indicate that the antidepressant 5-HT2A antagonists, cyproheptadine and pizotifen do exert antiplatelet and thromboprotective effects, but similar to clopidogrel and EMD 281014, their use may interfere with normal hemostasis. PMID:24466319

Coaction of Stress and Serotonin Transporter Genotype in Predicting Aggression at the Transition to Adulthood

ERIC Educational Resources Information Center

Conway, Christopher C.; Keenan-Miller, Danielle; Hammen, Constance; Lind, Penelope A.; Najman, Jake M.; Brennan, Patricia A.

2012-01-01

Despite consistent evidence that serotonin functioning affects stress reactivity and vulnerability to aggression, research on serotonin gene-stress interactions (G x E) in the development of aggression remains limited. The present study investigated variation in the promoter region of the serotonin transporter gene (5-HTTLPR) as a moderator of the…

Brief Report: Whole Blood Serotonin Levels and Gastrointestinal Symptoms in Autism Spectrum Disorder.

PubMed

Marler, Sarah; Ferguson, Bradley J; Lee, Evon Batey; Peters, Brittany; Williams, Kent C; McDonnell, Erin; Macklin, Eric A; Levitt, Pat; Gillespie, Catherine Hagan; Anderson, George M; Margolis, Kara Gross; Beversdorf, David Q; Veenstra-VanderWeele, Jeremy

2016-03-01

Elevated whole blood serotonin levels are observed in more than 25% of children with autism spectrum disorder (ASD). Co-occurring gastrointestinal (GI) symptoms are also common in ASD but have not previously been examined in relationship with hyperserotonemia, despite the synthesis of serotonin in the gut. In 82 children and adolescents with ASD, we observed a correlation between a quantitative measure of lower GI symptoms and whole blood serotonin levels. No significant association was seen between functional constipation diagnosis and serotonin levels in the hyperserotonemia range, suggesting that this correlation is not driven by a single subgroup. More specific assessment of gut function, including the microbiome, will be necessary to evaluate the contribution of gut physiology to serotonin levels in ASD.

Serotonin 1A Agonism Decreases Affiliative Behavior in Pair-Bonded Titi Monkeys

PubMed Central

Larke, Rebecca H.; Maninger, Nicole; Ragen, Benjamin J; Mendoza, Sally P.; Bales, Karen L.

2016-01-01

Relatively little is known about serotonergic involvement in pair-bonding despite its putative role in regulating social behavior. Here we sought to determine if pharmacological elevation of serotonin 1A (5-HT1A) receptor activity would lead to changes in social behavior in pair-bonded male titi monkeys (Callicebus cupreus). Adult males in established heterosexual pairs were injected daily with the selective 5-HT1A agonist 8-OH-DPAT or saline for 15 days using a within-subjects design. Social behavior with the female pair-mate was quantified, and plasma concentrations of oxytocin, vasopressin, and cortisol were measured. When treated with saline, subjects showed reduced plasma oxytocin concentrations, while 8-OH-DPAT treatment buffered this decrease. Treatment with 8-OH-DPAT also led to decreased plasma cortisol 15 minutes post-injection and decreased social behavior directed toward the pair-mate including approaching, initiating contact, lipsmacking, and grooming. The reduction in affiliative behavior seen with increased activity at 5-HT1A receptors indicates a substantial role of serotonin activity in the expression of social behavior. In addition, results indicate that the effects of 5-HT1A agonism on social behavior in adulthood differ between rodents and primates. PMID:27712925

Massage Therapy for Reducing Stress Hormones and Enhancing Immune Function in Breast Cancer Survivors

DTIC Science & Technology

2000-08-01

massage therapy (n=20), a relaxation therapy (n=20) or a control group (n=20). Women in the massage and relaxation therapies will receive 3 sessions a...women reveal that women in the massage therapy group showed (1) reduced anxiety, (2) improved mood, (3) increased serotonin levels and (4) increased...support for the hypotheses that massage therapy enhances mood and immune function for women with breast cancer.

An Exploration of the Serotonin System in Antisocial Boys with High Levels of Callous-Unemotional Traits

PubMed Central

Moul, Caroline; Dobson-Stone, Carol; Brennan, John; Hawes, David; Dadds, Mark

2013-01-01

Background The serotonin system is thought to play a role in the aetiology of antisocial and aggressive behaviour in both adults and children however previous findings have been inconsistent. Recently, research has suggested that the function of the serotonin system may be specifically altered in a sub-set of antisocial populations – those with psychopathic (callous-unemotional) personality traits. We explored the relationships between callous-unemotional traits and functional polymorphisms of selected serotonin-system genes, and tested the association between callous-unemotional traits and serum serotonin levels independently of antisocial and aggressive behaviour. Method Participants were boys with antisocial behaviour problems aged 3–16 years referred to University of New South Wales Child Behaviour Research Clinics. Participants volunteered either a blood or saliva sample from which levels of serum serotonin (N = 66) and/or serotonin-system single nucleotide polymorphisms (N = 157) were assayed. Results Functional single nucleotide polymorphisms from the serotonin 1b receptor gene (HTR1B) and 2a receptor gene (HTR2A) were found to be associated with callous-unemotional traits. Serum serotonin level was a significant predictor of callous-unemotional traits; levels were significantly lower in boys with high callous-unemotional traits than in boys with low callous-unemotional traits. Conclusion Results provide support to the emerging literature that argues for a genetically-driven system-wide alteration in serotonin function in the aetiology of callous-unemotional traits. The findings should be interpreted as preliminary and future research that aims to replicate and further investigate these results is required. PMID:23457595

Serotonin passes through myoendothelial gap junctions to promote pulmonary arterial smooth muscle cell differentiation.

PubMed

Gairhe, Salina; Bauer, Natalie N; Gebb, Sarah A; McMurtry, Ivan F

2012-11-01

Myoendothelial gap junctional signaling mediates pulmonary arterial endothelial cell (PAEC)-induced activation of latent TGF-β and differentiation of cocultured pulmonary arterial smooth muscle cells (PASMCs), but the nature of the signal passing from PAECs to PASMCs through the gap junctions is unknown. Because PAECs but not PASMCs synthesize serotonin, and serotonin can pass through gap junctions, we hypothesized that the monoamine is the intercellular signal. We aimed to determine whether PAEC-derived serotonin mediates PAEC-induced myoendothelial gap junction-dependent activation of TGF-β signaling and differentiation of PASMCs. Rat PAECs and PASMCs were monocultured or cocultured with (touch) or without (no-touch) direct cell-cell contact. In all cases, tryptophan hydroxylase 1 (Tph1) transcripts were expressed predominantly in PAECs. Serotonin was detected by immunostaining in both PAECs and PASMCs in PAEC/PASMC touch coculture but was not found in PASMCs in either PAEC/PASMC no-touch coculture or in PASMC/PASMC touch coculture. Furthermore, inhibition of gap junctions but not of the serotonin transporter in PAEC/PASMC touch coculture prevented serotonin transfer from PAECs to PASMCs. Inhibition of serotonin synthesis pharmacologically or by small interfering RNAs to Tph1 in PAECs inhibited the PAEC-induced activation of TGF-β signaling and differentiation of PASMCs. We concluded that serotonin synthesized by PAECs is transferred through myoendothelial gap junctions into PASMCs, where it activates TGF-β signaling and induces a more differentiated phenotype. This finding suggests a novel role of gap junction-mediated intercellular serotonin signaling in regulation of PASMC phenotype.

An exploration of the serotonin system in antisocial boys with high levels of callous-unemotional traits.

PubMed

Moul, Caroline; Dobson-Stone, Carol; Brennan, John; Hawes, David; Dadds, Mark

2013-01-01

The serotonin system is thought to play a role in the aetiology of antisocial and aggressive behaviour in both adults and children however previous findings have been inconsistent. Recently, research has suggested that the function of the serotonin system may be specifically altered in a sub-set of antisocial populations - those with psychopathic (callous-unemotional) personality traits. We explored the relationships between callous-unemotional traits and functional polymorphisms of selected serotonin-system genes, and tested the association between callous-unemotional traits and serum serotonin levels independently of antisocial and aggressive behaviour. Participants were boys with antisocial behaviour problems aged 3-16 years referred to University of New South Wales Child Behaviour Research Clinics. Participants volunteered either a blood or saliva sample from which levels of serum serotonin (N = 66) and/or serotonin-system single nucleotide polymorphisms (N = 157) were assayed. Functional single nucleotide polymorphisms from the serotonin 1b receptor gene (HTR1B) and 2a receptor gene (HTR2A) were found to be associated with callous-unemotional traits. Serum serotonin level was a significant predictor of callous-unemotional traits; levels were significantly lower in boys with high callous-unemotional traits than in boys with low callous-unemotional traits. Results provide support to the emerging literature that argues for a genetically-driven system-wide alteration in serotonin function in the aetiology of callous-unemotional traits. The findings should be interpreted as preliminary and future research that aims to replicate and further investigate these results is required.

Changes in the serotonergic system in the main olfactory bulb of rats unilaterally deprived from birth to adulthood.

PubMed

Gómez, C; Briñón, J G; Orio, L; Colado, M I; Lawrence, A J; Zhou, F C; Vidal, M; Barbado, M V; Alonso, J R

2007-02-01

The serotonergic system plays a key role in the modulation of olfactory processing. The present study examined the plastic response of this centrifugal system after unilateral naris occlusion, analysing both serotonergic afferents and receptors in the main olfactory bulb. After 60 days of sensory deprivation, the serotonergic system exhibited adaptive changes. Olfactory deprivation caused a general increase in the number of fibres immunopositive for serotonin but not of those immunopositive for the serotonin transporter. HPLC data revealed an increase in serotonin levels but not in those of its major metabolite, 5-hydroxyindole acetic acid, resulting in a decrease in the 5-hydroxyindole acetic acid/serotonin ratio. These changes were observed not only in the deprived but also in the contralateral olfactory bulb. Double serotonin-tyrosine hydroxylase immunolabelling revealed that the glomerular regions of the deprived olfactory bulb with a high serotonergic fibre density showed a strong reduction in tyrosine hydroxylase. Finally, the serotonin(2A) receptor distribution density and the number of juxtaglomerular cells immunopositive for serotonin(2A) receptor remained unaltered after olfactory deprivation. Environmental stimulation modulated the serotonergic afferents to the olfactory bulb. Our results indicate the presence of a bilateral accumulation of serotonin in the serotonergic axon network, with no changes in serotonin(2A) receptor density after unilateral olfactory deprivation.

Resistance of rice to insect pests mediated by suppression of serotonin biosynthesis.

PubMed

Lu, Hai-Ping; Luo, Ting; Fu, Hao-Wei; Wang, Long; Tan, Yuan-Yuan; Huang, Jian-Zhong; Wang, Qing; Ye, Gong-Yin; Gatehouse, Angharad M R; Lou, Yong-Gen; Shu, Qing-Yao

2018-05-07

Rice is one of the world's most important foods, but its production suffers from insect pests, causing losses of billions of dollars, and extensive use of environmentally damaging pesticides for their control 1,2 . However, the molecular mechanisms of insect resistance remain elusive. Although a few resistance genes for planthopper have been cloned, no rice germplasm is resistant to stem borers. Here, we report that biosynthesis of serotonin, a neurotransmitter in mammals 3 , is induced by insect infestation in rice, and its suppression confers resistance to planthoppers and stem borers, the two most destructive pests of rice 2 . Serotonin and salicylic acid derive from chorismate 4 . In rice, the cytochrome P450 gene CYP71A1 encodes tryptamine 5-hydroxylase, which catalyses conversion of tryptamine to serotonin 5 . In susceptible wild-type rice, planthopper feeding induces biosynthesis of serotonin and salicylic acid, whereas in mutants with an inactivated CYP71A1 gene, no serotonin is produced, salicylic acid levels are higher and plants are more insect resistant. The addition of serotonin to the resistant rice mutant and other brown planthopper-resistant genotypes results in a loss of insect resistance. Similarly, serotonin supplementation in artificial diet enhances the performance of both insects. These insights demonstrate that regulation of serotonin biosynthesis plays an important role in defence, and may prove valuable for breeding insect-resistant cultivars of rice and other cereal crops.

Association between salivary serotonin and the social sharing of happiness

PubMed Central

Ishii, Keiko; Ohtsubo, Yohsuke; Noguchi, Yasuki; Ochi, Misaki; Yamasue, Hidenori

2017-01-01

Although human saliva contains the monoamine serotonin, which plays a key role in the modulation of emotional states, the association between salivary serotonin and empathic ability remains unclear. In order to elucidate the associations between salivary serotonin levels, trait empathy, and the sharing effect of emotions (i.e., sharing emotional experiences with others), we performed a vignette-based study. Participants were asked to evaluate their happiness when they experience several hypothetical life events, whereby we manipulated the valence of the imagined event (positive, neutral, or negative), as well as the presence of a friend (absent, positive, or negative). Results indicated that the presence of a happy friend significantly enhanced participants’ happiness. Correlation analysis demonstrated that salivary serotonin levels were negatively correlated with happiness when both the self and friend conditions were positive. Correlation analysis also indicated a negative relationship between salivary serotonin levels and trait empathy (particularly in perspective taking), which was measured by the Interpersonal Reactivity Index. Furthermore, an exploratory multiple regression analysis suggested that mothers’ attention during childhood predicted salivary serotonin levels. Our findings indicate that empathic abilities and the social sharing of happiness decreases as a function of salivary serotonin levels. PMID:28683075

Association between salivary serotonin and the social sharing of happiness.

PubMed

Matsunaga, Masahiro; Ishii, Keiko; Ohtsubo, Yohsuke; Noguchi, Yasuki; Ochi, Misaki; Yamasue, Hidenori

2017-01-01

Although human saliva contains the monoamine serotonin, which plays a key role in the modulation of emotional states, the association between salivary serotonin and empathic ability remains unclear. In order to elucidate the associations between salivary serotonin levels, trait empathy, and the sharing effect of emotions (i.e., sharing emotional experiences with others), we performed a vignette-based study. Participants were asked to evaluate their happiness when they experience several hypothetical life events, whereby we manipulated the valence of the imagined event (positive, neutral, or negative), as well as the presence of a friend (absent, positive, or negative). Results indicated that the presence of a happy friend significantly enhanced participants' happiness. Correlation analysis demonstrated that salivary serotonin levels were negatively correlated with happiness when both the self and friend conditions were positive. Correlation analysis also indicated a negative relationship between salivary serotonin levels and trait empathy (particularly in perspective taking), which was measured by the Interpersonal Reactivity Index. Furthermore, an exploratory multiple regression analysis suggested that mothers' attention during childhood predicted salivary serotonin levels. Our findings indicate that empathic abilities and the social sharing of happiness decreases as a function of salivary serotonin levels.

Serotonin toxicity caused by moclobemide too soon after paroxetine-selegiline.

PubMed

Wu, Ming-Ling; Deng, Jou-Fang

2009-08-01

Serotonin toxicity is an iatrogenic complication of serotonergic drug therapy. It is due to an overstimulation of central and peripheral serotonin receptors that lead to neuromuscular, mental and autonomic changes. Moclobemide is a reversible inhibitor of monoamine oxidase (MAO)-A, selegiline is an irreversible selective inhibitor of MAO-B, and paroxetine is a selective serotonin reuptake inhibitor. Combined use of these agents is known to cause serotonin toxicity. A 53-year-old woman had been treated with paroxetine and selegiline. After moclobemide was prescribed in place of paroxetine without a washout period, she quickly developed confusion, agitation, ataxia, diaphoresis, tremor, mydriasis, ocular clonus, hyperreflexia, tachycardia, moderately elevated blood pressure and high fever, symptoms that were consistent with serotonin toxicity. Discontinuation of the drugs, hydration and supportive care were followed by remarkable improvement of baseline status within 3 days. This case demonstrates that serotonin toxicity may occur even with small doses of paroxetine, selegiline and moclobemide in combination. Physicians managing patients with depression must be aware of the potential for serotonin toxicity and should be able to recognize and treat or, ideally, anticipate and avoid this pharmacodynamically-mediated interaction that may occur between prescribed drugs.

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

PubMed

Schafer, W R; Kenyon, C J

1995-05-04

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 alpha-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 postsynaptic response to serotonin, perhaps by inhibiting the release of a potentiating neuropeptide.

Norepinephrine-deficient mice lack responses to antidepressant drugs, including selective serotonin reuptake inhibitors

PubMed Central

Cryan, John F.; O'Leary, Olivia F.; Jin, Sung-Ha; Friedland, Julie C.; Ouyang, Ming; Hirsch, Bradford R.; Page, Michelle E.; Dalvi, Ashutosh; Thomas, Steven A.; Lucki, Irwin

2004-01-01

Mice unable to synthesize norepinephrine (NE) and epinephrine due to targeted disruption of the dopamine β-hydroxylase gene, Dbh, were used to critically test roles for NE in mediating acute behavioral changes elicited by different classes of antidepressants. To this end, we used the tail suspension test, one of the most widely used paradigms for assessing antidepressant activity and depression-related behaviors in normal and genetically modified mice. Dbh–/– mice failed to respond to the behavioral effects of various antidepressants, including the NE reuptake inhibitors desipramine and reboxetine, the monoamine oxidase inhibitor pargyline, and the atypical antidepressant bupropion, even though they did not differ in baseline immobility from Dbh+/– mice, which have normal levels of NE. Surprisingly, the effects of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, sertraline, and paroxetine were also absent or severely attenuated in the Dbh–/– mice. In contrast, citalopram (the most selective SSRI) was equally effective at reducing immobility in mice with and without NE. Restoration of NE by using l-threo-3,4-dihydroxyphenylserine reinstated the behavioral effects of both desipramine and paroxetine in Dbh–/– mice, thus demonstrating that the reduced sensitivity to antidepressants is related to NE function, as opposed to developmental abnormalities resulting from chronic NE deficiency. Microdialysis studies demonstrated that the ability of fluoxetine to increase hippocampal serotonin was blocked in Dbh–/– mice, whereas citalopram's effect was only partially attenuated. These data show that NE plays an important role in mediating acute behavioral and neurochemical actions of many antidepressants, including most SSRIs. PMID:15148402

Early-Life Social Isolation Impairs the Gonadotropin-Inhibitory Hormone Neuronal Activity and Serotonergic System in Male Rats.

PubMed

Soga, Tomoko; Teo, Chuin Hau; Cham, Kai Lin; Idris, Marshita Mohd; Parhar, Ishwar S

2015-01-01

Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH) neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinizing hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic-GnIH neuronal system using enhanced green fluorescent protein (EGFP)-tagged GnIH transgenic rats. Socially isolated rats were observed for anxious and depressive behaviors. Using immunohistochemistry, we examined c-Fos protein expression in EGFP-GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group housing. We also inspected serotonergic fiber juxtapositions in EGFP-GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviors. The total number of EGFP-GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fiber juxtapositions on EGFP-GnIH neurons were also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early-life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure.

Enhanced central serotonin release from slices of rat hypothalamus following repeated nialamide administration: evidence supporting the overactive serotonin receptor theory of depression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Offord, S.J.

1986-01-01

Researchers are suggesting unipolar affective disorders may be related to an abnormality in biogenic amine receptor-sensitivity. This abnormality may be a result of a dysfunction in central serotonin (5-HT) release mechanisms. 5-HT neurotransmission is modulated by presynaptic autoreceptors, which are members of the 5-HT/sub 1/ receptor subtype. The autoreceptor is thought to play an important role in the homeostasis of the central 5-HT synapse and could be a site at which some antidepressants mediate their therapeutic effect. The number of 5-HT/sub 1/ type receptor binding sites are reduced and behavior mediated by this receptor is abolished following repeated injections ofmore » monoamine oxidase inhibitor type antidepressants. These changes did not occur following a single injection. It was hypothesized that repeated treatment with a monoamine oxidase inhibitor would reduce the sensitivity of 5-HT autoreceptors and enhance 5-HT release. Rats were pretreated with single or repeated (twice daily for 7 days) intraperitoneal injections of nialamide (40 mg/kg) or chlorimipramine (10 mg/kg) and the ability of the autoreceptor agonist to inhibit potassium-induced /sup 3/H-5-HT release was evaluated using an in vitro superfusion system. These changes in 5-HT autoreceptor activity are consistent with other reports evaluating monoamine oxidase inhibitors on 5-HT/sub 1/ type receptors. It is hypothesized that the changes in 5-HT neurotransmission are related to the antidepressant mechanism of monoamine oxidase inhibitors.« less

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

PubMed Central

Carta, Manolo; Tronci, Elisabetta

2014-01-01

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

Activity patterns of serotonin neurons underlying cognitive flexibility

PubMed Central

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

2017-01-01

Serotonin is implicated in mood and affective disorders. However, growing evidence suggests that a core endogenous role is to promote flexible adaptation to changes in the causal structure of the environment, through behavioral inhibition and enhanced plasticity. We used long-term photometric recordings in mice to study a population of dorsal raphe serotonin neurons, whose activity we could link to normal reversal learning using pharmacogenetics. We found that these neurons are activated by both positive and negative prediction errors, and thus report signals similar to those proposed to promote learning in conditions of uncertainty. Furthermore, by comparing the cue responses of serotonin and dopamine neurons, we found differences in learning rates that could explain the importance of serotonin in inhibiting perseverative responding. Our findings show how the activity patterns of serotonin neurons support a role in cognitive flexibility, and suggest a revised model of dopamine–serotonin opponency with potential clinical implications. DOI: http://dx.doi.org/10.7554/eLife.20552.001 PMID:28322190

A Single Pair of Serotonergic Neurons Counteracts Serotonergic Inhibition of Ethanol Attraction in Drosophila

PubMed Central

Kaiser, Andrea; Gräber, Nikolas; Schläger, Laura; Ritze, Yvonne; Scholz, Henrike

2016-01-01

Attraction to ethanol is common in both flies and humans, but the neuromodulatory mechanisms underlying this innate attraction are not well understood. Here, we dissect the function of the key regulator of serotonin signaling—the serotonin transporter–in innate olfactory attraction to ethanol in Drosophila melanogaster. We generated a mutated version of the serotonin transporter that prolongs serotonin signaling in the synaptic cleft and is targeted via the Gal4 system to different sets of serotonergic neurons. We identified four serotonergic neurons that inhibit the olfactory attraction to ethanol and two additional neurons that counteract this inhibition by strengthening olfactory information. Our results reveal that compensation can occur on the circuit level and that serotonin has a bidirectional function in modulating the innate attraction to ethanol. Given the evolutionarily conserved nature of the serotonin transporter and serotonin, the bidirectional serotonergic mechanisms delineate a basic principle for how random behavior is switched into targeted approach behavior. PMID:27936023

A Single Pair of Serotonergic Neurons Counteracts Serotonergic Inhibition of Ethanol Attraction in Drosophila.

PubMed

Xu, Li; He, Jianzheng; Kaiser, Andrea; Gräber, Nikolas; Schläger, Laura; Ritze, Yvonne; Scholz, Henrike

2016-01-01

Attraction to ethanol is common in both flies and humans, but the neuromodulatory mechanisms underlying this innate attraction are not well understood. Here, we dissect the function of the key regulator of serotonin signaling-the serotonin transporter-in innate olfactory attraction to ethanol in Drosophila melanogaster. We generated a mutated version of the serotonin transporter that prolongs serotonin signaling in the synaptic cleft and is targeted via the Gal4 system to different sets of serotonergic neurons. We identified four serotonergic neurons that inhibit the olfactory attraction to ethanol and two additional neurons that counteract this inhibition by strengthening olfactory information. Our results reveal that compensation can occur on the circuit level and that serotonin has a bidirectional function in modulating the innate attraction to ethanol. Given the evolutionarily conserved nature of the serotonin transporter and serotonin, the bidirectional serotonergic mechanisms delineate a basic principle for how random behavior is switched into targeted approach behavior.

Liquiritigenin reverses depression-like behavior in unpredictable chronic mild stress-induced mice by regulating PI3K/Akt/mTOR mediated BDNF/TrkB pathway.

PubMed

Tao, Weiwei; Dong, Yu; Su, Qiang; Wang, Hanqing; Chen, Yanyan; Xue, Wenda; Chen, Chang; Xia, Baomei; Duan, Jinao; Chen, Gang

2016-07-15

Major depression is a common long-lasting or recurrent psychiatric disease with high lifetime prevalence and high incidence of suicide. The main purpose of the current study was to verify whether liquiritigenin conferred an antidepressant-like effect on the depressive mouse model established by unpredictable chronic mild stress (UCMS) and explore its possible mechanism. The results of depression-related behaviors including sucrose preference test (SPT), open field test (OFT), forced swimming test (FST) and tail suspension test (TST) indicated that both liquiritigenin (7.5mg/kg, 15mg/kg) and fluoxetine (20mg/kg) dramatically improved the depression symptoms. Enzyme-linked immunosorbent assay (ELISA) revealed that treatment with liquiritigenin significantly reduced the concentrations of pro-inflammatory cytokines including interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α in serum and hippocampus. Compared with the UCMS group, the administrations of liquiritigenin, increased levels of superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), and decreased Malondialdehyde (MDA) content. Meanwhile, glucocorticoids (GC) content was reduced in the liquiritigenin group, which suggested that liquiritigenin exhibiting the ameliorative effect on activated hypothalamic-pituitary-adrenal (HPA) axis stimulated with UCMS. Mice treated with liquiritigenin showed restored levels of neurotransmitter norepinephrine (NE) and serotonin (5-HT). Western blot analysis displayed up-regulated expressions of p-phosphatidylinositol 3-kinase (PI3K), p-Akt, p- mammalian target of rapamycin (mTOR), p-tropomyosin-related kinase B (TrkB), brain-derived neurotrophic factor (BDNF). Thus, it was supposed that liquiritigenin might be useful for the treatment of chronic depression possibly through PI3K/Akt/mTOR mediated BDNF/TrkB pathway. Copyright © 2016 Elsevier B.V. All rights reserved.

Serotonin signaling in the brain of adult female mice is required for sexual preference

PubMed Central

Zhang, Shasha; Liu, Yan; Rao, Yi

2013-01-01

A role for serotonin in male sexual preference was recently uncovered by our finding that male mutant mice lacking serotonin have lost sexual preference. Here we show that female mouse mutants lacking either central serotonergic neurons or serotonin prefer female over male genital odors when given a choice, and displayed increased female–female mounting when presented either with a choice of a male and a female target or only with a female target. Pharmacological manipulations and genetic rescue experiments showed that serotonin is required in adults. Behavioral changes caused by deficient serotonergic signaling were not due to changes in plasma concentrations of sex hormones. We demonstrate that a genetic manipulation reverses sexual preference without involving sex hormones. Our results indicate that serotonin controls sexual preference. PMID:23716677

[Immunological aspects of depressive disorders].

PubMed

Müller, N; Schwarz, M J

2007-11-01

Beside the monoaminergic deficiency concept as a pathophysiological correlate of depressive disorder, the role of increased glutamatergic neurotransmission is increasingly being discussed. Causes and interactions of these neurotransmitter disturbances are not fully understood to date. This review presents a concept integrating actual findings of the neurotransmitter dysregulations with immunological and morphological findings in depressive disorder. Several intertwined mechanisms seem to be important: The common cause of serotonin deficiency and increased glutamatergic neurotransmission seems to be the increase of proinflammatory cytokines. Immune activation with increased production of proinflammatory cytokines activate the tryptophan- and serotonin-degradating enzyme indolamine-2,3-dioxygenase (IDO). The increased consumption of serotonin and its precursor tryptophan due to IDO activation may explain the reduced availability of serotonin in depression. In inflammatory somatic disorders, depressive mood is associated with an increase of proinflammatory cytokines and increased consumption of tryptophan. This activation of IDO by proinflammatory cytokines leads to the production of glutamatergic agonists. In the CNS, IDO is activated during inflammatory processes primarily in microglial cells. Therefore the astrocyte:microglial balance in depression is important. The observed decrease of astrocytes in the CNS of depressive patients may contribute to a regulatory fault in the activity of IDO in microglial cells but also can cause an alteration of the glutamatergic neurotransmission. By this mechanism, the dysbalance of the immune response and the astrocyte:microglia dysbalance may contribute to serotonergic deficiency and glutamatergic overproduction in depression. The further search for new antidepressant therapeutic mechanisms should take into regard anti-inflammatory substances, e.g. cyclo-oxygenase-2 (COX-2)-inhibitors.

Response inhibition and serotonin in autism: a functional MRI study using acute tryptophan depletion

PubMed Central

Ecker, Christine; Hallahan, Brian; Deeley, Quinton; Craig, Michael; Murphy, Clodagh; Johnston, Patrick; Spain, Debbie; Gillan, Nicola; Gudbrandsen, Maria; Brammer, Michael; Giampietro, Vincent; Lamar, Melissa; Page, Lisa; Toal, Fiona; Schmitz, Nicole; Cleare, Anthony; Robertson, Dene; Rubia, Katya; Murphy, Declan G. M.

2014-01-01

It has been suggested that the restricted, stereotyped and repetitive behaviours typically found in autism are underpinned by deficits of inhibitory control. The biological basis of this is unknown but may include differences in the modulatory role of neurotransmitters, such as serotonin, which are implicated in the condition. However, this has never been tested directly. We therefore assessed the modifying role of serotonin on inhibitory brain function during a Go/No-Go task in 14 adults with autism and normal intelligence and 14 control subjects that did not differ in gender, age and intelligence. We undertook a double-blind, placebo-controlled, crossover trial of acute tryptophan depletion using functional magnetic resonance imaging. Following sham, adults with autism relative to controls had reduced activation in key inhibitory regions of inferior frontal cortex and thalamus, but increased activation of caudate and cerebellum. However, brain activation was modulated in opposite ways by depletion in each group. Within autistic individuals depletion upregulated fronto-thalamic activations and downregulated striato-cerebellar activations toward control sham levels, completely ‘normalizing’ the fronto-cerebellar dysfunctions. The opposite pattern occurred in controls. Moreover, the severity of autism was related to the degree of differential modulation by depletion within frontal, striatal and thalamic regions. Our findings demonstrate that individuals with autism have abnormal inhibitory networks, and that serotonin has a differential, opposite, effect on them in adults with and without autism. Together these factors may partially explain the severity of autistic behaviours and/or provide a novel (tractable) treatment target. PMID:25070512

Response inhibition and serotonin in autism: a functional MRI study using acute tryptophan depletion.

PubMed

Daly, Eileen; Ecker, Christine; Hallahan, Brian; Deeley, Quinton; Craig, Michael; Murphy, Clodagh; Johnston, Patrick; Spain, Debbie; Gillan, Nicola; Gudbrandsen, Maria; Brammer, Michael; Giampietro, Vincent; Lamar, Melissa; Page, Lisa; Toal, Fiona; Schmitz, Nicole; Cleare, Anthony; Robertson, Dene; Rubia, Katya; Murphy, Declan G M

2014-09-01

It has been suggested that the restricted, stereotyped and repetitive behaviours typically found in autism are underpinned by deficits of inhibitory control. The biological basis of this is unknown but may include differences in the modulatory role of neurotransmitters, such as serotonin, which are implicated in the condition. However, this has never been tested directly. We therefore assessed the modifying role of serotonin on inhibitory brain function during a Go/No-Go task in 14 adults with autism and normal intelligence and 14 control subjects that did not differ in gender, age and intelligence. We undertook a double-blind, placebo-controlled, crossover trial of acute tryptophan depletion using functional magnetic resonance imaging. Following sham, adults with autism relative to controls had reduced activation in key inhibitory regions of inferior frontal cortex and thalamus, but increased activation of caudate and cerebellum. However, brain activation was modulated in opposite ways by depletion in each group. Within autistic individuals depletion upregulated fronto-thalamic activations and downregulated striato-cerebellar activations toward control sham levels, completely 'normalizing' the fronto-cerebellar dysfunctions. The opposite pattern occurred in controls. Moreover, the severity of autism was related to the degree of differential modulation by depletion within frontal, striatal and thalamic regions. Our findings demonstrate that individuals with autism have abnormal inhibitory networks, and that serotonin has a differential, opposite, effect on them in adults with and without autism. Together these factors may partially explain the severity of autistic behaviours and/or provide a novel (tractable) treatment target. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.

Behavioral Impulsivity Does Not Predict Naturalistic Alcohol Consumption or Treatment Outcomes

PubMed Central

Mullen, Jillian; Mathias, Charles W.; Karns, Tara E.; Liang, Yuanyuan; Hill-Kapturczak, Nathalie; Roache, John D.; Lamb, Richard J.; Dougherty, Donald M.

2016-01-01

Objective The purpose of this study was to determine if behavioral impulsivity under multiple conditions (baseline, after alcohol consumption or after serotonin depletion) predicted naturalistic alcohol use or treatment outcomes from a moderation-based contingency management intervention. Method The current data analysis pulls information from three phases of a large study: 1) Phase 1 examined baseline and the effects of alcohol use and serotonin depletion on three types of behavioral impulsivity: response initiation (IMT task), response inhibition (GoStop task), and delay discounting (SKIP task); 2) Phase 2 involved 28 days of naturalistic drinking; and 3) Phase 3 involved 3 months of contingency management. During phases 2 and 3 alcohol use was measured objectively using transdermal alcohol monitors. The results of each individual phase has been previously published showing that at a group level the effects of alcohol consumption on impulsivity were dependent on the component of impulsivity being measured and the dose of alcohol consumed but serotonin depletion had no effect on impulsivity, and that a moderation-based contingency management intervention reduced heavy drinking. Results The current analysis combining data from those who completed all three phases (n = 67) showed that impulsivity measured at baseline, after alcohol consumption, or after serotonin depletion did not predict naturalistic drinking or treatment outcomes from a moderation-based CM treatment. Conclusions Contingency management interventions may prove to be an effective intervention for impulsive individuals, however, normal variations in measured impulsivity do not seem to relate to normal variations in drinking pattern or response to moderation-based contingency management. PMID:27746702

Playing it safe but losing anyway – serotonergic signaling of aversive outcomes in dorsomedial prefrontal cortex in the context of risk-aversion

PubMed Central

Macoveanu, Julian; Rowe, James B; Hornboll, Bettina; Elliott, Rebecca; Paulson, Olaf B; Knudsen, Gitte M; Siebner, Hartwig R

2015-01-01

Risk avoidance is an important determinant of human behavior. The neurotransmitter serotonin has long been implicated in processing aversive outcomes caused by risky decisions. However, it is unclear whether serotonin provides a neurobiological link between making a risk aversive decision and the response to an aversive outcome. Using pharmacological fMRI, we manipulated the availability of serotonin in healthy volunteers while performing a gambling task. The same group of participants was studied in three fMRI sessions: (i) during intravenous administration of the SSRI citalopram to increase the serotonergic tone, (ii) after acute tryptophan depletion (ATD) to reduce central serotonin levels, or (iii) without interventions. ATD and citalopran had opposite effects on outcome related activity in dorsomedial prefrontal cortex (dmPFC) and amygdala. Relative to the control condition, ATD increased and citalopram decreased the neural response to aversive outcomes in dmPFC. Conversely, ATD decreased and citalopram increased the neural response to aversive outcomes in left amygdala. Critically, these pharmacological effects were restricted to aversive outcomes that were caused by low-risk decision and led to a high missed reward. ATD and citalopram did not alter the neural response to positive outcomes in dmPFC, but relative to ATD, citalopram produced a bilateral increase in the amygdala response to large wins caused by high-risk choices. The results show a selective involvement of the serotonergic system in neocortical processing of aversive outcomes resulting from risk-averse decisions, thereby linking risk aversion and processing of aversive outcomes in goal-directed behaviors. PMID:23051938

Therapeutic Potential of 5-HT2C Receptor Agonists for Addictive Disorders.

PubMed

Higgins, Guy A; Fletcher, Paul J

2015-07-15

The neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) has long been associated with the control of a variety of motivated behaviors, including feeding. Much of the evidence linking 5-HT and feeding behavior was obtained from studies of the effects of the 5-HT releaser (dex)fenfluramine in laboratory animals and humans. Recently, the selective 5-HT2C receptor agonist lorcaserin received FDA approval for the treatment of obesity. This review examines evidence to support the use of selective 5-HT2C receptor agonists as treatments for conditions beyond obesity, including substance abuse (particularly nicotine, psychostimulant, and alcohol dependence), obsessive compulsive, and excessive gambling disorder. Following a brief survey of the early literature supporting a role for 5-HT in modulating food and drug reinforcement, we propose that intrinsic differences between SSRI and serotonin releasers may have underestimated the value of serotonin-based pharmacotherapeutics to treat clinical forms of addictive behavior beyond obesity. We then highlight the critical involvement of the 5-HT2C receptor in mediating the effect of (dex)fenfluramine on feeding and body weight gain and the evidence that 5-HT2C receptor agonists reduce measures of drug reward and impulsivity. A recent report of lorcaserin efficacy in a smoking cessation trial further strengthens the idea that 5-HT2C receptor agonists may have potential as a treatment for addiction. This review was prepared as a contribution to the proceedings of the 11th International Society for Serotonin Research Meeting held in Hermanus, South Africa, July 9-12, 2014.

Importance of the Extracellular Loop 4 in the Human Serotonin Transporter for Inhibitor Binding and Substrate Translocation*

PubMed Central

Rannversson, Hafsteinn; Wilson, Pamela; Kristensen, Kristina Birch; Sinning, Steffen; Kristensen, Anders Skov; Strømgaard, Kristian; Andersen, Jacob

2015-01-01

The serotonin transporter (SERT) terminates serotonergic neurotransmission by performing reuptake of released serotonin, and SERT is the primary target for antidepressants. SERT mediates the reuptake of serotonin through an alternating access mechanism, implying that a central substrate site is connected to both sides of the membrane by permeation pathways, of which only one is accessible at a time. The coordinated conformational changes in SERT associated with substrate translocation are not fully understood. Here, we have identified a Leu to Glu mutation at position 406 (L406E) in the extracellular loop 4 (EL4) of human SERT, which induced a remarkable gain-of-potency (up to >40-fold) for a range of SERT inhibitors. The effects were highly specific for L406E relative to six other mutations in the same position, including the closely related L406D mutation, showing that the effects induced by L406E are not simply charge-related effects. Leu406 is located >10 Å from the central inhibitor binding site indicating that the mutation affects inhibitor binding in an indirect manner. We found that L406E decreased accessibility to a residue in the cytoplasmic pathway. The shift in equilibrium to favor a more outward-facing conformation of SERT can explain the reduced turnover rate and increased association rate of inhibitor binding we found for L406E. Together, our findings show that EL4 allosterically can modulate inhibitor binding within the central binding site, and substantiates that EL4 has an important role in controlling the conformational equilibrium of human SERT. PMID:25903124

Tryptophan Depletion Promotes Habitual over Goal-Directed Control of Appetitive Responding in Humans.

PubMed

Worbe, Yulia; Savulich, George; de Wit, Sanne; Fernandez-Egea, Emilio; Robbins, Trevor W

2015-02-05

Optimal behavioral performance results from a balance between goal-directed and habitual systems of behavioral control, which are modulated by ascending monoaminergic projections. While the role of the dopaminergic system in behavioral control has been recently addressed, the extent to which changes in global serotonin neurotransmission could influence these 2 systems is still poorly understood. We employed the dietary acute tryptophan depletion procedure to reduce serotonin neurotransmission in 18 healthy volunteers and 18 matched controls. We used a 3-stage instrumental learning paradigm that includes an initial instrumental learning stage, a subsequent outcome-devaluation test, and a slip-of-action stage, which directly tests the balance between hypothetical goal-directed and habitual systems. We also employed a separate response inhibition control test to assess the behavioral specificity of the results. Acute tryptophan depletion produced a shift of behavioral performance towards habitual responding as indexed by performance on the slip-of-action test. Moreover, greater habitual responding in the acute tryptophan depletion group was predicted by a steeper decline in plasma tryptophan levels. In contrast, acute tryptophan depletion left intact the ability to use discriminative stimuli to guide instrumental choice as indexed by the instrumental learning stage and did not impair inhibitory response control. The major implication of this study is that serotonin modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. Our findings thus imply that diminished serotonin neurotransmission shifts behavioral control towards habitual responding. © The Author 2015. Published by Oxford University Press on behalf of CINP.

[The effect of mineral water on serotonin and insulin production (an experimental study)].

PubMed

Polushina, N D

1998-01-01

Radioimmunoassay (DRG kits) and orthotoluidine test were conducted to measure blood serotonin, insulin and glucose in 70 intact Wistar rat males before and after a course of drinking mineral water Essentuki 17 (MW). After the MW drinking course, a single dose of mineral water increases basal levels of serotonin and insulin, sensitivity of endocrine cells to MW. Serotonin and insulin rose maximally on minute 5 after the drink while in contrast to minute 15 and 30 before initiation of the MW drinking course. A direct correlation was found between blood concentrations of serotonin and insulin.

The intestinal microbiome and skeletal fitness: connecting bugs and bones

PubMed Central

Charles, Julia F.; Ermann, Joerg; Aliprantis, Antonios O.

2015-01-01

Recent advances have dramatically increased our understanding of how organ systems interact. This has been especially true for immunology and bone biology, where the term “osteoimmunology” was coined to capture this relationship. The importance of the microbiome to the immune system has also emerged as a driver of health and disease. It makes sense therefore to ask the question: how does the intestinal microbiome influence bone biology and does dysbiosis promote bone disease? Surprisingly, few studies have analyzed this connection. A broader interpretation of this question reveals many mechanisms whereby the microbiome may affect bone cells. These include effects of the microbiome on immune cells, including myeloid progenitors and Th17 cells, as well as steroid hormones, fatty acids, serotonin and vitamin D. As mechanistic interactions of the microbiome and skeletal system are revealed within and without the immune system, novel strategies to optimize skeletal fitness may emerge. PMID:25840106

A real reason for patients with pseudobulbar affect to smile.

PubMed

Rosen, Howard J; Cummings, Jeffrey

2007-02-01

Pseudobulbar affect (PBA) is a dramatic disorder of emotional expression and regulation characterized by uncontrollable episodes of laughing and crying that often cause embarrassment, curtailment of social activities, and reduction in quality of life. The disorder occurs in patients with brain injury caused by many types of neurological disease, including stroke, tumors, and neurodegenerative gray and white matter disorders. Although the pathophysiology is unknown, PBA may relate to release of brainstem emotional control centers from regulation by the frontal lobes. Diagnosis of PBA can be difficult and relies on careful characterization of episodes and differentiation from depression. Although there are no US Food and Drug Administration-approved treatments for PBA, several agents have been shown to be effective, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and a new agent containing dextromethorphan and quinidine. The growing number of treatment options, some of great benefit to patients, highlights the importance of accurate diagnosis of this disorder.

Positive regulation of raphe serotonin neurons by serotonin 2B receptors.

PubMed

Belmer, Arnauld; Quentin, Emily; Diaz, Silvina L; Guiard, Bruno P; Fernandez, Sebastian P; Doly, Stéphane; Banas, Sophie M; Pitychoutis, Pothitos M; Moutkine, Imane; Muzerelle, Aude; Tchenio, Anna; Roumier, Anne; Mameli, Manuel; Maroteaux, Luc

2018-06-01

Serotonin is a neurotransmitter involved in many psychiatric diseases. In humans, a lack of 5-HT 2B receptors is associated with serotonin-dependent phenotypes, including impulsivity and suicidality. A lack of 5-HT 2B receptors in mice eliminates the effects of molecules that directly target serotonergic neurons including amphetamine derivative serotonin releasers, and selective serotonin reuptake inhibitor antidepressants. In this work, we tested the hypothesis that 5-HT 2B receptors directly and positively regulate raphe serotonin neuron activity. By ex vivo electrophysiological recordings, we report that stimulation by the 5-HT 2B receptor agonist, BW723C86, increased the firing frequency of serotonin Pet1-positive neurons. Viral overexpression of 5-HT 2B receptors in these neurons increased their excitability. Furthermore, in vivo 5-HT 2B -receptor stimulation by BW723C86 counteracted 5-HT 1A autoreceptor-dependent reduction in firing rate and hypothermic response in wild-type mice. By a conditional genetic ablation that eliminates 5-HT 2B receptor expression specifically and exclusively from Pet1-positive serotonin neurons (Htr2b 5-HTKO mice), we demonstrated that behavioral and sensitizing effects of MDMA (3,4-methylenedioxy-methamphetamine), as well as acute behavioral and chronic neurogenic effects of the antidepressant fluoxetine, require 5-HT 2B receptor expression in serotonergic neurons. In Htr2b 5-HTKO mice, dorsal raphe serotonin neurons displayed a lower firing frequency compared to control Htr2b lox/lox mice as assessed by in vivo extracellular recordings and a stronger hypothermic effect of 5-HT 1A -autoreceptor stimulation was observed. The increase in head-twitch response to DOI (2,5-dimethoxy-4-iodoamphetamine) further confirmed the lower serotonergic tone resulting from the absence of 5-HT 2B receptors in serotonin neurons. Together, these observations indicate that the 5-HT 2B receptor acts as a direct positive modulator of serotonin Pet1-positive neurons in an opposite way as the known 5-HT 1A -negative autoreceptor.

Providing straw to allow exploratory behaviour in a pig experimental system does not modify putative indicators of positive welfare: peripheral oxytocin and serotonin.

PubMed

Marcet Rius, M; Cozzi, A; Bienboire-Frosini, C; Teruel, E; Chabaud, C; Monneret, P; Leclercq, J; Lafont-Lecuelle, C; Pageat, P

2018-01-22

Numerous studies have shown that providing straw to pigs can reduce undesirable behaviours such as aggression, tail biting and stereotypy. The measurement of various neuromodulators can be helpful in assessing the development of positive behaviours and overall animal welfare. The oxytocin release is frequently linked to positive emotions and positive welfare. It has been suggested that oxytocin modulates the serotoninergic system. This study aims to investigate the potential effect of straw provision in pigs on peripheral levels of oxytocin and serotonin. In total, 18 mini-pigs were involved in an exploratory study conducted in two parallel groups, Enriched (n=10) and Control (n=8) groups. Pigs were divided by group and housed in pens of two individuals. Straw was provided continuously only in Enriched group and renewed each day for 2 weeks. Two blood samples were drawn from each animal 5 to 10 min before providing the straw, and 15 min after providing straw, during the 1st week, to analyse peripheral changes in oxytocin and serotonin before and after straw provision, and determine the existence of a putative short-term effect. The same procedure was carried out for Control group, without straw provision. Long-term effects of straw provision were also examined using blood samples drawn at the same hour from each animal in the 2nd and 3rd weeks. During this time, animals had the permanent possibility to explore the straw in Enriched group but not in Control group. At the end of each week, one animal-keeper completed two visual analogue scales for each mini-pig regarding the difficulty/ease to work with and handle it and its trust in humans. Results showed peripheral oxytocin increases in both groups after 2 weeks (P=0.02). Results did not demonstrate any effect of providing straw to allow exploratory behaviour on peripheral serotonin. Other results were not significant. This preliminary study explored the relationship between peripheral oxytocin and serotonin and the presence of straw that allow pigs to perform exploratory behaviour, suggesting that there was no relationship between them. Some future studies may include crossing oxytocin and serotonin with other parameters, such as behavioural measures, to obtain more information about the true state of the animal and any possible relationship with pig welfare.

Peripheral Serotonin 1B Receptor Transcription Predicts the Effect of Acute Tryptophan Depletion on Risky Decision-Making.

PubMed

Faulkner, Paul; Mancinelli, Federico; Lockwood, Patricia L; Matarin, Mar; Dolan, Raymond J; Wood, Nick W; Dayan, Peter; Roiser, Jonathan P

2017-01-01

The effects of acute tryptophan depletion on human decision-making suggest that serotonin modulates the processing of rewards and punishments. However, few studies have assessed which of the many types of serotonin receptors are responsible. Using a within-subject, double-blind, sham-controlled design in 26 subjects, we examined whether individual differences in serotonin system gene transcription, measured in peripheral blood, predicted the effect of acute tryptophan depletion on decision-making. Participants performed a task in which they chose between successive pairs of fixed, lower-stakes (control) and variable, higher-stakes (experimental) gambles, each involving wins or losses. In 21 participants, mRNA from 9 serotonin system genes was measured in whole blood prior to acute tryptophan depletion: 5-HT1B, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT3A, 5-HT3E, 5-HT7 (serotonin receptors), 5-HTT (the serotonin transporter), and tryptophan hydroxylase 1. Acute tryptophan depletion did not significantly influence participants' sensitivity to probability, wins, or losses, although there was a trend for a lower tendency to choose experimental gambles overall following depletion. Significant positive correlations, which survived correction for multiple comparisons, were detected between baseline 5-HT1B mRNA levels and acute tryptophan depletion-induced increases in both the overall tendency to choose the experimental gamble and sensitivity to wins. No significant relationship was observed with any other peripheral serotonin system markers. Computational analyses of decision-making data provided results consistent with these findings. These results suggest that the 5-HT1B receptor may modulate the effects of acute tryptophan depletion on risky decision-making. Peripheral levels of serotonin markers may predict response to treatments that act upon the serotonin system, such as selective serotonin reuptake inhibitors. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Serotonin blood test

MedlinePlus

5-HT level; 5-hydroxytryptamine level; Serotonin test ... Chernecky CC, Berger BJ. Serotonin (5-hydroxytryptamine) - serum or blood. In: Chernecky CC, Berger BJ, eds. Laboratory Tests and Diagnostic Procedures . 6th ed. St Louis, MO: Elsevier ...

Similar anxiolytic effects of agonists targeting serotonin 5-HT1A or cannabinoid CB receptors on zebrafish behavior in novel environments

PubMed Central

Connors, Kristin A.; Valenti, Theodore W.; Lawless, Kelly; Sackerman, James; Onaivi, Emmanuel S.; Brooks, Bryan W.; Gould, Georgianna G.

2014-01-01

The discovery that selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are present and bioaccumulate in aquatic ecosystems have spurred studies of fish serotonin transporters (SERTs) and changes in SSRI-sensitive behaviors as adverse outcomes relevant for risk assessment. Many SSRIs also act at serotonin 5-HT1A receptors. Since capitolizing on this action may improve treatments of clinical depression and other psychiatric disorders, novel multimodal drugs that agonize 5-HT1A and block SERT were introduced. In mammals both 5-HT1A and CB agonists, such as buspirone and WIN55,212-2, reduce anxious behaviors. Immunological and behavioral evidence suggests that 5-HT1A-like receptors may function similarly in zebrafish (Danio rerio), yet their pharmacological properties are not well characterized. Herein we compared the density of [3H] 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT) binding to 5-HT1A-like sites in the zebrafish brain, to that of simalarly Gαi/o-coupled cannabinoid receptors. [3H] 8-OH-DPAT specific binding was 176 ± 8, 275 ± 32, and 230 ± 36 fmol/mg protein in the hypothalamus, optic tectum, and telencephalon. [3H] WIN55,212-2 binding density was higher in those same brain regions at 6 ± 0.3, 5.5 ± 0.4 and 7.3 ± 0.3 pm/mg protein. The aquatic light-dark plus maze was used to examine behavioral effects of 5-HT1A and CB receptor agonists on zebrafish novelty-based anxiety. With acute exposure to the 5-HT1A partial-agonist buspirone (50 mg/L), or dietary exposure to WIN55,212-2 (7 μg/week) zebrafish spent more time in and/or entered white arms more often than controls (p < 0.05). Acute exposure to WIN55,212-2 at 0.5-50 mg/L, reduced mobility. These behavioral findings suggest that azipirones, like cannabinoid agonists, have anxiolytic and/or sedative properties on fish in novel environments. These observations highlight the need to consider potential ecological risks of azapirones and multimodal antidepressants in the future. PMID:24411165

Hypothermic and antipyretic effects of ACTH (1-24) and alpha-melanotropin in guinea-pigs

NASA Technical Reports Server (NTRS)

Kandasamy, S. B.; Williams, B. A.

1984-01-01

Intracerebroventricular administration of adrenocorticotropin (ACTH 1-24) and alpha-melanotropin (alpha-MSH), peptides which occur naturally in brain induced dose-related hypothermia in guinea-pigs at room temperature (21 C) and also produced greater hypothermia at low (10 C) ambient temperature. However, when the experiments were repeated in a warm (30 C) environment, no effect on body temperature was observed. These results indicate that the peptides did not reduce the central set-point of temperature control. The hypothermia induced by ACTH and alpha-MSH was not mediated via histamine H1- or H2-receptors and serotonin since the H1-receptor antagonist, mepyramine, the H2-receptor antagonist, cimetidine, and the serotonin antagonist, methysergide, had no antagonistic effects. The peptides were antipyretic since they reduced pyrogen-induced-fever and hyperthermia due to prostaglandin E2, norepinephrine and dibutyryl cAMP, at a dose which did not affect normal body temperature. The powerful central effects of these peptides on normal body temperature, fever and hyperthermia, together with their presence of the brain regions important to temperature control, suggest that they participate in thermoregulation.

Ecstasy use and serotonin syndrome: a neglected danger to adolescents and young adults prescribed selective serotonin reuptake inhibitors.

PubMed

Dobry, Yuriy; Rice, Timothy; Sher, Leo

2013-01-01

At present, there are scarce clinical and basic lab data concerning the risk of acute serotonin toxicity from selective serotonin reuptake inhibitors (SSRIs) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) co-administration. The health care community can strongly benefit from efforts to address the high risks associated with serotonin syndrome from this specific drug combination. The aim of this work is to review the risk of serotonin syndrome in adolescents and young adults prescribed with SSRIs and are concurrently using ecstasy. An electronic search of the major behavioral science bibliographic databases (Pubmed, PsycINFO, Medline) was conducted to retrieve peer-reviewed articles, which detail the clinical characteristics, biological mechanisms and social implications of SSRIs, MDMA, and their potential synergism in causing serotonin syndrome in the pediatric and young adult population. Search terms included "serotonin syndrome", "ecstasy", "MDMA", "pediatric", and "SSRI". Additional references were incorporated from the bibliographies of these retrieved articles. MDMA, in combination with the widely-prescribed SSRI antidepressant class, can lead to rapid, synergistic rise of serotonin (5-HT) concentration in the central nervous system, leading to the acute medical emergency known as serotonin syndrome. This review addresses such complication through an exploration of the theoretical mechanisms and clinical manifestations of this life-threatening pharmacological interaction. The increasing incidences of recreational ecstasy use and SSRI pharmacotherapy among multiple psychiatric disorders in the adolescent population have made this an overlooked yet increasingly relevant danger, which poses a threat to public health. This can be curbed through further research, as well as greater health care provision and attention from a regulatory body owing.

Incidence and prognostic value of serotonin secretion in pancreatic neuroendocrine tumours.

PubMed

Zandee, Wouter T; van Adrichem, Roxanne C; Kamp, Kimberly; Feelders, Richard A; van Velthuysen, Marie-Louise F; de Herder, Wouter W

2017-08-01

Serotonin secretion occurs in approximately 1%-4% of patients with a pancreatic neuroendocrine tumour (PNET), but the incidence is not well defined. The aim of this study was to determine the incidence of serotonin secretion with and without carcinoid syndrome and the prognostic value for overall survival (OS). Data were collected from 255 patients with a PNET if 24-hours urinary 5-hydroxyindoleacetic acid excretion (5-HIAA) was assessed. Patients were diagnosed with serotonin secretion if 24-hours urinary 5-HIAA excretion was more than 3× the upper limit of normal (ULN) of 50 μmol/24 hours during follow-up. The effect of serotonin secretion on OS was estimated with uni- and multivariate analyses using a Cox regression. Two (0.8%) patients were diagnosed with carcinoid syndrome, and another 20 (7.8%) had a serotonin-secreting PNET without symptoms. These patients mostly had ENETS stage IV disease with high chromogranin A (CgA). Serotonin secretion was a negative prognostic factor in univariate analysis (HR 2.2, 95% CI: 1.27-3.81), but in multivariate analysis, only CgA>10× ULN (HR: 1.81, 95% CI: 1.10-2.98) and neuron-specific enolase (NSE) >ULN (HR: 3.51, 95% CI: 2.26-5.46) were predictors for OS. Immunohistochemical staining for serotonin was positive in 28.6% of serotonin-secreting PNETs (one with carcinoid syndrome) and negative in all controls. Carcinoid syndrome is rare in patients with a PNET, but serotonin secretion occurs often. This is a negative prognostic factor for OS, but after correction for CgA and NSE, it is no longer a predictor and probably only a "not-so innocent bystander" in patients with high tumour burden. © 2017 John Wiley & Sons Ltd.

How Studies of the Serotonin System in Macaque Models of Menopause Relate to Alzheimer's Disease1.

PubMed

Bethea, Cynthia L; Reddy, Arubala P; Christian, Fernanda Lima

2017-01-01

Serotonin plays a key role in mood or affect, and dysfunction of the serotonin system has been linked to depression in humans and animal models. Depression appears prior to or coincident with overt symptoms of Alzheimer's disease (AD) in about 50% of patients, and some experts consider it a risk factor for the development of AD. In addition, AD is more prevalent in women, who also show increased incidence of depression. Indeed, it has been proposed that mechanisms underlying depression overlap the mechanisms thought to hasten AD. Women undergo ovarian failure and cessation of ovarian steroid production in middle age and the postmenopausal period correlates with an increase in the onset of depression and AD. This laboratory has examined the many actions of ovarian steroids in the serotonin system of non-human primates using a rhesus macaque model of surgical menopause with short or long-term estradiol (E) or estradiol plus progesterone (E+P) replacement therapy. In this mini-review, we present a brief synopsis of the relevant literature concerning AD, depression, and serotonin. We also present some of our data on serotonin neuron viability, the involvement of the caspase-independent pathway, and apoptosis-inducing factor in serotonin-neuron viability, as well as gene expression related to neurodegeneration and neuron viability in serotonin neurons from adult and aged surgical menopausal macaques. We show that ovarian steroids, particularly E, are crucial for serotonin neuron function and health. In the absence of E, serotonin neurons are endangered and deteriorating toward apoptosis. The possibility that this scenario may proceed or accompany AD in postmenopausal women seems likely.

Subsecond Sensory Modulation of Serotonin Levels in a Primary Sensory Area and Its Relation to Ongoing Communication Behavior in a Weakly Electric Fish.

PubMed

Fotowat, Haleh; Harvey-Girard, Erik; Cheer, Joseph F; Krahe, Rüdiger; Maler, Leonard

2016-01-01

Serotonergic neurons of the raphe nuclei of vertebrates project to most regions of the brain and are known to significantly affect sensory processing. The subsecond dynamics of sensory modulation of serotonin levels and its relation to behavior, however, remain unknown. We used fast-scan cyclic voltammetry to measure serotonin release in the electrosensory system of weakly electric fish, Apteronotus leptorhynchus . These fish use an electric organ to generate a quasi-sinusoidal electric field for communicating with conspecifics. In response to conspecific signals, they frequently produce signal modulations called chirps. We measured changes in serotonin concentration in the hindbrain electrosensory lobe (ELL) with a resolution of 0.1 s concurrently with chirping behavior evoked by mimics of conspecific electric signals. We show that serotonin release can occur phase locked to stimulus onset as well as spontaneously in the ELL region responsible for processing these signals. Intense auditory stimuli, on the other hand, do not modulate serotonin levels in this region, suggesting modality specificity. We found no significant correlation between serotonin release and chirp production on a trial-by-trial basis. However, on average, in the trials where the fish chirped, there was a reduction in serotonin release in response to stimuli mimicking similar-sized same-sex conspecifics. We hypothesize that the serotonergic system is part of an intricate sensory-motor loop: serotonin release in a sensory area is triggered by sensory input, giving rise to motor output, which can in turn affect serotonin release at the timescale of the ongoing sensory experience and in a context-dependent manner.

Placenta-derived hypo-serotonin situations in the developing forebrain cause autism.

PubMed

Sato, Kohji

2013-04-01

Autism is a pervasive developmental disorder that is characterized by the behavioral traits of impaired social cognition and communication, and repetitive and/or obsessive behavior and interests. Although there are many theories and speculations about the pathogenetic causes of autism, the disruption of the serotonergic system is one of the most consistent and well-replicated findings. Recently, it has been reported that placenta-derived serotonin is the main source in embryonic day (E) 10-15 mouse forebrain, after that period, the serotonergic fibers start to supply serotonin into the forebrain. E 10-15 is the very important developing period, when cortical neurogenesis, migration and initial axon targeting are processed. Since all these events have been considered to be involved in the pathogenesis of autism and they are highly controlled by serotonin signals, the paucity of placenta-derived serotonin should have potential importance when the pathogenesis of autism is considered. I, thus, postulate a hypothesis that placenta-derived hypo-serotonin situations in the developing forebrain cause autism. The hypothesis is as follows. Various factors, such as inflammation, dysfunction of the placenta, together with genetic predispositions cause a decrease of placenta-derived serotonin levels. The decrease of placenta-derived serotonin levels leads to hypo-serotonergic situations in the forebrain of the fetus. The paucity of serotonin in the forebrain leads to mis-wiring in important regions which are responsible for the theory of mind. The paucity of serotonin in the forebrain also causes over-growth of serotonergic fibers. These disturbances result in network deficiency and aberration of the serotonergic system, leading to the autistic phenotypes. Copyright © 2013 Elsevier Ltd. All rights reserved.

Subsecond Sensory Modulation of Serotonin Levels in a Primary Sensory Area and Its Relation to Ongoing Communication Behavior in a Weakly Electric Fish

PubMed Central

Krahe, Rüdiger; Maler, Leonard

2016-01-01

Abstract Serotonergic neurons of the raphe nuclei of vertebrates project to most regions of the brain and are known to significantly affect sensory processing. The subsecond dynamics of sensory modulation of serotonin levels and its relation to behavior, however, remain unknown. We used fast-scan cyclic voltammetry to measure serotonin release in the electrosensory system of weakly electric fish, Apteronotus leptorhynchus. These fish use an electric organ to generate a quasi-sinusoidal electric field for communicating with conspecifics. In response to conspecific signals, they frequently produce signal modulations called chirps. We measured changes in serotonin concentration in the hindbrain electrosensory lobe (ELL) with a resolution of 0.1 s concurrently with chirping behavior evoked by mimics of conspecific electric signals. We show that serotonin release can occur phase locked to stimulus onset as well as spontaneously in the ELL region responsible for processing these signals. Intense auditory stimuli, on the other hand, do not modulate serotonin levels in this region, suggesting modality specificity. We found no significant correlation between serotonin release and chirp production on a trial-by-trial basis. However, on average, in the trials where the fish chirped, there was a reduction in serotonin release in response to stimuli mimicking similar-sized same-sex conspecifics. We hypothesize that the serotonergic system is part of an intricate sensory–motor loop: serotonin release in a sensory area is triggered by sensory input, giving rise to motor output, which can in turn affect serotonin release at the timescale of the ongoing sensory experience and in a context-dependent manner. PMID:27844054

Peripheral Serotonin Regulates Maternal Calcium Trafficking in Mammary Epithelial Cells during Lactation in Mice

PubMed Central

Laporta, Jimena; Keil, Kimberly P.; Vezina, Chad M.; Hernandez, Laura L.

2014-01-01

Lactation is characterized by massive transcellular flux of calcium, from the basolateral side of the mammary alveolar epithelium (blood) into the ductal lumen (milk). Regulation of calcium transport during lactation is critical for maternal and neonatal health. The monoamine serotonin (5-HT) is synthesized by the mammary gland and functions as a homeostatic regulation of lactation. Genetic ablation of tryptophan hydroxylase 1 (Tph1), which encodes the rate-limiting enzyme in non-neuronal serotonin synthesis, causes a deficiency in circulating serotonin. As a consequence maternal calcium concentrations decrease, mammary epithelial cell morphology is altered, and cell proliferation is decreased during lactation. Here we demonstrate that serotonin deficiency decreases the expression and disrupts the normal localization of calcium transporters located in the apical (PMCA2) and basolateral (CaSR, ORAI-1) membranes of the lactating mammary gland. In addition, serotonin deficiency decreases the mRNA expression of calcium transporters located in intracellular compartments (SERCA2, SPCA1 and 2). Mammary expression of serotonin receptor isoform 2b and its downstream pathways (PLCβ3, PKC and MAP-ERK1/2) are also decreased by serotonin deficiency, which might explain the numerous phenotypic alterations described above. In most cases, addition of exogenous 5-hydroxy-L-tryptophan to the Tph1 deficient mice rescued the phenotype. Our data supports the hypothesis that serotonin is necessary for proper mammary gland structure and function, to regulate blood and mammary epithelial cell transport of calcium during lactation. These findings can be applicable to the treatment of lactation-induced hypocalcemia in dairy cows and can have profound implications in humans, given the wide-spread use of selective serotonin reuptake inhibitors as antidepressants during pregnancy and lactation. PMID:25299122

On the Mechanism of Serotonin-Induced Dipsogenesis in the Rat

NASA Technical Reports Server (NTRS)

Kikta, Dianne C.; Barney, Christopher C.; Threatte, Rose M.; Fregly, Melvin J.; Rowland, Neil E.; Greenleaf, John E.

1983-01-01

Subcutaneous administration of 1-5-hydroxytryptophan (5-HTP), the precursor of serotonin, to female rats induces copious drinking accompanied by activation of the renin-angiotensin system. Neither a reduction in blood pressure nor body temperature accompanied administration of 5-HTP. The objective of the present study was to determine whether serotonin-induced dipsogenesis, like that of 5-HTP, is mediated via the renin-angiotensin system. Serotonin (2 mg/kg, SC)-induced drinking was inhibited by the dopaminergic antagonist, haloperidol (150 /micro g/kg, IP), which also inhibits angiotensin II-induced drinking, Both captopril (35 mg/kg, IP), an angiotensin converting enzyme inhibitor, and propranolol (6 micro g/kg, IP), a beta-adrenergic antagonist, blocked serotonin-induced dipsogenesis. The alpha(sub a),-adrenergic agonist, clonidine (6.25 micro g/kg, SC), which suppresses renin release from the kidney, attenuated serotonin-induced water intake. The dipsogenic responses to submaximal concentrations of both serotonin (1 mg/kg, SC) and isoproterenol (8 micro g/kg, SC) were additive rather than interactive suggesting that similar pathways mediate both responses. The serotonergic receptor antagonist, methysergide (3 mg/kg, IP), inhibited serotonin-induced drinking but had no effect on isoproterenol (25micro g/kg, SC)-induced dipsogenesis. However, neither serotonin (2 mg/kg, SC) nor isoproterenol (25 micro g/kg, SC)-induced drinking was inhibited by cinansefin (25 micro g/kg, IP). These data indicate that serotonin induces drinking in rats via the renin-angiotensin system. However, the results of the studies using methysergide suggest that scrotonin appears to act at a point prior to activation of beta-adrenoceptors in the pathway leading to release of renin from the kidneys.

Selective Serotonin Reuptake Inhibitors (SSRIs)

MedlinePlus

... dangerous reactions when combined with certain medications or herbal supplements. Serotonin syndrome. Rarely, an antidepressant can cause high ... antidepressants, certain pain or headache medications, and the herbal supplement St. John's wort. Signs and symptoms of serotonin ...

Intact coding region of the serotonin transporter gene in obsessive-compulsive disorder

DOE Office of Scientific and Technical Information (OSTI.GOV)

Altemus, M.; Murphy, D.L.; Greenberg, B.

1996-07-26

Epidemiologic studies indicate that obsessive-compulsive disorder is genetically transmitted in some families, although no genetic abnormalities have been identified in individuals with this disorder. The selective response of obsessive-compulsive disorder to treatment with agents which block serotonin reuptake suggests the gene coding for the serotonin transporter as a candidate gene. The primary structure of the serotonin-transporter coding region was sequenced in 22 patients with obsessive-compulsive disorder, using direct PCR sequencing of cDNA synthesized from platelet serotonin-transporter mRNA. No variations in amino acid sequence were found among the obsessive-compulsive disorder patients or healthy controls. These results do not support a rolemore » for alteration in the primary structure of the coding region of the serotonin-transporter gene in the pathogenesis of obsessive-compulsive disorder. 27 refs.« less

Serotonin research: contributions to understanding psychoses.

PubMed

Geyer, Mark A; Vollenweider, Franz X

2008-09-01

The history of serotonin research is closely related to the study of hallucinogenic drugs that function as agonists at serotonin-2A receptors. The fundamental idea that psychotic states seen in psychiatric disorders such as schizophrenia might be attributable, in part, to abnormalities in serotonergic systems began with the almost simultaneous discovery of lysergic acid diethylamide (LSD), psilocybin and serotonin. Sixty years of study have confirmed early speculations regarding the important relationship between serotonin and both drug-induced and disorder-based psychotic states. Now, modern biochemical, pharmacological, behavioral, neuroimaging, genetic and molecular biological sciences are converging to understand how serotonergic systems interact with other monoaminergic and glutamatergic systems to modulate states of consciousness and contribute to psychotic disorders such as the group of schizophrenias. This review summarizes experimental assessments of the serotonergic hallucinogen model psychosis in relation to the serotonin hypothesis of schizophrenia.

Ligand Induced Conformational Changes of the Human Serotonin Transporter Revealed by Molecular Dynamics Simulations

PubMed Central

Grouleff, Julie; Schiøtt, Birgit

2013-01-01

The competitive inhibitor cocaine and the non-competitive inhibitor ibogaine induce different conformational states of the human serotonin transporter. It has been shown from accessibility experiments that cocaine mainly induces an outward-facing conformation, while the non-competitive inhibitor ibogaine, and its active metabolite noribogaine, have been proposed to induce an inward-facing conformation of the human serotonin transporter similar to what has been observed for the endogenous substrate, serotonin. The ligand induced conformational changes within the human serotonin transporter caused by these three different types of ligands, substrate, non-competitive and competitive inhibitors, are studied from multiple atomistic molecular dynamics simulations initiated from a homology model of the human serotonin transporter. The results reveal that diverse conformations of the human serotonin transporter are captured from the molecular dynamics simulations depending on the type of the ligand bound. The inward-facing conformation of the human serotonin transporter is reached with noribogaine bound, and this state resembles a previously identified inward-facing conformation of the human serotonin transporter obtained from molecular dynamics simulation with bound substrate, but also a recently published inward-facing conformation of a bacterial homolog, the leucine transporter from Aquifex Aoelicus. The differences observed in ligand induced behavior are found to originate from different interaction patterns between the ligands and the protein. Such atomic-level understanding of how an inhibitor can dictate the conformational response of a transporter by ligand binding may be of great importance for future drug design. PMID:23776432

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

1988-01-01

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

Characterization of a novel serotonin receptor coupled to adenylate cyclase in the hybrid neuroblastoma cell line NCB. 20

DOE Office of Scientific and Technical Information (OSTI.GOV)

Conner, D.A.

1988-01-01

Pharmacological characterization of the serotonin activation of adenylate cyclase in membrane preparation using over 40 serotonergic and non-serotonergic compounds demonstrated that the receptor mediating the response was distinct from previously described mammalian serotonin receptors. Agonist activity was only observed with tryptamine and ergoline derivatives. Potent antagonism was observed with several ergoline derivatives and with compounds such as mianserin and methiothepine. A comparison of the rank order of potency of a variety of compounds for the NCB.20 cell receptor with well characterized mammalian and non-mammalian serotonin receptors showed a pharmacological similarity, but not identity, with the mammalian 5-HT{sub 1C} receptor, whichmore » modulates phosphatidylinositol metabolism, and with serotonin receptors in the parasitic trematodes Fasciola hepatica and Schistosoma mansoni, which are coupled to adenylate cyclase. Equilibrium binding analysis utilizing ({sup 3}H)serotonin, ({sup 3}H)lysergic acid diethylamide or ({sup 3}H)dihydroergotamine demonstrated that there are no abundant high affinity serotonergic sites, which implies that the serotonin activation of adenylate cyclase is mediated by receptors present in low abundance. Incubation of intact NCB.20 cells with serotinin resulted in a time and concentration dependent desensitization of the serotonin receptor.« less

Development of resistance to serotonin-induced itch in bile duct ligated mice.

PubMed

Ostadhadi, Sattar; Haddadi, Nazgol-Sadat; Foroutan, Arash; Azimi, Ehsan; Elmariah, Sarina; Dehpour, Ahmad-Reza

2017-06-01

Cholestatic itch can be severe and significantly impair the quality of life of patients. The serotonin system is implicated in cholestatic itch; however, the pruritogenic properties of serotonin have not been evaluated in cholestatic mice. Here, we investigated the serotonin-induced itch in cholestatic mice which was induced by bile duct ligation (BDL). Serotonin, sertraline or saline were administered intradermally to the rostral back area in BDL and sham operated (SHAM) mice, and the scratching behaviour was videotaped for 1 hour. Bile duct ligated mice had significantly increased scratching responses to saline injection on the seventh day after surgery. Additionally, serotonin or sertraline significantly induced scratching behaviour in BDL mice compared to saline at day 7 after surgery, while it did not induce itch at day 5. The scratching behaviour induced by serotonin or sertraline was significantly less in BDL mice compared to SHAM mice. Likewise, the locomotor activity of BDL or SHAM mice was not significantly different from unoperated (UNOP) mice on the fifth and seventh day, suggesting that the scratching behaviour was not affected by motor dysfunctions. Our data suggest that despite the potentiation of evoked itch, a resistance to serotonin-induced itch is developed in cholestatic mice. © 2017 John Wiley & Sons Australia, Ltd.

Increased serotonin axons (immunoreactive to 5-HT transporter) in postmortem brains from young autism donors.

PubMed

Azmitia, Efrain C; Singh, Jorawer S; Whitaker-Azmitia, Patricia M

2011-06-01

Imaging studies of serotonin transporter binding or tryptophan retention in autistic patients suggest that the brain serotonin system is decreased. However, treatment with drugs which increase serotonin (5-HT) levels, specific serotonin reuptake inhibitors (SSRIs), commonly produce a worsening of the symptoms. In this study we examined 5-HT axons that were immunoreactive to a serotonin transporter (5-HTT) antibody in a number of postmortem brains from autistic patients and controls with no known diagnosis who ranged in age from 2 to 29 years. Fine, highly branched, and thick straight fibers were found in forebrain pathways (e.g. medial forebrain bundle, stria terminalis and ansa lenticularis). Many immunoreactive varicose fine fibers were seen in target areas (e.g. globus pallidus, amygdala and temporal cortex). Morphometric analysis of the stained axons at all ages studied indicated that the number of serotonin axons was increased in both pathways and terminal regions in cortex from autism donors. Our findings provide morphological evidence to warrant caution when using serotonin enhancing drugs (e.g. SSRIs and receptor agonist) to treat autistic children. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. Copyright © 2011 Elsevier Ltd. All rights reserved.

Electrochemical quantification of serotonin in the live embryonic zebrafish intestine

PubMed Central

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

2010-01-01

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

Serotonin syndrome following methylene blue administration during cardiothoracic surgery.

PubMed

Smith, Christina J; Wang, Dorothy; Sgambelluri, Anna; Kramer, Robert S; Gagnon, David J

2015-04-01

Despite its favorable safety profile, there have been reports of methylene blue-induced encephalopathy and serotonin syndrome in patients undergoing parathyroidectomy. We report a case of serotonin syndrome following methylene blue administration in a cardiothoracic surgery patient. A 59-year-old woman taking preoperative venlafaxine and trazodone was given a single dose of 2 mg/kg methylene blue (167 mg) during a planned coronary artery bypass and mitral valve repair. Postoperatively, she was febrile to 38.7°C and developed full-body tremors, rhythmic twitching of the perioral muscles, slow conjugate roving eye movements, and spontaneous movements of the upper extremities. Electroencephalography revealed generalized diffuse slowing consistent with toxic encephalopathy, and a computed tomography scan showed no acute process. The patient's symptoms were most consistent with a methylene blue-induced serotonin syndrome. Her motor symptoms resolved within 48 hours and she was eventually discharged home. Only 2 cases of methylene blue-induced serotonin syndrome during cardiothoracic surgery have been described in the literature, with this report representing the third case. Methylene blue and its metabolite, azure B, are potent, reversible inhibitors of monoamine oxidase A which is responsible for serotonin metabolism. Concomitant administration of methylene blue with serotonin-modulating agents may precipitate serotonin syndrome. © The Author(s) 2015.

Serotonin Transporter-Independent Actions of the Antidepressant Vortioxetine As Revealed Using the SERT Met172 Mouse.

PubMed

Nackenoff, Alex G; Simmler, Linda D; Baganz, Nicole L; Pehrson, Alan L; Sánchez, Connie; Blakely, Randy D

2017-05-17

Selective serotonin (5-HT, SERT) reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression. However, they have delayed efficacy and can induce side-effects that can encourage discontinuation. Recently, agents have been developed, including vortioxetine (Trintellix), that augment SERT blockade with interactions at other targets. At therapeutic doses, vortioxetine interacts with SERT as well as 5-HT 1A , 5-HT 1B , 5-HT 3 , and 5-HT 7 receptors. We assessed the SERT-dependency of vortioxetine action using the SERT Met172 mouse model, which disrupts high-affinity interactions of many antidepressants with the transporter. We demonstrate that the SERT Met172 substitution induces an ∼19-fold loss in vortioxetine potency for SERT inhibition in midbrain synaptosomes. Moreover, in these mice, we observed reduced SERT occupancy, a diminished ability to prolong 5-HT clearance, and a reduced capacity to elevate extracellular 5-HT. Despite reduced interactions with SERT, vortioxetine maintained its ability to enhance mobility in tail suspension and forced swim tests, reduce consumption latency in the novelty induced hypophagia test, and promoted proliferation and survival of subgranular zone hippocampal stem cells. Our findings suggest that the antidepressant actions of vortioxetine may be SERT-independent, and encourage consideration of agents that mimic one or more actions of the drug in the development of improved depression treatments.

Repeated intermittent MDMA binges reduce DAT density in mice and SERT density in rats in reward regions of the adolescent brain.

PubMed

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

2007-11-01

The popular recreational drug, 3,4-methylenedioxymethamphetamine (MDMA) is often taken as intermittent binges by adolescents at dance clubs. The neurobiological mechanisms that underlie MDMA-induced psychiatric conditions are still poorly understood. In the present study, mimicking adolescent patterns of administration, repeated intermittent MDMA binges (3x5 mg/(kg day) given 3h apart, every 7th day for 4 weeks) were given to adolescent mice and rats. Behavioral responses in the open-field and autoradiographic ligand-binding to dopamine (DAT) and serotonin (SERT) transporters in reward regions of the brain were measured. In the open-field, total horizontal activity (HA) was significantly increased in both mice and rats following the first and third weekly administered MDMA binge. However, rats, but not mice, exhibited an enhanced activity in the centre of the open-field arena, indicating on reduced anxiety or enhanced impulsivity, which is known to be associated with altered serotonin activity. Specific binding of DAT, but not SERT, was significantly reduced in the mouse AcbSh and CPU using in vitro autoradiography. On the contrary, SERT, but not DAT density was significantly reduced in the AcbSh of rats. Taken together, our data provide evidence for differential regulation of DAT and SERT densities in reward-related brain regions of rats and mice after long-term intermittent administration of MDMA.

Serotonin receptors influencing cell proliferation in the jejunal crypt epithelium and in colonic adenocarcinomas.

PubMed

Tutton, P J; Barkla, D H

1986-01-01

Serotonin has previously been shown to stimulate cell proliferation in the jejunal crypt epithelium and in colonic tumours. The original classification of serotonin receptors into D and M groups was not conductive to the understanding of these observations. The more recent classification of serotonin receptors into 5HT1 and 5HT2 groups is considered in this report. On the balance of evidence it appears that similar receptors mediate the response to serotonin in the two tissues under consideration and that these receptors resemble those of the 5HT1 group. Such receptors are usually positively linked to adenylate cyclase.

Increasing brain serotonin corrects CO2 chemosensitivity in methyl-CpG-binding protein 2 (Mecp2)-deficient mice

PubMed Central

Toward, Marie A.; Abdala, Ana P.; Knopp, Sharon J.; Paton, Julian F. R.; Bissonnette, John M.

2013-01-01

Mice deficient in the transcription factor methyl-CpG-binding protein 2 (Mecp2), a mouse model of Rett syndrome, display reduced CO2 chemosensitivity, which may contribute to their breathing abnormalities. In addition, patients with Rett syndrome and male mice that are null for Mecp2 show reduced levels of brain serotonin (5-HT). Serotonin is known to play a role in central chemosensitivity, and we hypothesized that increasing the availability of 5-HT in this mouse model would improve their respiratory response to CO2. Here we determined the apnoeic threshold in heterozygous Mecp2-deficient female mice and examined the effects of blocking 5-HT reuptake on the CO2 response in Mecp2-null male mice. Studies were performed in B6.129P2(C)-Mecp2τm1.1Bird null males and heterozygous females. In an in situ preparation, seven of eight Mecp2-deficient heterozygous females showed arrest of phrenic nerve activity when arterial CO2 was lowered to 3%, whereas the wild-types maintained phrenic nerve amplitude at 53 ± 3% of maximal. In vivo plethysmography studies were used to determine CO2 chemosensitivity in null males. These mice were exposed sequentially to 1, 3 and 5% CO2. The percentage increase in minute ventilation in response to increased inspired CO2 was less in Mecp2−/y than in Mecp2+/y mice. Pretreatment with citalopram, a selective 5-HT reuptake inhibitor (2.5 mg kg−1 I.P.), 40 min prior to CO2 exposure, in Mecp2−/y mice resulted in an improvement in CO2 chemosensitivity to wild-type levels. These results suggest that decreased 5-HT in Mecp2-deficient mice reduces CO2 chemosensitivity, and restoring 5-HT levels can reverse this effect. PMID:23180809

Sleep deprivation decreases phase-shift responses of circadian rhythms to light in the mouse: role of serotonergic and metabolic signals.

PubMed

Challet, E; Turek, F W; Laute, M; Van Reeth, O

2001-08-03

The circadian pacemaker in the suprachiasmatic nuclei is primarily synchronized to the daily light-dark cycle. The phase-shifting and synchronizing effects of light can be modulated by non-photic factors, such as behavioral, metabolic or serotonergic cues. The present experiments examine the effects of sleep deprivation on the response of the circadian pacemaker to light and test the possible involvement of serotonergic and/or metabolic cues in mediating the effects of sleep deprivation. Photic phase-shifting of the locomotor activity rhythm was analyzed in mice transferred from a light-dark cycle to constant darkness, and sleep-deprived for 8 h from Zeitgeber Time 6 to Zeitgeber Time 14. Phase-delays in response to a 10-min light pulse at Zeitgeber Time 14 were reduced by 30% in sleep-deprived mice compared to control mice, while sleep deprivation without light exposure induced no significant phase-shifts. Stimulation of serotonin neurotransmission by fluoxetine (10 mg/kg), a serotonin reuptake inhibitor that decreases light-induced phase-delays in non-deprived mice, did not further reduce light-induced phase-delays in sleep-deprived mice. Impairment of serotonin neurotransmission with p-chloroamphetamine (three injections of 10 mg/kg), which did not increase light-induced phase-delays in non-deprived mice significantly, partially normalized light-induced phase-delays in sleep-deprived mice. Injections of glucose increased light-induced phase-delays in control and sleep-deprived mice. Chemical damage of the ventromedial hypothalamus by gold-thioglucose (600 mg/kg) prevented the reduction of light-induced phase-delays in sleep-deprived mice, without altering phase-delays in control mice. Taken together, the present results indicate that sleep deprivation can reduce the light-induced phase-shifts of the mouse suprachiasmatic pacemaker, due to serotonergic and metabolic changes associated with the loss of sleep.

Early life environmental and pharmacological stressors result in persistent dysregulations of the serotonergic system

PubMed Central

Wong, Peiyan; Sze, Ying; Gray, Laura Jane; Chang, Cecilia Chin Roei; Cai, Shiwei; Zhang, Xiaodong

2015-01-01

Dysregulations in the brain serotonergic system and exposure to environmental stressors have been implicated in the development of major depressive disorder. Here, we investigate the interactions between the stress and serotonergic systems by characterizing the behavioral and biochemical effects of chronic stress applied during early-life or adulthood in wild type (WT) mice and mice with deficient tryptophan hydroxylase 2 (TPH2) function. We showed that chronic mild stress applied in adulthood did not affect the behaviors and serotonin levels of WT and TPH2 knock-in (KI) mice. Whereas, maternal separation (MS) stress increased anxiety- and depressive-like behaviors of WT mice, with no detectable behavioral changes in TPH2 KI mice. Biochemically, we found that MS WT mice had reduced brain serotonin levels, which was attributed to increased expression of monoamine oxidase A (MAO A). The increased MAO A expression was detected in MS WT mice at 4 weeks old and adulthood. No change in TPH2 expression was detected. To determine whether a pharmacological stressor, dexamethasone (Dex), will result in similar biochemical results obtained from MS, we used an in vitro system, SH-SY5Y cells, and found that Dex treatment resulted in increased MAO A expression levels. We then treated WT mice with Dex for 5 days, either during postnatal days 7–11 or adulthood. Both groups of Dex treated WT mice had reduced basal corticosterone and glucocorticoid receptors expression levels. However, only Dex treatment during PND7–11 resulted in reduced serotonin levels and increased MAO A expression. Just as with MS WT mice, TPH2 expression in PND7–11 Dex-treated WT mice was unaffected. Taken together, our findings suggest that both environmental and pharmacological stressors affect the expression of MAO A, and not TPH2, when applied during the critical postnatal period. This leads to long-lasting perturbations in the serotonergic system, and results in anxiety- and depressive-like behaviors. PMID:25964750

Effect of plasma membrane fluidity on serotonin transport by endothelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Block, E.R.; Edwards, D.

1987-11-01

To evaluate the effect of plasma membrane fluidity of lung endothelial cells on serotonin transport, porcine pulmonary artery endothelial cells were incubated for 3 h with either 0.1 mM cholesterol hemisuccinate, 0.1 mM cis-vaccenic acid, or vehicle (control), after which plasma membrane fluidity and serotinin transport were measured. Fluorescence spectroscopy was used to measure fluidity in the plasma membrane. Serotonin uptake was calculated from the disappearance of ({sup 14}C)-serotonin from the culture medium. Cholesterol decreased fluidity in the subpolar head group and central and midacyl side-chain regions of the plasma membrane and decreased serotonin transport, whereas cis-vaccenic acid increased fluiditymore » in the central and midacyl side-chain regions of the plasma membrane and also increased serotonin transport. Cis-vaccenic acid had no effect of fluidity in the subpolar head group region of the plasma membrane. These results provide evidence that the physical state of the central and midacyl chains within the pulmonary artery endothelial cell plasma membrane lipid bilayer modulates transmembrane transport of serotonin by these cells.« less

Relation between mast cells concentration and serotonin expression in chagasic megacolon development.

PubMed

Freitas, M A R; Segatto, N; Tischler, N; de Oliveira, E C; Brehmer, A; da Silveira, A B M

2017-03-01

Chagas' disease is still reaching about 10 million people in the world. In South America, one of the most severe forms of this disease is the megacolon, characterized by severe constipation, dilated sigmoid colon and rectum and severe malnutrition. Previous data suggested that mast cells and serotonin (5-hydroxytryptamine [5-HT]) expression could be involved in intestinal homeostasis control, avoiding the chagasic megacolon development. The aim at this study was to characterize the presence of mast cells and expression of serotonin in chagasic patients with and without megacolon and evaluate the relation between mast cells, serotonin and megacolon development. Our results demonstrated that patients without megacolon feature a large amount of serotonin and few mast cells, while patients with megacolon feature low serotonin expression and a lot of mast cells. We believe that serotonin may be involved in the inflammatory process control, triggered by mast cells, and the presence of this substance in large quantities of the intestine could represent a mechanism of megacolon prevention. © 2017 John Wiley & Sons Ltd.

Approach to novel functional foods for stress control 4. Regulation of serotonin transporter by food factors.

PubMed

Ito, Mikiko; Haito, Sakiko; Furumoto, Mari; Kawai, Yoshichika; Terao, Junji; Miyamoto, Ken-ichi

2005-11-01

Serotonin transporters (SERTs) are pre-synaptic proteins specialized for the clearance of serotonin following vesicular release at central nervous system (CNS) and enteric nervous system synapses. SERTs are high affinity targets in vivo for antidepressants such as serotonin selective reuptake inhibitors (SSRIs). These include 'medical' psychopharmacological agents such as analgesics and antihistamines, a plant extract called St John's Wort (Hypericum). Osteoclasts are the primary cells responsible for bone resorption. They arise by the differentiation of osteoclast precursors of the monocyte/macrophage lineage. The expression of SERTs was increased in RANKL-induced osteoclast-like cells. Using RANKL stimulation of RAW264.7 cells as a model system for osteoclast differentiation, we studied the direct effects of food factor on serotonin uptake. The SSRIs (fluoxetine and fluvoxamine) inhibited markedly (approximately 95%) in serotonin transport in differentiated osteoclast cells. The major components of St. John's Wort, hyperforin and hypericine were significantly decreased in serotonin transport activity. Thus, a new in vitro model using RANKL-induced osteoclast-like cells may be useful to analyze the regulation of SERT by food factors and SSRIs.

Serotonin induces peripheral antinociception via the opioidergic system.

PubMed

Diniz, Danielle Aguiar; Petrocchi, Júlia Alvarenga; Navarro, Larissa Caldeira; Souza, Tâmara Cristina; Castor, Marina Gomes Miranda E; Duarte, Igor Dimitri Gama; Romero, Thiago Roberto Lima

2018-01-01

Studies conducted since 1969 have shown that the release of serotonin (5-HT) in the dorsal horn of the spinal cord contributes to opioid analgesia. In the present study, the participation of the opioidergic system in antinociceptive effect serotonin at the peripheral level was examined. The paw pressure test was used with mice (Swiss, males from 35 g) which had increased pain sensitivity by intraplantar injection of PGE 2 (2 μg). Serotonin (250 ng), administered locally to the right paw of animals, produces antinociception in this model. The selective antagonists for mu, delta and kappa opioid receptors, clocinnamox clocinnamox (40 μg), naltrindole (60 μg) and nor-binaltorfimina (200 μg), respectively, inhibited the antinociceptive effect induced by serotonin. Additionally, bestatin (400 μg), an inhibitor of enkephalinases that degrade peptides opioids, enhanced the antinociceptive effect induced by serotonin (low dose of 62.5 ng). These results suggest that serotonin possibly induce peripheral antinociception through the release of endogenous opioid peptides, possible from immune cells or keratinocytes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Established amyloid-β pathology is unaffected by chronic treatment with the selective serotonin reuptake inhibitor paroxetine.

PubMed

Severino, Maurizio; Sivasaravanaparan, Mithula; Olesen, Louise Ø; von Linstow, Christian U; Metaxas, Athanasios; Bouzinova, Elena V; Khan, Asif Manzoor; Lambertsen, Kate L; Babcock, Alicia A; Gramsbergen, Jan Bert; Wiborg, Ove; Finsen, Bente

2018-01-01

Treatment with selective serotonin reuptake inhibitors has been suggested to mitigate amyloid-β (Aβ) pathology in Alzheimer's disease, in addition to an antidepressant mechanism of action. We investigated whether chronic treatment with paroxetine, a selective serotonin reuptake inhibitor, mitigates Aβ pathology in plaque-bearing double-transgenic amyloid precursor protein (APP) swe /presenilin 1 (PS1) ΔE9 mutants. In addition, we addressed whether serotonin depletion affects Aβ pathology. Treatments were assessed by measurement of serotonin transporter occupancy and high-performance liquid chromatography. The effect of paroxetine on Aβ pathology was evaluated by stereological plaque load estimation and Aβ 42 /Aβ 40 ratio by enzyme-linked immunosorbent assay. Contrary to our hypothesis, paroxetine therapy did not mitigate Aβ pathology, and depletion of brain serotonin did not exacerbate Aβ pathology. However, chronic paroxetine therapy increased mortality in APP swe /PS1 ΔE9 transgenic mice. Our results question the ability of selective serotonin reuptake inhibitor therapy to ameliorate established Aβ pathology. The severe adverse effect of paroxetine may discourage its use for disease-modifying purposes in Alzheimer's disease.

Cinanserin reduces plasma extravasation after burn plasma transfer in rats.

PubMed

Hernekamp, Jochen-Frederick; Hu, Sissi; Schmidt, Karsten; Walther, Andreas; Kneser, Ulrich; Kremer, Thomas

2013-09-01

Thermal injuries greater than 20% body surface area (BSA) lead to systemic edema and hypovolemic shock. Capillary leakage is induced by different immunomodulative cytokines. Serotonin (5-HT) plays an important role in inflammation, vasodilatation and vasoconstriction and many other pathways such as systemic inflammation in endotoxemia and burns. Cinanserin, a specific 5-HT2 receptor blocking agent was administered to observe whether burn induced systemic edema can be reduced. Donor animals underwent thermal injury (100°C water, 30% BSA, 12s) for positive controls and negative controls underwent a shamburn procedure (37°C water, 30% BSA, 12s). Donor rat-plasma was transferred to healthy individuals after bolus injection of Cinanserin (5mg/kg body weight) was performed in recipient animals. Intravital microscopy was performed in mesenteric venules (0/60/120min) to asses systemic edema by FITC-albumin extravasation. Additionally, leukocyte activation (cells/mm(2)) was observed. Burnplasma-transfer results in systemic capillary leakage that is not observed in sham burn controls. Intraveneous application of Cinanserin significantly reduces systemic burn edema to shamburn levels. Leukocyte-endothelial interactions are significantly reduced by administration of Cinanserin. Specific 5-HT2 antagonism reduces systemic burn edema and leukocyte activation after plasma transfer. Reduction of capillary leakage may be partially mediated by leukocyte dependent as well as independent mechanisms. Future studies need to evaluate specific 5-HT2 receptor subtypes to distinguish between local and systemic effects of serotonin antagonists. Copyright © 2013 Elsevier Ltd and ISBI. All rights reserved.

5-HT2A SEROTONIN RECEPTOR BIOLOGY: Interacting proteins, kinases and paradoxical regulation

PubMed Central

Roth, Bryan L

2011-01-01

5-hydroxytryptamine2A (5-HT2A) serotonin receptors are important pharmacological targets for a large number of central nervous system and peripheral serotonergic medications. In this review article I summarize work mainly from my lab regarding serotonin receptor anatomy, pharmacology, signaling and regulation. I highlight the role of serotonin receptor interacting proteins and the emerging paradigm of G-protein coupled receptor functional selectivity. PMID:21288474

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

PubMed

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

2012-05-01

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.

Serotonin-related pathways and developmental plasticity: relevance for psychiatric disorders

PubMed Central

Dayer, Alexandre

2014-01-01

Risk for adult psychiatric disorders is partially determined by early-life alterations occurring during neural circuit formation and maturation. In this perspective, recent data show that the serotonin system regulates key cellular processes involved in the construction of cortical circuits. Translational data for rodents indicate that early-life serotonin dysregulation leads to a wide range of behavioral alterations, ranging from stress-related phenotypes to social deficits. Studies in humans have revealed that serotonin-related genetic variants interact with early-life stress to regulate stress-induced cortisol responsiveness and activate the neural circuits involved in mood and anxiety disorders. Emerging data demonstrate that early-life adversity induces epigenetic modifications in serotonin-related genes. Finally, recent findings reveal that selective serotonin reuptake inhibitors can reinstate juvenile-like forms of neural plasticity, thus allowing the erasure of long-lasting fear memories. These approaches are providing new insights on the biological mechanisms and clinical application of antidepressants. PMID:24733969

A specific role for serotonin in overcoming effort cost.

PubMed

Meyniel, Florent; Goodwin, Guy M; Deakin, Jf William; Klinge, Corinna; MacFadyen, Christine; Milligan, Holly; Mullings, Emma; Pessiglione, Mathias; Gaillard, Raphaël

2016-11-08

Serotonin is implicated in many aspects of behavioral regulation. Theoretical attempts to unify the multiple roles assigned to serotonin proposed that it regulates the impact of costs, such as delay or punishment, on action selection. Here, we show that serotonin also regulates other types of action costs such as effort. We compared behavioral performance in 58 healthy humans treated during 8 weeks with either placebo or the selective serotonin reuptake inhibitor escitalopram. The task involved trading handgrip force production against monetary benefits. Participants in the escitalopram group produced more effort and thereby achieved a higher payoff. Crucially, our computational analysis showed that this effect was underpinned by a specific reduction of effort cost, and not by any change in the weight of monetary incentives. This specific computational effect sheds new light on the physiological role of serotonin in behavioral regulation and on the clinical effect of drugs for depression. ISRCTN75872983.

A new balancing act: The many roles of melatonin and serotonin in plant growth and development

PubMed Central

Erland, Lauren A E; Murch, Susan J; Reiter, Russel J; Saxena, Praveen K

2015-01-01

Melatonin and serotonin are indoleamines first identified as neurotransmitters in vertebrates; they have now been found to be ubiquitously present across all forms of life. Both melatonin and serotonin were discovered in plants several years after their discovery in mammals, but their presence has now been confirmed in almost all plant families. The mechanisms of action of melatonin and serotonin are still poorly defined. Melatonin and serotonin possess important roles in plant growth and development, including functions in chronoregulation and modulation of reproductive development, control of root and shoot organogenesis, maintenance of plant tissues, delay of senescence, and responses to biotic and abiotic stresses. This review focuses on the roles of melatonin and serotonin as a novel class of plant growth regulators. Their roles in reproductive and vegetative plant growth will be examined including an overview of current hypotheses and knowledge regarding their mechanisms of action in specific responses. PMID:26418957

A new balancing act: The many roles of melatonin and serotonin in plant growth and development.

PubMed

Erland, Lauren A E; Murch, Susan J; Reiter, Russel J; Saxena, Praveen K

2015-01-01

Melatonin and serotonin are indoleamines first identified as neurotransmitters in vertebrates; they have now been found to be ubiquitously present across all forms of life. Both melatonin and serotonin were discovered in plants several years after their discovery in mammals, but their presence has now been confirmed in almost all plant families. The mechanisms of action of melatonin and serotonin are still poorly defined. Melatonin and serotonin possess important roles in plant growth and development, including functions in chronoregulation and modulation of reproductive development, control of root and shoot organogenesis, maintenance of plant tissues, delay of senescence, and responses to biotic and abiotic stresses. This review focuses on the roles of melatonin and serotonin as a novel class of plant growth regulators. Their roles in reproductive and vegetative plant growth will be examined including an overview of current hypotheses and knowledge regarding their mechanisms of action in specific responses.

Decreased cerebral cortical serotonin transporter binding in ecstasy users: a positron emission tomography/[(11)C]DASB and structural brain imaging study.

PubMed

Kish, Stephen J; Lerch, Jason; Furukawa, Yoshiaki; Tong, Junchao; McCluskey, Tina; Wilkins, Diana; Houle, Sylvain; Meyer, Jeffrey; Mundo, Emanuela; Wilson, Alan A; Rusjan, Pablo M; Saint-Cyr, Jean A; Guttman, Mark; Collins, D Louis; Shapiro, Colin; Warsh, Jerry J; Boileau, Isabelle

2010-06-01

Animal data indicate that the recreational drug ecstasy (3,4-methylenedioxymethamphetamine) can damage brain serotonin neurons. However, human neuroimaging measurements of serotonin transporter binding, a serotonin neuron marker, remain contradictory, especially regarding brain areas affected; and the possibility that structural brain differences might account for serotonin transporter binding changes has not been explored. We measured brain serotonin transporter binding using [(11)C] N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine in 50 control subjects and in 49 chronic (mean 4 years) ecstasy users (typically one to two tablets bi-monthly) withdrawn from the drug (mean 45 days). A magnetic resonance image for positron emission tomography image co-registration and structural analyses was acquired. Hair toxicology confirmed group allocation but also indicated use of other psychoactive drugs in most users. Serotonin transporter binding in ecstasy users was significantly decreased throughout all cerebral cortices (range -19 to -46%) and hippocampus (-21%) and related to the extent of drug use (years, maximum dose), but was normal in basal ganglia and midbrain. Substantial overlap was observed between control and user values except for insular cortex, in which 51% of ecstasy user values fell below the lower limit of the control range. Voxel-based analyses confirmed a caudorostral gradient of cortical serotonin transporter binding loss with occipital cortex most severely affected. Magnetic resonance image measurement revealed no overall regional volume differences between groups; however, a slight left-hemispheric biased cortical thinning was detected in methamphetamine-using ecstasy users. The serotonin transporter binding loss was not related to structural changes or partial volume effect, use of other stimulant drugs, blood testosterone or oestradiol levels, major serotonin transporter gene promoter polymorphisms, gender, psychiatric status, or self-reported hyperthermia or tolerance. The ecstasy group, although 'grossly behaviourally normal', reported subnormal mood and demonstrated generally modest deficits on some tests of attention, executive function and memory, with the latter associated with serotonin transporter decrease. Our findings suggest that the 'typical'/low dose (one to two tablets/session) chronic ecstasy-polydrug user might display a highly selective mild to marked loss of serotonin transporter in cerebral cortex/hippocampus in the range of that observed in Parkinson's disease, which is not gender-specific or completely accounted for by structural brain changes, recent use of other drugs (as assessed by hair analyses) or other potential confounds that we could address. The striking sparing of serotonin transporter-rich striatum (although possibly affected in 'heavier' users) suggests that serotonergic neurons innervating cerebral cortex are more susceptible, for unknown reasons, to ecstasy than those innervating subcortical regions and that behavioural problems in some ecstasy users during abstinence might be related to serotonin transporter changes limited to cortical regions.

Genetic contributions of the serotonin transporter to social learning of fear and economic decision making.

PubMed

Crişan, Liviu G; Pana, Simona; Vulturar, Romana; Heilman, Renata M; Szekely, Raluca; Druğa, Bogdan; Dragoş, Nicolae; Miu, Andrei C

2009-12-01

Serotonin (5-HT) modulates emotional and cognitive functions such as fear conditioning (FC) and decision making. This study investigated the effects of a functional polymorphism in the regulatory region (5-HTTLPR) of the human 5-HT transporter (5-HTT) gene on observational FC, risk taking and susceptibility to framing in decision making under uncertainty, as well as multidimensional anxiety and autonomic control of the heart in healthy volunteers. The present results indicate that in comparison to the homozygotes for the long (l) version of 5-HTTLPR, the carriers of the short (s) version display enhanced observational FC, reduced financial risk taking and increased susceptibility to framing in economic decision making. We also found that s-carriers have increased trait anxiety due to threat in social evaluation, and ambiguous threat perception. In addition, s-carriers also show reduced autonomic control over the heart, and a pattern of reduced vagal tone and increased sympathetic activity in comparison to l-homozygotes. This is the first genetic study that identifies the association of a functional polymorphism in a key neurotransmitter-related gene with complex social-emotional and cognitive processes. The present set of results suggests an endophenotype of anxiety disorders, characterized by enhanced social learning of fear, impaired decision making and dysfunctional autonomic activity.

Genetic contributions of the serotonin transporter to social learning of fear and economic decision making

PubMed Central

Crişan, Liviu G.; Pană, Simona; Vulturar, Romana; Heilman, Renata M.; Szekely, Raluca; Drugă, Bogdan; Dragoş, Nicolae

2009-01-01

Serotonin (5-HT) modulates emotional and cognitive functions such as fear conditioning (FC) and decision making. This study investigated the effects of a functional polymorphism in the regulatory region (5-HTTLPR) of the human 5-HT transporter (5-HTT) gene on observational FC, risk taking and susceptibility to framing in decision making under uncertainty, as well as multidimensional anxiety and autonomic control of the heart in healthy volunteers. The present results indicate that in comparison to the homozygotes for the long (l) version of 5-HTTLPR, the carriers of the short (s) version display enhanced observational FC, reduced financial risk taking and increased susceptibility to framing in economic decision making. We also found that s-carriers have increased trait anxiety due to threat in social evaluation, and ambiguous threat perception. In addition, s-carriers also show reduced autonomic control over the heart, and a pattern of reduced vagal tone and increased sympathetic activity in comparison to l-homozygotes. This is the first genetic study that identifies the association of a functional polymorphism in a key neurotransmitter-related gene with complex social–emotional and cognitive processes. The present set of results suggests an endophenotype of anxiety disorders, characterized by enhanced social learning of fear, impaired decision making and dysfunctional autonomic activity. PMID:19535614

Context-dependent fluctuation of serotonin in the auditory midbrain: the influence of sex, reproductive state and experience

PubMed Central

Hanson, Jessica L.; Hurley, Laura M.

2014-01-01

In the face of changing behavioral situations, plasticity of sensory systems can be a valuable mechanism to facilitate appropriate behavioral responses. In the auditory system, the neurotransmitter serotonin is an important messenger for context-dependent regulation because it is sensitive to both external events and internal state, and it modulates neural activity. In male mice, serotonin increases in the auditory midbrain region, the inferior colliculus (IC), in response to changes in behavioral context such as restriction stress and social contact. Female mice have not been measured in similar contexts, although the serotonergic system is sexually dimorphic in many ways. In the present study, we investigated the effects of sex, experience and estrous state on the fluctuation of serotonin in the IC across contexts, as well as potential relationships between behavior and serotonin. Contrary to our expectation, there were no sex differences in increases of serotonin in response to a restriction stimulus. Both sexes had larger increases in second exposures, suggesting experience plays a role in serotonergic release in the IC. In females, serotonin increased during both restriction and interactions with males; however, the increase was more rapid during restriction. There was no effect of female estrous phase on the serotonergic change for either context, but serotonin was related to behavioral activity in females interacting with males. These results show that changes in behavioral context induce increases in serotonin in the IC by a mechanism that appears to be uninfluenced by sex or estrous state, but may depend on experience and behavioral activity. PMID:24198252

Role of serotonin in the regulation of renal proximal tubular epithelial cells.

PubMed

Erikci, Acelya; Ucar, Gulberk; Yabanoglu-Ciftci, Samiye

2016-08-01

In various renal injuries, tissue damage occurs and platelet activation is observed. Recent studies suggest that some factors, such as serotonin, are released into microenvironment upon platelet activation following renal injury. In the present study, we aimed to investigate whether platelets and platelet-released serotonin are involved in the functional regulation of renal proximal tubular epithelial cells (PTECs). PTECs were obtained by primary cell culture and treated with platelet lysate (PL) (2 × 10(6)/mL, 4 × 10(6)/mL, 8 × 10(6)/mL) or serotonin (1 μM or 5 μM) for 12 or 24 h. Phenotypic transdifferentiation of epithelial cells into myofibroblasts were demonstrated under light microscope and confirmed by the determination of α-smooth muscle actin gene expression. Serotonin and PL were shown to induce epithelial-mesenchymal transdifferentiation of PTECs. After stimulation of PTECs with serotonin or PL, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1, and collagen-α1 gene expressions, which were reported to be elevated in renal injury, were determined by real-time PCR and found to be upregulated. Expressions of some inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and transforming growth factor-β1 were found to be increased in both protein and gene levels. Recently there is no published report on the effect of serotonin on renal PTECs. Results obtained in this study have lightened the role of serotonin and platelet-mediated effects of serotonin on fibrotic and inflammatory processes in PTECs.

Serotonin-containing neurons in basal insects: In search of ground patterns among tetraconata.

PubMed

Stemme, Torben; Stern, Michael; Bicker, Gerd

2017-01-01

The ventral nerve cord of Tetraconata contains a comparably low number of serotonin-immunoreactive neurons, facilitating individual identification of cells and their characteristic neurite morphology. This offers the rather unique possibility of establishing homologies at the single cell level. Because phylogenetic relationships within Tetraconata are still discussed controversially, comparisons of individually identifiable neurons can help to unravel these issues. Serotonin immunoreactivity has been investigated in numerous tetraconate taxa, leading to reconstructions of hypothetical ground patterns for major lineages. However, detailed descriptions of basal insects are still missing, but are crucial for meaningful evolutionary considerations. We investigated the morphology of individually identifiable serotonin-immunoreactive neurons in the ventral nerve cord of Zygentoma (Thermobia domestica, Lepisma saccharina, Atelura formicaria) and Archaeognatha (Machilis germanica, Dilta hibernica). To improve immunocytochemical resolution, we also performed preincubation experiments with 5-hydroxy-L-tryptophan and serotonin. Additionally, we checked for immunolabeling of tryptophan hydroxylase, an enzyme associated with the synthesis of serotonin. Besides the generally identified groups of anterolateral, medial, and posterolateral neurons within each ganglion of the ventral nerve cord, we identified several other immunoreactive cells, which seem to have no correspondence in other tetraconates. Furthermore, we show that not all immunoreactive neurons produce serotonin, but have the capability for serotonin uptake. Comparisons with the patterns of serotonin-containing neurons in major tetraconate taxa suggest a close phylogenetic relationship of Remipedia, Cephalocarida, and Hexapoda, supporting the Miracrustacea hypothesis. J. Comp. Neurol., 2016. © 2016 Wiley Periodicals, Inc. J. Comp. Neurol. 525:79-115, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Fluctuations in [11C]SB207145 PET Binding Associated with Change in Threat-Related Amygdala Reactivity in Humans

PubMed Central

Fisher, Patrick MacDonald; Haahr, Mette Ewers; Jensen, Christian Gaden; Frokjaer, Vibe Gedsoe; Siebner, Hartwig Roman; Knudsen, Gitte Moos

2015-01-01

Serotonin critically affects the neural processing of emotionally salient stimuli, including indices of threat; however, how alterations in serotonin signaling contribute to changes in brain function is not well understood. Recently, we showed in a placebo-controlled study of 32 healthy males that brain serotonin 4 receptor (5-HT4) binding, assessed with [11C]SB207145 PET, was sensitive to a 3-week intervention with the selective serotonin reuptake inhibitor fluoxetine, supporting it as an in vivo model for fluctuations in central serotonin levels. Participants also underwent functional magnetic resonance imaging while performing a gender discrimination task of fearful, angry, and neutral faces. This offered a unique opportunity to evaluate whether individual fluctuations in central serotonin levels, indexed by change in [11C]SB207145 binding, predicted changes in threat-related reactivity (ie, fear and angry vs neutral faces) within a corticolimbic circuit including the amygdala and medial prefrontal and anterior cingulate cortex. We observed a significant association such that decreased brain-wide [11C]SB207145 binding (ie, increased brain serotonin levels) was associated with lower threat-related amygdala reactivity, whereas intervention group status did not predict change in corticolimbic reactivity. This suggests that in the healthy brain, interindividual responses to pharmacologically induced and spontaneously occurring fluctuations in [11C]SB207145 binding, a putative marker of brain serotonin levels, affect amygdala reactivity to threat. Our finding also supports that change in brain [11C]SB207145 binding may be a relevant marker for evaluating neurobiological mechanisms underlying sensitivity to threat and serotonin signaling. PMID:25560201

Serotonin and aggressive motivation in crustaceans: altering the decision to retreat.

PubMed

Huber, R; Smith, K; Delago, A; Isaksson, K; Kravitz, E A

1997-05-27

In crustaceans, as in most animal species, the amine serotonin has been suggested to serve important roles in aggression. Here we show that injection of serotonin into the hemolymph of subordinate, freely moving animals results in a renewed willingness of these animals to engage the dominants in further agonistic encounters. By multivariate statistical analysis, we demonstrate that this reversal results principally from a reduction in the likelihood of retreat and an increase in the duration of fighting. Serotonin infusion does not alter other aspects of fighting behavior, including which animal initiates an encounter, how quickly fighting escalates, or which animal eventually retreats. Preliminary studies suggest that serotonin uptake plays an important role in this behavioral reversal.

Activity of etv5a and etv5b genes in the hypothalamus of fasted zebrafish is influenced by serotonin.

PubMed

Mechaly, Alejandro S; Richardson, Ebony; Rinkwitz, Silke

2017-05-15

Serotonin has been implicated in the inhibition of food intake in vertebrates. However, the mechanisms through which serotonin acts has yet to be elucidated. Recently, ETV5 (ets variant gene 5) has been associated with obesity and food intake control mechanisms in mammals. We have analyzed a putative physiological function of the two etv5 paralogous genes (etv5a and etv5b) in neuronal food intake control in adult zebrafish that have been exposed to different nutritional conditions. A feeding assay was established and fluoxetine, a selective serotonin re-uptake inhibitor (SSRI), was applied. Gene expression changes in the hypothalamus were determined using real-time PCR. Fasting induced an up-regulation of etv5a and etv5b in the hypothalamus, whereas increased serotonin levels in the fasted fish counteracted the increase in expression. To investigate potential mechanisms the expression of further food intake control genes was determined. The results show that an increase of serotonin in fasting fish causes a reduction in the activity of genes stimulating food intake. This is in line with a previously demonstrated anorexigenic function of serotonin. Our results suggest that obesity-associated ETV5 has a food intake stimulating function and that this function is modulated through serotonin. Copyright © 2016 Elsevier Inc. All rights reserved.

Plasma Serotonin in Heart Failure: Possible Marker and Potential Treatment Target.

PubMed

Selim, Ahmed M; Sarswat, Nitasha; Kelesidis, Iosif; Iqbal, Muhammad; Chandra, Ramesh; Zolty, Ronald

2017-05-01

The relationship between heart failure (HF) and the serotonergic system has been established in animal studies. However, data on human plasma serotonin level in HF and its significance over the course of the disease is lacking. Serotonin levels were measured in 173 patients (108 males, 65 females), 116 were stable HF and 40 were acute decompensated HF patients. The normal control group included 17 healthy volunteers with no known medical or psychiatric conditions. Patients receiving medications affecting serotonin receptors and those with pulmonary hypertension were excluded. All patients, except for those in the decompensated group, were on stable doses of HF medications. Plasma serotonin levels were significantly elevated in decompensated HF patients compared with stable patients (P=0.002). Higher plasma serotonin levels were associated with worse HF symptoms (NYHA class) and the presence of systolic dysfunction, and was borderline associated with low peak oxygen consumption during cardiopulmonary exercise testing (P=0.055). These results were independent of age, gender, race, hypertension, diabetes, renal failure, weight, coronary artery disease (CAD), atrial fibrillation and medication use. Serotonin is a marker for decompensation in patients with chronic heart failure. Higher serotonin levels were associated with worse HF symptoms and systolic dysfunction. Copyright © 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Increased Release of Serotonin in the Spinal Cord During Low, But Not High, Frequency Transcutaneous Electric Nerve Stimulation in Rats With Joint Inflammation

PubMed Central

Sluka, Kathleen A.; Lisi, Tammy L.; Westlund, Karin N.

2009-01-01

Objective To determine the release pattern of serotonin and noradrenaline in the spinal cord in response to transcutaneous electric nerve stimulation (TENS) delivered at low or high frequency. Design Prospective randomized allocation of 3 treatments. Setting Research laboratory. Animals Male Sprague-Dawley rats (weight range, 250–350g). Intervention Knee joints of rats were inflamed with a mixture of 3% carrageenan and 3% kaolin for 24 hours prior to placement of push-pull cannulae into the dorsal horn of the spinal cord. Push-pull samples were collected in 10-minute intervals before, during, and after treatment with low-frequency TENS (4Hz), high-frequency TENS (100Hz), or sham TENS. TENS was applied to the inflamed knee joint for 20 minutes at sensory intensity and 100-μs pulse duration. Push-pull samples were analyzed for serotonin and noradrenaline by high performance liquid chromatography with coulemetric detection. Main Outcome Measures Spinal concentrations of serotonin and noradrenaline. Results Low-frequency TENS significantly increased serotonin concentrations during and immediately after treatment. There was no change in serotonin with high-frequency TENS, nor was there a change in noradrenaline with low- or high-frequency TENS. Conclusions Low-frequency TENS releases serotonin in the spinal cord to produce antihyperalgesia by activation of serotonin receptors. PMID:16876561

Toward Serotonin Fluorescent False Neurotransmitters: Development of Fluorescent Dual Serotonin and Vesicular Monoamine Transporter Substrates for Visualizing Serotonin Neurons.

PubMed

Henke, Adam; Kovalyova, Yekaterina; Dunn, Matthew; Dreier, Dominik; Gubernator, Niko G; Dincheva, Iva; Hwu, Christopher; Šebej, Peter; Ansorge, Mark S; Sulzer, David; Sames, Dalibor

2018-05-16

Ongoing efforts in our laboratories focus on design of optical reporters known as fluorescent false neurotransmitters (FFNs) that enable the visualization of uptake into, packaging within, and release from individual monoaminergic neurons and presynaptic sites in the brain. Here, we introduce the molecular probe FFN246 as an expansion of the FFN platform to the serotonergic system. Combining the acridone fluorophore with the ethylamine recognition element of serotonin, we identified FFN54 and FFN246 as substrates for both the serotonin transporter and the vesicular monoamine transporter 2 (VMAT2). A systematic structure-activity study revealed the basic structural chemotype of aminoalkyl acridones required for serotonin transporter (SERT) activity and enabled lowering the background labeling of these probes while maintaining SERT activity, which proved essential for obtaining sufficient signal in the brain tissue (FFN246). We demonstrate the utility of FFN246 for direct examination of SERT activity and SERT inhibitors in 96-well cell culture assays, as well as specific labeling of serotonergic neurons of the dorsal raphe nucleus in the living tissue of acute mouse brain slices. While we found only minor FFN246 accumulation in serotonergic axons in murine brain tissue, FFN246 effectively traces serotonin uptake and packaging in the soma of serotonergic neurons with improved photophysical properties and loading parameters compared to known serotonin-based fluorescent tracers.

Serotonin receptor, SERT mRNA and correlations with symptoms in males with alcohol dependence and suicide.

PubMed

Thompson, P M; Cruz, D A; Olukotun, D Y; Delgado, P L

2012-09-01

This study tested the hypothesis that abnormalities in components of the serotonin (5HT) system in the prefrontal cortex are associated with suicide in alcohol-dependent subjects. Second, we assessed the relationship of lifetime impulsivity and mood symptoms with prefrontal cortex 5-HT measures. Tissue was obtained from Brodmann's areas (BA) 9 and 24 in postmortem samples of individuals who were alcohol dependent with suicide (n = 5), alcohol dependent without suicide (n = 9) and normal controls (n = 5). Serotonin receptor (5HT) and serotonin reuptake transporter (SERT) mRNA were measured. Interviews with next of kin estimated lifetime impulsivity and mood symptoms in the last week of life. Serotonin receptor 1A (5HT1A) mRNA in BA 9 was elevated in the alcohol dependence without suicide group compared with controls. In the alcohol dependence with suicide group, anxiety symptoms were associated with decreased BA 24 SERT mRNA and depressive symptoms with BA 9 5HT1A mRNA expression. In the alcohol dependent only group impulsivity is correlated with increased BA 9, and BA 24 serotonin receptor 2A mRNA. Our data suggest region-specific change, rather than global serotonin blunting is involved in alcohol dependence and suicide. It also suggests that symptoms are differentially influenced by prefrontal cortex serotonin receptor mRNA levels. © 2011 John Wiley & Sons A/S.

Prediction and prevention of suicide in patients with unipolar depression and anxiety

PubMed Central

Gonda, Xenia; Fountoulakis, Konstantinos N; Kaprinis, George; Rihmer, Zoltan

2007-01-01

Epidemiological data suggest that between 59 and 87% of suicide victims suffered from major depression while up to 15% of these patients will eventually commit suicide. Male gender, previous suicide attempt(s), comorbid mental disorders, adverse life-situations, acute psycho-social stressors etc. also constitute robust risk factors. Anxiety and minor depression present with a low to moderate increase in suicide risk but anxiety-depression comorbidity increases this risk dramatically Contrary to the traditional psychoanalytic approach which considers suicide as a retrospective murder or an aggression turned in-wards, more recent studies suggest that the motivations to commit suicide may vary and are often too obscure. Neurobiological data suggest that low brain serotonin activity might play a key role along with the tryptophan hydroxylase gene. Social factors include social support networks, religion etc. It is proven that most suicide victims had asked for professional help just before committing suicide, however they were either not diagnosed (particularly males) or the treatment they received was inappropriate or inadequate. The conclusion is that promoting suicide prevention requires the improving of training and skills of both psychiatrists and many non-psychiatrists and especially GPs in recognizing and treating depression and anxiety. A shift of focus of attention is required in primary care to detect potentially suicidal patients presenting with psychological problems. The proper use of antidepressants, after a careful diagnostic evaluation, is important and recent studies suggest that successful acute and long-term antidepressant pharmacotherapy reduces suicide morbidity and mortality. PMID:17803824

Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients

PubMed Central

Politis, Marios; Wu, Kit; Loane, Clare; Brooks, David J.; Kiferle, Lorenzo; Turkheimer, Federico E.; Bain, Peter; Molloy, Sophie; Piccini, Paola

2014-01-01

Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson’s disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD. PMID:24531549

The selective serotonin reuptake inhibitor, escitalopram, enhances inhibition of prepotent responding and spatial reversal learning

PubMed Central

Brown, Holden D.; Amodeo, Dionisio A.; Sweeney, John A.; Ragozzino, Michael E.

2011-01-01

Previous findings indicate treatment with a selective serotonin reuptake inhibitor (SSRI) facilitates behavioral flexibility when conditions require inhibition of a learned response pattern. The present experiment investigated whether acute treatment with the SSRI, escitalopram, affects behavioral flexibility when conditions require inhibition of a naturally-biased response pattern (elevated conflict test) and/or reversal of a learned response pattern (spatial reversal learning). An additional experiment was carried out to determine whether escitalopram, at doses that affected behavioral flexibility, also reduced anxiety as tested in the elevated plus-maze. In each experiment, Long-Evans rats received an intraperitoneal injection of either saline or escitalopram (0.03, 0.3 or 1.0 mg/kg) 30 minutes prior to behavioral testing. Escitalopram, at all doses tested, enhanced acquisition in the elevated conflict test, but did not affect performance in the elevated plus-maze. Escitalopram (0.3 and 1.0 mg/kg) did not alter acquisition of the spatial discrimination, but facilitated reversal learning. In the elevated conflict and spatial reversal learning test, escitalopram enhanced the ability to maintain the relevant strategy after being initially selected. The present findings suggest that enhancing serotonin transmission with a SSRI facilitates inhibitory processes when conditions require a shift away from either a naturally-biased response pattern or a learned choice pattern. PMID:22219222

Selective serotonin reuptake inhibitors: measurement of effect on platelet function.

PubMed

McCloskey, Donna Jo; Postolache, Teodor T; Vittone, Bernard J; Nghiem, Khanh L; Monsale, Jude L; Wesley, Robert A; Rick, Margaret E

2008-03-01

Selective serotonin reuptake inhibitors (SSRIs) reduce platelet serotonin and are associated with increased gastrointestinal bleeding, an effect that is enhanced when taken with NSAIDs or aspirin. The best method to evaluate hemorrhagic events in patients taking SSRIs has not been determined. Platelet aggregation, which is not widely available, shows SSRI inhibition of platelet function; we tested whether a platelet function analyzer could detect SSRI inhibition of platelet function. Two groups of outpatients with mood disorders were recruited; each patient was taking a stable dose of either an SSRI or bupropion for at least 6 weeks. They were tested using the platelet function analyzer-100 (PFA-100; Dade International Inc, Miami, Fla) concomitantly with platelet aggregation. Fifty-eight patients were analyzed. We detected significant differences between the groups using aggregation methods with arachidonic acid (aggregation, P = 0.00001; release, P = 0.009) and collagen (aggregation, P = 0.016; release, P = 0.006). The PFA-100 did not detect differences between the groups or results outside the reference range. The PFA-100 does not detect the inhibitory effects of SSRIs on platelet function, but it can be used to direct evaluation of bleeding in a patient taking an SSRI. Abnormal PFA-100 results suggest additional evaluation for von Willebrand disease, other platelet inhibitory medications, or underlying intrinsic platelet dysfunction.

Targeting circuits of sexual desire as a treatment strategy for hypoactive sexual desire disorder.

PubMed

Stahl, Stephen M

2010-07-01

Hypoactive sexual desire disorder (HSDD) is hypothesized to be a disorder of the brain's reward circuitry. Neurotransmitters in reward circuits are thus therapeutic targets for improving sexual desire. Novel treatment strategies are to enhance dopamine (DA) actions, reduce serotonin (5-HT) actions, or both. (c) Copyright 2010 Physicians Postgraduate Press, Inc.

Whey protein rich in alpha-lactalbumin increases the ratio of plasma tryptophan to the sum of the other large neutral amino acids and improves cognitive performance in stress-vulnerable subjects.

PubMed

Markus, C Rob; Olivier, Berend; de Haan, Edward H F

2002-06-01

Cognitive performance often declines under chronic stress exposure. The negative effect of chronic stress on performance may be mediated by reduced brain serotonin function. The uptake of the serotonin precursor tryptophan into the brain depends on nutrients that influence the availability of tryptophan by changing the ratio of plasma tryptophan to the sum of the other large neutral amino acids (Trp-LNAA ratio). In addition, a diet-induced increase in tryptophan may increase brain serotonergic activity levels and improve cognitive performance, particularly in high stress-vulnerable subjects. We tested whether alpha-lactalbumin, a whey protein with a high tryptophan content, would increase the plasma Trp-LNAA ratio and improve cognitive performance in high stress- vulnerable subjects. Twenty-three high stress-vulnerable subjects and 29 low stress-vulnerable subjects participated in a double-blind, placebo-controlled, crossover study. All subjects conducted a memory-scanning task after the intake of a diet enriched with either alpha-lactalbumin (alpha-lactalbumin diet) or sodium caseinate (control diet). Blood samples were taken to measure the effect of dietary manipulation on the plasma Trp-LNAA ratio. A significantly greater increase in the plasma Trp-LNAA ratio after consumption of the alpha-lactalbumin diet than after the control diet (P = 0.0001) was observed; memory scanning improved significantly only in the high stress-vulnerable subjects (P = 0.019). Because an increase in the plasma Trp-LNAA ratio is considered to be an indirect indication of increased brain serotonin function, the results suggest that dietary protein rich in alpha-lactalbumin improves cognitive performance in stress-vulnerable subjects via increased brain tryptophan and serotonin activities.

Tryptophan depletion decreases the recognition of fear in female volunteers.

PubMed

Harmer, C J; Rogers, R D; Tunbridge, E; Cowen, P J; Goodwin, G M

2003-06-01

Serotonergic processes have been implicated in the modulation of fear conditioning in humans, postulated to occur at the level of the amygdala. The processing of other fear-relevant cues, such as facial expressions, has also been associated with amygdala function, but an effect of serotonin depletion on these processes has not been assessed. The present study investigated the effects of reducing serotonin function, using acute tryptophan depletion, on the recognition of basic facial expressions of emotions in healthy male and female volunteers. A double-blind between-groups design was used, with volunteers being randomly allocated to receive an amino acid drink specifically lacking tryptophan or a control mixture containing a balanced mixture of these amino acids. Participants were given a facial expression recognition task 5 h after drink administration. This task featured examples of six basic emotions (fear, anger, disgust, surprise, sadness and happiness) that had been morphed between each full emotion and neutral in 10% steps. As a control, volunteers were given a famous face classification task matched in terms of response selection and difficulty level. Tryptophan depletion significantly impaired the recognition of fearful facial expressions in female, but not male, volunteers. This was specific since recognition of other basic emotions was comparable in the two groups. There was also no effect of tryptophan depletion on the classification of famous faces or on subjective state ratings of mood or anxiety. These results confirm a role for serotonin in the processing of fear related cues, and in line with previous findings also suggest greater effects of tryptophan depletion in female volunteers. Although acute tryptophan depletion does not typically affect mood in healthy subjects, the present results suggest that subtle changes in the processing of emotional material may occur with this manipulation of serotonin function.

Effects of acute tryptophan depletion on central processing of CT-targeted and discriminatory touch in humans.

PubMed

Trotter, Paula Diane; McGlone, Francis; McKie, Shane; McFarquhar, Martyn; Elliott, Rebecca; Walker, Susannah Claire; Deakin, John Francis William

2016-08-01

C-tactile afferents (CTs) are slowly conducting nerve fibres, present only in hairy skin. They are optimally activated by slow, gentle stroking touch, such as those experienced during a caress. CT stimulation activates affective processing brain regions, alluding to their role in affective touch perception. We tested a theory that CT-activating touch engages the pro-social functions of serotonin, by determining whether reducing serotonin, through acute tryptophan depletion, diminishes subjective pleasantness and affective brain responses to gentle touch. A tryptophan depleting amino acid drink was administered to 16 healthy females, with a further 14 receiving a control drink. After 4 h, participants underwent an fMRI scan, during which time CT-innervated forearm skin and CT non-innervated finger skin was stroked with three brushes of differing texture, at CT-optimal force and velocity. Pleasantness ratings were obtained post scanning. The control group showed a greater response in ipsilateral orbitofrontal cortex to CT-activating forearm touch compared to touch to the finger where CTs are absent. This differential response was not present in the tryptophan depleted group. This interaction effect was significant. In addition, control participants showed a differential primary somatosensory cortex response to brush texture applied to the finger, a purely discriminatory touch response, which was not observed in the tryptophan depleted group. This interaction effect was also significant. Pleasantness ratings were similar across treatment groups. These results implicate serotonin in the differentiation between CT-activating and purely discriminatory touch responses. Such effects could contribute to some of the social abnormalities seen in psychiatric disorders associated with abnormal serotonin function. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Mice lacking the serotonin 5-HT2B receptor as an animal model of resistance to selective serotonin reuptake inhibitors antidepressants.

PubMed

Diaz, Silvina Laura; Narboux-Nême, Nicolas; Boutourlinsky, Katia; Doly, Stéphane; Maroteaux, Luc

2016-02-01

Depressive disorders are among the most prevalent neuropsychiatric dysfunctions worldwide, with high rates of resistance to antidepressant treatment. Genetic factors clearly contribute to the manifestation of depression as well as to the response to antidepressants. Transgenic mouse models appear as seminal tools to disentangle this complex disorder. Here, we analyzed new key aspects of the phenotype of knock-out mice for the gene encoding the serotonin 2B receptor (Htr(2B)(-/-)), including basal phenotype, ability to develop a depressive-like phenotype upon chronic isolation, and effect of chronic exposure to fluoxetine on chronically stressed Htr(2B)(-/-) mice. We find, here, that Htr(2B)(-/-) mice display an antidepressant-like phenotype, which includes reduced latency to feed in the novelty suppressed feeding test, basal increase in hippocampal BDNF levels, no change in TrkB and p75 protein levels, and an increased preference for sucrose consumption compared to wild type (Htr(2B)(+/+)) mice. Nevertheless, we show that these mice can develop depressive-like behaviors when socially isolated during four weeks. Selective serotonin reuptake inhibitors (SSRI) have been previously shown to be ineffective in non-stressed Htr(2B)(-/-) mice. We evaluated, here, the effects of the SSRI fluoxetine in chronically stressed Htr(2B)(-/-) mice and similarly no behavioral or plastic effect was induced by this antidepressant. All together, these results highlight the suitability to study resistance to SSRI antidepressants of this mouse model displaying panoply of conditions among which behavioral, neurotrophic and plastic causative factors can be analyzed. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Playing it safe but losing anyway--serotonergic signaling of negative outcomes in dorsomedial prefrontal cortex in the context of risk-aversion.

PubMed

Macoveanu, Julian; Rowe, James B; Hornboll, Bettina; Elliott, Rebecca; Paulson, Olaf B; Knudsen, Gitte M; Siebner, Hartwig R

2013-08-01

Risk avoidance is an important determinant of human behavior. The neurotransmitter serotonin has been implicated in processing negative outcomes caused by risky decisions. However, it is unclear whether serotonin provides a neurobiological link between making a risk aversive decision and the response to a negative outcome. Using pharmacological fMRI, we manipulated the availability of serotonin in healthy volunteers while performing a gambling task. The same group of participants was studied in three fMRI sessions: (i) during intravenous administration of the SSRI citalopram to increase the serotonergic tone, (ii) after acute tryptophan depletion (ATD) to reduce central serotonin levels, or (iii) without interventions. ATD and citalopram had opposite effects on outcome related activity in dorsomedial prefrontal cortex (dmPFC) and amygdala. Relative to the control condition, ATD increased and citalopram decreased the neural response to negative outcomes in dmPFC. Conversely, ATD decreased and citalopram increased the neural response to negative outcomes in left amygdala. Critically, these pharmacological effects were restricted to negative outcomes that were caused by low-risk decisions and led to a high missed reward. ATD and citalopram did not alter the neural response to positive outcomes in dmPFC, but relative to ATD, citalopram produced a bilateral increase in the amygdala response to large wins caused by high-risk choices. The results show a selective involvement of the serotonergic system in neocortical processing of negative outcomes resulting from risk-averse decisions, thereby linking risk aversion and processing of negative outcomes in goal-directed behaviors. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

17β-Estradiol augments antidepressant efficacy of escitalopram in ovariectomized rats: Neuroprotective and serotonin reuptake transporter modulatory effects.

PubMed

Ibrahim, Weam W; Safar, Marwa M; Khattab, Mahmoud M; Agha, Azza M

2016-12-01

The prevalence or recurrence of depression is seriously increased in women during the transition to and after menopause. The chronic hypo-estrogenic state of menopause may reduce the response to antidepressants; however the influence of estrogen therapy on their efficacy is still controversial. This study aimed at investigating the effects of combining escitalopram with 17β-estradiol on depression and cognitive impairment induced by ovariectomy, an experimental model of human menopause. Young adult female Wistar rats were subjected to either sham operation or ovariectomy. Ovariectomized animals were treated chronically with escitalopram (10mg/kg/day, i.p) alone or with four doses of 17β-estradiol (40μg/kg, s.c) given prior to the behavioral tests. Co-administration of 17β-estradiol improved escitalopram-induced antidepressant effect in forced swimming test verified as more prominent decrease in the immobility time without opposing its memory enhancing effect in Morris water maze. 17β-estradiol augmented the modulatory effects of escitalopram on the hippocampal levels of brain-derived neurotrophic factor and serotonin reuptake transporter as well as tumor necrosis factor-alpha without altering its effects on the gene expressions of serotonin receptor 1A, estrogen receptors alpha and beta, or acetylcholinestearase content. This combined therapy afforded synergistic protective effects on the brain histopathological architecture, particularly, the hippocampus. The antidepressant effect of 17β-estradiol was abolished by pretreatment with estrogen receptor antagonist, tamoxifen (10mg/kg, p.o). In conclusion, 17β-estradiol-induced antidepressant effect was confined to intracellular estrogen receptors activation. Moreover, 17β-estradiol enhanced escitalopram's efficiency in ameliorating menopausal-like depression, via exerting synergistic neuroprotective and serotonin reuptake transporter modulatory effects, without impeding escitalopram-mediated cognitive improvement. Copyright © 2016 Elsevier Ltd. All rights reserved.

Primum Non Nocere: An Evolutionary Analysis of Whether Antidepressants Do More Harm than Good

PubMed Central

Andrews, Paul W.; Thomson, J. Anderson; Amstadter, Ananda; Neale, Michael C.

2012-01-01

Antidepressant medications are the first-line treatment for people meeting current diagnostic criteria for major depressive disorder. Most antidepressants are designed to perturb the mechanisms that regulate the neurotransmitter serotonin – an evolutionarily ancient biochemical found in plants, animals, and fungi. Many adaptive processes evolved to be regulated by serotonin, including emotion, development, neuronal growth and death, platelet activation and the clotting process, attention, electrolyte balance, and reproduction. It is a principle of evolutionary medicine that the disruption of evolved adaptations will degrade biological functioning. Because serotonin regulates many adaptive processes, antidepressants could have many adverse health effects. For instance, while antidepressants are modestly effective in reducing depressive symptoms, they increase the brain’s susceptibility to future episodes after they have been discontinued. Contrary to a widely held belief in psychiatry, studies that purport to show that antidepressants promote neurogenesis are flawed because they all use a method that cannot, by itself, distinguish between neurogenesis and neuronal death. In fact, antidepressants cause neuronal damage and mature neurons to revert to an immature state, both of which may explain why antidepressants also cause neurons to undergo apoptosis (programmed death). Antidepressants can also cause developmental problems, they have adverse effects on sexual and romantic life, and they increase the risk of hyponatremia (low sodium in the blood plasma), bleeding, stroke, and death in the elderly. Our review supports the conclusion that antidepressants generally do more harm than good by disrupting a number of adaptive processes regulated by serotonin. However, there may be specific conditions for which their use is warranted (e.g., cancer, recovery from stroke). We conclude that altered informed consent practices and greater caution in the prescription of antidepressants are warranted. PMID:22536191

Serotonin (1A) receptor involvement in acute 3,4-methylenedioxymethamphetamine (MDMA) facilitation of social interaction in the rat.

PubMed

Morley, Kirsten C; Arnold, Jonathon C; McGregor, Iain S

2005-06-01

The current study assessed whether various co-administered serotonin (5-HT) receptor antagonists could prevent some of the acute behavioral effects of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") in rats. In the social interaction test, MDMA (5 mg/kg) significantly increased the duration of total social interaction between two conspecifics meeting for the first time. Microanalysis showed that MDMA increased adjacent lying and approach behaviours while reducing anogenital sniffing. MDMA (5 mg/kg) also caused elements of the serotonin syndrome including low body posture and piloerection. In the emergence test, MDMA significantly increased hide time and emergence latency indicating increased anxiety-like behavior. Pretreatment with the 5HT 1A receptor antagonist, WAY 100635 (1 mg/kg), prevented MDMA-induced increases in social interaction and markers of the serotonin syndrome while the 5-HT 1B receptor antagonist GR 55562 (1 mg/kg) and 5-HT 2A receptor antagonist ketanserin (1 mg/kg) were ineffective. The 5-HT 2B/2C receptor antagonist, SB 206553 (2 mg/kg), prevented MDMA-induced prosocial effects but caused pronounced thigmotaxis (hyperactivity at the periphery of the testing chamber). The anxiogenic effect of MDMA on the emergence test was not prevented by pretreatment with any of the 5-HT receptor antagonists tested. These results indicate that prosocial effect of MDMA may involve 5-HT 1A and possibly 5-HT 2B/2C receptors. In contrast, MDMA-induced generalised anxiety, as measured by the emergence test, seems unlikely to involve the 5-HT 1A, 5-HT 1B or 5-HT 2A, 5-HT 2B or 5-HT 2C receptors.

Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls—antagonistic effects between opioid and serotonin-related genes

PubMed Central

Tour, Jeanette; Löfgren, Monika; Mannerkorpi, Kaisa; Gerdle, Björn; Larsson, Anette; Palstam, Annie; Bileviciute-Ljungar, Indre; Bjersing, Jan; Martin, Ingvar; Ernberg, Malin; Schalling, Martin; Kosek, Eva

2017-01-01

Abstract Chronic pain is associated with dysfunctional endogenous pain modulation, involving both central opioid and serotonergic (5-HT) signaling. Fibromyalgia (FM) is a chronic pain syndrome, characterized by widespread musculoskeletal pain and reduced exercise-induced hypoalgesia (EIH). In this study, we assessed the effects of 3 functional genetic polymorphisms on EIH in 130 patients with FM and 132 healthy controls. Subjects were genotyped regarding the mu-opioid receptor (OPRM1) gene (rs1799971), the serotonin transporter (5-HTT) gene (5-HTTLPR/rs25531), and the serotonin-1a receptor (5-HT1a) gene (rs6296). The patients with FM had increased pain sensitivity and reduced EIH compared with healthy controls. None of the polymorphisms had an effect on EIH on their own. We found significant gene-to-gene interactions between OPRM1 x 5-HTT and OPRM1 x 5-HT1a regarding activation of EIH, with no statistically significant difference between groups. Better EIH was found in individuals with genetically inferred strong endogenous opioid signaling (OPRM1 G) in combination with weak 5-HT tone (5-HTT low/5-HT1a G), compared with strong 5-HT tone (5-HTT high/5-HT1a CC). Based on the proposed mechanisms of these genetic variants, the findings indicate antagonistic interactions between opioid and serotonergic mechanisms during EIH. Moreover, despite different baseline pain level, similar results were detected in FM and controls, not supporting an altered interaction between opioid and 5-HT mechanisms as the basis for dysfunction of EIH in patients with FM. In summary, our results suggest that, by genetic association, the mu-opioid receptor interacts with 2 major serotonergic structures involved in 5-HT reuptake and release, to modulate EIH. PMID:28282362

Social isolation reduces serotonergic fiber density in the inferior colliculus of female, but not male, mice.

PubMed

Keesom, Sarah M; Morningstar, Mitchell D; Sandlain, Rebecca; Wise, Bradley M; Hurley, Laura M

2018-05-12

Early-life experiences, including maternal deprivation and social isolation during adolescence, have a profound influence on a range of adult social behaviors. Post-weaning social isolation in rodents influences behavior in part through the alteration of neuromodulatory systems, including the serotonergic system. Of significance to social behavior, the serotonergic system richly innervates brain areas involved in vocal communication, including the auditory system. However, the influence of isolation on serotonergic input to the auditory system remains underexplored. Here, we assess whether 4 weeks of post-weaning individual housing alters serotonergic fiber density in the inferior colliculus (IC), an auditory midbrain nucleus in which serotonin alters auditory-evoked activity. Individually housed male and female mice were compared to conspecifics housed socially in groups of three. Serotonergic projections were subsequently visualized with an antibody to the serotonin transporter, which labels serotonergic fibers with relatively high selectivity. Fiber densities were estimated in the three major subregions of the IC using line-scan intensity analysis. Individually housed female mice showed a significantly reduced fiber density relative to socially housed females, which was accompanied by a lower body weight in individually housed females. In contrast, social isolation did not affect serotonergic fiber density in the IC of males. This finding suggests that sensitivity of the serotonergic system to social isolation is sex-dependent, which could be due to a sex difference in the effect of isolation on psychosocial stress. Since serotonin availability depends on social context, this finding further suggests that social isolation can alter the acute social regulation of auditory processing. Copyright © 2018. Published by Elsevier B.V.

High Leucine Diets Stimulate Cerebral Branched-Chain Amino Acid Degradation and Modify Serotonin and Ketone Body Concentrations in a Pig Model

PubMed Central

Wessels, Anna G.; Kluge, Holger; Hirche, Frank; Kiowski, Andreas; Schutkowski, Alexandra; Corrent, Etienne; Bartelt, Jörg; König, Bettina; Stangl, Gabriele I.

2016-01-01

In addition to its role as an essential protein component, leucine (Leu) displays several other metabolic functions such as activation of protein synthesis. This property makes it an interesting amino acid for the therapy of human muscle atrophy and for livestock production. However, Leu can stimulate its own degradation via the branched-chain keto acid dehydrogenase complex (BCKDH). To examine the response of several tissues to excessive Leu, pigs were fed diets containing two- (L2) and four-fold (L4) higher Leu contents than the recommended amount (control). We found that the L4 diet led to a pronounced increase in BCKDH activity in the brain (2.5-fold, P < 0.05), liver (1.8-fold, P < 0.05) and cardiac muscle (1.7-fold, P < 0.05), whereas we found no changes in enzyme activity in the pancreas, skeletal muscle, adipose tissue and intestinal mucosa. The L2 diet had only weak effects on BCKDH activity. Both high Leu diets reduced the concentrations of free valine and isoleucine in nearly all tissues. In the brain, high Leu diets modified the amount of tryptophan available: for serotonin synthesis. Compared to the controls, pigs treated with the high Leu diets consumed less food, showed increased plasma concentrations of 3-hydroxybutyrate and reduced levels of circulating serotonin. In conclusion, excessive Leu can stimulate BCKDH activity in several tissues, including the brain. Changes in cerebral tryptophan, along with the changes in amino acid-derived metabolites in the plasma may limit the use of high Leu diets to treat muscle atrophy or to increase muscle growth. PMID:26930301

Early-Life Social Isolation Impairs the Gonadotropin-Inhibitory Hormone Neuronal Activity and Serotonergic System in Male Rats

PubMed Central

Soga, Tomoko; Teo, Chuin Hau; Cham, Kai Lin; Idris, Marshita Mohd; Parhar, Ishwar S.

2015-01-01

Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH) neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinizing hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic–GnIH neuronal system using enhanced green fluorescent protein (EGFP)-tagged GnIH transgenic rats. Socially isolated rats were observed for anxious and depressive behaviors. Using immunohistochemistry, we examined c-Fos protein expression in EGFP–GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group housing. We also inspected serotonergic fiber juxtapositions in EGFP–GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviors. The total number of EGFP–GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fiber juxtapositions on EGFP–GnIH neurons were also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early-life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure. PMID:26617573

Lifelong disturbance of serotonin transporter functioning results in fear learning deficits: Reversal by blockade of CRF1 receptors.

PubMed

Bijlsma, Elisabeth Y; Hendriksen, Hendrikus; Baas, Johanna M P; Millan, Mark J; Groenink, Lucianne

2015-10-01

The inability to associate aversive events with relevant cues (i.e. fear learning) may lead to maladaptive anxiety. To further study the role of the serotonin transporter (SERT) in fear learning, classical fear conditioning was studied in SERT knockout rats (SERT(-/-)) using fear potentiation of the startle reflex. Next, fear acquisition and concomitant development of contextual conditioned fear were monitored during training. To differentiate between developmental and direct effects of reduced SERT functioning, effects of acute and chronic SSRI treatment were studied in adult rats. Considering the known interactions between serotonin and corticotropin-releasing factor (CRF), we studied the effect of the CRFR1 antagonist CP154,526 on behavioral changes observed and determined CRF1 receptor levels in SERT(-/-) rats. SERT(-/-) showed blunted fear potentiation and enhanced contextual fear, which resulted from a deficit in fear acquisition. Paroxetine treatment did not affect acquisition or expression of fear-potentiated startle, suggesting that disturbed fear learning in SERT(-/-) results from developmental changes and not from reduced SERT functioning. Although CRF1 receptor levels did not differ significantly between genotypes, CP154,526 treatment normalized both cue- and contextual fear in SERT(-/-) during acquisition, but not expression of fear-potentiated startle. The disrupted fear acquisition and concomitant increase in contextual conditioned fear-potentiated startle fear in SERT(-/-) resembles the associative learning deficit seen in patients with panic disorder and suggests that normal SERT functioning is crucial for the development of an adequate fear neuro-circuitry. Moreover, the normalization of fear acquisition by CP154,526 suggests a role for central CRF signaling in the generalization of fear. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Constitutively active 5-HT2/α1 receptors facilitate muscle spasms after human spinal cord injury

PubMed Central

D'Amico, Jessica M.; Murray, Katherine C.; Li, Yaqing; Chan, K. Ming; Finlay, Mark G.; Bennett, David J.

2013-01-01

In animals, the recovery of motoneuron excitability in the months following a complete spinal cord injury is mediated, in part, by increases in constitutive serotonin (5-HT2) and norepinephrine (α1) receptor activity, which facilitates the reactivation of calcium-mediated persistent inward currents (CaPICs) without the ligands serotonin and norepinephrine below the injury. In this study we sought evidence for a similar role of constitutive monoamine receptor activity in the development of spasticity in human spinal cord injury. In chronically injured participants with partially preserved sensory and motor function, the serotonin reuptake inhibitor citalopram facilitated long-lasting reflex responses (spasms) previously shown to be mediated by CaPICs, suggesting that in incomplete spinal cord injury, functional descending sources of monoamines are present to activate monoamine receptors below the lesion. However, in participants with motor or motor/sensory complete injuries, the inverse agonist cyproheptadine, which blocks both ligand and constitutive 5-HT2/α1 receptor activity, decreased long-lasting reflexes, whereas the neutral antagonist chlorpromazine, which only blocks ligand activation of these receptors, had no effect. When tested in noninjured control participants having functional descending sources of monoamines, chlorpromazine was effective in reducing CaPIC-mediated motor unit activity. On the basis of these combined results, it appears that in severe spinal cord injury, facilitation of persistent inward currents and muscle spasms is mainly mediated by the activation of constitutive 5-HT2 and α1 receptor activity. Drugs that more selectively block these constitutively active monoamine receptors may provide better oral control of spasticity, especially in motor complete spinal cord injury where reducing motoneuron excitability is the primary goal. PMID:23221402

Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls-antagonistic effects between opioid and serotonin-related genes.

PubMed

Tour, Jeanette; Löfgren, Monika; Mannerkorpi, Kaisa; Gerdle, Björn; Larsson, Anette; Palstam, Annie; Bileviciute-Ljungar, Indre; Bjersing, Jan; Martin, Ingvar; Ernberg, Malin; Schalling, Martin; Kosek, Eva

2017-07-01

Chronic pain is associated with dysfunctional endogenous pain modulation, involving both central opioid and serotonergic (5-HT) signaling. Fibromyalgia (FM) is a chronic pain syndrome, characterized by widespread musculoskeletal pain and reduced exercise-induced hypoalgesia (EIH). In this study, we assessed the effects of 3 functional genetic polymorphisms on EIH in 130 patients with FM and 132 healthy controls. Subjects were genotyped regarding the mu-opioid receptor (OPRM1) gene (rs1799971), the serotonin transporter (5-HTT) gene (5-HTTLPR/rs25531), and the serotonin-1a receptor (5-HT1a) gene (rs6296). The patients with FM had increased pain sensitivity and reduced EIH compared with healthy controls. None of the polymorphisms had an effect on EIH on their own. We found significant gene-to-gene interactions between OPRM1 x 5-HTT and OPRM1 x 5-HT1a regarding activation of EIH, with no statistically significant difference between groups. Better EIH was found in individuals with genetically inferred strong endogenous opioid signaling (OPRM1 G) in combination with weak 5-HT tone (5-HTT low/5-HT1a G), compared with strong 5-HT tone (5-HTT high/5-HT1a CC). Based on the proposed mechanisms of these genetic variants, the findings indicate antagonistic interactions between opioid and serotonergic mechanisms during EIH. Moreover, despite different baseline pain level, similar results were detected in FM and controls, not supporting an altered interaction between opioid and 5-HT mechanisms as the basis for dysfunction of EIH in patients with FM. In summary, our results suggest that, by genetic association, the mu-opioid receptor interacts with 2 major serotonergic structures involved in 5-HT reuptake and release, to modulate EIH.

Perinatal Fluoxetine Exposure Impairs the CO2 Chemoreflex. Implications for Sudden Infant Death Syndrome.

PubMed

Bravo, Karina; Eugenín, Jaime L; Llona, Isabel

2016-09-01

High serotonin levels during pregnancy affect central nervous system development. Whether a commonly used antidepressant such as fluoxetine (a selective serotonin reuptake inhibitor) taken during pregnancy may adversely affect respiratory control in offspring has not been determined. The objective was to determine the effect of prenatal-perinatal fluoxetine exposure on the respiratory neural network in offspring, particularly on central chemoreception. Osmotic minipumps implanted into CF-1 mice on Days 5-7 of pregnancy delivered 7 milligrams per kilogram per day of fluoxetine, achieving plasma levels within the range found in patients. Ventilation was assessed in offspring at postnatal Days 0-40 using head-out body plethysmography. Neuronal activation was evaluated in the raphe nuclei and in the nucleus tractus solitarius by c-Fos immunohistochemistry during normoxic eucapnia and hypercapnia (10% CO2). Respiratory responses to acidosis were evaluated in brainstem slices. Prenatal-perinatal fluoxetine did not affect litter size, birth weight, or the postnatal growth curve. Ventilation under eucapnic normoxic conditions was similar to that of control offspring. Fluoxetine exposure reduced ventilatory responses to hypercapnia at P8-P40 (P < 0.001) but not at P0-P5. At P8, it reduced hypercapnia-induced neuronal activation in raphe nuclei (P < 0.05) and nucleus tractus solitarius (P < 0.01) and the acidosis-induced increase in the respiratory frequency in brainstem slices (P < 0.05). Fluoxetine applied acutely on control slices did not modify their respiratory response to acidosis. We concluded that prenatal-perinatal fluoxetine treatment impairs central respiratory chemoreception during postnatal life. These results are relevant in understanding the pathogenesis of respiratory failures, such as sudden infant death syndrome, associated with brainstem serotonin abnormalities and the failure of respiratory chemoreflexes.

Serotonin Decreases the Gain of Visual Responses in Awake Macaque V1.

PubMed

Seillier, Lenka; Lorenz, Corinna; Kawaguchi, Katsuhisa; Ott, Torben; Nieder, Andreas; Pourriahi, Paria; Nienborg, Hendrikje

2017-11-22

Serotonin, an important neuromodulator in the brain, is implicated in affective and cognitive functions. However, its role even for basic cortical processes is controversial. For example, in the mammalian primary visual cortex (V1), heterogenous serotonergic modulation has been observed in anesthetized animals. Here, we combined extracellular single-unit recordings with iontophoresis in awake animals. We examined the role of serotonin on well-defined tuning properties (orientation, spatial frequency, contrast, and size) in V1 of two male macaque monkeys. We find that in the awake macaque the modulatory effect of serotonin is surprisingly uniform: it causes a mainly multiplicative decrease of the visual responses and a slight increase in the stimulus-selective response latency. Moreover, serotonin neither systematically changes the selectivity or variability of the response, nor the interneuronal correlation unexplained by the stimulus ("noise-correlation"). The modulation by serotonin has qualitative similarities with that for a decrease in stimulus contrast, but differs quantitatively from decreasing contrast. It can be captured by a simple additive change to a threshold-linear spiking nonlinearity. Together, our results show that serotonin is well suited to control the response gain of neurons in V1 depending on the animal's behavioral or motivational context, complementing other known state-dependent gain-control mechanisms. SIGNIFICANCE STATEMENT Serotonin is an important neuromodulator in the brain and a major target for drugs used to treat psychiatric disorders. Nonetheless, surprisingly little is known about how it shapes information processing in sensory areas. Here we examined the serotonergic modulation of visual processing in the primary visual cortex of awake behaving macaque monkeys. We found that serotonin mainly decreased the gain of the visual responses, without systematically changing their selectivity, variability, or covariability. This identifies a simple computational function of serotonin for state-dependent sensory processing, depending on the animal's affective or motivational state. Copyright © 2017 Seillier, Lorenz et al.

Behavioral and cellular consequences of increasing serotonergic activity during brain development: a role in autism?

PubMed

Whitaker-Azmitia, Patricia M

2005-02-01

The hypothesis explored in this review is that the high levels of serotonin in the blood seen in some autistic children (the so-called hyperserotonemia of autism) may lead to some of the behavioral and cellular changes also observed in the disorder. At early stages of development, when the blood-brain Barrier is not yet fully formed, the high levels of serotonin in the blood can enter the brain of a developing fetus and cause loss of serotonin terminals through a known negative feedback function of serotonin during development. The loss of serotonin innervation persists throughout subsequent development and the symptoms of autism appear. A review of the basic scientific literature on prenatal treatments affecting serotonin is given, in support of this hypothesis, with an emphasis on studies using the serotonin agonist, 5-methoxytryptamine (5-MT). In work using 5-MT to mimic hyperserotonemia, Sprague-Dawley rats are treated from gestational day 12 until postnatal 20. In published reports, these animals have been found to have a significant loss of serotonin terminals, decreased metabolic activity in cortex, changes in columnar development in cortex, changes in serotonin receptors, and "autistic-like" behaviors. In preliminary cellular findings given in this review, the animals have also been found to have cellular changes in two relevant brain regions: 1. Central nucleus of the amygdala, a brain region involved in fear-responding, where an increase in calcitonin gene related peptide (CGRP) was found 2. Paraventricular nucleus of the hypothalamus, a brain region involved in social memory and bonding, where a decrease in oxytocin was found. Both of these cellular changes could result from loss of serotonin innervation, possibly due to loss of terminal outgrowth from the same cells of the raphe nuclei. Thus, increased serotonergic activity during development could damage neurocircuitry involved in emotional responding to social stressors and may have relevance to the symptoms of autism.

Serotonin Decreases the Gain of Visual Responses in Awake Macaque V1

PubMed Central

Seillier, Lenka; Lorenz, Corinna; Kawaguchi, Katsuhisa; Ott, Torben; Pourriahi, Paria

2017-01-01

Serotonin, an important neuromodulator in the brain, is implicated in affective and cognitive functions. However, its role even for basic cortical processes is controversial. For example, in the mammalian primary visual cortex (V1), heterogenous serotonergic modulation has been observed in anesthetized animals. Here, we combined extracellular single-unit recordings with iontophoresis in awake animals. We examined the role of serotonin on well-defined tuning properties (orientation, spatial frequency, contrast, and size) in V1 of two male macaque monkeys. We find that in the awake macaque the modulatory effect of serotonin is surprisingly uniform: it causes a mainly multiplicative decrease of the visual responses and a slight increase in the stimulus-selective response latency. Moreover, serotonin neither systematically changes the selectivity or variability of the response, nor the interneuronal correlation unexplained by the stimulus (“noise-correlation”). The modulation by serotonin has qualitative similarities with that for a decrease in stimulus contrast, but differs quantitatively from decreasing contrast. It can be captured by a simple additive change to a threshold-linear spiking nonlinearity. Together, our results show that serotonin is well suited to control the response gain of neurons in V1 depending on the animal's behavioral or motivational context, complementing other known state-dependent gain-control mechanisms. SIGNIFICANCE STATEMENT Serotonin is an important neuromodulator in the brain and a major target for drugs used to treat psychiatric disorders. Nonetheless, surprisingly little is known about how it shapes information processing in sensory areas. Here we examined the serotonergic modulation of visual processing in the primary visual cortex of awake behaving macaque monkeys. We found that serotonin mainly decreased the gain of the visual responses, without systematically changing their selectivity, variability, or covariability. This identifies a simple computational function of serotonin for state-dependent sensory processing, depending on the animal's affective or motivational state. PMID:29042433

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

PubMed Central

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

2008-01-01

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

Serotonin Regulates the Feeding and Reproductive Behaviors of Pratylenchus penetrans.

PubMed

Han, Ziduan; Boas, Stephanie; Schroeder, Nathan E

2017-07-01

The success of all plant-parasitic nematodes is dependent on the completion of several complex behaviors. The lesion nematode Pratylenchus penetrans is an economically important parasite of a diverse range of plant hosts. Unlike the cyst and root-knot nematodes, P. penetrans moves both within and outside of the host roots and can feed from both locations. Adult females of P. penetrans require insemination by actively moving males for reproduction and can lay eggs both within and outside of the host roots. We do not have a complete understanding of the molecular basis for these behaviors. One candidate modulator of these behaviors is the neurotransmitter serotonin. Previous research demonstrated an effect of exogenously applied serotonin on the feeding and male mating behaviors of cyst and root-knot nematodes. However, there are no data on the role of exogenous serotonin on lesion nematodes. Similarly, there are no data on the presence and function of endogenous serotonin in any plant-parasitic nematode. Here, we establish that exogenous serotonin applied to P. penetrans regulates both feeding and sex-specific behaviors. Furthermore, using immunohistochemistry and pharmacological assays, our data suggest that P. penetrans utilizes endogenous serotonin to regulate both feeding and sex-specific behaviors.

The developmental disruptions of serotonin signaling may involved in autism during early brain development.

PubMed

Yang, C-J; Tan, H-P; Du, Y-J

2014-05-16

Autism is a developmental disorder defined by the presence of a triad of communication, social and stereo typical behavioral characteristics with onset before 3years of age. In spite of the fact that there are potential environmental factors for autistic behavior, the dysfunction of serotonin during early development of the brain could be playing a role in this prevalence rise. Serotonin can modulate a number of developmental events, including cell division, neuronal migration, cell differentiation and synaptogenesis. Hyperserotonemia during fetal development results in the loss of serotonin terminals through negative feedback. The increased serotonin causes a decrease of oxytocin in the paraventricular nucleus of the hypothalamus and an increase in calcitonin gene-related peptide (CGRP) in the central nucleus of the amygdale, which are associated with social interactions and vital in autism. However, hyposerotonemia may be also relevant to the development of sensory as well as motor and cognitive faculties. And the paucity of placenta-derived serotonin should have potential importance when the pathogenesis of autism is considered. This review briefly summarized the developmental disruptions of serotonin signaling involved in the pathogenesis of autism during early development of the brain. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

The modulation role of serotonin in Pacific oyster Crassostrea gigas in response to air exposure.

PubMed

Dong, Wenjing; Liu, Zhaoqun; Qiu, Limei; Wang, Weilin; Song, Xiaorui; Wang, Xiudan; Li, Yiqun; Xin, Lusheng; Wang, Lingling; Song, Linsheng

2017-03-01

Serotonin, also known as 5-hydroxytryptamine (5-HT), is a critical neurotransmitter in the neuroendocrine-immune regulatory network and involved in regulation of the stress response in vertebrates and invertebrates. In the present study, serotonin was found to be widely distributed in the tissues of Pacific oyster Crassostrea gigas, including haemolymph, gonad, visceral ganglion, mantle, gill, labial palps and hepatopancreas, and its concentration increased significantly in haemolymph and mantle after the oysters were exposed to air for 1 d. The apoptosis rate of haemocytes was significantly declined after the oysters received an injection of extra serotonin, while the activity of superoxide dismutase (SOD) in haemolymph increased significantly. After the stimulation of serotonin during air exposure, the apoptosis rate of oyster haemocytes and the concentration of H 2 O 2 in haemolymph were significantly decreased, while the SOD activity was significantly elevated. Furthermore, the survival rate of oysters from 4 th to 6 th d after injection of serotonin was higher than that of FSSW group and air exposure group. The results clearly indicated that serotonin could modulate apoptotic effect and redox during air exposure to protect oysters from stress. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cholesterol depletion modulates detergent resistant fraction of human serotonin(1A) receptors.

PubMed

Sahu, Santosh Kumar; Saxena, Roopali; Chattopadhyay, Amitabha

2012-11-01

Insolubility of membrane components in non-ionic detergents such as Triton X-100 at low temperature is a widely used biochemical criterion to identify, isolate and characterize membrane domains. In this work, we monitored the detergent insolubility of the serotonin(1A) receptor in CHO cell membranes and its modulation by membrane cholesterol. The serotonin(1A) receptor is an important member of the G-protein coupled receptor family. It is implicated in the generation and modulation of various cognitive, behavioral and developmental functions and serves as a drug target. Our results show that a significant fraction (∼28%) of the serotonin(1A) receptor resides in detergent-resistant membranes (DRMs). Interestingly, the fraction of the serotonin(1A) receptor in DRMs exhibits a reduction upon membrane cholesterol depletion. In addition, we show that contents of DRM markers such as flotillin-1, caveolin-1 and GM₁ are altered in DRMs upon cholesterol depletion. These results assume significance since the function of the serotonin(1A) receptor has previously been shown to be affected by membrane lipids, specifically cholesterol. Our results are relevant in the context of membrane organization of the serotonin(1A) receptor in particular, and G-protein coupled receptors in general.

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

PubMed Central

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

2015-01-01

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

Increased hypothalamic serotonin turnover in inflammation-induced anorexia.

PubMed

Dwarkasing, J T; Witkamp, R F; Boekschoten, M V; Ter Laak, M C; Heins, M S; van Norren, K

2016-05-20

Anorexia can occur as a serious complication of disease. Increasing evidence suggests that inflammation plays a major role, along with a hypothalamic dysregulation characterized by locally elevated serotonin levels. The present study was undertaken to further explore the connections between peripheral inflammation, anorexia and hypothalamic serotonin metabolism and signaling pathways. First, we investigated the response of two hypothalamic neuronal cell lines to TNFα, IL-6 and LPS. Next, we studied transcriptomic changes and serotonergic activity in the hypothalamus of mice after intraperitoneal injection with TNFα, IL-6 or a combination of TNFα and IL-6. In vitro, we showed that hypothalamic neurons responded to inflammatory mediators by releasing cytokines. This inflammatory response was associated with an increased serotonin release. Mice injected with TNFα and IL-6 showed decreased food intake, associated with altered expression of inflammation-related genes in the hypothalamus. In addition, hypothalamic serotonin turnover showed to be elevated in treated mice. Overall, our results underline that peripheral inflammation reaches the hypothalamus where it affects hypothalamic serotoninergic metabolism. These hypothalamic changes in serotonin pathways are associated with decreased food intake, providing evidence for a role of serotonin in inflammation-induced anorexia.

Positron emission tomography quantification of serotonin(1A) receptor binding in suicide attempters with major depressive disorder.

PubMed

Sullivan, Gregory M; Oquendo, Maria A; Milak, Matthew; Miller, Jeffrey M; Burke, Ainsley; Ogden, R Todd; Parsey, Ramin V; Mann, J John

2015-02-01

Serotonergic system dysfunction has been associated with increased lethal suicide attempts and suicide. Dysfunction includes higher binding of serotonin(1A) autoreceptor in the brainstem raphe of individuals who die by suicide. To determine the relationships between brain serotonin(1A) binding and suicidal behavior in vivo in major depressive disorder (MDD) using positron emission tomography and the serotonin(1A) antagonist radiotracer carbon C 11 [11C]-labeled WAY-100635. Cross-sectional positron emission tomography study at an academic medical center from 1999 through 2009. We compared serotonin(1A) binding between individuals with MDD who did not attempt suicide (nonattempters) (n = 62) and those who attempted suicide (attempters) (n = 29). We subdivided the attempters into those with lower (n = 16) and higher (n = 13) levels of lethality. The binding potential (BPF) of [11C]WAY-100635 (calculated as the number of receptors available divided by affinity) in the prefrontal cortex (PFC) and brainstem, estimated by kinetic modeling with an arterial input function; the severity of suicidal behaviors, including lethality and intent of suicide attempts; and suicidal ideation. Using a linear mixed-effects model, we found no difference between attempters and nonattempters with MDD in serotonin(1A) BPF in the PFC regions (F1,88 = 0.03; P = .87) or in the raphe nuclei (F1,88 = 0.29; P = .59). Raphe nuclei serotonin(1A) BPF was 45.1% greater in higher-lethality attempters compared with lower-lethality attempters (F1,25 = 7.33; P = .01), whereas no difference was observed in the PFC regions (F1,25 = 0.12; P = .73). Serotonin(1A )BPF in the raphe nuclei of suicide attempters was positively correlated with the lethality rating (F1,25 = 10.56; P = .003) and the subjective lethal intent factor (F1,25 = 10.63; P = .003; R2 = 0.32) based on the most recent suicide attempt. Suicide ideation in participants with MDD was positively correlated with serotonin(1A) BPF in the PFC regions (F1,88 = 5.19; P = .03) and in the raphe nuclei (F1,87 = 7.38; P = .008; R2 = 0.12). Higher brainstem raphe serotonin(1A)BPF observed in higher-lethality suicide attempters with MDD is in agreement with findings in suicide studies and also with the finding of low cerebrospinal fluid levels of 5-hydroxyindoleacetic acid in higher-lethality suicide attempters. Higher brainstem raphe serotonin(1A) BPF would be consistent with lower levels of serotonin neuron firing and release and supports a model of impaired serotonin signaling in suicide and higher-lethality suicidal behavior. Severity of suicidal ideation in MDD is related to brainstem and prefrontal serotonin(1A) BPF, suggesting a role for both regions in suicidal ideation. Lower levels of serotonin release at key brain projection sites, such as the prefrontal regions, may favor more severe suicidal ideation and higher-lethality suicide attempts.

Positron Emission Tomography Quantification of Serotonin1A Receptor Binding in Suicide Attempters With Major Depressive Disorder

PubMed Central

Sullivan, Gregory M.; Oquendo, Maria A.; Milak, Matthew; Miller, Jeffrey M.; Burke, Ainsley; Ogden, R. Todd; Parsey, Ramin V.; Mann, J. John

2015-01-01

IMPORTANCE Serotonergic system dysfunction has been associated with increased lethal suicide attempts and suicide. Dysfunction includes higher binding of serotonin1A autoreceptor in the brainstem raphe of individuals who die by suicide. OBJECTIVES To determine the relationships between brain serotonin1A binding and suicidal behavior in vivo in major depressive disorder (MDD) using positron emission tomography and the serotonin1A antagonist radiotracer carbon C 11 [11C]–labeled WAY-100635. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional positron emission tomography study at an academic medical center from 1999 through 2009. We compared serotonin1A binding between individuals with MDD who did not attempt suicide (nonattempters) (n = 62) and those who attempted suicide (attempters) (n = 29). We subdivided the attempters into those with lower (n = 16) and higher (n = 13) levels of lethality. MAIN OUTCOMES AND MEASURES The binding potential (BPF) of [11C]WAY-100635 (calculated as the number of receptors available divided by affinity) in the prefrontal cortex (PFC) and brainstem, estimated by kinetic modeling with an arterial input function; the severity of suicidal behaviors, including lethality and intent of suicide attempts; and suicidal ideation. RESULTS Using a linear mixed-effects model, we found no difference between attempters and nonattempters with MDD in serotonin1A BPF in the PFC regions (F1,88 = 0.03; P = .87) or in the raphe nuclei (F1,88 = 0.29; P = .59). Raphe nuclei serotonin1A BPF was 45.1% greater in higher-lethality attempters compared with lower-lethality attempters (F1,25 = 7.33; P = .01), whereas no difference was observed in the PFC regions (F1,25 = 0.12; P = .73). Serotonin1A BPF in the raphe nuclei of suicide attempters was positively correlated with the lethality rating (F1,25 = 10.56; P = .003) and the subjective lethal intent factor (F1,25 = 10.63; P = .003; R2 = 0.32) based on the most recent suicide attempt. Suicide ideation in participants with MDD was positively correlated with serotonin1A BPF in the PFC regions (F1,88 = 5.19; P = .03) and in the raphe nuclei (F1,87 = 7.38; P = .008; R2 = 0.12). CONCLUSIONS AND RELEVANCE Higher brainstem raphe serotonin1A BPF observed in higher-lethality suicide attempters with MDD is in agreement with findings in suicide studies and also with the finding of low cerebrospinal fluid levels of 5-hydroxyindoleacetic acid in higher-lethality suicide attempters. Higher brainstem raphe serotonin1A BPF would be consistent with lower levels of serotonin neuron firing and release and supports a model of impaired serotonin signaling in suicide and higher-lethality suicidal behavior. Severity of suicidal ideation in MDD is related to brainstem and prefrontal serotonin1A BPF, suggesting a role for both regions in suicidal ideation. Lower levels of serotonin release at key brain projection sites, such as the prefrontal regions, may favor more severe suicidal ideation and higher-lethality suicide attempts. PMID:25549105

Serotonin Receptors in Hippocampus

PubMed Central

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

2012-01-01

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

Decreased cerebral cortical serotonin transporter binding in ecstasy users: a positron emission tomography/[11C]DASB and structural brain imaging study

PubMed Central

Lerch, Jason; Furukawa, Yoshiaki; Tong, Junchao; McCluskey, Tina; Wilkins, Diana; Houle, Sylvain; Meyer, Jeffrey; Mundo, Emanuela; Wilson, Alan A.; Rusjan, Pablo M.; Saint-Cyr, Jean A.; Guttman, Mark; Collins, D. Louis; Shapiro, Colin; Warsh, Jerry J.; Boileau, Isabelle

2010-01-01

Animal data indicate that the recreational drug ecstasy (3,4-methylenedioxymethamphetamine) can damage brain serotonin neurons. However, human neuroimaging measurements of serotonin transporter binding, a serotonin neuron marker, remain contradictory, especially regarding brain areas affected; and the possibility that structural brain differences might account for serotonin transporter binding changes has not been explored. We measured brain serotonin transporter binding using [11C] N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine in 50 control subjects and in 49 chronic (mean 4 years) ecstasy users (typically one to two tablets bi-monthly) withdrawn from the drug (mean 45 days). A magnetic resonance image for positron emission tomography image co-registration and structural analyses was acquired. Hair toxicology confirmed group allocation but also indicated use of other psychoactive drugs in most users. Serotonin transporter binding in ecstasy users was significantly decreased throughout all cerebral cortices (range –19 to –46%) and hippocampus (–21%) and related to the extent of drug use (years, maximum dose), but was normal in basal ganglia and midbrain. Substantial overlap was observed between control and user values except for insular cortex, in which 51% of ecstasy user values fell below the lower limit of the control range. Voxel-based analyses confirmed a caudorostral gradient of cortical serotonin transporter binding loss with occipital cortex most severely affected. Magnetic resonance image measurement revealed no overall regional volume differences between groups; however, a slight left-hemispheric biased cortical thinning was detected in methamphetamine-using ecstasy users. The serotonin transporter binding loss was not related to structural changes or partial volume effect, use of other stimulant drugs, blood testosterone or oestradiol levels, major serotonin transporter gene promoter polymorphisms, gender, psychiatric status, or self-reported hyperthermia or tolerance. The ecstasy group, although ‘grossly behaviourally normal’, reported subnormal mood and demonstrated generally modest deficits on some tests of attention, executive function and memory, with the latter associated with serotonin transporter decrease. Our findings suggest that the ‘typical’/low dose (one to two tablets/session) chronic ecstasy-polydrug user might display a highly selective mild to marked loss of serotonin transporter in cerebral cortex/hippocampus in the range of that observed in Parkinson’s disease, which is not gender-specific or completely accounted for by structural brain changes, recent use of other drugs (as assessed by hair analyses) or other potential confounds that we could address. The striking sparing of serotonin transporter-rich striatum (although possibly affected in ‘heavier’ users) suggests that serotonergic neurons innervating cerebral cortex are more susceptible, for unknown reasons, to ecstasy than those innervating subcortical regions and that behavioural problems in some ecstasy users during abstinence might be related to serotonin transporter changes limited to cortical regions. PMID:20483717

Quantitative analysis of serotonin secreted by human embryonic stem cells-derived serotonergic neurons via pH-mediated online stacking-CE-ESI-MRM.

PubMed

Zhong, Xuefei; Hao, Ling; Lu, Jianfeng; Ye, Hui; Zhang, Su-Chun; Li, Lingjun

2016-04-01

A CE-ESI-MRM-based assay was developed for targeted analysis of serotonin released by human embryonic stem cells-derived serotonergic neurons in a chemically defined environment. A discontinuous electrolyte system was optimized for pH-mediated online stacking of serotonin. Combining with a liquid-liquid extraction procedure, LOD of serotonin in the Krebs'-Ringer's solution by CE-ESI-MS/MS on a 3D ion trap MS was0.15 ng/mL. The quantitative results confirmed the serotonergic identity of the in vitro developed neurons and the capacity of these neurons to release serotonin in response to stimulus. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The influence of serotonin on the mitotic rate in the colonic crypt epithelium and in colonic adenocarcinoma in rats.

PubMed

Tutton, P J; Barkla, D H

1978-01-01

1. The mitotic rate in the crypts of Lieberkühn of the descending colon and in dimethylhydrazine-induced adenocarcinomata of the descending colon of rat was measured using a stathmokinetic technique. 2. Intraperitoneal injection of a small dose (10 microgram/kg) of serotonin resulted in an increase in the tumour cell mitotic rate. 3. Blockade of serotonin receptors by 2-bromolysergic acid diethylamide and depletion of tissue serotonin levels following injection of DL-6-fluorotryptophan both result in a decrease in the tumour cell mitotic rate. 4. Treatment with serotonin, 2-bromolysergic acid diethylamide and DL-6-fluorotryptophan were all without effect on the colonic crypt cell mitotic rate.

[Metabolism of serotonin in autism in children].

PubMed

Bursztejn, C; Ferrari, P; Dreux, C; Braconnier, A; Lancrenon, S

1988-01-01

In this controlled study of 22 autistic children and 22 normal controls matched for age and sex, the frequency of hyperserotonemia in infantile autism was confirmed. Platelet serotonin was elevated in patients. Comparative to controls, serotonin was also high in urine of autistic patients, while, on the contrary there was no difference for the urinary excretion of 5-HIAA. No difference was observed either for serotonin uptake and efflux or for MAO activity, in isolated platelets. The elevation of plasma free tryptophan - significant only with the Kolmogorov Smirnov test - suggests that 5-HT biosynthesis might be enhanced. In the group of patient reported in this study, disorders of serotonin metabolism are associated with disturbances of platelet catecholamines, and also with elevated immunoglobulins and enhanced cellular immunity reactions.

Serotonin-mediated central fatigue underlies increased endurance capacity in mice from lines selectively bred for high voluntary wheel running.

PubMed

Claghorn, Gerald C; Fonseca, Ivana A T; Thompson, Zoe; Barber, Curtis; Garland, Theodore

2016-07-01

Serotonin (5-hydroxytryptamine; 5-HT) is implicated in central fatigue, and 5-HT1A pharmaceuticals are known to influence locomotor endurance in both rodents and humans. We studied the effects of a 5-HT1A agonist and antagonist on both forced and voluntary exercise in the same set of mice. This cohort of mice was taken from 4 replicate lines of mice that have been selectively bred for high levels of voluntary wheel running (HR) as compared with 4 non-selected control (C) lines. HR mice run voluntarily on wheels about 3× as many revolutions per day as compared with C, and have greater endurance during forced treadmill exercise. We hypothesized that drugs targeting serotonin receptors would have differential effects on locomotor behavior of HR and C mice. Subcutaneous injections of a 5-HT1A antagonist (WAY-100,635), a combination of 5-HT1A agonist and a 5-HT1A/1B partial agonist (8-OH-DPAT+pindolol), or physiological saline were given to separate groups of male mice before the start of each of three treadmill trials. The same manipulations were used later during voluntary wheel running on three separate nights. WAY-100,635 decreased treadmill endurance in HR but not C mice (dose by linetype interaction, P=0.0014). 8-OH-DPAT+pindolol affected treadmill endurance (P<0.0001) in a dose-dependent manner, with no dose by linetype interaction. Wheel running was reduced in HR but not C mice at the highest dose of 8-OH-DPAT+pindolol (dose by linetype, P=0.0221), but was not affected by WAY-100,635 treatment. These results provide further evidence that serotonin signaling is an important determinant of performance during both forced and voluntary exercise. Although the elevated wheel running of HR mice does not appear related to alterations in serotonin signaling, their enhanced endurance capacity does. More generally, our results indicate that both forced and voluntary exercise can be affected by an intervention that acts (primarily) centrally. Copyright © 2016 Elsevier Inc. All rights reserved.

Estrous cycle modulation of extracellular serotonin in mediobasal hypothalamus: role of the serotonin transporter and terminal autoreceptors.

PubMed

Maswood, S; Truitt, W; Hotema, M; Caldarola-Pastuszka, M; Uphouse, L

1999-06-12

In vivo microdialysis was used to examine extracellular serotonin (5-HT) in the mediobasal hypothalamus (MBH) of male and female Fischer (CDF-344) rats. Females from the stages of diestrus, proestrus, and estrus were used. Additionally, ovariectomized rats, primed subcutaneously (s.c.) with estradiol benzoate or estradiol benzoate plus progesterone were examined. Extracellular 5-HT in the MBH varied with stage of the estrous cycle and with the light/dark cycle. Proestrous females had the highest microdialysate concentrations of 5-HT during the light portion of the light/dark cycle and lowest concentrations during the dark portion of the cycle. Diestrous females had the highest levels during the dark portion of the cycle, while males and estrous females showed little change between light and dark portions of the cycle. In ovariectomized rats, there was no effect of 2.5 microg or 25 microg estradiol benzoate (s.c.) on extracellular 5-HT; but the addition of 500 microg progesterone, 48 h after estrogen priming, reduced microdialysate 5-HT near the threshold for detection. In intact females and in males, reverse perfusion with 3 microM fluoxetine, a selective serotonin reuptake inhibitor (SSRI), or 2 microM methiothepin, a 5-HT receptor antagonist, increased microdialysate concentrations of 5-HT. Estrous females and males showed nearly a 4-fold increase in microdialysate 5-HT in response to fluoxetine while smaller responses were seen in diestrous and proestrous rats. In contrast, proestrous rats showed the largest response to methiothepin. Estrous females showed a delayed response to methiothepin, but there was no methiothepin-induced increase in extracellular 5-HT in males. These findings are discussed in reference to the suggestion that extracellular 5-HT in the MBH is regulated in a manner that is gender and estrous cycle dependent. The 5-HT terminal autoreceptor may exert a greater role in proestrous females; the serotonin transporter appears to play a more active role in the regulation of extracellular 5-HT in estrous females and in males. Copyright 1999 Elsevier Science B.V.

The expression and role of serotonin receptor 5HTR2A in canine osteoblasts and an osteosarcoma cell line.

PubMed

Bracha, Shay; Viall, Austin; Goodall, Cheri; Stang, Bernadette; Ruaux, Craig; Seguin, Bernard; Chappell, Patrick E

2013-12-12

The significance of the serotonergic system in bone physiology and, more specifically, the importance of the five hydroxytryptamine receptor 2A (5HTR2A) in normal osteoblast proliferation have been previously described; however the role of serotonin in osteosarcoma remains unclear. Particularly, the expression and function of 5HTR2A in canine osteosarcoma has not yet been studied, thus we sought to determine if this indoleamine modulates cellular proliferation in vitro. Using real time quantitative reverse transcription PCR and immunoblot analyses, we explored receptor expression and signaling differences between non-neoplastic canine osteoblasts (CnOb) and an osteosarcoma cell line (COS). To elucidate specific serotonergic signaling pathways triggered by 5HTR2A, we performed immunoblots for ERK and CREB. Finally, we compared cell viability and the induction of apoptosis in the presence 5HTR2A agonists and antagonists. 5HTR2A was overexpressed in the malignant cell line in comparison to normal cells. In CnOb cells, ERK phosphorylation (ERK-P) decreased in response to both serotonin and a specific 5HTR2A antagonist, ritanserin. In contrast, ERK-P abundance increased in COS cells following either treatment. While endogenous CREB was undetectable in CnOb, CREB was observed constitutively in COS, with expression and exhibited increased CREB phosphorylation following escalating concentrations of ritanserin. To determine the influence of 5HTR2A signaling on cell viability we challenged cells with ritanserin and serotonin. Our findings confirmed that serotonin treatment promoted cell viability in malignant cells but not in normal osteoblasts. Conversely, ritanserin reduced cell viability in both the normal and osteosarcoma cells. Further, ritanserin induced apoptosis in COS at the same concentrations associated with decreased cell viability. These findings confirm the existence of a functional 5HTR2A in a canine osteosarcoma cell line. Results indicate that intracellular second messenger signal coupling of 5HTR2A is different between normal and malignant cells, warranting further research to investigate its potential as a novel therapeutic target for canine osteosarcoma.

Flibanserin

MedlinePlus

... be used for the treatment of HSDD in women who have gone through menopause or in men or to improve sexual performance. Flibanserin is in a class of medications called a serotonin receptor 1A agonist/serotonin receptor 2A antagonist. It works by changing the activity of serotonin and other ...

Evidence for serotonin function as a neurochemical difference between fear and anxiety disorders in humans?

PubMed

Corchs, Felipe; Nutt, David J; Hince, Dana A; Davies, Simon J C; Bernik, Marcio; Hood, Sean D

2015-10-01

The relationships between serotonin and fear and anxiety disorders have been much studied yet many important questions remain, despite selective serotonin reuptake inhibitors having been the primary treatments for these disorders for some time. In order to explore this issue we performed a pooled analysis of six of our studies in remitted patients with a fear/anxiety disorder who were exposed to syndrome-specific aversive stimulation under acute tryptophan depletion. We based our analysis on the hypothesis that the inconsistencies observed in the studies could be predicted by Deakin and Graeff's theory about the dual role of serotonin in responses to threats, whereby serotonin is critical to prevent fear (panic) but not anxiety. In accordance with this view, our results give support to a dissociation of the disorders traditionally grouped under fear and anxiety-related disorders in terms of different roles of serotonin in modulation of responses to aversive stimulation. Implications for future studies and psychiatric nosology are discussed. © The Author(s) 2015.

Triptans, serotonin agonists, and serotonin syndrome (serotonin toxicity): a review.

PubMed

Gillman, P Ken

2010-02-01

The US Food and Drug Administration (FDA) have suggested that fatal serotonin syndrome (SS) is possible with selective serotonin reuptake inhibitors (SSRIs) and triptans: this warning affects millions of patients as these drugs are frequently given simultaneously. SS is a complex topic about which there is much misinformation. The misconception that 5-HT1A receptors can cause serious SS is still widely perpetuated, despite quality evidence that it is activation of the 5-HT2A receptor that is required for serious SS. This review considers SS involving serotonin agonists: ergotamine, lysergic acid diethylamide, bromocriptine, and buspirone, as well as triptans, and reviews the experimental foundation underpinning the latest understanding of SS. It is concluded that there is neither significant clinical evidence, nor theoretical reason, to entertain speculation about serious SS from triptans and SSRIs. The misunderstandings about SS exhibited by the FDA, and shared by the UK Medicines and Healthcare products Regulatory Agency (in relation to methylene blue), are an important issue with wide ramifications.

A tachykinin-like neuroendocrine signalling axis couples central serotonin action and nutrient sensing with peripheral lipid metabolism

PubMed Central

Palamiuc, Lavinia; Noble, Tallie; Witham, Emily; Ratanpal, Harkaranveer; Vaughan, Megan; Srinivasan, Supriya

2017-01-01

Serotonin, a central neuromodulator with ancient ties to feeding and metabolism, is a major driver of body fat loss. However, mechanisms by which central serotonin action leads to fat loss remain unknown. Here, we report that the FLP-7 neuropeptide and its cognate receptor, NPR-22, function as the ligand-receptor pair that defines the neuroendocrine axis of serotonergic body fat loss in Caenorhabditis elegans. FLP-7 is secreted as a neuroendocrine peptide in proportion to fluctuations in neural serotonin circuit functions, and its release is regulated from secretory neurons via the nutrient sensor AMPK. FLP-7 acts via the NPR-22/Tachykinin2 receptor in the intestine and drives fat loss via the adipocyte triglyceride lipase ATGL-1. Importantly, this ligand-receptor pair does not alter other serotonin-dependent behaviours including food intake. For global modulators such as serotonin, the use of distinct neuroendocrine peptides for each output may be one means to achieve phenotypic selectivity. PMID:28128367

Structure and Function of Serotonin G protein Coupled Receptors

PubMed Central

McCorvy, John D.; Roth, Bryan L.

2015-01-01

Serotonin receptors are prevalent throughout the nervous system and the periphery, and remain one of the most lucrative and promising drug discovery targets for disorders ranging from migraine headaches to neuropsychiatric disorders such as schizophrenia and depression. There are 14 distinct serotonin receptors, of which 13 are G protein coupled receptors (GPCRs), which are targets for approximately 40% of the approved medicines. Recent crystallographic and biochemical evidence has provided a converging understanding of the basic structure and functional mechanics of GPCR activation. Currently, two GPCR crystal structures exist for the serotonin family, the 5-HT1B and 5-HT2B receptor, with the antimigraine and valvulopathic drug ergotamine bound. The first serotonin crystal structures not only provide the first evidence of serotonin receptor topography but also provide mechanistic explanations into functional selectivity or biased agonism. This review will detail the findings of these crystal structures from a molecular and mutagenesis perspective for driving rational drug design for novel therapeutics incorporating biased signaling. PMID:25601315

Effects of calcium antagonists on isolated bovine cerebral arteries: inhibition of constriction and calcium-45 uptake induced by potassium or serotonin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wendling, W.W.; Harakal, C.

1987-05-01

The purpose of this study was to determine the mechanisms by which organic calcium channel blockers inhibit cerebral vasoconstriction. Isolated bovine middle cerebral arteries were cut into rings to measure contractility or into strips to measure radioactive calcium (/sup 45/Ca) influx and efflux. Calcium channel blockers (10(-5) M verapamil or 3.3 X 10(-7) M nifedipine) and calcium-deficient solutions all produced near-maximal inhibition of both potassium- and serotonin-induced constriction. In calcium-deficient solutions containing potassium or serotonin, verapamil and nifedipine each blocked subsequent calcium-induced constriction in a competitive manner. Potassium and serotonin significantly increased /sup 45/Ca uptake into cerebral artery strips duringmore » 5 minutes of /sup 45/Ca loading; for potassium /sup 45/Ca uptake increased from 62 to 188 nmol/g, and for serotonin from 65 to 102 nmol/g. Verapamil or nifedipine had no effect on basal /sup 45/Ca uptake but significantly blocked the increase in /sup 45/Ca uptake induced by potassium or serotonin. Potassium, and to a lesser extent serotonin, each induced a brief increase in the rate of /sup 45/Ca efflux into calcium-deficient solutions. Verapamil or nifedipine had no effect on basal or potassium-stimulated /sup 45/Ca efflux. The results demonstrate that verapamil and nifedipine block /sup 45/Ca uptake through both potential-operated (potassium) and receptor-operated (serotonin) channels in bovine middle cerebral arteries.« less

Correlation of 125I-LSD autoradiographic labeling with serotonin voltage clamp responses in Aplysia neurons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Evans, M.L.; Kadan, M.J.; Hartig, P.R.

Autoradiographic receptor binding studies using 125I-LSD (2-(125I)lysergic acid diethyamide) revealed intense labelling on the soma of a symmetrically located pair of cells in the abdominal ganglion of Aplysia californica. This binding was blocked by micromolar concentrations of serotonin and lower concentrations of the serotonergic antagonists, cyproheptadine and mianserin. Electrophysiological investigation of responses to serotonin of neurons in the left upper quadrant, where one of the labeled neurons is located, revealed a range of serotonin responses. Cells L3 and L6 have a K+ conductance increase in response to serotonin that is not blocked by cyproheptadine or mianserin. Cells L2 and L4more » have a biphasic response to serotonin: a Na+ conductance increase, which can be blocked by cyproheptadine and mianserin, followed by a voltage dependent Ca2+ conductance which is blocked by Co2+ but not the serotonergic antagonists. Cell L1, and its symmetrical pair, R1, have in addition to the Na+ and Ca2+ responses observed in L2 and L4, a Cl- conductance increase blocked by LSD, cyproheptadine and mianserin. LSD had little effect on the other responses. The authors conclude that the symmetrically located cells L1 and R1 have a Cl- channel linked to a cyproheptadine- and mianserin-sensitive serotonin receptor that is selectively labelled by 125I-LSD. This receptor has many properties in common with the mammalian serotonin 1C receptor.« less

Case-Control Study Examining the Association between Selective Serotonin Reuptake Inhibitors Use and Hepatocellular Carcinoma.

PubMed

Lai, Shih-Wei; Liao, Kuan-Fu; Lin, Cheng-Li; Lin, Hsien-Feng

2017-01-01

Objectives: The purpose of the study was to assess the relationship between selective serotonin reuptake inhibitors use and hepatocellular carcinoma in Taiwan. Methods: Using the database of the Taiwan National Health Insurance Program, we conducted a case-control study to identify 4901 subjects aged 20 years and more with newly diagnosed hepatocellular carcinoma in 2000-2013 as the cases. We randomly selected 19604 subjects aged 20 years and more without hepatocellular carcinoma as the controls. Both cases and controls were matched with sex and age. Ever use of selective serotonin reuptake inhibitors was defined as a subject who had at least a prescription for selective serotonin reuptake inhibitors before index date. Never use was defined as a subject who never had a prescription for selective serotonin reuptake inhibitors before index date. The odds ratio (OR) and 95% confidence interval (CI) for hepatocellular carcinoma associated with selective serotonin reuptake inhibitors use was estimated by the multivariable logistic regression model. Results: Among subjects with any one of the comorbid conditions associated with hepatocellular carcinoma, the adjusted OR of hepatocellular carcinoma was 0.89 (95% CI 0.75, 1.06) for subjects with ever use of selective serotonin reuptake inhibitors, comparing with never use. Conclusion: The findings indicate that among subjects with any one of the comorbid conditions associated with hepatocellular carcinoma, no significant association can be detected between selective serotonin reuptake inhibitors use and hepatocellular carcinoma.

Serotonin Transporter Gene (SLC6A4) Polymorphism and Mucosal Serotonin Levels in Southeastern Iranian Patients with Irritable Bowel Syndrome

PubMed Central

Mohammadi, Mojgan; Tahmasebi Abdar, Hossein; Mollaei, Hamid Reza; Hajghani, Hossein; Baneshi, Mohammad Reza; Hayatbakhsh, Mohammad Mahdi

2017-01-01

BACKGROUND Irritable bowel syndrome (IBS) is a digestive system disorder with an unknown etiology. Serotonin has a key role in the secretion and motility of the intestine. Polymorphism in serotonin re-uptake transporter (SERT or SLC6A4) gene may have a functional role in the gut of patients with IBS. The aims of the present study were to investigate the association between SLC6A4 gene polymorphism and IBS and to detect the correlation between rectal serotonin levels and IBS sub-types. METHODS SLC6A4 gene polymorphism in 131 patients with IBS and 211 healthy controls were analysed using the quantitative polymerase chain reaction high-resolution melting (qPCR-HRM) curve technique. Serotonin was measured in rectal biopsies of patients with IBS using the enzyme-linked immunosorbent assay (ELISA) method. RESULTS The patients were categorized into three groups: IBS with diarrhoea (IBS-D): 70 patients, IBS with constipation (IBS-C): 18 patients, and IBS with mixed symptoms (IBS-M): 43 patients. The frequency of SLC6A4 s/s and l/s genotypes was significantly higher in IBS-C than IBS-D, IBS-M, and controls (p=0.036). Serotonin levels were similar in IBS sub-types. CONCLUSION SLC6A4 polymorphism is a possible candidate gene associated with the pathogenesis of IBS-C. Although serotonin levels did not differ in rectal biopsies of IBS sub-types, further investigation is recommended. PMID:28316763

Sarizotan, a serotonin 5-HT1A receptor agonist and dopamine receptor ligand. 1. Neurochemical profile.

PubMed

Bartoszyk, G D; Van Amsterdam, C; Greiner, H E; Rautenberg, W; Russ, H; Seyfried, C A

2004-02-01

Sarizotan exhibited high affinities only to serotonin 5-HT1A receptors and dopamine DA D4>D3>D2 receptors with the profile of a 5-HT1A agonist and DA antagonist demonstrated by the inhibition of cAMP-stimulation and guinea pig ileum contraction, decreased accumulation of the 5-HT precursor 5-hydroxytryptophan and increased levels of 5-HT metabolites, increased accumulation of DA precursor dihydroxyphenylalanine (DOPA) and the reduced levels of DA metabolites in intact rats. However, sarizotan at higher doses decreased DA precursor accumulation in reserpinized rats and induced contralateral rotational behavior in unilaterally substantia nigra lesioned rats, indicating some intrinsic dopaminergic activity; at D2 receptors sarizotan may act as a partial agonist, depending on the dopaminergic impulse flow. Sarizotan represents a new approach for the treatment of extrapyramidal motor complications such as l-DOPA-induced dyskinesia in Parkinson's disease.

LSD, 5-HT (serotonin), and the evolution of a behavioral assay.

PubMed

Appel, James B; West, William B; Buggy, James

2004-01-01

Research in our laboratory, supported by NIDA and facilitated by Roger Brown, has indicated that serotonergic neuronal systems are involved in the discriminative stimulus effects of LSD. However, the only compounds that fully antagonize the LSD cue act at both serotonin (5-HT) and dopamine (DA) receptors. In addition, substitution for LSD in standard drug vs. no-drug (DND) discriminations does not necessarily predict either similar mechanisms of action or hallucinogenic potency because 'false positives' occur when animals are given drugs such as lisuride (LHM), quipazine, or, possibly, yohimbine. These effects can be greatly reduced by using drug vs. drug (D-D), drug vs. drug vs. no drug (D-ND), or drug vs. ' other' drug (saline, cocaine, pentobarbital) training procedures. Additional studies, in which drugs were administered directly into the cerebral ventricles or specific brain areas, suggest that structures containing terminal fields of serotonergic neurons might be involved in the stimulus effects of LSD.

Reducing anxiety in stutterers through the association between "purpose in life/Ikigai" and emotions.

PubMed

Ishida, Riichiro

2012-08-09

The human prefrontal lobe is more evolved than those of other mammals. As such, every person has an innate need to establish a meaningful life, often referred to as "Purpose in life (PIL)/ikigai", using the functioning of their prefrontal lobes. PIL/ikigai psychologically, and the prefrontal lobe physiologically, have common functions such as ambition, regulating emotion, and integrating psychological events. PIL/ikigai contributes to a decrease in anxiety influenced by a need for approval from others and stimulates pleasure and comfort, which may be related to the well-balanced secretion of neurotransmitters such as serotonin, dopamine, and ?-endorphin. Thus, a stutterer feels stress, i.e., anxiety, caused by perceived failure when engaging in conversations with others, which may be related to an imbalanced secretion of serotonin and dopamine. Therefore, previous work has suggested that PIL/ikigai may decrease anxiety in stutterers by decreasing the symptoms associated with stuttering.

Hypoactivation of reward motivational system in patients with newly diagnosed hypertension grade I-II.

PubMed

Aftanas, L I; Brak, I V; Gilinskaya, O M; Korenek, V V; Pavlov, S V; Reva, N V

2014-08-01

In patients with newly diagnosed untreated grade I-II hypertension, EEG oscillations were recorded under conditions activation of the two basic motivational systems, defensive motivational system and positive reinforcement system, evoked by recall of personally meaningful emotional events. The 64-channel EEG and cardiovascular reactivity (beat-by-beat technology) were simultaneously recorded. At rest, hypertensive patients had significantly reduced platelet serotonin concentrations in comparison with healthy individuals. The patients experiencing emotional activation were characterized by significantly lower intensity of positive emotions associated with more pronounced suppression of EEG activity in the delta (2-4 Hz) and theta (ranges of frequency 4-6 and 6-8 Hz) oscillators in the parieto-occipital cortex (zones P and PO) in both hemispheres of the brain. The findings attest to insufficient function of the brain serotonin system and hypoactivation of the reward/reinforcement system in patients with primary hypertension.

Serotonin: Modulator of a Drive to Withdraw

ERIC Educational Resources Information Center

Tops, Mattie; Russo, Sascha; Boksem, Maarten A. S.; Tucker, Don M.

2009-01-01

Serotonin is a fundamental neuromodulator in both vertebrate and invertebrate nervous systems, with a suspected role in many human mental disorders. Yet, because of the complexity of serotonergic function, researchers have been unable to agree on a general theory. One function suggested for serotonin systems is the avoidance of threat. We propose…

Dietary Precursors of Serotonin and Newborn State Behavior.

ERIC Educational Resources Information Center

Yogman, Michael W.; Zeisel, Steven

Although previous research with adult humans and nonhumans has suggested a relationship between sleep behavior and brain serotonin levels, no studies have been made of the relationship of normal children's or infants' sleep patterns to serotonin levels, tryptophan metabolism, or diet. This study investigates the relationship between dietary…

Effects of early serotonin programming on behavior and central monoamine concentrations in an avian model

USDA-ARS?s Scientific Manuscript database

Serotonin (5-HT) acts as a neurogenic compound in the developing brain; however serotonin altering drugs such as SSRIs are often prescribed to pregnant and lactating mothers. Early agonism of 5-HT receptors could alter the development of serotonergic circuitry, altering neurotransmission and behavio...

Regulated release of serotonin from axonal growth cones isolated from the fetal rat brain.

PubMed

Mercado, R; Floran, B; Hernandez, J

1998-01-01

In the present work we propose an hypothetical model related to a molecular recognizing system for serotonin in isolated growth cone particles. This model is supported by previous results from our laboratory plus new ones which show that growth cones release serotonin tonically and such release can be stimulated by potassium in a calcium-dependent manner. The present results, together with other author's data, suggest a physiological basis for the putative role of serotonin as a trophic factor during nervous system development.

Positive association between a DNA sequence variant in the serotonin 2A receptor gene and schizophrenia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Inayama, Y.; Yoneda, H.; Sakai, T.

Sixty-two patients with schizophrenia and 96 normal controls were investigated for genetic association with restriction fragment length polymorphisms (RFLPs) in the serotonin receptor genes. A positive association between the serotonin 2A receptor gene (HTR2A) and schizophrenia was found, but not between schizophrenia and the serotonin 1A receptor gene. The positive association we report here would suggest that the DNA region with susceptibility to schizophrenia lies in the HTR2A on the long arm of chromosome 13. 15 refs., 2 tabs.

4-haloethenylphenyl tropane:serotonin transporter imaging agents

DOEpatents

Goodman, Mark M.; Martarello, Laurent

2005-01-18

A series of compounds in the 4-fluoroalkyl-3-halophenyl nortropanes and 4-haloethenylphenyl tropane families are described as diagnostic and therapeutic agents for diseases associated with serotonin transporter dysfunction. These compounds bind to serotonin transporter protein with high affinity and selectivity. The invention provides methods of synthesis which incorporate radioisotopic halogens at a last step which permit high radiochemical yield and maximum usable product life. The radiolabeled compounds of the invention are useful as imaging agents for visualizing the location and density of serotonin transporter by PET and SPECT imaging.

Aggressive Behavior and Altered Amounts of Brain Serotonin and Norepinephrine in Mice Lacking MAOA

PubMed Central

Cases, Olivier; Grimsby, Joseph; Gaspar, Patricia; Chen, Kevin; Pournin, Sandrine; Müller, Ulrike; Aguet, Michel; Babinet, Charles; Shih, Jean Chen; De Maeyer, Edward

2010-01-01

Deficiency in monoamine oxidase A (MAOA), an enzyme that degrades serotonin and norepinephrine, has recently been shown to be associated with aggressive behavior in men of a Dutch family. A line of transgenic mice was isolated in which transgene integration caused a deletion in the gene encoding MAOA, providing an animal model of MAOA deficiency. In pup brains, serotonin concentrations were increased up to ninefold, and serotonin-like immunoreactivity was present in catecholaminergic neurons. In pup and adult brains, norepinephrine concentrations were increased up to twofold, and cytoarchitectural changes were observed in the somatosensory cortex. Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were reversed by the serotonin synthesis inhibitor parachlorophenylalanine. Adults manifested a distinct behavioral syndrome, including enhanced aggression in males. PMID:7792602

Noninvasive measurement of lung carbon-11-serotonin extraction in man

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coates, G.; Firnau, G.; Meyer, G.J.

1991-04-01

The fraction of serotonin extracted on a single passage through the lungs is being used as an early indicator of lung endothelial damage but the existing techniques require multiple arterial blood samples. We have developed a noninvasive technique to measure lung serotonin uptake in man. We utilized the double indicator diffusion principle, a positron camera, {sup 11}C-serotonin as the substrate, and {sup 11}CO-erythrocytes as the vascular marker. From regions of interest around each lung, we recorded time-activity curves in 0.5-sec frames for 30 sec after a bolus injection of first the vascular marker {sup 11}CO-erythrocytes and 10 min later {supmore » 11}C-serotonin. A second uptake measurement was made after imipramine 25-35 mg was infused intravenously. In three normal volunteers, the single-pass uptake of {sup 11}C-serotonin was 63.9% +/- 3.6%. This decreased in all subjects to a mean of 53.6% +/- 1.4% after imipramine. The rate of lung washout of {sup 11}C was also significantly prolonged after imipramine. This noninvasive technique can be used to measure lung serotonin uptake to detect early changes in a variety of conditions that alter the integrity of the pulmonary endothelium.« less

A study of blood serotonin and serotonin transporter promoter variant (5-HTTLPR) polymorphism in Egyptian autistic children.

PubMed

Meguid, Nagwa A; Gebril, Ola H; Khalil, Rehab O

2015-01-01

Autism spectrum disorder (ASD) is a complex, heterogeneous neurodevelopmental disorder with onset during early childhood. Most studies have reported an elevation in platelet serotonin in persons with autism. The serotonin (5-hydroxytryptamine; 5-HT) transporter in the brain uptakes 5-HT from extracellular spaces. It is also present in platelets, where it takes up 5-HT from plasma. Polymorphisms in serotonin transporter gene (SLC6A4) were frequently studied in many neuropsychiatric disorders. We have measured the plasma 5-HT levels in 20 autistic male children and 20 control male children by the enzyme-linked immunosorbent assay (ELISA) method. In addition, the SLC6A4 promoter region (5-HTTLPR) insertion/deletion (I/D) polymorphism was studied, using whole genomic DNA. Plasma serotonin was significantly low in autistic children compared to control (P = 0.001), although correlation to severity of autism was not significant. The frequency of short (S) allele in autism cases was 10% and in the control group it was absent. Our study demonstrated an increased prevalence of 5-HTTLPR S allele in autism subjects. Significantly decreased plasma serotonin was detected in autism subjects, with no significant relationship between 5-HTTLPR genotype and plasma 5-HT being evident.

A study of blood serotonin and serotonin transporter promoter variant (5-HTTLPR) polymorphism in Egyptian autistic children

PubMed Central

Meguid, Nagwa A.; Gebril, Ola H.; Khalil, Rehab O.

2015-01-01

Background: Autism spectrum disorder (ASD) is a complex, heterogeneous neurodevelopmental disorder with onset during early childhood. Most studies have reported an elevation in platelet serotonin in persons with autism. The serotonin (5-hydroxytryptamine; 5-HT) transporter in the brain uptakes 5-HT from extracellular spaces. It is also present in platelets, where it takes up 5-HT from plasma. Polymorphisms in serotonin transporter gene (SLC6A4) were frequently studied in many neuropsychiatric disorders. Materials and Methods: We have measured the plasma 5-HT levels in 20 autistic male children and 20 control male children by the enzyme-linked immunosorbent assay (ELISA) method. In addition, the SLC6A4 promoter region (5-HTTLPR) insertion/deletion (I/D) polymorphism was studied, using whole genomic DNA. Results: Plasma serotonin was significantly low in autistic children compared to control (P = 0.001), although correlation to severity of autism was not significant. The frequency of short (S) allele in autism cases was 10% and in the control group it was absent. Conclusion: Our study demonstrated an increased prevalence of 5-HTTLPR S allele in autism subjects. Significantly decreased plasma serotonin was detected in autism subjects, with no significant relationship between 5-HTTLPR genotype and plasma 5-HT being evident. PMID:26015920

Multiple Cellular Responses to Serotonin Contribute to Epithelial Homeostasis

PubMed Central

Pai, Vaibhav P.; Horseman, Nelson D.

2011-01-01

Epithelial homeostasis incorporates the paradoxical concept of internal change (epithelial turnover) enabling the maintenance of anatomical status quo. Epithelial cell differentiation and cell loss (cell shedding and apoptosis) form important components of epithelial turnover. Although the mechanisms of cell loss are being uncovered the crucial triggers that modulate epithelial turnover through regulation of cell loss remain undetermined. Serotonin is emerging as a common autocrine-paracine regulator in epithelia of multiple organs, including the breast. Here we address whether serotonin affects epithelial turnover. Specifically, serotonin's roles in regulating cell shedding, apoptosis and barrier function of the epithelium. Using in vivo studies in mouse and a robust model of differentiated human mammary duct epithelium (MCF10A), we show that serotonin induces mammary epithelial cell shedding and disrupts tight junctions in a reversible manner. However, upon sustained exposure, serotonin induces apoptosis in the replenishing cell population, causing irreversible changes to the epithelial membrane. The staggered nature of these events induced by serotonin slowly shifts the balance in the epithelium from reversible to irreversible. These finding have very important implications towards our ability to control epithelial regeneration and thus address pathologies of aberrant epithelial turnover, which range from degenerative disorders (e.g.; pancreatitis and thyrioditis) to proliferative disorders (e.g.; mastitis, ductal ectasia, cholangiopathies and epithelial cancers). PMID:21390323

Bright versus dim ambient light affects subjective well-being but not serotonin-related biological factors.

PubMed

Stemer, Bettina; Melmer, Andreas; Fuchs, Dietmar; Ebenbichler, Christoph; Kemmler, Georg; Deisenhammer, Eberhard A

2015-10-30

Light falling on the retina is converted into an electrical signal which stimulates serotonin synthesis. Previous studies described an increase of plasma and CNS serotonin levels after bright light exposure. Ghrelin and leptin are peptide hormones which are involved in the regulation of hunger/satiety and are related to serotonin. Neopterin and kynurenine are immunological markers which are also linked to serotonin biosynthesis. In this study, 29 healthy male volunteers were exposed to bright (5000lx) and dim (50lx) light conditions for 120min in a cross-over manner. Subjective well-being and hunger as well as various serotonin associated plasma factors were assessed before and after light exposure. Subjective well-being showed a small increase under bright light and a small decrease under dim light, resulting in a significant interaction between light condition and time. Ghrelin concentrations increased significantly under both light conditions, but there was no interaction between light and time. Correspondingly, leptin decreased significantly under both light conditions. Hunger increased significantly with no light-time interaction. We also found a significant decrease of neopterin, tryptophan and tyrosine levels, but no interaction between light and time. In conclusion, ambient light was affecting subjective well-being rather than serotonin associated biological factors. Copyright © 2015. Published by Elsevier Ireland Ltd.

Generation of a Tph2 Conditional Knockout Mouse Line for Time- and Tissue-Specific Depletion of Brain Serotonin

PubMed Central

Migliarini, Sara; Pacini, Giulia; Pasqualetti, Massimo

2015-01-01

Serotonin has been gaining increasing attention during the last two decades due to the dual function of this monoamine as key regulator during critical developmental events and as neurotransmitter. Importantly, unbalanced serotonergic levels during critical temporal phases might contribute to the onset of neuropsychiatric disorders, such as schizophrenia and autism. Despite increasing evidences from both animal models and human genetic studies have underpinned the importance of serotonin homeostasis maintenance during central nervous system development and adulthood, the precise role of this molecule in time-specific activities is only beginning to be elucidated. Serotonin synthesis is a 2-step process, the first step of which is mediated by the rate-limiting activity of Tph enzymes, belonging to the family of aromatic amino acid hydroxylases and existing in two isoforms, Tph1 and Tph2, responsible for the production of peripheral and brain serotonin, respectively. In the present study, we generated and validated a conditional knockout mouse line, Tph2 flox/flox, in which brain serotonin can be effectively ablated with time specificity. We demonstrated that the Cre-mediated excision of the third exon of Tph2 gene results in the production of a Tph2 null allele in which we observed the near-complete loss of brain serotonin, as well as the growth defects and perinatal lethality observed in serotonin conventional knockouts. We also revealed that in mice harbouring the Tph2 null allele, but not in wild-types, two distinct Tph2 mRNA isoforms are present, namely Tph2Δ3 and Tph2Δ3Δ4, with the latter showing an in-frame deletion of amino acids 84–178 and coding a protein that could potentially retain non-negligible enzymatic activity. As we could not detect Tph1 expression in the raphe, we made the hypothesis that the Tph2Δ3Δ4 isoform can be at the origin of the residual, sub-threshold amount of serotonin detected in the brain of Tph2 null/null mice. Finally, we set up a tamoxifen administration protocol that allows an efficient, time-specific inactivation of brain serotonin synthesis. On the whole, we generated a suitable genetic tool to investigate how serotonin depletion impacts on time-specific events during central nervous system development and adulthood life. PMID:26291320

Asenapine reduces anxiety-related behaviours in rat conditioned fear stress model.

PubMed

Ohyama, Masayo; Kondo, Maho; Yamauchi, Miki; Imanishi, Taiichiro; Koyama, Tsukasa

2016-12-01

Asenapine is an atypical antipsychotic that is currently available for the treatment of schizophrenia and bipolar I disorder. Although the atypical antipsychotics clozapine and olanzapine are effective for depression and anxiety in schizophrenia, as demonstrated by animal model studies, this has not been clarified for asenapine. Therefore, we compared the effects of asenapine in the conditioned fear stress model with those of clozapine and olanzapine. Rats were individually fear conditioned using electrical foot shock in a Skinner box. Approximately 24 h later, individual animals were returned to the same Skinner box (without electrical shock) and their freezing behaviour was observed for 5 min. Animals were treated with asenapine, clozapine, olanzapine, the 5-HT1A receptor partial agonist buspirone, or the 5-HT2C receptor antagonist SB242084 at 30 min before freezing behaviour assessment. The 5-HT1A receptor antagonist WAY100635 or the 5-HT2C receptor agonist Ro60-0175 was also used concomitantly with asenapine. The effects of asenapine, clozapine, and olanzapine on serotonin release in the rat hippocampus were also measured using in vivo microdialysis. Asenapine reduced freezing behaviour, while neither clozapine nor olanzapine reduced freezing behaviour. Buspirone and SB242084 also reduced freezing behaviour. The effect of asenapine in reducing freezing behaviour was not altered by the concomitant administration of WAY100635 or Ro60-0175. Both asenapine and clozapine, but not olanzapine, increased serotonin release in the rat hippocampus. Asenapine may have superior therapeutic effect on anxiety symptoms than other agents, although the underlying mechanism of its anxiolytic activity remains unknown.

Carcinoid syndrome.

PubMed

Zambrzycki, J K; Elliott, C G

1993-12-01

Carcinoid tumors stimulate the release of specific hormones that lead to flushing, diarrhea, and bronchospasm. Serotonin is the most significant of these substances. Recently, a somatostatin analogue as well as the longer acting octreotide have been used to inhibit tumor secretions and reduce their untoward actions. This is a case report in which somatostatin was used perioperatively for removal of carcinoid tumors with an uneventful course.

Dopamine and Serotonin Transporter Genotypes Moderate Sensitivity to Maternal Expressed Emotion: The Case of Conduct and Emotional Problems in Attention Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Sonuga-Barke, Edmund J. S.; Oades, Robert D.; Psychogiou, Lamprini; Chen, Wai; Franke, Barbara; Buitelaar, Jan; Banaschewski, Tobias; Ebstein, Richard P.; Gil, Michael; Anney, Richard; Miranda, Ana; Roeyers, Herbert; Rothenberger, Aribert; Sergeant, Joseph; Steinhausen, Hans Christoph; Thompson, Margaret; Asherson, Philip; Faraone, Stephen V.

2009-01-01

Background: Mothers' positive emotions expressed about their children with attention deficit/hyperactivity disorder (ADHD) are associated with a reduced likelihood of comorbid conduct problems (CP). We examined whether this association with CP, and one with emotional problems (EMO), is moderated by variants within three genes, previously reported…

Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies.

PubMed

Wile, Daryl J; Agarwal, Pankaj A; Schulzer, Michael; Mak, Edwin; Dinelle, Katherine; Shahinfard, Elham; Vafai, Nasim; Hasegawa, Kazuko; Zhang, Jing; McKenzie, Jessamyn; Neilson, Nicole; Strongosky, Audrey; Uitti, Ryan J; Guttman, Mark; Zabetian, Cyrus P; Ding, Yu-Shin; Adam, Mike; Aasly, Jan; Wszolek, Zbigniew K; Farrer, Matthew; Sossi, Vesna; Stoessl, A Jon

2017-05-01

People with Parkinson's disease can show premotor neurochemical changes in the dopaminergic and non-dopaminergic systems. Using PET, we assessed whether dopaminergic and serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinson's disease and individuals with sporadic Parkinson's disease, and whether LRRK2 mutation carriers without motor symptoms show PET changes. We did two cross-sectional PET studies at the Pacific Parkinson's Research Centre in Vancouver, BC, Canada. We included LRRK2 mutation carriers with or without manifest Parkinson's disease, people with sporadic Parkinson's disease, and age-matched healthy controls, all aged 18 years or older. People with Parkinson's disease were diagnosed by a neurologist with movement disorder training, in accordance with the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. In the first study, LRRK2 mutation carriers with or without manifest Parkinson's disease who were referred for investigation between July, 1999, and January, 2012, were scanned with PET tracers for the membrane dopamine transporter, and dopamine synthesis and storage ( 18 F-6-fluoro-L-dopa; 18 F-FDOPA). We compared findings with those in people with sporadic Parkinson's disease and age-matched healthy controls. In the second study, distinct groups of LRRK2 mutation carriers, individuals with sporadic Parkinson's disease, and age-matched healthy controls seen from November, 2012, to May, 2016, were studied with tracers for the serotonin transporter and vesicular monoamine transporter 2 (VMAT2). Striatal dopamine transporter binding, VMAT2 binding, 18 F-FDOPA uptake, and serotonin transporter binding in multiple brain regions were compared by ANCOVA, adjusted for age. Between January, 1997, and January, 2012, we obtained data for our first study from 40 LRRK2 mutation carriers, 63 individuals with sporadic Parkinson's disease, and 35 healthy controls. We identified significant group differences in striatal dopamine transporter binding (all age ranges in caudate and putamen, p<0·0001) and 18 F-FDOPA uptake (in caudate: age ≤50 years, p=0·0002; all other age ranges, p<0·0001; in putamen: all age ranges, p<0·0001). LRRK2 mutation carriers with manifest Parkinson's disease (n=15) had reduced striatal dopamine transporter binding and 18 F-FDOPA uptake, comparable with amounts seen in individuals with sporadic Parkinson's disease of similar duration. LRRK2 mutation carriers without manifest Parkinson's disease (n=25) had greater 18 F-FDOPA uptake and dopamine transporter binding than did individuals with sporadic Parkinson's disease, with 18 F-FDOPA uptake comparable with controls and dopamine transporter binding lower than in controls. Between November, 2012, and May, 2016, we obtained data for our second study from 16 LRRK2 mutation carriers, 13 individuals with sporadic Parkinson's disease, and nine healthy controls. Nine LRRK2 mutation carriers without manifest Parkinson's disease had significantly elevated serotonin transporter binding in the hypothalamus (compared with controls, individuals with LRRK2 Parkinson's disease, and people with sporadic Parkinson's disease, p<0·0001), striatum (compared with people with sporadic Parkinson's disease, p=0·02), and brainstem (compared with LRRK2 mutation carriers with manifest Parkinson's disease, p=0·01), after adjustment for age. Serotonin transporter binding in the cortex did not differ significantly between groups after age adjustment. Striatal VMAT2 binding was reduced in all individuals with manifest Parkinson's disease and reduced asymmetrically in one LRRK2 mutation carrier without manifest disease. Dopaminergic and serotonergic changes progress in a similar fashion in LRRK2 mutation carriers with manifest Parkinson's disease and individuals with sporadic Parkinson's disease, but LRRK2 mutation carriers without manifest Parkinson's disease show increased serotonin transporter binding in the striatum, brainstem, and hypothalamus, possibly reflecting compensatory changes in serotonergic innervation preceding the motor onset of Parkinson's disease. Increased serotonergic innervation might contribute to clinical differences in LRRK2 Parkinson's disease, including the emergence of non-motor symptoms and, potentially, differences in the long-term response to levodopa. Canada Research Chairs, Michael J Fox Foundation, National Institutes of Health, Pacific Alzheimer Research Foundation, Pacific Parkinson's Research Institute, National Research Council of Canada. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Pharmacological, toxicological, deontologic, and medico-legal aspects of the use of appetite suppressant agents in "weight-loss cures"].

PubMed

Carolei, L; Ermio, G; Accorinti, N; Meo, G; Lamberti, V; De Sarro, G

1997-01-01

The pharmacological, deontologic and medico-legal aspects in the use of appetite suppressant drugs have been evaluated. Appetite suppressant drugs used in the treatment of obesity are divided into 2 broad pharmacological categories: those acting via brain catecholamine pathways and those acting via serotonin pathways. Of the former group, amphetamines and phenimetrazines are no longer used because of their stimulant properties and addictive potential. The remaining drugs of this group have some sympathomimetic and stimulant properties. Anorectic drugs which promote serotonin neurotransmission have no such stimulant or sympathomimetic properties. They reduce appetite and food intake and are effective in the treatment of obesity. If they are not used appropriately, appetite suppressants can be of no therapeutic benefit and cause marked health risks. As regards to anorectic drugs, the 13/4/1995 act "Rules and limits in preparing drugs containing anorectic substances", precisely defines rules about selling and use of those substances. Behavior of health care personnel neglecting observance of the rule, could be interpreted as "imprudence", "negligence" and "inexpertness" in designing and managing a fat-reducing diet, that may imply, in case of damage to the patient, a professional fault.

Flavonoids inhibit both rice and sheep serotonin N-acetyltransferases and reduce melatonin levels in plants.

PubMed

Lee, Kyungjin; Hwang, Ok Jin; Reiter, Russel J; Back, Kyoungwhan

2018-05-31

The plant melatonin biosynthetic pathway has been well characterized, but inhibitors of melatonin synthesis have not been well studied. Here, we found that flavonoids potently inhibited plant melatonin synthesis. For example, flavonoids including morin and myricetin significantly inhibited purified, recombinant sheep serotonin N-acetyltransferase (SNAT). Flavonoids also dose-dependently and potently inhibited purified rice SNAT1 and SNAT2. Thus, myricetin (100 μmol/L) reduced rice SNAT1 and SNAT2 activity 7- and 10-fold, respectively, and also strongly inhibited the N-acetylserotonin methyltransferase activity of purified, recombinant rice caffeic acid O-methyltransferase. To explore the in vivo effects, rice leaves were treated with flavonoids and then cadmium. Flavonoid-treated leaves had lower melatonin levels than the untreated control. To explore the direct roles of flavonoids in melatonin biosynthesis, we first functionally characterized a putative rice flavonol synthase (FLS) in vitro and generated flavonoid-rich transgenic rice plants that overexpressed FLS. Such plants produced more flavonoids but less melatonin than the wild-type, which suggests that flavonoids indeed inhibit plant melatonin biosynthesis. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Induced thermal stress on serotonin levels in the blue swimmer crab, Portunus pelagicus.

PubMed

Rajendiran, Saravanan; Muhammad Iqbal, Beema Mahin; Vasudevan, Sugumar

2016-03-01

The temperature of habitat water has a drastic influence on the behavioral, physiological and biochemical mechanisms of crustaceans. Hyperglycemia is a typical response of many aquatic animals to harmful physical and chemical environmental changes. In crustaceans increased circulating crustacean hyperglycemic hormone (CHH) and hyperglycemia are reported to occur following exposure to several environmental stress. The biogenic amine, serotonin has been found to modulate the CHH levels and oxidation of serotonin into its metabolites is catalysed by monoamine oxidase. The blue swimmer crab, Portunus pelagicus is a dominant intertidal species utilized throughout the indo-pacific region and is a particularly important species of Palk bay. It has high nutritional value and delicious taste and hence their requirements of capture and cultivation of this species are constantly increasing. This species experiences varying and increasing temperature levels as it resides in an higher intertidal zone of Thondi coast. The present study examines the effect of thermal stress on the levels of serotonin and crustacean hyperglycemic hormone in the hemolymph of P. pelagicus and analyzes the effect of the monoamine oxidase inhibitor, pargyline on serotonin and CHH level after thermal stress. The results showed increased levels of glucose, CHH and serotonin on exposure to 26 °C in control animals. Pargyline injected crabs showed highly significant increase in the levels of CHH and serotonin on every 2 °C increase or decrease in temperature. A greater CHH level of 268.86±2.87 fmol/ml and a greater serotonin level of 177.69±10.10 ng/ml was observed at 24 °C. This could be due to the effect of in maintaining the level of serotonin in the hemolymph and preventing its oxidation, which in turn induces hyperglycemia by releasing CHH into hemolymph. Thus, the study demonstrates the effect of thermal stress on the hemolymph metabolites studied and the role of pargyline in elevating the levels of serotonin and CHH on thermal stress in the blue swimmer crab, P. pelagicus .

Antidepressant Use Is Associated With an Increased Risk of Developing Microbleeds.

PubMed

Akoudad, Saloua; Aarts, Nikkie; Noordam, Raymond; Ikram, M Arfan; Tiemeier, Henning; Hofman, Albert; Stricker, Bruno H; Vernooij, Meike W; Visser, Loes E

2016-01-01

Serotonin-specific antidepressants may increase the risk of adverse bleeding events. In a previous cross-sectional study, we did not observe an association between antidepressant use and presence of subclinical cerebral bleedings. In this study, we investigated longitudinally whether antidepressant use is associated with an increased risk of new subclinical cerebral microbleeds. In total, 2559 participants aged ≥45 years of the population-based Rotterdam Study, all without microbleeds at baseline, underwent baseline and repeat brain magnetic resonance imaging between 2005 and 2013 (mean time interval, 3.9 years; SD, 0.5) to determine the incidence of microbleeds. Antidepressant use (yes versus no) was assessed between baseline and follow-up scan. In additional analyses, antidepressants were classified as low, intermediate, or high affinity for the serotonin transporter, and alternatively as selective serotonin reuptake inhibitors or non-selective serotonin reuptake inhibitors. We used multivariable logistic regression models to investigate the association of antidepressants with incident microbleeds. Antidepressant use was associated with a higher cerebral microbleed incidence (odds ratio, 2.22; 95% confidence interval, 1.31-3.76) than nonuse. When stratified by affinity for the serotonin transporter, intermediate serotonin affinity antidepressant use was associated with an increased risk of developing microbleeds (odds ratio, 3.07; 95% confidence interval, 1.53-6.17). Finally, selective serotonin reuptake inhibitor and non-selective serotonin reuptake inhibitor use were both associated with increased microbleed incidence. Antidepressant use was associated with an increased risk of developing microbleeds. Our results may support findings from previous clinical studies about increased intracranial and extracranial bleeding risk in antidepressant users. © 2015 American Heart Association, Inc.

The serotonin-N-acetylserotonin-melatonin pathway as a biomarker for autism spectrum disorders.

PubMed

Pagan, C; Delorme, R; Callebert, J; Goubran-Botros, H; Amsellem, F; Drouot, X; Boudebesse, C; Le Dudal, K; Ngo-Nguyen, N; Laouamri, H; Gillberg, C; Leboyer, M; Bourgeron, T; Launay, J-M

2014-11-11

Elevated whole-blood serotonin and decreased plasma melatonin (a circadian synchronizer hormone that derives from serotonin) have been reported independently in patients with autism spectrum disorders (ASDs). Here, we explored, in parallel, serotonin, melatonin and the intermediate N-acetylserotonin (NAS) in a large cohort of patients with ASD and their relatives. We then investigated the clinical correlates of these biochemical parameters. Whole-blood serotonin, platelet NAS and plasma melatonin were assessed in 278 patients with ASD, their 506 first-degree relatives (129 unaffected siblings, 199 mothers and 178 fathers) and 416 sex- and age-matched controls. We confirmed the previously reported hyperserotonemia in ASD (40% (35-46%) of patients), as well as the deficit in melatonin (51% (45-57%)), taking as a threshold the 95th or 5th percentile of the control group, respectively. In addition, this study reveals an increase of NAS (47% (41-54%) of patients) in platelets, pointing to a disruption of the serotonin-NAS-melatonin pathway in ASD. Biochemical impairments were also observed in the first-degree relatives of patients. A score combining impairments of serotonin, NAS and melatonin distinguished between patients and controls with a sensitivity of 80% and a specificity of 85%. In patients the melatonin deficit was only significantly associated with insomnia. Impairments of melatonin synthesis in ASD may be linked with decreased 14-3-3 proteins. Although ASDs are highly heterogeneous, disruption of the serotonin-NAS-melatonin pathway is a very frequent trait in patients and may represent a useful biomarker for a large subgroup of individuals with ASD.

The serotonin-N-acetylserotonin–melatonin pathway as a biomarker for autism spectrum disorders

PubMed Central

Pagan, C; Delorme, R; Callebert, J; Goubran-Botros, H; Amsellem, F; Drouot, X; Boudebesse, C; Le Dudal, K; Ngo-Nguyen, N; Laouamri, H; Gillberg, C; Leboyer, M; Bourgeron, T; Launay, J-M

2014-01-01

Elevated whole-blood serotonin and decreased plasma melatonin (a circadian synchronizer hormone that derives from serotonin) have been reported independently in patients with autism spectrum disorders (ASDs). Here, we explored, in parallel, serotonin, melatonin and the intermediate N-acetylserotonin (NAS) in a large cohort of patients with ASD and their relatives. We then investigated the clinical correlates of these biochemical parameters. Whole-blood serotonin, platelet NAS and plasma melatonin were assessed in 278 patients with ASD, their 506 first-degree relatives (129 unaffected siblings, 199 mothers and 178 fathers) and 416 sex- and age-matched controls. We confirmed the previously reported hyperserotonemia in ASD (40% (35–46%) of patients), as well as the deficit in melatonin (51% (45–57%)), taking as a threshold the 95th or 5th percentile of the control group, respectively. In addition, this study reveals an increase of NAS (47% (41–54%) of patients) in platelets, pointing to a disruption of the serotonin-NAS–melatonin pathway in ASD. Biochemical impairments were also observed in the first-degree relatives of patients. A score combining impairments of serotonin, NAS and melatonin distinguished between patients and controls with a sensitivity of 80% and a specificity of 85%. In patients the melatonin deficit was only significantly associated with insomnia. Impairments of melatonin synthesis in ASD may be linked with decreased 14-3-3 proteins. Although ASDs are highly heterogeneous, disruption of the serotonin-NAS–melatonin pathway is a very frequent trait in patients and may represent a useful biomarker for a large subgroup of individuals with ASD. PMID:25386956

Revisiting the Serotonin-Aggression Relation in Humans: A Meta-analysis

PubMed Central

Duke, Aaron A.; Bègue, Laurent; Bell, Rob; Eisenlohr-Moul, Tory

2013-01-01

The inverse relation between serotonin and human aggression is often portrayed as “reliable,” “strong,” and “well-established” despite decades of conflicting reports and widely recognized methodological limitations. In this systematic review and meta-analysis we evaluate the evidence for and against the serotonin deficiency hypothesis of human aggression across four methods of assessing serotonin: (a) cerebrospinal fluid levels of 5-hydroxyindoleacetic acid (CSF 5-HIAA), (b) acute tryptophan depletion, (c) pharmacological challenge, and (d) endocrine challenge. Results across 175 independent samples and over 6,500 total participants were heterogeneous, but, in aggregate, revealed a small, inverse correlation between central serotonin functioning and aggression, anger, and hostility, r = −.12. Pharmacological challenge studies had the largest mean weighted effect size, r = −.21, and CSF 5-HIAA studies had the smallest, r = −.06, p = .21. Potential methodological and demographic moderators largely failed to account for variability in study outcomes. Notable exceptions included year of publication (effect sizes tended to diminish with time) and self-versus other-reported aggression (other-reported aggression was positively correlated to serotonin functioning). We discuss four possible explanations for the pattern of findings: unreliable measures, ambient correlational noise, an unidentified higher-order interaction, and a selective serotonergic effect. Finally, we provide four recommendations for bringing much needed clarity to this important area of research: acknowledge contradictory findings and avoid selective reporting practices; focus on improving the reliability and validity of serotonin and aggression measures; test for interactions involving personality and/or environmental moderators; and revise the serotonin deficiency hypothesis to account for serotonin’s functional complexity. PMID:23379963

Stress enables reinforcement-elicited serotonergic consolidation of fear memory

PubMed Central

Baratta, Michael V.; Kodandaramaiah, Suhasa B.; Monahan, Patrick E.; Yao, Junmei; Weber, Michael D.; Lin, Pei-Ann; Gisabella, Barbara; Petrossian, Natalie; Amat, Jose; Kim, Kyungman; Yang, Aimei; Forest, Craig R.; Boyden, Edward S.; Goosens, Ki A.

2015-01-01

Background Prior exposure to stress is a risk factor for developing post-traumatic stress disorder (PTSD) in response to trauma, yet the mechanisms by which this occurs are unclear. Using a rodent model of stress-based susceptibility to PTSD, we investigated the role of serotonin in this phenomenon. Methods Adult mice were exposed to repeated immobilization stress or handling, and the role of serotonin in subsequent fear learning was assessed using pharmacological manipulation and western blot detection of serotonin receptors, measurements of serotonin, high-speed optogenetic silencing, and behavior. Results Both dorsal raphe serotonergic activity during aversive reinforcement and amygdala serotonin 2c receptor (5-HT2CR) activity during memory consolidation are necessary for stress enhancement of fear memory, but neither process affects fear memory in unstressed mice. Additionally, prior stress increases amygdala sensitivity to serotonin by promoting surface expression of 5-HT2CR without affecting tissue levels of serotonin in the amygdala. We also show that the serotonin that drives stress enhancement of associative cued fear memory can arise from paired or unpaired footshock, an effect not predicted by theoretical models of associative learning. Conclusion Stress bolsters the consequences of aversive reinforcement, not by simply enhancing the neurobiological signals used to encode fear in unstressed animals, but rather by engaging distinct mechanistic pathways. These results reveal that predictions from classical associative learning models do not always hold for stressed animals, and suggest that 5-HT2CR blockade may represent a promising therapeutic target for psychiatric disorders characterized by excessive fear responses such as that observed in PTSD. PMID:26248536

Effect of chronic d-fenfluramine administration on rat hypothalamic serotonin levels and release

NASA Technical Reports Server (NTRS)

Schaechter, Judith D.; Wurtman, Richard J.

1988-01-01

D-fenfluramine, an anorectic agent in rats and man, was administered daily at doses 1.25, 2.5, 5, or 10 mg/kg/day for 10 days, and sacrificed 6 days later. Hypothalamic serotonin (5-HT) levels were unchanged in rats receiving 1.25-5 mg/kg/day of d-fenfluramine but reduced by 22 percent (p less than 0.01) at the highest drug dose (10 mg/kg/day); hypothalamic 5-hydroxyindole acetic acid (5-HIAA) levels were reduced by 15 percent (p less than 0.05) or 28 percent (p less than 0.01) in rats receiving 5 or 10 mg/kg/day of the drug, respectively. Hypothalamic slices prepared from rats which were previously treated with any of the drug doses spontaneously released endogenous 5-HT at rates that did not differ from those of vehicle-treated rats. 5-HT released with electrical field-stimulation was unaffected by prior d-fenfluramine treatment at doses of 1.25-5 mg/kg/day, and was reduced by 20 percent (p less than 0.05) from slices prepared from rats which received 10 mg/kg/day. 5-HIAA efflux was also attenuated by the highest drug dose. These data indicate that chronic administration to rats of customary anorectic doses of d-fenfluramine (i.e. 0.06-1.25 mg/kg) fail to cause long-lasting reductions in brain 5-HT release.

The Effect of Gastric Bypass on the Pharmacokinetics of Serotonin Reuptake Inhibitors

PubMed Central

Hamad, Giselle G.; Helsel, Joseph C.; Perel, James M.; Kozak, Gina M.; McShea, Mary C.; Hughes, Carolyn; Confer, Andrea L.; Sit, Dorothy K.; McCloskey, Carol A.; Wisner, Katherine L.

2013-01-01

Objective Morbidly obese patients frequently present with mood and anxiety disorders, which are often treated with serotonin reuptake inhibitors (SRIs). Having observed that patients treated with SRIs frequently relapse after Rouxen-Y gastric bypass surgery, the authors sought to assess whether SRI bioavailability is reduced postoperatively. Method Twelve gastric bypass candidates treated with an SRI for primary mood or anxiety disorders were studied prospectively. Timed blood samples for SRI plasma levels were drawn for pharmacokinetic studies before surgery and 1, 6, and 12 months afterward. Maximum concentration, time to maximum concentration, and area under the concentration/time curve (AUC) were determined. Results In eight of the 12 patients, AUC values 1 month after surgery dropped to an average of 54% (SD=18) of preoperative levels (range=36%–80%); in six of these patients, AUC values returned to baseline levels (or greater) by 6 months. Four patients had an exacerbation of depressive symptoms, which resolved by 12 months in three of them. Three of the four patients had a reduced AUC level at 1 month and either gained weight or failed to lose weight between 6 and 12 months. Normalization of the AUC was associated with improvement in symptom scores. Conclusions Patients taking SRIs in this study were at risk for reduced drug bioavailability 1 month after Rouxen-Y gastric bypass. The authors recommend close psychiatric monitoring after surgery. PMID:22407114

Atomoxetine, a norepinephrine reuptake inhibitor, reduces seizure-induced respiratory arrest.

PubMed

Zhang, Honghai; Zhao, Haiting; Feng, Hua-Jun

2017-08-01

Sudden unexpected death in epilepsy (SUDEP) is a devastating epilepsy complication, and no effective preventive strategies are currently available for this fatal disorder. Clinical and animal studies of SUDEP demonstrate that seizure-induced respiratory arrest (S-IRA) is the primary event leading to death after generalized seizures in many cases. Enhancing brain levels of serotonin reduces S-IRA in animal models relevant to SUDEP, including the DBA/1 mouse. Given that serotonin in the brain plays an important role in modulating respiration and arousal, these findings suggest that deficits in respiration and/or arousal may contribute to S-IRA. It is well known that norepinephrine is an important neurotransmitter that modulates respiration and arousal in the brain as well. Therefore, we hypothesized that enhancing noradrenergic neurotransmission suppresses S-IRA. To test this hypothesis, we examined the effect of atomoxetine, a norepinephrine reuptake inhibitor (NRI), on S-IRA evoked by either acoustic stimulation or pentylenetetrazole in DBA/1 mice. We report the original observation that atomoxetine specifically suppresses S-IRA without altering the susceptibility to seizures evoked by acoustic stimulation, and atomoxetine also reduces S-IRA evoked by pentylenetetrazole in DBA/1 mice. Our data suggest that the noradrenergic signaling is importantly involved in S-IRA, and that atomoxetine, a medication widely used to treat attention deficit hyperactivity disorder (ADHD), is potentially useful to prevent SUDEP. Copyright © 2017 Elsevier Inc. All rights reserved.

Serotonin enhances the impact of health information on food choice.

PubMed

Vlaev, Ivo; Crockett, Molly J; Clark, Luke; Müller, Ulrich; Robbins, Trevor W

2017-06-01

Serotonin has been implicated in promoting self-control, regulation of hunger and physiological homeostasis, and regulation of caloric intake. However, it remains unclear whether the effects of serotonin on caloric intake reflect purely homeostatic mechanisms, or whether serotonin also modulates cognitive processes involved in dietary decision making. We investigated the effects of an acute dose of the serotonin reuptake inhibitor citalopram on choices between food items that differed along taste and health attributes, compared with placebo and the noradrenaline reuptake inhibitor atomoxetine. Twenty-seven participants attended three sessions and received single doses of atomoxetine, citalopram, and placebo in a double-blind randomised cross-over design. Relative to placebo, citalopram increased choices of more healthy foods over less healthy foods. Citalopram also increased the emphasis on health considerations in decisions. Atomoxetine did not affect decision making relative to placebo. The results support the hypothesis that serotonin may influence food choice by enhancing a focus on long-term goals. The findings are relevant for understanding decisions about food consumption and also for treating health conditions such as eating disorders and obesity.

Evaluation of Postmortem Cerebrospinal Fluid S100B Protein and Serotonin Levels: Comparison of Suicidal Versus Nonsuicidal Deaths in Konya, Turkey.

PubMed

Dogan, Kamil Hakan; Unaldi, Mustafa; Demirci, Serafettin

2016-09-01

Although suicide is a preventable public health problem, objective assays for suicide risk are limited. In this study, it was aimed to determine levels of S100B protein and serotonin as a marker for risk of suicide. S100B protein and serotonin levels were investigated with ELISA method in the cerebrospinal fluid (CSF) in medicolegal autopsy cases, including those of suicide cases (n = 32) and nonsuicide cases (n = 56). The CSF S100B levels were higher (9.3 ± 2.9 ng/mL vs. 5.4 ± 2.0 ng/mL), and serotonin levels were lower (10.4 ± 4.9 ng/mL vs. 19.0 ± 5.7 ng/mL) in suicide group than nonsuicide group (p < 0.05). There was no correlation between S100B protein and serotonin levels with gender, age groups, postmortem interval, and cause of death. It is concluded that both S100B protein and serotonin in CSF may be useful for determination of suicide risk. © 2016 American Academy of Forensic Sciences.

Medium-Throughput Screen of Microbially Produced Serotonin via a G-Protein-Coupled Receptor-Based Sensor.

PubMed

Ehrenworth, Amy M; Claiborne, Tauris; Peralta-Yahya, Pamela

2017-10-17

Chemical biosensors, for which chemical detection triggers a fluorescent signal, have the potential to accelerate the screening of noncolorimetric chemicals produced by microbes, enabling the high-throughput engineering of enzymes and metabolic pathways. Here, we engineer a G-protein-coupled receptor (GPCR)-based sensor to detect serotonin produced by a producer microbe in the producer microbe's supernatant. Detecting a chemical in the producer microbe's supernatant is nontrivial because of the number of other metabolites and proteins present that could interfere with sensor performance. We validate the two-cell screening system for medium-throughput applications, opening the door to the rapid engineering of microbes for the increased production of serotonin. We focus on serotonin detection as serotonin levels limit the microbial production of hydroxystrictosidine, a modified alkaloid that could accelerate the semisynthesis of camptothecin-derived anticancer pharmaceuticals. This work shows the ease of generating GPCR-based chemical sensors and their ability to detect specific chemicals in complex aqueous solutions, such as microbial spent medium. In addition, this work sets the stage for the rapid engineering of serotonin-producing microbes.

Upper gastrointestinal bleeding in a patient with depression receiving selective serotonin reuptake inhibitor therapy.

PubMed

Kumar, Deepak; Saaraswat, Tanuj; Sengupta, S N; Mehrotra, Saurabh

2009-02-01

Serotonin plays an important role in the normal clotting phenomenon and is released by platelets. Platelets are dependent on a serotonin transporter for the uptake of serotonin, as they cannot synthesize it themselves. Selective serotonin reuptake inhibitors (SSRIs) block the uptake of serotonin into platelets and can cause problems with clotting leading to bleeding. This case report highlights the occurrence of upper gastrointestinal bleeding in the index case on initiating SSRI therapy for depression and the prompt resolution of the same on its discontinuation on two separate occasions. SSRIs may cause upper gastrointestinal (GI) bleeding. Physicians should be aware of the same and should try to rule out previous episodes of upper GI bleed or the presence of other risk factors which might predispose to it before prescribing SSRIs; they should also warn the patients about this potential side effect. Also, the presence of thalassemia trait in the index patient deserves special attention and needs to be explored to see if it might in any way contribute in potentiating this side effect of SSRIs.