Chromatographic analysis of age-related changes in mucosal serotonin transmission in the murine distal ileum

PubMed Central

2012-01-01

Background In the upper bowel, alterations in motility and absorption of key nutrients have been observed as part of the normal ageing process. Serotonin (5-HT) is a key signalling molecule in the gastrointestinal tract and is known to influence motility, however little is known of how the ageing process alters 5-HT signalling processes in the bowel. Results An isocratic chromatographic method was able to detect all 5-HT precursors and metabolites. Using extracellular and intracellular sampling approaches, we were able to monitor all key parameters associated with the transmission process. There was no alteration in the levels of tryptophan and 5-HTP between 3 and 18 month old animals. There was a significant increase in the ratio of 5-HT:5-HTP and an increase in intracellular 5-HT between 3 and 18 month old animals suggesting an increase in 5-HT synthesis. There was also a significant increase in extracellular 5-HT with age, suggesting increased 5-HT release. There was an age-related decrease in the ratio of intracellular 5-HIAA:extracellular 5-HT, whilst the amount of 5-HIAA did not change with age. In the presence of an increase in extracellular 5-HT, the lack of an age-related change in 5-HIAA is suggestive of a decrease in re-uptake via the serotonin transporter (SERT). Conclusions We have used intracellular and extracellular sampling to provide more insight into alterations in the neurotransmission process of 5-HT during normal ageing. We observed elevated 5-HT synthesis and release and a possible decrease in the activity of SERT. Taken together these changes lead to increased 5-HT availability and may alter motility function and could lead to the changes in adsorption observed in the elderly. PMID:22494644

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.

Tryptophan: the key to boosting brain serotonin synthesis in depressive illness.

PubMed

Badawy, Abdulla A-B

2013-10-01

It has been proposed that focusing on brain serotonin synthesis can advance antidepressant drug development. Biochemical aspects of the serotonin deficiency in major depressive disorder (MDD) are discussed here in detail. The deficiency is caused by a decreased availability of the serotonin precursor tryptophan (Trp) to the brain. This decrease is caused by accelerated Trp degradation, most likely induced by enhancement of the hepatic enzyme tryptophan 2,3-dioxygenase (TDO) by glucocorticoids and/or catecholamines. Induction of the extrahepatic Trp-degrading enzyme indolylamine 2,3-dioxygenase (IDO) by the modest immune activation in MDD has not been demonstrated and, if it occurs, is unlikely to make a significant contribution. Liver TDO appears to be a target of many antidepressants, the mood stabilisers Li(+) and carbamazepine and possibly other adjuncts to antidepressant therapy. The poor, variable and modest antidepressant efficacy of Trp is due to accelerated hepatic Trp degradation, and efficacy can be restored or enhanced by combination with antidepressants or other existing or new TDO inhibitors. Enhancing Trp availability to the brain is thus the key to normalisation of serotonin synthesis and could form the basis for future antidepressant drug development.

[Tyramine and serotonin syndromes. Pharmacological, medical and legal remarks].

PubMed

Toro-Martínez, Esteban

2005-01-01

The tyramine syndrome and the serotonin syndrome are a complex of signs and symptoms that are thought to be largely attributable to drug - drug interactions or drug - food interactions that enhances norepinephrine o serotonin activity. This article reviews: pharmacological basis of those syndromes; clinical features; forbidden foods, drug-drug interactions, and treatment options. Finally a set of legal recommendations are proposed to avoid liability litigations.

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

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.

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.

Genetic linkage study of bipolar disorder and the serotonin transporter

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

Kelsoe, J.R.; Morison, M.; Mroczkowski-Parker, Z.

1996-04-09

The serotonin transporter (HTT) is an important candidate gene for the genetic transmission of bipolar disorder. It is the site of action of many antidepressants, and plays a key role in the regulation of serotonin neurotransmission. Many studies of affectively ill patients have found abnormalities in serotonin metabolism, and dysregulation of the transporter itself. The human serotonin transporter has been recently cloned and mapped to chromosome 17. We have identified a PstI RFLP at the HTT locus, and here report our examination of this polymorphism for possible linkage to bipolar disorder. Eighteen families were examined from three populations: the Oldmore » Order Amish, Iceland, and the general North American population. In addition to HTT, three other microsatellite markers were examined, which span an interval known to contain HTT. Linkage analyses were conducted under both dominant and recessive models, as well as both narrow (bipolar only) and broad (bipolar + recurrent unipolar) diagnostic models. Linkage could be excluded to HTT under all models examined. Linkage to the interval spanned by the microsatellites was similarly excluded under the dominant models. In two individual families, maximum lod scores of 1.02 and 0.84 were obtained at D17S798 and HTT, respectively. However, these data overall do not support the presence of a susceptibility locus for bipolar disorder near the serotonin transporter. 20 refs., 2 tabs.« less

Exercise and sleep in aging: emphasis on serotonin.

PubMed

Melancon, M O; Lorrain, D; Dionne, I J

2014-10-01

Reductions in central serotonin activity with aging might be involved in sleep-related disorders in later life. Although the beneficial effects of aerobic exercise on sleep are not new, sleep represents a complex recurring state of unconsciousness involving many lines of transmitters which remains only partly clear despite intense ongoing research. It is known that serotonin released into diencephalon and cerebrum might play a key inhibitory role to help promote sleep, likely through an active inhibition of supraspinal neural networks. Several lines of evidence support the stimulatory effects of exercise on higher serotonergic pathways. Hence, exercise has proved to elicit acute elevations in forebrain serotonin concentrations, an effect that waned upon cessation of exercise. While adequate exercise training might lead to adaptations in higher serotonergic networks (desensitization of forebrain receptors), excessive training has been linked to serious brain serotonergic maladaptations accompanied by insomnia. Dietary supplementation of tryptophan (the only serotonin precursor) is known to stimulate serotonergic activity and promote sleep, whereas acute tryptophan depletion causes deleterious effects on sleep. Regarding sleep-wake regulation, exercise has proved to accelerate resynchronization of the biological clock to new light-dark cycles following imposition of phase shifts in laboratory animals. Noteworthy, the effect of increased serotonergic transmission on wake state appears to be biphasic, i.e. promote wake and thereafter drowsiness. Therefore, it might be possible that acute aerobic exercise would act on sleep by increasing activity of ascending brain serotonergic projections, though additional work is warranted to better understand the implication of serotonin in the exercise-sleep axis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

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.

Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder.

PubMed

Betancur, C; Corbex, M; Spielewoy, C; Philippe, A; Laplanche, J L; Launay, J M; Gillberg, C; Mouren-Siméoni, M C; Hamon, M; Giros, B; Nosten-Bertrand, M; Leboyer, M

2002-01-01

Previous studies have provided conflicting evidence regarding the association of the serotonin transporter (5-HTT) gene with autism. Two polymorphisms have been identified in the human 5-HTT gene, a VNTR in intron 2 and a functional deletion/insertion in the promoter region (5-HTTLPR) with short and long variants. Positive associations of the 5-HTTLPR polymorphism with autism have been reported by two family-based studies, but one found preferential transmission of the short allele and the other of the long allele. Two subsequent studies failed to find evidence of transmission disequilibrium at the 5-HTTLPR locus. These conflicting results could be due to heterogeneity of clinical samples with regard to serotonin (5-HT) blood levels, which have been found to be elevated in some autistic subjects. Thus, we examined the association of the 5-HTTLPR and VNTR polymorphisms of the 5-HTT gene with autism, and we investigated the relationship between 5-HTT variants and whole-blood 5-HT. The transmission/disequilibrium test (TDT) revealed no linkage disequilibrium at either loci in a sample of 96 families comprising 43 trios and 53 sib pairs. Furthermore, no significant relationship between 5-HT blood levels and 5-HTT gene polymorphisms was found. Our results suggest that the 5-HTT gene is unlikely to play a major role as a susceptibility factor in autism.

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.

Serotonin and pituitary-adrenal function. [in rat under stress

NASA Technical Reports Server (NTRS)

Berger, P. A.; Barchas, J. D.; Vernikos-Danellis, J.

1974-01-01

An investigation is conducted to evaluate the response of the pituitary-adrenal system to a stress stimulus in the rat. In the investigation brain serotonin synthesis was inhibited with p-chlorophenylalanine. In other tests the concentration of serotonin was enhanced with precursors such as tryptophan or 5-hydroxytryptophan. On the basis of the results obtained in the study it is speculated that in some disease states there is a defect in serotonergic neuronal processes which impairs pituitary-adrenal feedback mechanisms.

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.

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.

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

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.

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.

A physiologic role for serotonergic transmission in adult rat taste buds.

PubMed

Jaber, Luc; Zhao, Fang-li; Kolli, Tamara; Herness, Scott

2014-01-01

Of the multiple neurotransmitters and neuropeptides expressed in the mammalian taste bud, serotonin remains both the most studied and least understood. Serotonin is expressed in a subset of taste receptor cells that form synapses with afferent nerve fibers (type III cells) and was once thought to be essential to neurotransmission (now understood as purinergic). However, the discovery of the 5-HT1A serotonin receptor in a subset of taste receptor cells paracrine to type III cell suggested a role in cell-to-cell communication during the processing of taste information. Functional data describing this role are lacking. Using anatomical and neurophysiological techniques, this study proposes a modulatory role for serotonin during the processing of taste information. Double labeling immunocytochemical and single cell RT-PCR technique experiments documented that 5-HT1A-expressing cells co-expressed markers for type II cells, cells which express T1R or T2R receptors and release ATP. These cells did not co-express type III cells markers. Neurophysiological recordings from the chorda tympani nerve, which innervates anterior taste buds, were performed prior to and during intravenous injection of a 5-HT1A receptor antagonist. These experiments revealed that serotonin facilitates processing of taste information for tastants representing sweet, sour, salty, and bitter taste qualities. On the other hand, injection of ondansetron, a 5-HT3 receptor antagonist, was without effect. Collectively, these data support the hypothesis that serotonin is a crucial element in a finely-tuned feedback loop involving the 5-HT1A receptor, ATP, and purinoceptors. It is hypothesized that serotonin facilitates gustatory signals by regulating the release of ATP through ATP-release channels possibly through phosphatidylinositol 4,5-bisphosphate resynthesis. By doing so, 5-HT1A activation prevents desensitization of post-synaptic purinergic receptors expressed on afferent nerve fibers and enhances the

A Physiologic Role for Serotonergic Transmission in Adult Rat Taste Buds

PubMed Central

Jaber, Luc; Zhao, Fang-li; Kolli, Tamara; Herness, Scott

2014-01-01

Of the multiple neurotransmitters and neuropeptides expressed in the mammalian taste bud, serotonin remains both the most studied and least understood. Serotonin is expressed in a subset of taste receptor cells that form synapses with afferent nerve fibers (type III cells) and was once thought to be essential to neurotransmission (now understood as purinergic). However, the discovery of the 5-HT1A serotonin receptor in a subset of taste receptor cells paracrine to type III cell suggested a role in cell-to-cell communication during the processing of taste information. Functional data describing this role are lacking. Using anatomical and neurophysiological techniques, this study proposes a modulatory role for serotonin during the processing of taste information. Double labeling immunocytochemical and single cell RT-PCR technique experiments documented that 5-HT1A-expressing cells co-expressed markers for type II cells, cells which express T1R or T2R receptors and release ATP. These cells did not co-express type III cells markers. Neurophysiological recordings from the chorda tympani nerve, which innervates anterior taste buds, were performed prior to and during intravenous injection of a 5-HT1A receptor antagonist. These experiments revealed that serotonin facilitates processing of taste information for tastants representing sweet, sour, salty, and bitter taste qualities. On the other hand, injection of ondansetron, a 5-HT3 receptor antagonist, was without effect. Collectively, these data support the hypothesis that serotonin is a crucial element in a finely-tuned feedback loop involving the 5-HT1A receptor, ATP, and purinoceptors. It is hypothesized that serotonin facilitates gustatory signals by regulating the release of ATP through ATP-release channels possibly through phosphatidylinositol 4,5-bisphosphate resynthesis. By doing so, 5-HT1A activation prevents desensitization of post-synaptic purinergic receptors expressed on afferent nerve fibers and enhances the

Serotonin involvement in pituitary-adrenal function

NASA Technical Reports Server (NTRS)

Vernikos-Danellis, J.; Kellar, K. J.; Kent, D.; Gonzales, C.; Berger, P. A.; Barchas, J. D.

1977-01-01

Experiments clarifying the effects of serotonin (5-HT) in the regulation of the hypothalamic-pituitary-adrenocortical system are surveyed. Lesion experiments which seek to determine functional maps of serotonergic input to areas involved in regulation are reported. Investigations of the effects of 5-HT levels on the plasma ACTH response to stress and the diurnal variation in basal plasma corticosterone are summarized, and the question of whether serotonergic transmission is involved in the regulation of all aspects of pituitary-adrenal function is considered with attention to the stimulatory and inhibitory action of 5-HT.

Serotonin transporter gene promoter polymorphism and autism: a family-based genetic association study in Japanese population.

PubMed

Koishi, Shinko; Yamamoto, Kenji; Matsumoto, Hideo; Koishi, Seiji; Enseki, Youichi; Oya, Akitoshi; Asakura, Arata; Aoki, Yutaka; Atsumi, Mariko; Iga, Tomiei; Inomata, Jyoji; Inoko, Hidetoshi; Sasaki, Tsukasa; Nanba, Eiji; Kato, Nobumasa; Ishii, Tetsuo; Yamazaki, Kosuke

2006-05-01

Autism is now widely accepted as a biological disorder which, by and large, starts before birth. It has been shown that serotonin (5-HT) is associated with several psychological processes and hyperserotoninemia is observed in some autistic patients. The results of previous reports about family-based association studies between the serotonin transporter (5-HTT) gene promoter polymorphism and autism are controversial. In this study, an analysis using the transmission/disequilibrium test (TDT) between the 5-HTT gene promoter polymorphism and autism in 104 trios, all ethnically Japanese, showed no significant linkage disequilibrium (P=0.17). Recently, it has been reported that some haplotypes at the serotonin transporter locus may be associated with the pathogenesis of autism. Therefore, further investigations by haplotype analyses are necessary to confirm the implications of genetic variants of the serotonin transporter in the etiology of autism.

A Conserved Asparagine Residue in Transmembrane Segment 1 (TM1) of Serotonin Transporter Dictates Chloride-coupled Neurotransmitter Transport*

PubMed Central

Henry, L. Keith; Iwamoto, Hideki; Field, Julie R.; Kaufmann, Kristian; Dawson, Eric S.; Jacobs, Miriam T.; Adams, Chelsea; Felts, Bruce; Zdravkovic, Igor; Armstrong, Vanessa; Combs, Steven; Solis, Ernesto; Rudnick, Gary; Noskov, Sergei Y.; DeFelice, Louis J.; Meiler, Jens; Blakely, Randy D.

2011-01-01

Na+- and Cl−-dependent uptake of neurotransmitters via transporters of the SLC6 family, including the human serotonin transporter (SLC6A4), is critical for efficient synaptic transmission. Although residues in the human serotonin transporter involved in direct Cl− coordination of human serotonin transport have been identified, the role of Cl− in the transport mechanism remains unclear. Through a combination of mutagenesis, chemical modification, substrate and charge flux measurements, and molecular modeling studies, we reveal an unexpected role for the highly conserved transmembrane segment 1 residue Asn-101 in coupling Cl− binding to concentrative neurotransmitter uptake. PMID:21730057

Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder

PubMed Central

Betancur, Catalina; Corbex, Marylis; Spielewoy, Cécile; Philippe, Anne; Laplanche, Jean-Louis; Launay, Jean-Marie; Gillberg, Christopher; Mouren-Simeoni, Marie-Christine; Hamon, Michel; Giros, Bruno; Nosten-Bertrand, Marika; Leboyer, Marion

2002-01-01

Previous studies have provided conflicting evidence regarding the association of the serotonin transporter (5-HTT) gene with autism. Two polymorphisms have been identified in the human 5-HTT gene, a VNTR in intron 21 and a functional deletion/insertion in the promoter region (5-HTTLPR) with short and long variants.2 Positive associations of the 5-HTTLPR polymorphism with autism have been reported by two family-based studies, but one found preferential transmission of the short allele3 and the other of the long allele.4 Two subsequent studies failed to find evidence of transmission disequilibrium at the 5-HTTLPR locus.5,6 These conflicting results could be due to heterogeneity of clinical samples with regard to serotonin (5-HT) blood levels, which have been found to be elevated in some autistic subjects.7–9 Thus, we examined the association of the 5-HTTLPR and VNTR polymorphisms of the 5-HTT gene with autism, and we investigated the relationship between 5-HTT variants and whole-blood 5-HT. The transmission/disequilibrium test (TDT) revealed no linkage disequilibrium at either loci in a sample of 96 families comprising 43 trios and 53 sib pairs. Furthermore, no significant relationship between 5-HT blood levels and 5-HTT gene polymorphisms was found. Our results suggest that the 5-HTT gene is unlikely to play a major role as a susceptibility factor in autism. PMID:11803447

Serotonin and brain function: a tale of two receptors.

PubMed

Carhart-Harris, R L; Nutt, D J

2017-09-01

Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain's default response to adversity but that an improved ability to change one's situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important - and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.

Serotonin and brain function: a tale of two receptors

PubMed Central

Carhart-Harris, RL; Nutt, DJ

2017-01-01

Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain’s default response to adversity but that an improved ability to change one’s situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important – and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes. PMID:28858536

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.

An extraordinary transmission analogue for enhancing microwave antenna performance

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

Pushpakaran, Sarin V., E-mail: sarincrema@gmail.com; Purushothaman, Jayakrishnan M.; Chandroth, Aanandan

2015-10-15

The theory of diffraction limit proposed by H.A Bethe limits the total power transfer through a subwavelength hole. Researchers all over the world have gone through different techniques for boosting the transmission through subwavelength holes resulting in the Extraordinary Transmission (EOT) behavior. We examine computationally and experimentally the concept of EOT nature in the microwave range for enhancing radiation performance of a stacked dipole antenna working in the S band. It is shown that the front to back ratio of the antenna is considerably enhanced without affecting the impedance matching performance of the design. The computational analysis based on Finitemore » Difference Time Domain (FDTD) method reveals that the excitation of Fabry-Perot resonant modes on the slots is responsible for performance enhancement.« less

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.

Label-Free SERS Selective Detection of Dopamine and Serotonin Using Graphene-Au Nanopyramid Heterostructure.

PubMed

Wang, Pu; Xia, Ming; Liang, Owen; Sun, Ke; Cipriano, Aaron F; Schroeder, Thomas; Liu, Huinan; Xie, Ya-Hong

2015-10-20

Ultrasensitive detection and spatially resolved mapping of neurotransmitters, dopamine and serotonin, are critical to facilitate understanding brain functions and investigate the information processing in neural networks. In this work, we demonstrated single molecule detection of dopamine and serotonin using a graphene-Au nanopyramid heterostructure platform. The quasi-periodic Au structure boosts high-density and high-homogeneity hotspots resulting in ultrahigh sensitivity with a surface enhanced Raman spectroscopic (SERS) enhancement factor ∼10(10). A single layer graphene superimposed on a Au structure not only can locate SERS hot spots but also modify the surface chemistry to realize selective enhancement Raman yield. Dopamine and serotonin could be detected and distinguished from each other at 10(-10) M level in 1 s data acquisition time without any pretreatment and labeling process. Moreover, the heterostructure realized nanomolar detection of neurotransmitters in the presence of simulated body fluids. These findings represent a step forward in enabling in-depth studies of neurological processes including those closely related to brain activity mapping (BAM).

An experimental verification of metamaterial coupled enhanced transmission for antenna applications

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

Pushpakaran, Sarin V.; Raj, Rohith K.; Pradeep, Anju

2014-02-10

Inspired by the work of Bethe on electromagnetic transmission through subwavelength hole, there has been immense interest on the extraordinary transmission through subwavelength slot/slit on metal plates. The invention of metamaterials has boosted the extra ordinary transmission through subwavelength slots. We examine computationally and experimentally the concept of metamaterial cover using an array of split ring resonators (SRRs), for enhancing the transmission in a stacked dipole antenna working in the S band. The front to back ratio is considerably improved by enhancing the magnetic resonant strength in close proximity of the slit of the upper parasitic dipole. The effect ofmore » stacking height of the SRR monolayer on the resonant characteristics of the split ring resonators and its effect on antenna radiation characteristics has been studied.« less

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 ...

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.

Serotonin increases synaptic activity in olfactory bulb glomeruli

PubMed Central

Brill, Julia; Shao, Zuoyi; Puche, Adam C.; Wachowiak, Matt

2016-01-01

Serotoninergic fibers densely innervate olfactory bulb glomeruli, the first sites of synaptic integration in the olfactory system. Acting through 5HT2A receptors, serotonin (5HT) directly excites external tufted cells (ETCs), key excitatory glomerular neurons, and depolarizes some mitral cells (MCs), the olfactory bulb's main output neurons. We further investigated 5HT action on MCs and determined its effects on the two major classes of glomerular interneurons: GABAergic/dopaminergic short axon cells (SACs) and GABAergic periglomerular cells (PGCs). In SACs, 5HT evoked a depolarizing current mediated by 5HT2C receptors but did not significantly impact spike rate. 5HT had no measurable direct effect in PGCs. Serotonin increased spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) in PGCs and SACs. Increased sEPSCs were mediated by 5HT2A receptors, suggesting that they are primarily due to enhanced excitatory drive from ETCs. Increased sIPSCs resulted from elevated excitatory drive onto GABAergic interneurons and augmented GABA release from SACs. Serotonin-mediated GABA release from SACs was action potential independent and significantly increased miniature IPSC frequency in glomerular neurons. When focally applied to a glomerulus, 5HT increased MC spontaneous firing greater than twofold but did not increase olfactory nerve-evoked responses. Taken together, 5HT modulates glomerular network activity in several ways: 1) it increases ETC-mediated feed-forward excitation onto MCs, SACs, and PGCs; 2) it increases inhibition of glomerular interneurons; 3) it directly triggers action potential-independent GABA release from SACs; and 4) these network actions increase spontaneous MC firing without enhancing responses to suprathreshold sensory input. This may enhance MC sensitivity while maintaining dynamic range. PMID:26655822

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.

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

Enhanced transmission in rolled-up hyperlenses utilizing Fabry-Pérot resonances

NASA Astrophysics Data System (ADS)

Kerbst, Jochen; Schwaiger, Stephan; Rottler, Andreas; Koitmäe, Aune; Bröll, Markus; Ehlermann, Jens; Stemmann, Andrea; Heyn, Christian; Heitmann, Detlef; Mendach, Stefan

2011-11-01

We experimentally demonstrate that the transmission through rolled-up metal/semiconductor hyperlenses can be enhanced at desired frequencies utilizing Fabry-Pérot resonances. By means of finite difference time domain simulations, we prove that hyperlensing occurs at frequencies of high transmission.

Reconfigurable terahertz grating with enhanced transmission of TE polarized light

NASA Astrophysics Data System (ADS)

He, J. W.; Wang, X. K.; Xie, Z. W.; Xue, Y. Z.; Wang, S.; Zhang, Y.

2017-07-01

We demonstrate an optically reconfigurable grating with enhanced transmission of TE-polarized waves in the terahertz (THz) waveband. This kind of grating is realized by projecting a grating image onto a thin Si wafer with a digital micromirror device (DMD). The enhanced transmission is caused by a resonance of the electromagnetic fields between the photoexcited strips. The position of the transmission peak shifts with the variation of the period and duty cycle of the photoinduced grating, which can be readily controlled by the DMD. Furthermore, a flattened Gaussian model was applied to describe the distribution of the photoexcited free carriers in the Si wafer, and the simulated transmittance spectra are shown to be in good agreement with the experimental results. In future, the photoexcited carriers could also be used to produce THz diffractive elements with reconfigurable functionality.

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.

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 increases synaptic activity in olfactory bulb glomeruli.

PubMed

Brill, Julia; Shao, Zuoyi; Puche, Adam C; Wachowiak, Matt; Shipley, Michael T

2016-03-01

Serotoninergic fibers densely innervate olfactory bulb glomeruli, the first sites of synaptic integration in the olfactory system. Acting through 5HT2A receptors, serotonin (5HT) directly excites external tufted cells (ETCs), key excitatory glomerular neurons, and depolarizes some mitral cells (MCs), the olfactory bulb's main output neurons. We further investigated 5HT action on MCs and determined its effects on the two major classes of glomerular interneurons: GABAergic/dopaminergic short axon cells (SACs) and GABAergic periglomerular cells (PGCs). In SACs, 5HT evoked a depolarizing current mediated by 5HT2C receptors but did not significantly impact spike rate. 5HT had no measurable direct effect in PGCs. Serotonin increased spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) in PGCs and SACs. Increased sEPSCs were mediated by 5HT2A receptors, suggesting that they are primarily due to enhanced excitatory drive from ETCs. Increased sIPSCs resulted from elevated excitatory drive onto GABAergic interneurons and augmented GABA release from SACs. Serotonin-mediated GABA release from SACs was action potential independent and significantly increased miniature IPSC frequency in glomerular neurons. When focally applied to a glomerulus, 5HT increased MC spontaneous firing greater than twofold but did not increase olfactory nerve-evoked responses. Taken together, 5HT modulates glomerular network activity in several ways: 1) it increases ETC-mediated feed-forward excitation onto MCs, SACs, and PGCs; 2) it increases inhibition of glomerular interneurons; 3) it directly triggers action potential-independent GABA release from SACs; and 4) these network actions increase spontaneous MC firing without enhancing responses to suprathreshold sensory input. This may enhance MC sensitivity while maintaining dynamic range. Copyright © 2016 the American Physiological Society.

Revisiting the Serotonin Hypothesis: Implications for Major Depressive Disorders.

PubMed

Fakhoury, Marc

2016-07-01

Major depressive disorder (MDD) is a heritable neuropsychiatric disease associated with severe changes at cellular and molecular levels. Its diagnosis mainly relies on the characterization of a wide range of symptoms including changes in mood and behavior. Despite the availability of antidepressant drugs, 10 to 30 % of patients fail to respond after a single or multiple treatments, and the recurrence of depression among responsive patients is very high. Evidence from the past decades suggests that the brain neurotransmitter serotonin (5-HT) is incriminated in MDD, and that a dysfunction of 5-HT receptors may play a role in the genesis of this disease. The 5-HT membrane transporter protein (SERT), which helps regulate the serotonergic transmission, is also implicated in MDD and is one of the main targets of antidepressant therapy. Although a number of behavioral tests and animal models have been developed to study depression, little is known about the neurobiological bases of MDD. Understanding the role of the serotonergic pathway will significantly help improve our knowledge of the pathophysiology of depression and may open up avenues for the development of new antidepressant drugs. The overarching goal of this review is to present recent findings from studies examining the serotonergic pathway in MDD, with a focus on SERT and the serotonin 1A (5-HT1A), serotonin 1B (5-HT1B), and serotonin 2A (5-HT2A) receptors. This paper also describes some of the main molecules involved in the internalization of 5-HT receptors and illustrates the changes in 5-HT neurotransmission in knockout mice and animal model of depression.

The role of serotonin in schizophrenia.

PubMed

Iqbal, N; van Praag, H M

1995-01-01

The hypothesis that the LSD psychosis and by inference schizophrenic psychoses are related to dysfunctions in central serotonergic systems, formulated by Woolley and Shaw in the early 1950s was the first testable theory of modern biological psychiatry. Initially, it did not get the scientific attention it deserved. First, because LSD fell into disrepute and was to all intents and purposes banned from human experimentation. Secondly, the antipsychotics were discovered in the same period, and it became clear that these compounds block dopaminergic transmission and hence for many years thereafter the dopaminergic system occupied center stage in biological schizophrenia research. Presently, interest in the relation between serotonin and schizophrenia has been revived, due to the development of serotonin-blocking agents that appear to exert therapeutic effects in schizophrenia. In this paper the evidence for and against a link between serotonergic defects and schizophrenia psychopathology is critically discussed. The conclusion to be reached is threefold. (1) Interruption of certain serotonergic circuits represents an antipsychotic principle. (2) Tentative evidence suggests the involvement of serotonergic dysfunctions in the pathogenesis of schizophrenic psychoses. (3) It is not yet known whether serotonergic lesions contribute directly to the occurrence of schizophrenic psychopathology or via alterations in the dopaminergic system.

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 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

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.

Genetic variation in HTR2A influences serotonin transporter binding potential as measured using PET and [11C]DASB.

PubMed

Laje, Gonzalo; Cannon, Dara M; Allen, Andrew S; Klaver, Jackie M; Peck, Summer A; Liu, Xinmin; Manji, Husseini K; Drevets, Wayne C; McMahon, Francis J

2010-07-01

In a previous study we showed that genetic variation in HTR2A, which encodes the serotonin 2A receptor, influenced outcome of citalopram treatment in patients with major depressive disorder. Since chronic administration of citalopram, which selectively and potently inhibits the serotonin transporter (5-HTT), putatively enhances serotonergic transmission, it is conceivable that genetic variation within HTR2A also influences pretreatment 5-HTT function or serotonergic transmission. The present study used positron emission tomography (PET) and the selective 5-HTT ligand, [11C]DASB, to investigate whether the HTR2A marker alleles that predict treatment outcome also predict differences in 5-HTT binding. Brain levels of 5-HTT were assessed in vivo using PET measures of the non-displaceable component of the [11C]DASB binding potential (BPND). DNA from 43 patients and healthy volunteers, all unmedicated, was genotyped with 14 single nucleotide polymorphisms located within or around HTR2A. Allelic association with BPND was assessed in eight brain regions, with covariates to control for race and ethnicity. We detected allelic association between [11C]DASB BPND in thalamus and three markers in a region spanning the 3' untranslated region and second intron of HTR2A (rs7333412, p=0.000045; rs7997012, p=0.000086; rs977003, p=0.000069). The association signal at rs7333412 remained significant (p<0.05) after applying corrections for multiple testing via permutation. Genetic variation in HTR2A that was previously associated with citalopram treatment outcome was also associated with thalamic 5-HTT binding. While further work is needed to identify the actual functional genetic variants involved, these results suggest that a relationship exists between genetic variation in HTR2A and either 5-HTT expression or central serotonergic transmission that influences the therapeutic response to 5-HTT inhibition in major depression.

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.

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.

Enhanced activity of human serotonin transporter variants associated with autism.

PubMed

Prasad, Harish C; Steiner, Jennifer A; Sutcliffe, James S; Blakely, Randy D

2009-01-27

Rare, functional, non-synonymous variants in the human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT) gene (SLC6A4) have been identified in both autism and obsessive-compulsive disorder (OCD). Within autism, rare hSERT coding variants associate with rigid-compulsive traits, suggesting both phenotypic overlap with OCD and a shared relationship with disrupted 5-HT signalling. Here, we document functional perturbations of three of these variants: Ile425Leu; Phe465Leu; and Leu550Val. In transiently transfected HeLa cells, the three variants confer a gain of 5-HT transport phenotype. Specifically, enhanced SERT activity was also observed in lymphoblastoid lines derived from mutation carriers. In contrast to previously characterized Gly56Ala, where increased transport activity derives from catalytic activation, the three novel variants exhibit elevated surface density as revealed through both surface antagonist-binding and biotinylation studies. Unlike Gly56Ala, mutants Ile425Leu, Phe465Leu and Leu550Val retain a capacity for acute PKG and p38 MAPK regulation. However, both Gly56Ala and Ile425Leu demonstrate markedly reduced sensitivity to PP2A antagonists, suggesting that deficits in trafficking and catalytic modulation may derive from a common basis in perturbed phosphatase regulation. When expressed stably from the same genomic locus in CHO cells, both Gly56Ala and Ile425Leu display catalytic activation, accompanied by a striking loss of SERT protein.

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.

Neuromodulation of activity-dependent synaptic enhancement at crayfish neuromuscular junction.

PubMed

Qian, S M; Delaney, K R

1997-10-17

Action potential-evoked transmitter release is enhanced for many seconds after moderate-frequency stimulation (e.g. 15 Hz for 30 s) at the excitor motorneuron synapse of the crayfish dactyl opener muscle. Beginning about 1.5 s after a train, activity-dependent synaptic enhancement (ADSE) is dominated by a process termed augmentation (G.D. Bittner, D.A. Baxter, Synaptic plasticity at crayfish neuromuscular junctions: facilitation and augmentation, Synapse 7 (1991) 235-243'[4]; K.L. Magleby, Short-term changes in synaptic efficacy, in: G.M. Edelman, L.E. Gall, C.W. Maxwell (Eds.), Synaptic Function, John Wiley and Sons, New York, 1987, pp. 21-56; K.L. Magleby; J.E. Zengel, Augmentation: a process that acts to increase transmitter release at the frog neuromuscular junction, J. Physiol. (Lond.) 257 (1976) 449-470) which decays approximately exponentially with a time constant of about 10 s at 16 degrees C, reflecting the removal of Ca2+ which accumulates during the train in presynaptic terminals (K.R. Delaney, D.W. Tank, R.S. Zucker, Serotonin-mediated enhancement of transmission at crayfish neuromuscular junction is independent of changes in calcium, J. Neurosci. 11 (1991) 2631-2643). Serotonin (5-HT, 1 microM) increases evoked and spontaneous transmitter release several-fold (D. Dixon, H.L. Atwood, Crayfish motor nerve terminal's response to serotonin examined by intracellular microelectrode, J. Neurobiol. 16 (1985) 409-424; J. Dudel, Modulation of quantal synaptic release by serotonin and forskolin in crayfish motor nerve terminals, in: Modulation of Synaptic Transmission and Plasticity in Nervous Systems, G. Hertting, H.-C. Spatz (Eds.), Springer-Verlag, Berlin, 1988; S. Glusman, E.A. Kravitz. The action of serotonin on excitatory nerve terminals in lobster nerve-muscle preparations, J. Physiol. (Lond.) 325 (1982) 223-241). We found that ADSE persists about 2-3 times longer after moderate-frequency presynaptic stimulation in the presence of 5-HT. This slowing of the

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.

In Vitro Effects of Serotonin, Melatonin, and Other Related Indole Compounds on Amyloid-β Kinetics and Neuroprotection.

PubMed

Hornedo-Ortega, Ruth; Da Costa, Grégory; Cerezo, Ana B; Troncoso, Ana M; Richard, Tristan; Garcia-Parrilla, M Carmen

2018-02-01

Amyloid-β peptide is the main component of senile plaques in Alzheimer's disease. The inhibition of amyloid-β peptide assembly, the destabilization of amyloid-β peptide aggregates, and the decrease of its cytotoxicity for the prevention of neuronal death are considered neuroprotective effects. In this work, the protective effects against amyloid-β peptide aggregation and cytotoxicity of eight indolic compounds are evaluated: tryptophan, tryptamine, serotonin, tryptophol, N-acetylserotonin, 3-indoleacetic acid, tryptophan ethyl ester, and melatonin. Thioflavin T spectroscopic assay, transmission electron microscopy, western blotting, circular dichroism, NMR, cell viability (thiazolyl blue tetrazolium bromide assay), quantitative PCR, and heme oxygenase activity are used. Serotonin is the most effective compound for inhibiting amyloid-β peptide aggregation. Almost all the indolic compounds tested prevent amyloid-β peptide-induced and increase cell viability, being between 9 and 25%. Melatonin and serotonin are the most active. Moreover, serotonin increased the expression of SIRT-1 and 2, heat shock protein 70, and heme oxygenase activity, this being a possible mechanism underlying the observed neuroprotective effect. Melatonin and other related indolic compounds, mainly serotonin, show an inhibitory and destabilizing effect on amyloid-β peptide fibril formation and they possess neuroprotective properties related to the vitagenes system. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

Brain serotonin, psychoactive drugs, and effects on reproduction.

PubMed

Ayala, María Elena

2009-12-01

Serotonin, a biogenic amine, is present in significant amounts in many structures of the CNS. It is involved in regulation of a wide variety of physiological functions, such as sensory and motor functions, memory, mood, and secretion of hormones including reproductive hormones. It has also been implicated in the etiology of a range of psychiatric disorders such as anxiety, depression, and eating disorders, along with other conditions such as obesity and migraine. While some drugs that affect serotonin, such as fenfluramine and fluoxetine, have been successfully used in treatment of a range of psychiatric diseases, others, such as the amphetamine analogues MDMA and METH, are potent psychostimulant drugs of abuse. Alterations in serotonergic neurons caused by many of these drugs are well characterized; however, little is known about the reproductive consequences of such alterations. This review evaluates the effects of drugs such as MDMA, pCA, fenfluramine, and fluoxetine on serotonergic transmission in the brain, examines the relationships of these drug effects with the neuroendocrine mechanisms modulating reproductive events such as gonadotropin secretion, ovulation, spermatogenesis, and sexual behavior in animal models, and discusses possible reproductive implications of these drugs in humans.

Unifying concept of serotonin transporter-associated currents.

PubMed

Schicker, Klaus; Uzelac, Zeljko; Gesmonde, Joan; Bulling, Simon; Stockner, Thomas; Freissmuth, Michael; Boehm, Stefan; Rudnick, Gary; Sitte, Harald H; Sandtner, Walter

2012-01-02

Serotonin (5-HT) uptake by the human serotonin transporter (hSERT) is driven by ion gradients. The stoichiometry of transported 5-HT and ions is predicted to result in electroneutral charge movement. However, hSERT mediates a current when challenged with 5-HT. This discrepancy can be accounted for by an uncoupled ion flux. Here, we investigated the mechanistic basis of the uncoupled currents and its relation to the conformational cycle of hSERT. Our observations support the conclusion that the conducting state underlying the uncoupled ion flux is in equilibrium with an inward facing state of the transporter with K+ bound. We identified conditions associated with accumulation of the transporter in inward facing conformations. Manipulations that increased the abundance of inward facing states resulted in enhanced steady-state currents. We present a comprehensive kinetic model of the transport cycle, which recapitulates salient features of the recorded currents. This study provides a framework for exploring transporter-associated currents.

Unifying Concept of Serotonin Transporter-associated Currents*

PubMed Central

Schicker, Klaus; Uzelac, Zeljko; Gesmonde, Joan; Bulling, Simon; Stockner, Thomas; Freissmuth, Michael; Boehm, Stefan; Rudnick, Gary; Sitte, Harald H.; Sandtner, Walter

2012-01-01

Serotonin (5-HT) uptake by the human serotonin transporter (hSERT) is driven by ion gradients. The stoichiometry of transported 5-HT and ions is predicted to result in electroneutral charge movement. However, hSERT mediates a current when challenged with 5-HT. This discrepancy can be accounted for by an uncoupled ion flux. Here, we investigated the mechanistic basis of the uncoupled currents and its relation to the conformational cycle of hSERT. Our observations support the conclusion that the conducting state underlying the uncoupled ion flux is in equilibrium with an inward facing state of the transporter with K+ bound. We identified conditions associated with accumulation of the transporter in inward facing conformations. Manipulations that increased the abundance of inward facing states resulted in enhanced steady-state currents. We present a comprehensive kinetic model of the transport cycle, which recapitulates salient features of the recorded currents. This study provides a framework for exploring transporter-associated currents. PMID:22072712

Broadband enhanced transmission of acoustic waves through serrated metal gratings

NASA Astrophysics Data System (ADS)

Qi, Dong-Xiang; Fan, Ren-Hao; Deng, Yu-Qiang; Peng, Ru-Wen; Wang, Mu; Jiangnan University Collaboration

In this talk, we present our studies on broadband properties of acoustic waves through metal gratings. We have demonstrated that serrated metal gratings, which introduce gradient coatings, can give rise to broadband transmission enhancement of acoustic waves. Here, we have experimentally and theoretically studied the acoustic transmission properties of metal gratings with or without serrated boundaries. The average transmission is obviously enhanced for serrated metal gratings within a wide frequency range, while the Fabry-Perot resonance is significantly suppressed. An effective medium hypothesis with varying acoustic impedance is proposed to analyze the mechanism, which was verified through comparison with finite-element simulation. The serrated boundary supplies gradient mass distribution and gradient normal acoustic impedance, which could efficiently reduce the boundary reflection. Further, by increasing the region of the serrated boundary, we present a broadband high-transmission grating for wide range of incident angle. Our results may have potential applications to broadband acoustic imaging, acoustic sensing and new acoustic devices. References: [1] Dong-Xiang Qi, Yu-Qiang Deng, Di-Hu Xu, Ren-Hao Fan, Ru-Wen Peng, Ze-Guo Chen, Ming-Hui Lu, X. R. Huang and Mu Wang, Appl. Phys. Lett. 106, 011906 (2015); [2] Dong-Xiang Qi, Ren-Hao Fan, Ru-Wen Peng, Xian-Rong Huang, Ming-Hui Lu, Xu Ni, Qing Hu, and Mu Wang, Applied Physics Letters 101, 061912 (2012).

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.

On the role of brain serotonin in expression of genetic predisposition to catalepsy in animal models

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

Popova, N.K.; Kulikov, A.V.

1995-06-19

The activity of the rate-limiting enzyme of serotonin biosynthesis, tryptophan hydroxylase, in the striatum but not in the hippocampus and midbrain of rats bred for predisposition to catalepsy was higher than in nonselected rats. Mice of the highly susceptible to catalepsy CBA strain also differed from other noncataleptic mouse strains by the highest tryptophan hydroxylase activity in the striatum. Inhibition of tryptophan hydroxylase with p-chlorophenylalanine and p-chloromethamphetamine drastically decreased immobility time in hereditary predisposed to catalepsy animals. A decrease in the {sup 3}H-ketanserin specific binding in the striatum of cataleptic rats and CBA mice was found. It was suggested thatmore » this decrease in 5-HT2A serotonin receptor density represented a down regulation of the receptors due to an activation of serotonergic transmission in striatum. It is suggested that hereditary catalepsy may be resulted from genetic changes in the regulation of serotonin metabolism in striatum. 32 refs., 6 figs.« less

Imperfect Vaccination Can Enhance the Transmission of Highly Virulent Pathogens

PubMed Central

Read, Andrew F.; Baigent, Susan J.; Powers, Claire; Kgosana, Lydia B.; Blackwell, Luke; Smith, Lorraine P.; Kennedy, David A.; Walkden-Brown, Stephen W.; Nair, Venugopal K.

2015-01-01

Could some vaccines drive the evolution of more virulent pathogens? Conventional wisdom is that natural selection will remove highly lethal pathogens if host death greatly reduces transmission. Vaccines that keep hosts alive but still allow transmission could thus allow very virulent strains to circulate in a population. Here we show experimentally that immunization of chickens against Marek's disease virus enhances the fitness of more virulent strains, making it possible for hyperpathogenic strains to transmit. Immunity elicited by direct vaccination or by maternal vaccination prolongs host survival but does not prevent infection, viral replication or transmission, thus extending the infectious periods of strains otherwise too lethal to persist. Our data show that anti-disease vaccines that do not prevent transmission can create conditions that promote the emergence of pathogen strains that cause more severe disease in unvaccinated hosts. PMID:26214839

Compact optical filter for dual-wavelength fluorescence-spectrometry based on enhanced transmission through metallic nano-slit array

NASA Astrophysics Data System (ADS)

Hu, X.; Zhan, L.; Xia, Y.

2009-03-01

A novel optical filter based on enhanced transmission through metallic nano-slit is proposed for dual-wavelength fluorescence-spectrometry. A special structure, sampled-period slit array, is utilized to meet the requirement of dual-wavelength transmission in this system. Structure parameters on the transmission property are analyzed by means of Fourier transformation. With the features both to enhance the fluorescence generation and to enhance light transmission, in addition with the feasibility for miniaturization, integration on one chip, and mass production, the proposed filters are promising for the realization of dual-wavelength fluorescence-spectrometry in micro-total-analysis-system.

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.

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.

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 ...

Clonidine prevents enhancement of spinal sympathetic transmission by phosphodiesterase inhibitors.

PubMed

Franz, D N; Madsen, P W

1982-02-12

Preganglionic sympathetic discharges, evoked by cervical stimulation in spinal cats, were rapidly and markedly enhanced for 1-2 h by aminophylline or isobutylmethylxanthine. Clonidine depressed intraspinal transmission and prevented enhancement by the xanthines; alpha 2-receptor antagonists blocked the effect of clonidine and not only restored but also markedly prolonged the enhancement by the xanthines. The results suggest that the excitability of sympathetic preganglionic neurons is regulated by cyclic AMP through activation of different subtypes of adrenergic receptors that are either positively or negatively coupled to adenylate cyclase.

Enhanced transmission by a grating composed of left-handed materials

NASA Astrophysics Data System (ADS)

Premlal, Prabhakaran Letha; Tiwari, Dinesh Chandra; Chaturvedi, Vandana

2018-04-01

We present a detailed theoretical analysis about the influence of surface polaritons on the transmission properties of electromagnetic waves at the periodically corrugated interface between the vacuum and left-handed material by using nonlinear boundary condition approach. The principle behind this approach is to match the wave fields across the grating interface by using a set of linear wave equation with nonlinear boundary conditions. The resonant transmission of the incident electromagnetic radiation in this structure is feasible within a certain frequency band, where there is a range of frequency over which both the electric permittivity and the magnetic permeability are simultaneously negative. The enhanced transmission is attributed to the coupling of the incident electromagnetic wave with the excited surface polaritons on grating interface. Finally, we present the numerical results illustrating the effect of the structural parameters and angle of incidence on the transmission spectra of a TM polarized electromagnetic wave.

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.

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.

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

PubMed

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

2007-08-01

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

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

Animal models of the serotonin syndrome: a systematic review.

PubMed

Haberzettl, Robert; Bert, Bettina; Fink, Heidrun; Fox, Meredith A

2013-11-01

The serotonin syndrome (SS) is a potentially life-threatening disorder in humans which is induced by ingestion of an overdose or by combination of two or more serotonin (5-HT)-enhancing drugs. In animals, acute administration of direct and indirect 5-HT agonists also leads to a set of behavioral and autonomic responses. In the current review, we provide an overview of the existing versions of the animal model of the SS. With a focus on studies in rats and mice, we analyze the frequency of behavioral and autonomic responses following administration of 5-HT-enhancing drugs and direct 5-HT agonists administered alone or in combination, and we briefly discuss the receptor mediation of these responses. Considering species differences, we identify a distinct set of behavioral and autonomic responses that are consistently observed following administration of direct and indirect 5-HT agonists. Finally, we discuss the importance of a standardized assessment of SS responses in rodents and the utility of animal models of the SS in translational studies, and provide suggestions for future research. Copyright © 2013 The Authors. Published by Elsevier B.V. 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

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.

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

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.

Aniracetam enhances cortical dopamine and serotonin release via cholinergic and glutamatergic mechanisms in SHRSP.

PubMed

Shirane, M; Nakamura, K

2001-10-19

Aniracetam, a cognition enhancer, has been recently found to preferentially increase extracellular levels of dopamine (DA) and serotonin (5-HT) in the prefrontal cortex (PFC), basolateral amygdala and dorsal hippocampus of the mesocorticolimbic system in stroke-prone spontaneously hypertensive rats. In the present study, we aimed to identify actually active substances among aniracetam and its major metabolites and to clarify the mode of action in DA and 5-HT release in the PFC. Local perfusion of mecamylamine, a nicotinic acetylcholine (nACh) and N-methyl-D-aspartate (NMDA) receptor antagonist, into the ventral tegmental area (VTA) and dorsal raphe nucleus (DRN) completely blocked DA and 5-HT release, respectively, in the PFC elicited by orally administered aniracetam. The effects of aniracetam were mimicked by local perfusion of N-anisoyl-gamma-aminobutyric acid [corrected] (N-anisoyl-GABA), one of the major metabolites of aniracetam, into the VTA and DRN. The cortical DA release induced by N-anisoyl-GABA applied to the VTA was also completely abolished by co-perfusion of mecamylamine. Additionally, when p-anisic acid, another metabolite of aniracetam, and N-anisoyl-GABA were locally perfused into the PFC, they induced DA and 5-HT release in the same region, respectively. These results indicate that aniracetam enhances DA and 5-HT release by mainly mediating the action of N-anisoyl-GABA that targets not only somatodendritic nACh and NMDA receptors but also presynaptic nACh receptors.

Enhanced responsiveness to selective serotonin reuptake inhibitors during lactation.

PubMed

Jury, Nicholas J; McCormick, Betsy A; Horseman, Nelson D; Benoit, Stephen C; Gregerson, Karen A

2015-01-01

The physiology of mood regulation in the postpartum is poorly understood despite the fact that postpartum depression (PPD) is a common pathology. Serotonergic mechanisms and their dysfunction are widely presumed to be involved, which has led us to investigate whether lactation induces changes in central or peripheral serotonin (5-HT) systems and related affective behaviors. Brain sections from lactating (day 10 postpartum) and age-matched nulliparous (non-pregnant) C57BL/6J mice were processed for 5-HT immunohistochemistry. The total number of 5-HT immunostained cells and optical density were measured. Lactating mice exhibited lower immunoreactive 5-HT and intensity in the dorsal raphe nucleus when compared with nulliparous controls. Serum 5-HT was quantified from lactating and nulliparous mice using radioimmunoassay. Serum 5-HT concentrations were higher in lactating mice than in nulliparous controls. Affective behavior was assessed in lactating and non-lactating females ten days postpartum, as well as in nulliparous controls using the forced swim test (FST) and marble burying task (MBT). Animals were treated for the preceding five days with a selective serotonin reuptake inhibitor (SSRI, citalopram, 5mg/kg/day) or vehicle. Lactating mice exhibited a lower baseline immobility time during the FST and buried fewer marbles during the MBT as compared to nulliparous controls. Citalopram treatment changed these behaviors in lactating mice with further reductions in immobility during the FST and decreased marble burying. In contrast, the same regimen of citalopram treatment had no effect on these behaviors in either non-lactating postpartum or nulliparous females. Our findings demonstrate changes in both central and peripheral 5-HT systems associated with lactation, independent of pregnancy. They also demonstrate a significant interaction of lactation and responsiveness to SSRI treatment, which has important implications in the treatment of PPD. Although recent evidence

Enhanced Responsiveness to Selective Serotonin Reuptake Inhibitors during Lactation

PubMed Central

Jury, Nicholas J.; McCormick, Betsy A.; Horseman, Nelson D.; Benoit, Stephen C.; Gregerson, Karen A.

2015-01-01

The physiology of mood regulation in the postpartum is poorly understood despite the fact that postpartum depression (PPD) is a common pathology. Serotonergic mechanisms and their dysfunction are widely presumed to be involved, which has led us to investigate whether lactation induces changes in central or peripheral serotonin (5-HT) systems and related affective behaviors. Brain sections from lactating (day 10 postpartum) and age-matched nulliparous (non-pregnant) C57BL/6J mice were processed for 5-HT immunohistochemistry. The total number of 5-HT immunostained cells and optical density were measured. Lactating mice exhibited lower immunoreactive 5-HT and intensity in the dorsal raphe nucleus when compared with nulliparous controls. Serum 5-HT was quantified from lactating and nulliparous mice using radioimmunoassay. Serum 5-HT concentrations were higher in lactating mice than in nulliparous controls. Affective behavior was assessed in lactating and non-lactating females ten days postpartum, as well as in nulliparous controls using the forced swim test (FST) and marble burying task (MBT). Animals were treated for the preceding five days with a selective serotonin reuptake inhibitor (SSRI, citalopram, 5mg/kg/day) or vehicle. Lactating mice exhibited a lower baseline immobility time during the FST and buried fewer marbles during the MBT as compared to nulliparous controls. Citalopram treatment changed these behaviors in lactating mice with further reductions in immobility during the FST and decreased marble burying. In contrast, the same regimen of citalopram treatment had no effect on these behaviors in either non-lactating postpartum or nulliparous females. Our findings demonstrate changes in both central and peripheral 5-HT systems associated with lactation, independent of pregnancy. They also demonstrate a significant interaction of lactation and responsiveness to SSRI treatment, which has important implications in the treatment of PPD. Although recent evidence

Serotonin neurotransmission in anorexia nervosa.

PubMed

Haleem, Darakhshan Jabeen

2012-09-01

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

Effects of tryptophan depletion on selective serotonin reuptake inhibitor-remitted patients with obsessive compulsive disorder.

PubMed

Hood, Sean D; Broyd, Annabel; Robinson, Hayley; Lee, Jessica; Hudaib, Abdul-Rahman; Hince, Dana A

2017-12-01

Serotonergic antidepressants are first-line medication therapies for obsessive-compulsive disorder, however it is not known if synaptic serotonin availability is important for selective serotonin reuptake inhibitor efficacy. The present study tested the hypothesis that temporary reduction in central serotonin transmission, through acute tryptophan depletion, would result in an increase in anxiety in selective serotonin reuptake inhibitor-remitted obsessive-compulsive disorder patients. Eight patients (four males) with obsessive-compulsive disorder who showed sustained clinical improvement with selective serotonin reuptake inhibitor treatment underwent acute tryptophan depletion in a randomized, double-blind, placebo-controlled, within-subjects design, over two days one week apart. Five hours after consumption of the depleting/sham drink the participants performed a personalized obsessive-compulsive disorder symptom exposure task. Psychological responses were measured using the Spielberger State Anxiety Inventory, Yale-Brown Obsessive Compulsive Scale and Visual Analogue Scales. Free plasma tryptophan to large neutral amino acid ratio decreased by 93% on the depletion day and decreased by 1% on the sham day, as anticipated. Psychological rating scores as measured by Visual Analogue Scale showed a significant decrease in perceived control and increase in interfering thoughts at the time of provocation on the depletion day but not on the sham day. A measure of convergent validity, namely Visual Analogue Scale Similar to past, was significantly higher at the time of provocation on both the depletion and sham days. Both the depletion and time of provocation scores for Visual Analogue Scale Anxiety, Spielberger State Anxiety Inventory, Yale-Brown Obsessive Compulsive Scale and blood pressure were not significant. Acute tryptophan depletion caused a significant decrease in perceived control and increase in interfering thoughts at the time of provocation. Acute tryptophan

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

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

Inter-individual differences in serotonin and glutamate co-transmission reflect differentiation in context-induced conditioned 50-kHz USVs response after morphine withdrawal.

PubMed

Hamed, Adam; Kursa, Miron Bartosz

2018-05-17

A growing body of research provides compelling evidence that in rats 50-kHz USVs are a form of expression of positive emotions. Context-induced 50-kHz USVs emission is variable among rats, indicating individual differences in contextual response bound up with pharmacological reward. The aims of this study were to: extract the most important neurotransmitters related to context-induced conditioned 50-kHz USVs response; find biological basis of existing inter-individual differences in context-induced conditioned 50-kHz USVs response; create a model of all-to-all neurotransmitters correlations. The data collected here confirms that re-exposure to the context of morphine administration after the withdrawal period increases the level of 50-kHz USVs and this contextual response is associated with elevated serotonin concentrations in amygdala, hippocampus and mPFC and with increased Glu/Gln ratio in nucleus accumbens. The concentration of serotonin increases simultaneously in amygdala, nucleus accumbens and hippocampus. Moreover, 5-HT concentration in amygdala is bound up with glutamate level in this structure as well as in hippocampus. Furthermore, Glu/Gln ratio in nucleus accumbens has strong associations with Glu/Gln ratio simultaneously in VTA, amygdala, striatum and hippocampus. All-to-all-analysis indicate that concentration of glutamate in hippocampus is proportional to glutamate in VTA and GABA concentration in the hippocampus. We have also demonstrated that Glu/GABA ratio in VTA and amygdala was elevated after post withdrawal re-exposure to the pharmacological reward paired context. Presented analysis indicates a strong correlation between serotonergic and glutamatergic systems in context-induced conditioned response. The strength of this co-transmission correlates with the number of 50-kHz USVs emitted in response to morphine-paired context.

Terahertz Near-Field Imaging Using Enhanced Transmission through a Single Subwavelength Aperture

NASA Astrophysics Data System (ADS)

Ishihara, Kunihiko; Ikari, Tomofumi; Minamide, Hiroaki; Shikata, Jun-ichi; Ohashi, Keishi; Yokoyama, Hiroyuki; Ito, Hiromasa

2005-07-01

We demonstrate terahertz (THz) near-field imaging using resonantly enhanced transmission of THz-wave radiation (λ˜ 200 μm) through a bull’s eye structure (a single subwavelength aperture surrounded by concentric periodic grooves in a metal plate). The bull’s eye structure shows extremely large enhanced transmission, which has the advantage for a single subwavelength aperture. The spatial resolution for the bull’s eye structure (with an aperture diameter d=100 μm) is evaluated in the near-field region, and a resolution of 50 μm (corresponding to λ/4) is achieved. We obtain the THz near-field images of the subwavelength metal pattern with a spatial resolution below the diffraction limit.

Serotonin Activates Overall Feeding by Activating Two Separate Neural Pathways in Caenorhabditis elegans

PubMed Central

Song, Bo-mi; Avery, Leon

2012-01-01

Food intake in the nematode Caenorhabditis elegans requires two distinct feeding motions, pharyngeal pumping and isthmus peristalsis. Bacteria, the natural food of C. elegans, activate both feeding motions (Croll, 1978; Horvitz et al., 1982; Chiang et al., 2006). The mechanisms by which bacteria activate the feeding motions are largely unknown. To understand the process, we studied how serotonin, an endogenous pharyngeal pumping activator whose action is triggered by bacteria, activates feeding motions. Here, we show that serotonin, like bacteria, activates overall feeding by activating isthmus peristalsis as well as pharyngeal pumping. During active feeding, the frequencies and the timing of onset of the two motions were distinct, but each isthmus peristalsis was coupled to the preceding pump. We found that serotonin activates the two feeding motions mainly by activating two separate neural pathways in response to bacteria. For activating pumping, the SER-7 serotonin receptor in the MC motor neurons in the feeding organ activated cholinergic transmission from MC to the pharyngeal muscles by activating the Gsα signaling pathway. For activating isthmus peristalsis, SER-7 in the M4 (and possibly M2) motor neuron in the feeding organ activated the G12α signaling pathway in a cell-autonomous manner, which presumably activates neurotransmission from M4 to the pharyngeal muscles. Based on our results and previous calcium imaging of pharyngeal muscles (Shimozono et al., 2004), we propose a model that explains how the two feeding motions are separately regulated yet coupled. The feeding organ may have evolved this way to support efficient feeding. PMID:22323705

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

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 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

Selective labeling of serotonin receptors by d-[3H]lysergic acid diethylamide in calf caudate.

PubMed Central

Whitaker, P M; Seeman, P

1978-01-01

Since it was known that d-lysergic acid diethylamide (LSD) affected catecholaminergic as well as serotoninergic neurons, the objective in this study was to enhance the selectivity of [3H]LSD binding to serotonin receptors in vitro by using crude homogenates of calf caudate. In the presence of a combination of 50 nM each of phentolamine (added to preclude the binding of [3H]LSD to alpha-adrenoceptors), apomorphine, and spiperone (added to preclude the binding of [3H]LSD to dopamine receptors), it was found by Scatchard analysis that the total number of [3H]LSD sites went down to 300 fmol/mg, compared to 1100 fmol/mg in the absence of the catecholamine-blocking drugs. The IC50 values (concentrations to inhibit binding by 50%) for various drugs were tested on the binding of [3H]LSD in the presence of 50 nM each of apomorphine (A), phentolamine (P) and spiperone (S). With this combination, the IC50 for serotonin was 35 nM (compared to 1000 nM without it), indicating that [3H]LSD had become considerably more selectively displaceable by serotonin under these conditions whereas the effects of norepinephrine and dopamine on [3H]LSD binding were eliminated. Various ergots had approximately equal IC50 values against [3H]serotonin and [3H]LSD but tryptamines were much more selective against [3H]serotonin; the data may indicate the existence of the two types of serotonin receptors. PMID:32537

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

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)

Enhanced Optical Transmission Mediated by Localized Plasmons in Anisotropic, 3D Nanohole Arrays

PubMed Central

Yang, Jiun-Chan; Gao, Hanwei; Suh, Jae Yong; Zhou, Wei; Lee, Min Hyung; Odom, Teri W.

2010-01-01

This paper describes 3D nanohole arrays whose high optical transmission is mediated more by localized surface plasmon (LSP) excitations than by surface plasmon polaritons (SPPs). First, LSPs on 3D hole arrays lead to optical transmission an order of magnitude higher than 2D planar hole arrays. Second, LSP-mediated transmission is broadband and more tunable than SPP-enhanced transmission which is restricted by Bragg coupling. Third, for the first time, two types of surface plasmons can be selectively excited and manipulated on the same plasmonic substrate. This new plasmonic substrate fabricated by high-throughput nanolithography techniques paves the way for cutting-edge optoelectronic and biomedical applications. PMID:20698633

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

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.

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

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

Enhanced Wireless Power Transmission Using Strong Paramagnetic Response.

PubMed

Ahn, Dukju; Kiani, Mehdi; Ghovanloo, Maysam

2014-03-01

A method of quasi-static magnetic resonant coupling has been presented for improving the power transmission efficiency (PTE) in near-field wireless power transmission, which improves upon the state of the art. The traditional source resonator on the transmitter side is equipped with an additional resonator with a resonance frequency that is tuned substantially higher than the magnetic field excitation frequency. This additional resonator enhances the magnetic dipole moment and the effective permeability of the power transmitter, owing to a phenomenon known as the strong paramagnetic response. Both theoretical calculations and experimental results show increased PTE due to amplification of the effective permeability. In measurements, the PTE was improved from 57.8% to 64.2% at the nominal distance of 15 cm when the effective permeability was 2.6. The power delivered to load was also improved significantly, with the same 10 V excitation voltage, from 0.38 to 5.26 W.

Serotonin Test

MedlinePlus

... Cancer Therapy Glucose Tests Gonorrhea Testing Gram Stain Growth Hormone Haptoglobin hCG Pregnancy hCG Tumor Marker HDL Cholesterol ... Semen Analysis Serotonin Serum Free Light Chains Sex Hormone Binding Globulin ... Transferrin Receptor Stool Culture Stool Elastase Strep ...

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

Enhanced Heterosexual Transmission Hypothesis for the Origin of Pandemic HIV-1

PubMed Central

de Sousa, João Dinis; Alvarez, Carolina; Vandamme, Anne-Mieke; Müller, Viktor

2012-01-01

HIV-1 M originated from SIVcpz endemic in chimpanzees from southeast Cameroon or neighboring areas, and it started to spread in the early 20th century. Here we examine the factors that may have contributed to simian-to-human transmission, local transmission between humans, and export to a city. The region had intense ape hunting, social disruption, commercial sex work, STDs, and traffic to/from Kinshasa in the period 1899–1923. Injection treatments increased sharply around 1930; however, their frequency among local patients was far lower than among modern groups experiencing parenteral HIV-1 outbreaks. Recent molecular datings of HIV-1 M fit better the period of maximal resource exploitation and trade links than the period of high injection intensity. We conclude that although local parenteral outbreaks might have occurred, these are unlikely to have caused massive transmission. World War I led to additional, and hitherto unrecognized, risks of HIV-1 emergence. We propose an Enhanced Heterosexual Transmission Hypothesis for the origin of HIV-1 M, featuring at the time and place of its origin a coincidence of favorable co-factors (ape hunting, social disruption, STDs, and mobility) for both cross-species transmission and heterosexual spread. Our hypothesis does not exclude a role for parenteral transmission in the initial viral adaptation. PMID:23202448

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.

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.

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

Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment

PubMed Central

Muller, Christopher L; Anacker, Allison MJ; Rogers, Tiffany D; Goeden, Nick; Keller, Elizabeth H; Forsberg, C Gunnar; Kerr, Travis M; Wender, Carly LA; Anderson, George M; Stanwood, Gregg D; Blakely, Randy D; Bonnin, Alexandre; Veenstra-VanderWeele, Jeremy

2017-01-01

Biomarker, neuroimaging, and genetic findings implicate the serotonin transporter (SERT) in autism spectrum disorder (ASD). Previously, we found that adult male mice expressing the autism-associated SERT Ala56 variant have altered central serotonin (5-HT) system function, as well as elevated peripheral blood 5-HT levels. Early in gestation, before midbrain 5-HT projections have reached the cortex, peripheral sources supply 5-HT to the forebrain, suggesting that altered maternal or placenta 5-HT system function could impact the developing embryo. We therefore used different combinations of maternal and embryo SERT Ala56 genotypes to examine effects on blood, placenta and embryo serotonin levels and neurodevelopment at embryonic day E14.5, when peripheral sources of 5-HT predominate, and E18.5, when midbrain 5-HT projections have reached the forebrain. Maternal SERT Ala56 genotype was associated with decreased placenta and embryonic forebrain 5-HT levels at E14.5. Low 5-HT in the placenta persisted, but forebrain levels normalized by E18.5. Maternal SERT Ala56 genotype effects on forebrain 5-HT levels were accompanied by a broadening of 5-HT-sensitive thalamocortical axon projections. In contrast, no effect of embryo genotype was seen in concepti from heterozygous dams. Blood 5-HT levels were dynamic across pregnancy and were increased in SERT Ala56 dams at E14.5. Placenta RNA sequencing data at E14.5 indicated substantial impact of maternal SERT Ala56 genotype, with alterations in immune and metabolic-related pathways. Collectively, these findings indicate that maternal SERT function impacts offspring placental 5-HT levels, forebrain 5-HT levels, and neurodevelopment. PMID:27550733

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.

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

Structure-activity relationships for hallucinogenic N,N-dialkyltryptamines: photoelectron spectra and serotonin receptor affinities of methylthio and methylenedioxy derivatives

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

Kline, T.B.; Benington, F.; Morin, R.D.

1982-11-01

Serotonin receptor affinity and photelectron spectral data were obtained on a number of substituted N,N-dimethyltryptamines. Evidence is presented that electron-donating substituents in the 5-position lead to enhanced behavioral disruption activity and serotonin receptor affinity as compared to unsubstituted N,N-dimethyltryptamine and analogues substituted in the 4- or 6-position. Some correlation was found between ionization potentials and behavioral activity, which may have implications concerning the mechanism of receptor binding.

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.

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.

Glioblastoma chemotherapy adjunct via potent serotonin receptor-7 inhibition using currently marketed high-affinity antipsychotic medicines

PubMed Central

Kast, RE

2010-01-01

Glioblastoma treatment as now constituted offers increased survival measured in months over untreated patients. Because glioblastomas are active in synthesizing a bewildering variety of growth factors, a systematic approach to inhibiting these is being undertaken as treatment adjunct. The serotonin 7 receptor is commonly overexpressed in glioblastoma. Research documentation showing agonists at serotonin receptor 7 cause increased extracellular regulated kinase 1/2 activation, increased interleukin-6 synthesis, increased signal transducer and activator of transcription-3 activation, increased resistance to apoptosis and other growth enhancing changes in glioblastoma is reviewed in this paper. Because three drugs in wide use to treat thought disorders – paliperidone, pimozide and risperidone – are also potent and well-tolerated inhibitors at serotonin receptor 7, these drugs should be studied for growth factor deprivation in an adjunctive role in glioblastoma treatment. PMID:20880389

Using digital watermarking to enhance security in wireless medical image transmission.

PubMed

Giakoumaki, Aggeliki; Perakis, Konstantinos; Banitsas, Konstantinos; Giokas, Konstantinos; Tachakra, Sapal; Koutsouris, Dimitris

2010-04-01

During the last few years, wireless networks have been increasingly used both inside hospitals and in patients' homes to transmit medical information. In general, wireless networks suffer from decreased security. However, digital watermarking can be used to secure medical information. In this study, we focused on combining wireless transmission and digital watermarking technologies to better secure the transmission of medical images within and outside the hospital. We utilized an integrated system comprising the wireless network and the digital watermarking module to conduct a series of tests. The test results were evaluated by medical consultants. They concluded that the images suffered no visible quality degradation and maintained their diagnostic integrity. The proposed integrated system presented reasonable stability, and its performance was comparable to that of a fixed network. This system can enhance security during the transmission of medical images through a wireless channel.

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

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.

Site-specific activation of dopamine and serotonin transmission by aniracetam in the mesocorticolimbic pathway of rats.

PubMed

Nakamura, K; Shirane, M; Koshikawa, N

2001-04-06

The effects of aniracetam on extracellular levels of dopamine (DA), serotonin (5-HT) and their metabolites were examined in five brain regions in freely moving stroke-prone spontaneously hypertensive rats (SHRSP) using in vivo microdialysis. Basal DA release in SHRSP was uniformly lower in all regions tested than that in age-matched control Wistar Kyoto rats. 3,4-Dihydroxyphenylacetic acid and homovanillic acid levels were altered in the basolateral amygdala, dorsal hippocampus and prefrontal cortex of SHRSP. While basal 5-HT release decreased in the striatum and increased in the basolateral amygdala, there was no associated change in 5-hydroxyindoleacetic acid levels. Systemic administration of aniracetam to SHRSP enhanced both DA and 5-HT release with partly associated change in their metabolite levels in the prefrontal cortex, basolateral amygdala and dorsal hippocampus, but not in the striatum and nucleus accumbens shell, in a dose-dependent manner (30 and/or 100 mg/kg p.o.). Microinjection (1 and 10 ng) of aniracetam or its metabolites (N-anisoyl-GABA and 2-pyrrolidinone) into the nucleus accumbens shell produced no turning behavior. These findings indicate that SHRSP have a dopaminergic hypofunction throughout the brain and that aniracetam elicits a site-specific activation in mesocorticolimbic dopaminergic and serotonergic pathways in SHRSP, possibly via nicotinic acetylcholine receptors in the ventral tegmental area and raphe nuclei. The physiological roles in the aniracetam-sensitive brain regions may closely link with their clinical efficacy towards emotional disturbances appearing after cerebral infarction.

Involvement of Serotonin Transporter Gene Polymorphisms (5-HTT) in Impulsive Behavior in the Japanese Population

PubMed Central

Nomura, Michio; Kaneko, Masayuki; Okuma, Yasunobu; Nomura, Jun; Kusumi, Ichiro; Koyama, Tsukasa; Nomura, Yasuyuki

2015-01-01

The serotonergic pathway has been implicated in the pathogenesis of impulsivity, and sensitivity to aversive outcomes may be linked to serotonin (5-HT) levels. Polymorphisms in the gene that encodes the serotonin transporter (5-HTT), which have differential effects on the level of serotonin transmission, display alternate responses to aversive stimuli. However, recent studies have shown that 5-HT does not affect motor function, which suggests that the functioning of the serotonin-transporter-linked polymorphic region (5-HTTLPR) does not directly affect the behavioral regulatory process itself, but instead exerts an effect via the evaluation of the potential risk associated with particular behavioral outputs. The aim of the present study was to examine the effect of specific 5-HTTLPR genotypes on the motor regulatory process, as observed during a Go/Nogo punishment feedback task. 5-HTT gene-linked promoter polymorphisms were analyzed by polymerase chain reaction, using lymphocytes from 61 healthy Japanese volunteers. Impulsivity was defined as the number of commission errors (responding when one should not) made during a Go/Nogo task. We found that the s/s genotype group made fewer impulsive responses, specifically under aversive conditions for committing such errors, compared to those in the s/l group, without affecting overall motor inhibition. These results suggest that 5-HTTLPRs do not directly affect the behavioral regulatory process itself, but may instead exert an effect on the evaluation of potential risk. The results also indicate that under such aversive conditions, decreased expression of 5-HTT may promote motor inhibitory control. PMID:25775400

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.

Serotonin, carbohydrates, and atypical depression.

PubMed

Møller, S E

1992-01-01

At least three categories of atypical depression have been described. The hysteroid dysphoria is characterized by repeated episodes of depressed mood in response to feeling rejected, and a craving for sweets and chocolate. Two other issues are characterized by a cyclical occurrence of changes of mood and appetite, i.e., the late luteal phase dysphoric disorder (DSM-III-R, appendix), or "the premenstrual syndrome" (PMS), and the major depression with seasonal pattern (DSM-III-R), or seasonal affective disorder (SAD). The reactive mood changes are frequently accompanied by features as hypersomnia, lethargy and increased appetite, particularly with a preference for carbohydrates. Central serotonin pathways participate in the regulation of mood and behavioural impulsivity, and modulate eating patterns qualitatively and quantitatively. Depressives with PMS og SAD benefit, in general, from treatments with serotonin potentiating drugs, suggesting that brain serotonin plays a role in the pathophysiology. Ingestion of carbohydrates increases the plasma ratio of tryptophan to other large neutral amino acids in man and animal, and the serotonin synthesis in the rat brain. Based on these findings it has been suggested that the excessive carbohydrate intake by patients with PMS and SAD reflects a self-medication that temporarily relieves the vegetative symptoms via an increased central serotonergic activity.

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.

Minocycline enhances inhibitory transmission to substantia gelatinosa neurons of the rat spinal dorsal horn.

PubMed

Peng, H-Z; Ma, L-X; Lv, M-H; Hu, T; Liu, T

2016-04-05

Minocycline, a second-generation tetracycline, is well known for its antibiotic, anti-inflammatory, and antinociceptive effects. Modulation of synaptic transmission is one of the analgesic mechanisms of minocycline. Although it has been reported that minocycline may suppress excitatory glutamatergic synaptic transmission, it remains unclear whether it could affect inhibitory synaptic transmission, which also plays a key role in modulating pain signaling. To examine the effect of minocycline on synaptic transmission in rat spinal substantia gelatinosa (SG) neurons, we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) using whole-cell patch-clamp recording at a holding potential of 0 mV. Bath application of minocycline significantly increased the frequency but not the amplitude of sIPSCs in a reversible and concentration-dependent manner with an EC50 of 85. The enhancement of inhibitory synaptic transmission produced by minocycline was not affected by the glutamate receptor antagonists CNQX and D-APV or by the voltage-gated sodium channel blocker tetrodotoxin (TTX). Moreover, the potency of minocycline for facilitating sIPSC frequency was the same in both glycinergic and GABAergic sIPSCs without changing their decay phases. However, the facilitatory effect of minocycline on sIPSCs was eliminated in a Ca(2+)-free Krebs solution or by co-administration with calcium channel blockers. In summary, our data demonstrate that baseline inhibitory synaptic transmission in SG neurons is markedly enhanced by minocycline. This may function to decrease the excitability of SG neurons, thus leading to a modulation of nociceptive transmission. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Neither Serotonin nor Adenosine-dependent Mechanisms Preserve Ventilatory Capacity in ALS rats

PubMed Central

Nichols, N.L.; Johnson, R.A.; Satriotomo, I.; Mitchell, G.S.

2014-01-01

In rats over-expressing SOD1G93A, ventilation is preserved despite significant loss of respiratory motor neurons. Thus, unknown forms of compensatory respiratory plasticity may offset respiratory motor neuron cell death. Although mechanisms of such compensation are unknown, other models of respiratory motor plasticity may provide a conceptual guide. Multiple cellular mechanisms give rise to phrenic motor facilitation; one mechanism requires spinal serotonin receptor and NADPH oxidase activity whereas another requires spinal adenosine receptor activation. Here, we studied whether these mechanisms contribute to compensatory respiratory plasticity in SOD1G93A rats. Using plethysmography, we assessed ventilation in end-stage SOD1G93A rats after: 1) serotonin depletion with parachlorophenylalanine (PCPA), 2) serotonin (methysergide) and A2A (MSX-3) receptor inhibition, 3) NADPH oxidase inhibition (apocynin), and 4) combined treatments. The ability to increase ventilation was not decreased by individual or combined treatments; thus, these mechanisms do not maintain breathing capacity at end-stage motor neuron disease. Possible mechanisms giving rise to enhanced breathing capacity with combined treatment in end-stage SOD1G93A rats are discussed. PMID:24681328

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.

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

Water deficit enhances the transmission of plant viruses by insect vectors

PubMed Central

Yvon, Michel; Vile, Denis; Dader, Beatriz; Fereres, Alberto

2017-01-01

Drought is a major threat to crop production worldwide and is accentuated by global warming. Plant responses to this abiotic stress involve physiological changes overlapping, at least partially, the defense pathways elicited both by viruses and their herbivore vectors. Recently, a number of theoretical and empirical studies anticipated the influence of climate changes on vector-borne viruses of plants and animals, mainly addressing the effects on the virus itself or on the vector population dynamics, and inferring possible consequences on virus transmission. Here, we directly assess the effect of a severe water deficit on the efficiency of aphid-transmission of the Cauliflower mosaic virus (CaMV) or the Turnip mosaic virus (TuMV). For both viruses, our results demonstrate that the rate of vector-transmission is significantly increased from water-deprived source plants: CaMV transmission reproducibly increased by 34% and that of TuMV by 100%. In both cases, the enhanced transmission rate could not be explained by a higher virus accumulation, suggesting a more complex drought-induced process that remains to be elucidated. The evidence that infected plants subjected to drought are much better virus sources for insect vectors may have extensive consequences for viral epidemiology, and should be investigated in a wide range of plant-virus-vector systems. PMID:28467423

Water deficit enhances the transmission of plant viruses by insect vectors.

PubMed

van Munster, Manuella; Yvon, Michel; Vile, Denis; Dader, Beatriz; Fereres, Alberto; Blanc, Stéphane

2017-01-01

Drought is a major threat to crop production worldwide and is accentuated by global warming. Plant responses to this abiotic stress involve physiological changes overlapping, at least partially, the defense pathways elicited both by viruses and their herbivore vectors. Recently, a number of theoretical and empirical studies anticipated the influence of climate changes on vector-borne viruses of plants and animals, mainly addressing the effects on the virus itself or on the vector population dynamics, and inferring possible consequences on virus transmission. Here, we directly assess the effect of a severe water deficit on the efficiency of aphid-transmission of the Cauliflower mosaic virus (CaMV) or the Turnip mosaic virus (TuMV). For both viruses, our results demonstrate that the rate of vector-transmission is significantly increased from water-deprived source plants: CaMV transmission reproducibly increased by 34% and that of TuMV by 100%. In both cases, the enhanced transmission rate could not be explained by a higher virus accumulation, suggesting a more complex drought-induced process that remains to be elucidated. The evidence that infected plants subjected to drought are much better virus sources for insect vectors may have extensive consequences for viral epidemiology, and should be investigated in a wide range of plant-virus-vector systems.

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.

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.

Enhancement of the Laser Transmission Weldability between Polyethylene and Polyoxymethylene by Plasma Surface Treatment

PubMed Central

Tan, Wensheng; Wang, Xiao

2017-01-01

Due to their large compatibility difference, polyethylene (PE) and polyoxymethylene (POM) cannot be welded together by laser transmission welding. In this study, PE and POM are pretreated using plasma that significantly enhances their laser transmission welding strength. To understand the mechanism underlying the laser welding strength enhancement, surface modification is analyzed using contact angle measurements, atomic force microscopy (AFM), optical microscopy, and X-ray photoelectron spectroscopy (XPS). Characterization results show that the plasma surface treatment improves the surface free energy, significantly enhancing the wettability of the materials. The increase in surface roughness and the generation of homogeneous bubbles contribute to the formation of mechanical micro-interlocking. The oxygen-containing groups introduced by the oxygen plasma treatment improve the compatibility of PE and POM, and facilitate the diffusion and entanglement of molecular chains and the formation of van der Waals force. PMID:29278367

Enhancement of the Laser Transmission Weldability between Polyethylene and Polyoxymethylene by Plasma Surface Treatment.

PubMed

Liu, Huixia; Jiang, Yingjie; Tan, Wensheng; Wang, Xiao

2017-12-26

Due to their large compatibility difference, polyethylene (PE) and polyoxymethylene (POM) cannot be welded together by laser transmission welding. In this study, PE and POM are pretreated using plasma that significantly enhances their laser transmission welding strength. To understand the mechanism underlying the laser welding strength enhancement, surface modification is analyzed using contact angle measurements, atomic force microscopy (AFM), optical microscopy, and X-ray photoelectron spectroscopy (XPS). Characterization results show that the plasma surface treatment improves the surface free energy, significantly enhancing the wettability of the materials. The increase in surface roughness and the generation of homogeneous bubbles contribute to the formation of mechanical micro-interlocking. The oxygen-containing groups introduced by the oxygen plasma treatment improve the compatibility of PE and POM, and facilitate the diffusion and entanglement of molecular chains and the formation of van der Waals force.

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

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.

Tadalafil reversal of sexual dysfunction caused by serotonin enhancing medications in women.

PubMed

Ashton, Adam Keller; Weinstein, Wendy

2006-01-01

Sexual dysfunction is a common side effect of many antidepressants, especially those that increase serotonin. Many strategies have been reported to assist patients in minimizing impairment, with variable degrees of success. One of the newer approaches is to augment with phosphodiesterase type-5 inhibitors. Our report using the most recently released agent in this class, tadalafil is the first demonstrating potential benefit in women. We report here of three women who derived benefit from using 20 mg of tadalafil before anticipated sexual activity to reverse medication-induced sexual dysfunction. Tadalafil utility was maintained over time and was well tolerated.

Escherichia coli Nissle 1917 enhances bioavailability of serotonin in gut tissues through modulation of synthesis and clearance

PubMed Central

Nzakizwanayo, Jonathan; Dedi, Cinzia; Standen, Guy; Macfarlane, Wendy M.; Patel, Bhavik A.; Jones, Brian V.

2015-01-01

Accumulating evidence shows indigenous gut microbes can interact with the human host through modulation of serotonin (5-HT) signaling. Here we investigate the impact of the probiotic Escherichia coli Nissle 1917 (EcN) on 5-HT signalling in gut tissues. Ex-vivo mouse ileal tissue sections were treated with either EcN or the human gut commensal MG1655, and effects on levels of 5-HT, precursors, and metabolites, were evaluated using amperometry and high performance liquid chromatography with electrochemical detection (HPLC-EC). Exposure of tissue to EcN cells, but not MG1655 cells, was found to increase levels of extra-cellular 5-HT. These effects were not observed when tissues were treated with cell-free supernatant from bacterial cultures. In contrast, when supernatant recovered from untreated ileal tissue was pre-incubated with EcN, the derivative cell-free supernatant was able to elevate 5-HT overflow when used to treat fresh ileal tissue. Measurement of 5-HT precursors and metabolites indicated EcN also increases intracellular 5-HTP and reduces 5-HIAA. The former pointed to modulation of tryptophan hydroxylase-1 to enhance 5-HT synthesis, while the latter indicates an impact on clearance into enterocytes through SERT. Taken together, these findings show EcN is able to enhance 5-HT bioavailability in ileal tissues through interaction with compounds secreted from host tissues. PMID:26616662

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 and Blood Pressure Regulation

PubMed Central

Morrison, Shaun F.; Davis, Robert Patrick; Barman, Susan M.

2012-01-01

5-Hydroxytryptamine (5-HT; serotonin) was discovered more than 60 years ago as a substance isolated from blood. The neural effects of 5-HT have been well investigated and understood, thanks in part to the pharmacological tools available to dissect the serotonergic system and the development of the frequently prescribed selective serotonin-reuptake inhibitors. By contrast, our understanding of the role of 5-HT in the control and modification of blood pressure pales in comparison. Here we focus on the role of 5-HT in systemic blood pressure control. This review provides an in-depth study of the function and pharmacology of 5-HT in those tissues that can modify blood pressure (blood, vasculature, heart, adrenal gland, kidney, brain), with a focus on the autonomic nervous system that includes mechanisms of action and pharmacology of 5-HT within each system. We compare the change in blood pressure produced in different species by short- and long-term administration of 5-HT or selective serotonin receptor agonists. To further our understanding of the mechanisms through which 5-HT modifies blood pressure, we also describe the blood pressure effects of commonly used drugs that modify the actions of 5-HT. The pharmacology and physiological actions of 5-HT in modifying blood pressure are important, given its involvement in circulatory shock, orthostatic hypotension, serotonin syndrome and hypertension. PMID:22407614

[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.

Recent Enhancements to the NASA Langley Structural Acoustics Loads and Transmission (SALT) Facility

NASA Technical Reports Server (NTRS)

Rizzi, Stephen A.; Cabell, Randolph H.; Allen, Albert R.

2013-01-01

The Structural Acoustics Loads and Transmission (SALT) facility at the NASA Langley Research Center is comprised of an anechoic room and a reverberant room, and may act as a transmission loss suite when test articles are mounted in a window connecting the two rooms. In the latter configuration, the reverberant room acts as the noise source side and the anechoic room as the receiver side. The noise generation system used for qualification testing in the reverberant room was previously shown to achieve a maximum overall sound pressure level of 141 dB. This is considered to be marginally adequate for generating sound pressure levels typically required for launch vehicle payload qualification testing. Recent enhancements to the noise generation system increased the maximum overall sound pressure level to 154 dB, through the use of two airstream modulators coupled to 35 Hz and 160 Hz horns. This paper documents the acoustic performance of the enhanced noise generation system for a variety of relevant test spectra. Additionally, it demonstrates the capability of the SALT facility to conduct transmission loss and absorption testing in accordance with ASTM and ISO standards, respectively. A few examples of test capabilities are shown and include transmission loss testing of simple unstiffened and built up structures and measurement of the diffuse field absorption coefficient of a fibrous acoustic blanket.

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

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

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

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

Encapsulation of serotonin in β-cyclodextrin nano-cavities: Fluorescence spectroscopic and molecular modeling studies

NASA Astrophysics Data System (ADS)

Chaudhuri, Sudip; Chakraborty, Sandipan; Sengupta, Pradeep K.

2010-06-01

Serotonin is a physiologically important biogenic amine, deficiency of which leads to mental disorders such as Alzheimer's disease, schizophrenia, infantile autism, and depression. Both β-cyclodextrin (β-CD) and its chemically substituted synthetic varieties (often possessing enhanced aqueous solubility and improved drug complexing abilities) are finding wide applications as drug delivery vehicles. Here we have studied the encapsulation of serotonin in β-CD and succinyl-2-hydroxypropyl β-cyclodextrin (SHP-β-CD) by exploiting the intrinsic serotonin fluorescence. Enhanced fluorescence emission intensity (which increases by ˜18% and 34% in β-CD and SHPβ-CD respectively) and anisotropy ( r) ( r = 0.075 and 0.1 in β-CD and SHPβ-CD respectively) are observed in presence of the cyclodextrins. From the fluorescence data host-guest interaction with 1:1 stoichiometry is evident, the association constants ( K) being 126.06 M -1 and 461.62 M -1 for β-CD and SHPβ-CD respectively. Additionally, molecular docking and semiempirical calculations have been carried out which provide, for the first time, detailed insights regarding the encapsulation process. In particular, it is evident that the indole ring is inserted within the β-CD cavity with the aliphatic amine side chain protruding towards the primary rim of the β-CD cavity. Docking calculations reveal that hydrogen bonding interactions are involved in the formation of the inclusion complex. Semiempirical calculations indicate that formation of the 1:1 inclusion complex is energetically favorable which is consistent with the fluorescence data.

Serotonin storage pools in basophil leukemia and mast cells: characterization of two types of serotonin binding protein and radioautographic analysis of the intracellular distribution of (/sup 3/H)serotonin

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

Tamir, H.; Theoharides, T.C.; Gershon, M.D.

1982-06-01

The binding of serotonin to protein(s) derived from rat basophil leukemia (RBL) cells and mast cells was studied. Two types of serotonin binding protein in RBL cells was found. These proteins differed from one another in molecular weight and eluted in separate peaks from sephadex G-200 columns. Peak I protein (KD = 1.9 x 10/sup -6/ M) was a glycoprotein that bound to concanavalin A (Con A); Peak II protein (KD/sub 1/ = 4.5 x 10/sup -/8 M; KD/sub 2/ = 3.9 x 10/sup -6/ M) did not bind to Con A. Moreover, binding of (/sup 3/H)serotonin to protein ofmore » Peak I was sensitive to inhibition by reserpine, while binding of (/sup 3/H)serotonin to protein of Peak II resisted inhibition by that drug. Other differences between the two types of binding protein were found, the most significant of which was the far more vigorous conditions of homogenization required to extract Peak I than Peak II protein. Electron microscope radioautographic analysis of the intracellular distribution of (/sup 3/H) serotonin taken up in vitro by RBL cells or in vivo by murine mast cells indicated that essentially all of the labeled amine was located in cytoplasmic granules.No evidence for a pool in the cytosol was found and all granules were capable of becoming labeled. The presence of two types of intracellular serotonin binding proteins in these cells may indicate that there are two intracellular storage compartments for the amine. Both may be intragranular, but Peak I protein may be associated with the granular membrane while Peak II protein may be more free within the granular core. Different storage proteins may help to explain the differential release of amines from mast cell granules.« 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

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

Serotonin synthesis rate and the tryptophan hydroxylase-2: G-703T polymorphism in social anxiety disorder.

PubMed

Furmark, Tomas; Marteinsdottir, Ina; Frick, Andreas; Heurling, Kerstin; Tillfors, Maria; Appel, Lieuwe; Antoni, Gunnar; Hartvig, Per; Fischer, Håkan; Långström, Bengt; Eriksson, Elias; Fredrikson, Mats

2016-10-01

It is disputed whether anxiety disorders, like social anxiety disorder, are characterized by serotonin over- or underactivity. Here, we evaluated whether our recent finding of elevated neural serotonin synthesis rate in patients with social anxiety disorder could be reproduced in a separate cohort, and whether allelic variation in the tryptophan hydroxylase-2 (TPH2) G-703T polymorphism relates to differences in serotonin synthesis assessed with positron emission tomography. Eighteen social anxiety disorder patients and six healthy controls were scanned during 60 minutes in a resting state using positron emission tomography and 5-hydroxy-L-[β -(11)C]tryptophan, [(11)C]5-HTP, a substrate of the second enzymatic step in serotonin synthesis. Parametric images were generated, using the reference Patlak method, and analysed using Statistical Parametric Mapping (SPM8). Blood samples for genotyping of the TPH2 G-703T polymorphism were obtained from 16 social anxiety disorder patients (T carriers: n=5, GG carriers: n=11). A significantly elevated [(11)C]5-HTP accumulation rate, indicative of enhanced decarboxylase activity and thereby serotonin synthesis capacity, was detected in social anxiety disorder patients compared with controls in the hippocampus and basal ganglia nuclei and, at a more lenient (uncorrected) statistical threshold, in the amygdala and anterior cingulate cortex. In patients, the serotonin synthesis rate in the amygdala and anterior cingulate cortex was significantly elevated in TPH2 T carriers in comparison with GG homozygotes. Our results support that social anxiety disorder entails an overactive presynaptic serotonergic system that, in turn, seems functionally influenced by the TPH2 G-703T polymorphism in emotionally relevant brain regions. © The Author(s) 2016.

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

5-HT2C receptors in the BNST are necessary for the enhancement of fear learning by selective serotonin reuptake inhibitors.

PubMed

Pelrine, Eliza; Pasik, Sara Diana; Bayat, Leyla; Goldschmiedt, Debora; Bauer, Elizabeth P

2016-12-01

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed to treat anxiety and depression, yet they paradoxically increase anxiety during initial treatment. Acute administration of these drugs prior to learning can also enhance Pavlovian cued fear conditioning. This potentiation has been previously reported to depend upon the bed nucleus of the stria terminalis (BNST). Here, using temporary inactivation, we confirmed that the BNST is not necessary for the acquisition of cued or contextual fear memory. Systemic administration of the SSRI citalopram prior to fear conditioning led to an upregulation of the immediate early gene Arc (activity-regulated cytoskeleton-associated protein) in the oval nucleus of the BNST, and a majority of these neurons expressed the 5-HT2C receptor. Finally, local infusions of a 5-HT2C receptor antagonist directly into the oval nucleus of the BNST prevented the fear memory-enhancing effects of citalopram. These findings highlight the ability of the BNST circuitry to be recruited into gating fear and anxiety-like behaviors. Copyright © 2016 Elsevier Inc. All rights reserved.

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

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

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

Enhanced and reduced transmission of acoustic waves with bubble meta-screens

NASA Astrophysics Data System (ADS)

Bretagne, Alice; Tourin, Arnaud; Leroy, Valentin

2011-11-01

We present a class of sonic meta-screens for manipulating air-borne acoustic waves at ultrasonic or audible frequencies. Our screens consist of periodic arrangements of air bubbles in water or possibly embedded in a soft elastic matrix. They can be used for soundproofing but also for exalting transmission at an air/water interface or even to achieve enhanced absorption.

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 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.

Serotonergic transmission at Merkel discs: modulation by exogenously applied chemical messengers and involvement of Ih currents.

PubMed

Chang, Weipang; Kanda, Hirosato; Ikeda, Ryo; Ling, Jennifer; Gu, Jianguo G

2017-05-01

The Merkel disc is a main type of tactile end organ consisting of Merkel cells and Aβ-afferent endings that responds to tactile stimulation with slowly adapting type 1 (SA1) afferent impulses. Our recent study has shown that Merkel discs in whisker hair follicles are serotonergic synapses using endogenous serotonin to transmit tactile signals from Merkel cells to Aβ-afferent endings. In this study, we hypothesize that tactile sensitivity of Merkel discs can be modulated by chemical messengers. We tested this hypothesis by determining whether and how SA1 responses of mouse whisker hair follicles may be affected by exogenously applied chemical messengers. We found that SA1 responses were potentiated by serotonin at low concentration (10 μM) but almost completely occluded by serotonin at high concentration (2 mM). In contrast, SA1 responses were not significantly affected by ATP and its metabolically stable analog α,β-methylene-ATP, glutamate, γ-aminobutyric acid (GABA), and histamine. SA1 responses were also not affected by antagonists for P2X receptors, ionotropic glutamate receptors, and ionotropic GABA and glycine receptors. Whole-cell patch-clamp recordings reconfirm the presence of both ionotropic and metabotropic 5-HT receptors on afferent neurons and their terminals innervating whisker hair follicles. All whisker afferent neurons expressed hyperpolarization-activated inward currents (I h ), which are potentiated by serotonin through the activation of metabotropic 5-HT receptors. Taken together, the findings substantiate the serotonergic mechanism of tactile transmission at Merkel discs and identify the involvement of I h currents in postsynaptic excitatory actions of serotonin. In addition, the findings do not favor any significant involvement of ATP, glutamate, histamine, GABA, or glycine in tactile transmission at the Merkel discs of whisker hair follicles. © 2017 International Society for Neurochemistry.

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…

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.

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

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

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

Selective serotonin reuptake inhibitors and adverse pregnancy outcomes.

PubMed

Wen, Shi Wu; Yang, Qiuying; Garner, Peter; Fraser, William; Olatunbosun, Olufemi; Nimrod, Carl; Walker, Mark

2006-04-01

The purpose of this study was to assess the safety of the use of selective serotonin reuptake inhibitors in pregnancy. We carried out a retrospective cohort study of 972 pregnant women who had been given at least 1 selective serotonin reuptake inhibitor prescription in the year before delivery and 3878 pregnant women who did not receive selective serotonin reuptake inhibitors and who were matched by the year of the infant's birth, the type of institute at birth, and the mother's postal code from 1990 to 2000 in the Canadian province of Saskatchewan. The risks of low birth weight (adjusted odds ratio, 1.58; 95% CI, 1.19, 2.11), preterm birth (adjusted odds ratio, 1.57; 95% CI, 1.28, 1.92), fetal death (adjusted odds ratio, 2.23; 95% CI, 1.01, 4.93), and seizures (adjusted odds ratio, 3.87; 95% CI, 1.00, 14.99) were increased in infants who were born to mothers who had received selective serotonin reuptake inhibitor therapy. The use of selective serotonin reuptake inhibitors in pregnancy may increase the risks of low birth weight, preterm birth, fetal death, and seizures.

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

Honesty mediates the relationship between serotonin and reaction to unfairness

PubMed Central

Takahashi, Hidehiko; Takano, Harumasa; Camerer, Colin F.; Ideno, Takashi; Okubo, Shigetaka; Matsui, Hiroshi; Tamari, Yuki; Takemura, Kazuhisa; Arakawa, Ryosuke; Kodaka, Fumitoshi; Yamada, Makiko; Eguchi, Yoko; Murai, Toshiya; Okubo, Yoshiro; Kato, Motoichiro; Ito, Hiroshi; Suhara, Tetsuya

2012-01-01

How does one deal with unfair behaviors? This subject has long been investigated by various disciplines including philosophy, psychology, economics, and biology. However, our reactions to unfairness differ from one individual to another. Experimental economics studies using the ultimatum game (UG), in which players must decide whether to accept or reject fair or unfair offers, have also shown that there are substantial individual differences in reaction to unfairness. However, little is known about psychological as well as neurobiological mechanisms of this observation. We combined a molecular imaging technique, an economics game, and a personality inventory to elucidate the neurobiological mechanism of heterogeneous reactions to unfairness. Contrary to the common belief that aggressive personalities (impulsivity or hostility) are related to the high rejection rate of unfair offers in UG, we found that individuals with apparently peaceful personalities (straightforwardness and trust) rejected more often and were engaged in personally costly forms of retaliation. Furthermore, individuals with a low level of serotonin transporters in the dorsal raphe nucleus (DRN) are honest and trustful, and thus cannot tolerate unfairness, being candid in expressing their frustrations. In other words, higher central serotonin transmission might allow us to behave adroitly and opportunistically, being good at playing games while pursuing self-interest. We provide unique neurobiological evidence to account for individual differences of reaction to unfairness. PMID:22371595

Honesty mediates the relationship between serotonin and reaction to unfairness.

PubMed

Takahashi, Hidehiko; Takano, Harumasa; Camerer, Colin F; Ideno, Takashi; Okubo, Shigetaka; Matsui, Hiroshi; Tamari, Yuki; Takemura, Kazuhisa; Arakawa, Ryosuke; Kodaka, Fumitoshi; Yamada, Makiko; Eguchi, Yoko; Murai, Toshiya; Okubo, Yoshiro; Kato, Motoichiro; Ito, Hiroshi; Suhara, Tetsuya

2012-03-13

How does one deal with unfair behaviors? This subject has long been investigated by various disciplines including philosophy, psychology, economics, and biology. However, our reactions to unfairness differ from one individual to another. Experimental economics studies using the ultimatum game (UG), in which players must decide whether to accept or reject fair or unfair offers, have also shown that there are substantial individual differences in reaction to unfairness. However, little is known about psychological as well as neurobiological mechanisms of this observation. We combined a molecular imaging technique, an economics game, and a personality inventory to elucidate the neurobiological mechanism of heterogeneous reactions to unfairness. Contrary to the common belief that aggressive personalities (impulsivity or hostility) are related to the high rejection rate of unfair offers in UG, we found that individuals with apparently peaceful personalities (straightforwardness and trust) rejected more often and were engaged in personally costly forms of retaliation. Furthermore, individuals with a low level of serotonin transporters in the dorsal raphe nucleus (DRN) are honest and trustful, and thus cannot tolerate unfairness, being candid in expressing their frustrations. In other words, higher central serotonin transmission might allow us to behave adroitly and opportunistically, being good at playing games while pursuing self-interest. We provide unique neurobiological evidence to account for individual differences of reaction to unfairness.

Serotonin precursor (5-hydroxytryptophan) causes substantial changes in the fighting behavior of male crickets, Gryllus bimaculatus.

PubMed

Dyakonova, V E; Krushinsky, A L

2013-07-01

This study demonstrates that injection of the serotonin precursor 5-HTP causes substantial changes in the behavioral state, fighting behavior and ability to establish winner-loser relationships in male crickets (Gryllus bimaculatus). The characteristic features of 5-HTP-treated crickets include an elevated posture, enhanced general activity, longer duration of fighting, enhanced rival singing and a decreased ability to produce a clear fight loser. In addition, 5-HTP-treated males showed a slightly delayed latency to spread their mandibles, a decreased number of attacks and an equal potential to win in comparison to controls (physiological solution-treated males). The obtained results imply a significant role for serotonin in the regulation of social status-related behaviors in G. bimaculatus. Specifically, these data indicate that a decrease in serotonergic activity may be functionally important for the control of loser behavior and that some behavioral features of dominant male crickets are likely to be connected with the activation of the serotonergic system.

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.

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

Two-Stage Design Method for Enhanced Inductive Energy Transmission with Q-Constrained Planar Square Loops.

PubMed

Eteng, Akaa Agbaeze; Abdul Rahim, Sharul Kamal; Leow, Chee Yen; Chew, Beng Wah; Vandenbosch, Guy A E

2016-01-01

Q-factor constraints are usually imposed on conductor loops employed as proximity range High Frequency Radio Frequency Identification (HF-RFID) reader antennas to ensure adequate data bandwidth. However, pairing such low Q-factor loops in inductive energy transmission links restricts the link transmission performance. The contribution of this paper is to assess the improvement that is reached with a two-stage design method, concerning the transmission performance of a planar square loop relative to an initial design, without compromise to a Q-factor constraint. The first stage of the synthesis flow is analytical in approach, and determines the number and spacing of turns by which coupling between similar paired square loops can be enhanced with low deviation from the Q-factor limit presented by an initial design. The second stage applies full-wave electromagnetic simulations to determine more appropriate turn spacing and widths to match the Q-factor constraint, and achieve improved coupling relative to the initial design. Evaluating the design method in a test scenario yielded a more than 5% increase in link transmission efficiency, as well as an improvement in the link fractional bandwidth by more than 3%, without violating the loop Q-factor limit. These transmission performance enhancements are indicative of a potential for modifying proximity HF-RFID reader antennas for efficient inductive energy transfer and data telemetry links.

Enhanced Transmissions Through Three-dimensional Cascade Sharp Waveguide Bends Using C-slit Diaphragms.

PubMed

Yang, Rui; Hu, Bowei; Zhang, Aofang; Gao, Dongxing; Wang, Hui; Shi, Ayuan; Lei, Zhenya; Yang, Pei

2017-03-21

Transmission properties through sharp rectangular waveguide bends are investigated to determine the cut-off bending angles of the wave propagation. We show that a simple metallic diaphragm at the bending corner with properly devised sub-wavelength defect apertures of C-slits would be readily to turn on the transmissions with scarce reflections of the propagating modes, while preserving the integrity of the transmitting fields soon after the bends. In particularly, our design also demonstrates the capability of eliminating all the unwanted cavity resonant transmissions that exist in the three-dimensional cascade sharp waveguide bends, and solely let the desired signals travel along the whole passage of the waveguide. The present approach, using C-slit diaphragms to support the sharp bending behaviors of the guided waves with greatly enhanced transmissions, would be especially effective in constructing novel waveguides and pave the way for the development of more compact and miniaturized electromagnetic systems that exploit these waveguide bends.

Dopamine and serotonin: influences on male sexual behavior.

PubMed

Hull, Elaine M; Muschamp, John W; Sato, Satoru

2004-11-15

Steroid hormones regulate sexual behavior primarily by slow, genomically mediated effects. These effects are realized, in part, by enhancing the processing of relevant sensory stimuli, altering the synthesis, release, and/or receptors for neurotransmitters in integrative areas, and increasing the responsiveness of appropriate motor outputs. Dopamine has facilitative effects on sexual motivation, copulatory proficiency, and genital reflexes. Dopamine in the nigrostriatal tract influences motor activity; in the mesolimbic tract it activates numerous motivated behaviors, including copulation; in the medial preoptic area (MPOA) it controls genital reflexes, copulatory patterns, and specifically sexual motivation. Testosterone increases nitric oxide synthase in the MPOA; nitric oxide increases basal and female-stimulated dopamine release, which in turn facilitates copulation and genital reflexes. Serotonin (5-HT) is primarily inhibitory, although stimulation of 5-HT(2C) receptors increases erections and inhibits ejaculation, whereas stimulation of 5-HT(1A) receptors has the opposite effects: facilitation of ejaculation and, in some circumstances, inhibition of erection. 5-HT is released in the anterior lateral hypothalamus at the time of ejaculation. Microinjections of selective serotonin reuptake inhibitors there delay the onset of copulation and delay ejaculation after copulation begins. One means for this inhibition is a decrease in dopamine release in the mesolimbic tract.

Plasma serotonin in patients with chronic tension headaches.

PubMed

Anthony, M; Lance, J W

1989-02-01

Previous reports have suggested that platelet level of serotonin in chronic tension headache (CTH) is lower than in normal control subjects, and that there is continuous activation of platelets both in migraine and in CTH. In this study we compared platelet serotonin concentration in 95 patients with CTH, 166 patients with migraine and 35 normal control subjects. Mean platelet serotonin (ng/10(9) platelets) was 310 for the CTH group, 384 during migraine headache, 474 for normal control subjects and 514 in headache-free migrainous patients. There was significant statistical difference of values between CTH patients and those of normal control subjects as well as headache-free migrainous patients, but not of those of migrainous patients during headache. It is suggested that CTH is a low serotonin syndrome, representing one end of the spectrum of idiopathic headache, the other end being represented by migraine.

Neurochemical characterization of sea lamprey taste buds and afferent gustatory fibers: presence of serotonin, calretinin, and CGRP immunoreactivity in taste bud bi-ciliated cells of the earliest vertebrates.

PubMed

Barreiro-Iglesias, Antón; Villar-Cerviño, Verona; Villar-Cheda, Begoña; Anadón, Ramón; Rodicio, María Celina

2008-12-01

Neuroactive substances such as serotonin and other monoamines have been suggested to be involved in the transmission of gustatory signals from taste bud cells to afferent fibers. Lampreys are the earliest vertebrates that possess taste buds, although these differ in structure from taste buds in jawed vertebrates, and their neurochemistry remains unknown. We used immunofluorescence methods with antibodies raised against serotonin, tyrosine hydroxylase (TH), gamma-aminobutyric acid (GABA), glutamate, calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), calretinin, and acetylated alpha-tubulin to characterize the neurochemistry and innervation of taste buds in the sea lamprey, Petromyzon marinus L. For localization of proliferative cells in taste buds we used bromodeoxyuridine labeling and proliferating cell nuclear antigen immunohistochemistry. Results with both markers indicate that proliferating cells are restricted to a few basal cells and that almost all cells in taste buds are nonproliferating. A large number of serotonin-, calretinin-, and CGRP-immunoreactive bi-ciliated cells were revealed in lamprey taste buds. This suggests that serotonin participates in the transmission of gustatory signals and indicates that this substance appeared early on in vertebrate evolution. The basal surface of the bi-ciliated taste bud cells was contacted by tubulin-immunoreactive fibers. Some of the fibers surrounding the taste bud were calretinin immunoreactive. Lamprey taste bud cells or afferent fibers did not exhibit TH, GABA, glutamate, or NPY immunoreactivity, which suggests that expression of these substances evolved in taste buds of some gnathostomes lines after the separation of gnathostomes and lampreys. (c) 2008 Wiley-Liss, Inc.

Serotonin disrupts esophageal mucosal integrity: an investigation using a stratified squamous epithelial model.

PubMed

Wu, Liping; Oshima, Tadayuki; Tomita, Toshihiko; Ohda, Yoshio; Fukui, Hirokazu; Watari, Jiro; Miwa, Hiroto

2016-11-01

Serotonin regulates gastrointestinal function, and mast cells are a potential nonneuronal source of serotonin in the esophagus. Tight junction (TJ) proteins in the esophageal epithelium contribute to the barrier function, and the serotonin signaling pathway may contribute to epithelial leakage in gastroesophageal reflux disease. Therefore, the aim of this study was to investigate the role of serotonin on barrier function, TJ proteins, and related signaling pathways. Normal primary human esophageal epithelial cells were cultured with use of an air-liquid interface system. Serotonin was added to the basolateral compartment, and transepithelial electrical resistance (TEER) was measured. The expression of TJ proteins and serotonin receptor 7 (5-HT 7 ) was assessed by Western blotting. The involvement of 5-HT 7 was assessed with use of an antagonist and an agonist. The underlying cellular signaling pathways were examined with use of specific blockers. Serotonin decreased TEER and reduced the expression of TJ proteins ZO-1, occludin, and claudin 1, but not claudin 4. A 5-HT 7 antagonist blocked the serotonin-induced decrease in TEER, and a 5-HT 7 agonist decreased TEER. Inhibition of p38 mitogen-activated protein kinase (MAPK) reduced the serotonin-induced decrease in TEER. Inhibition of p38 MAPK blocked the decrease of ZO-1 levels, whereas extracellular-signal-regulated kinase (ERK) inhibition blocked the decrease in occludin levels. Cell signaling pathway inhibitors had no effect on serotonin-induced alterations in claudin 1 and claudin 4 levels. Serotonin induced phosphorylation of p38 MAPK and ERK, and a 5-HT 7 antagonist partially blocked serotonin-induced phosphorylation of p38 MAPK but not that of ERK. Serotonin disrupted esophageal squamous epithelial barrier function by modulating the levels of TJ proteins. Serotonin signaling pathways may mediate the pathogenesis of gastroesophageal reflux disease.

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

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

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.

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

Discrete Serotonin Systems Mediate Memory Enhancement and Escape Latencies after Unpredicted Aversive Experience in Drosophila Place Memory

PubMed Central

Sitaraman, Divya; Kramer, Elizabeth F.; Kahsai, Lily; Ostrowski, Daniela; Zars, Troy

2017-01-01

Feedback mechanisms in operant learning are critical for animals to increase reward or reduce punishment. However, not all conditions have a behavior that can readily resolve an event. Animals must then try out different behaviors to better their situation through outcome learning. This form of learning allows for novel solutions and with positive experience can lead to unexpected behavioral routines. Learned helplessness, as a type of outcome learning, manifests in part as increases in escape latency in the face of repeated unpredicted shocks. Little is known about the mechanisms of outcome learning. When fruit fly Drosophila melanogaster are exposed to unpredicted high temperatures in a place learning paradigm, flies both increase escape latencies and have a higher memory when given control of a place/temperature contingency. Here we describe discrete serotonin neuronal circuits that mediate aversive reinforcement, escape latencies, and memory levels after place learning in the presence and absence of unexpected aversive events. The results show that two features of learned helplessness depend on the same modulatory system as aversive reinforcement. Moreover, changes in aversive reinforcement and escape latency depend on local neural circuit modulation, while memory enhancement requires larger modulation of multiple behavioral control circuits. PMID:29321732

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.

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, atherosclerosis, and collateral vessel spasm

NASA Technical Reports Server (NTRS)

Hollenberg, N.

1988-01-01

Studies on animal models demonstrate that platelet products contribute to vascular spasm in ischemic syndromes and that this is reversible with administration of ketanserin and thromboxane synthesis inhibitors. Laboratory animals (dogs, rabbits, and rats) that had femoral artery ligations exhibited supersensitivity to serotonin within days in their collateral blood vessels. This supersensitivity lasted at least 6 months. The response to serotonin was reversed by ketanserin, but not by 5HT-1 antagonists. Supersensitivity does not extend to norepinephrine, and alpha blockers do not influence the response to serotonin. It appears that platelet activation by endothelial injury contributes to ischemia through blood vessel occlusion and vascular spasm. When platelet activation occurs in vivo, blood vessel occlusion and vascular spasm are reversible in part by using ketanserin or agents that block thromboxane synthesis or its action. Combining both classes of agents reverses spasm completely. These findings support existing evidence that platelet products contribute to vascular disease, and provide an approach to improved management with currently available pharmacologic agents.

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…

Studies on the mechanisms underlying amiloride enhancement of 3,4-methylenedioxymethamphetamine-induced serotonin depletion in rats.

PubMed

Goñi-Allo, Beatriz; Puerta, Elena; Hervias, Isabel; Di Palma, Richard; Ramos, Maria; Lasheras, Berta; Aguirre, Norberto

2007-05-21

Amiloride and several of its congeners known to block the Na(+)/Ca(2+) and/or Na(+)/H(+) antiporters potentiate methamphetamine-induced neurotoxicity without altering methamphetamine-induced hyperthermia. We now examine whether amiloride also exacerbates 3,4-methylenedioxymethamphetamine (MDMA)-induced long-term serotonin (5-HT) loss in rats. Amiloride (2.5 mg/kg, every 2 h x 3, i.p.) given at ambient temperature 30 min before MDMA (5 mg/kg, every 2 h x 3, i.p.), markedly exacerbated long-term 5-HT loss. However, in contrast to methamphetamine, amiloride also potentiated MDMA-induced hyperthermia. Fluoxetine (10 mg/kg i.p.) completely protected against 5-HT depletion caused by the MDMA/amiloride combination without significantly altering the hyperthermic response. By contrast, the calcium channel antagonists flunarizine or diltiazem did not afford any protection. Findings with MDMA and amiloride were extended to the highly selective Na(+)/H(+) exchange inhibitor dimethylamiloride, suggesting that the potentiating effects of amiloride are probably mediated by the blockade of Na(+)/H(+) exchange. When the MDMA/amiloride combination was administered at 15 degrees C hyperthermia did not develop and brain 5-HT concentrations remained unchanged 7 days later. Intrastriatal perfusion of MDMA (100 microM for 8 h) in combination with systemic amiloride caused a small depletion of striatal 5-HT content in animals made hyperthermic but not in the striatum of normothermic rats. These data suggest that enhancement of MDMA-induced 5-HT loss caused by amiloride or dimethylamiloride depends on their ability to enhance MDMA-induced hyperthermia. We hypothesise that blockade of Na(+)/H(+) exchange could synergize with hyperthermia to render 5-HT terminals more vulnerable to the toxic effects of MDMA.

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...

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.

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)

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.

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

Social regulation of serotonin in the auditory midbrain

PubMed Central

Hall, Ian C.; Sell, Gabrielle L.; Hurley, Laura M .

2011-01-01

The neuromodulator serotonin regulates auditory processing and can increase within minutes in response to stimuli like broadband noise as well as non-auditory stressors. Little is known about the serotonergic response in the auditory system to more natural stimuli such as social interactions, however. Using carbon-fiber voltammetry, we measured extracellular serotonin in the auditory midbrain of resident male mice during encounters with a male intruder. Serotonin increased in the inferior colliculus (IC) over the course of a 15 minute interaction, but not when mice were separated with a perforated barrier. Several behaviors, including the amount of immobility and anogenital investigation performed by the resident, were correlated with the serotonergic response. Multiple intrinsic factors associated with individual mice also correlated with the serotonergic response. One of these was age: older mice had smaller serotonergic responses to the social interaction. In a second interaction, individual identity predicted serotonergic responses that were highly consistent with those in the first interaction, even when mice were paired with different intruders. Serotonin was also significantly elevated in the second social interaction relative to the first, suggesting a role for social experience. These findings show that during social interaction, serotonin in the IC is influenced by extrinsic factors such as the directness of social interaction and intrinsic factors including age, individual identity, and experience. PMID:21787041

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

Effects of delayed laboratory processing on platelet serotonin levels.

PubMed

Sanner, Jennifer E; Frazier, Lorraine; Udtha, Malini

2013-01-01

Despite the availability of established guidelines for measuring platelet serotonin, these guidelines may be difficult to follow in a hospital setting where time to processing may vary from sample to sample. The purpose of this study was to evaluate the effect of the time to processing of human blood samples on the stability of the enzyme-linked immunosorbent assay (ELISA) for the determination of platelet serotonin levels in human plasma. Human blood samples collected from a convenience sample of eight healthy volunteers were analyzed to determine platelet serotonin levels from plasma collected in ethylene diamine tetra acetic acid (EDTA) tubes and stored at 4°C for 3 hr, 5 hr, 8 hr, and 12 hr. Refrigeration storage at 4°C for 3 hr, 5 hr, 8 hr, and 12 hr altered the platelet serotonin measurement when compared to immediate processing. The bias for the samples stored at 4°C for 3 hr was 102.3 (±217.39 ng/10(9) platelets), for 5 hr was 200.1 (±132.76 ng/10(9) platelets), for 8 hr was 146.9 (±221.41 ng/10(9) platelets), and for 12 hr was -67.6 (±349.60 ng/10(9) platelets). Results from this study show that accurate measurement of platelet serotonin levels is dependent on time to processing. Researchers should therefore follow a standardized laboratory guideline for obtaining immediate platelet serotonin levels after blood sample collection.

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 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.

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

PubMed

Rogers, Robert D

2011-01-01

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

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.

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

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.

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.

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

Serotonin and calcium homeostasis during the transition period.

PubMed

Weaver, S R; Laporta, J; Moore, S A E; Hernandez, L L

2016-07-01

The transition from pregnancy to lactation puts significant, sudden demands on maternal energy and calcium reserves. Although most mammals are able to effectively manage these metabolic adaptations, the lactating dairy cow is acutely susceptible to transition-related disorders because of the high amounts of milk being produced. Hypocalcemia is a common metabolic disorder that occurs at the onset of lactation. Hypocalcemia is also known to result in poor animal welfare conditions. In addition, cows that develop hypocalcemia are more susceptible to a host of other negative health outcomes. Different feeding tactics, including manipulating the dietary cation-anion difference and administering low-calcium diets, are commonly used preventative strategies. Despite these interventions, the incidence of hypocalcemia in the subclinical form is still as high as 25% to 30% in the United States dairy cow population, with a 5% to 10% incidence of clinical hypocalcemia. In addition, although there are various effective treatments in place, they are administered only after the cow has become noticeably ill, at which point there is already significant metabolic damage. This emphasizes the need for developing alternative prevention strategies, with the monoamine serotonin implicated as a potential therapeutic target. Our research in rodents has shown that serotonin is critical for the induction of mammary parathyroid hormone-related protein, which is necessary for the mobilization of bone tissue and subsequent restoration of maternal calcium stores during lactation. We have shown that circulating serotonin concentrations are positively correlated with serum total calcium on the first day of lactation in dairy cattle. Administration of serotonin's immediate precursor through feeding, injection, or infusion to various mammalian species has been shown to increase circulating serotonin concentrations, with positive effects on other components of maternal metabolism. Most recently

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

Selective serotonin reuptake inhibitor suppression of HIV infectivity and replication.

PubMed

Benton, Tami; Lynch, Kevin; Dubé, Benoit; Gettes, David R; Tustin, Nancy B; Ping Lai, Jian; Metzger, David S; Blume, Joshua; Douglas, Steven D; Evans, Dwight L

2010-11-01

To test the hypothesis that the selective serotonin reuptake inhibitor (SSRI) citalopram would down-regulate human immunodeficiency virus (HIV) infectivity and that the greatest effects would be seen in people with depression. Depression is a risk factor for morbidity and mortality in HIV/acquired immune deficiency syndrome. Serotonin (5-HT) neurotransmission has been implicated in the pathobiology of depression, and pharmacologic therapies for depression target this system. The 5-HT transporter and 5-HT receptors are widely distributed throughout the central nervous and immune systems. Depression has been associated with suppression of natural killer cells and CD8(+) lymphocytes, key regulators of HIV infection. Ex vivo models for acute and chronic HIV infection were used to study the effects of citalopram on HIV viral infection and replication in 48 depressed and nondepressed women. For both the acute and chronic infection models, HIV reverse transcriptase activity was measured in the citalopram treatment condition and the control condition. The SSRI significantly down-regulated the reverse transcriptase response in both the acute and chronic infection models. Specifically, citalopram significantly decreased the acute HIV infectivity of macrophages. Citalopram also significantly decreased HIV viral replication in the latently infected T-cell line and in the latently infected macrophage cell line. There was no difference in down-regulation by depression status. These studies suggest that an SSRI enhances natural killer/CD8 noncytolytic HIV suppression in HIV/acquired immune deficiency syndrome and decreases HIV viral infectivity of macrophages, ex vivo, suggesting the need for in vivo studies to determine a potential role for agents targeting serotonin in the host defense against HIV.

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

Enhanced light element imaging in atomic resolution scanning transmission electron microscopy.

PubMed

Findlay, S D; Kohno, Y; Cardamone, L A; Ikuhara, Y; Shibata, N

2014-01-01

We show that an imaging mode based on taking the difference between signals recorded from the bright field (forward scattering region) in atomic resolution scanning transmission electron microscopy provides an enhancement of the detectability of light elements over existing techniques. In some instances this is an enhancement of the visibility of the light element columns relative to heavy element columns. In all cases explored it is an enhancement in the signal-to-noise ratio of the image at the light column site. The image formation mechanisms are explained and the technique is compared with earlier approaches. Experimental data, supported by simulation, are presented for imaging the oxygen columns in LaAlO₃. Case studies looking at imaging hydrogen columns in YH₂ and lithium columns in Al₃Li are also explored through simulation, particularly with respect to the dependence on defocus, probe-forming aperture angle and detector collection aperture angles. © 2013 Elsevier B.V. All rights reserved.

Influenza A Virus Acquires Enhanced Pathogenicity and Transmissibility after Serial Passages in Swine

PubMed Central

Wei, Kai; Sun, Honglei; Sun, Zhenhong; Sun, Yipeng; Kong, Weili; Pu, Juan; Ma, Guangpeng; Yin, Yanbo; Yang, Hanchun; Guo, Xin; Chang, Kin-Chow

2014-01-01

ABSTRACT Genetic and phylogenetic analyses suggest that the pandemic H1N1/2009 virus was derived from well-established swine influenza lineages; however, there is no convincing evidence that the pandemic virus was generated from a direct precursor in pigs. Furthermore, the evolutionary dynamics of influenza virus in pigs have not been well documented. Here, we subjected a recombinant virus (rH1N1) with the same constellation makeup as the pandemic H1N1/2009 virus to nine serial passages in pigs. The severity of infection sequentially increased with each passage. Deep sequencing of viral quasispecies from the ninth passage found five consensus amino acid mutations: PB1 A469T, PA 1129T, NA N329D, NS1 N205K, and NEP T48N. Mutations in the hemagglutinin (HA) protein, however, differed greatly between the upper and lower respiratory tracts. Three representative viral clones with the five consensus mutations were selected for functional evaluation. Relative to the parental virus, the three viral clones showed enhanced replication and polymerase activity in vitro and enhanced replication, pathogenicity, and transmissibility in pigs, guinea pigs, and ferrets in vivo. Specifically, two mutants of rH1N1 (PB1 A469T and a combination of NS1 N205K and NEP T48N) were identified as determinants of transmissibility in guinea pigs. Crucially, one mutant viral clone with the five consensus mutations, which also carried D187E, K211E, and S289N mutations in its HA, additionally was able to infect ferrets by airborne transmission as effectively as the pandemic virus. Our findings demonstrate that influenza virus can acquire viral characteristics that are similar to those of the pandemic virus after limited serial passages in pigs. IMPORTANCE We demonstrate here that an engineered reassortant swine influenza virus, with the same gene constellation pattern as the pandemic H1N1/2009 virus and subjected to only nine serial passages in pigs, acquired greatly enhanced virulence and

Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala.

PubMed

Marcinkiewcz, Catherine A; Mazzone, Christopher M; D'Agostino, Giuseppe; Halladay, Lindsay R; Hardaway, J Andrew; DiBerto, Jeffrey F; Navarro, Montserrat; Burnham, Nathan; Cristiano, Claudia; Dorrier, Cayce E; Tipton, Gregory J; Ramakrishnan, Charu; Kozicz, Tamas; Deisseroth, Karl; Thiele, Todd E; McElligott, Zoe A; Holmes, Andrew; Heisler, Lora K; Kash, Thomas L

2016-09-01

Serotonin (also known as 5-hydroxytryptamine (5-HT)) is a neurotransmitter that has an essential role in the regulation of emotion. However, the precise circuits have not yet been defined through which aversive states are orchestrated by 5-HT. Here we show that 5-HT from the dorsal raphe nucleus (5-HT DRN ) enhances fear and anxiety and activates a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (CRF BNST ) in mice. Specifically, 5-HT DRN projections to the BNST, via actions at 5-HT 2C receptors (5-HT 2C Rs), engage a CRF BNST inhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area and lateral hypothalamus. Furthermore, we demonstrate that this CRF BNST inhibitory circuit underlies aversive behaviour following acute exposure to selective serotonin reuptake inhibitors (SSRIs). This early aversive effect is mediated via the corticotrophin-releasing factor type 1 receptor (CRF 1 R, also known as CRHR1), given that CRF 1 R antagonism is sufficient to prevent acute SSRI-induced enhancements in aversive learning. These results reveal an essential 5-HT DRN →CRF BNST circuit governing fear and anxiety, and provide a potential mechanistic explanation for the clinical observation of early adverse events to SSRI treatment in some patients with anxiety disorders.

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.

Enhancing the transmission efficiency by edge deletion in scale-free networks

NASA Astrophysics Data System (ADS)

Zhang, Guo-Qing; Wang, Di; Li, Guo-Jie

2007-07-01

How to improve the transmission efficiency of Internet-like packet switching networks is one of the most important problems in complex networks as well as for the Internet research community. In this paper we propose a convenient method to enhance the transmission efficiency of scale-free networks dramatically by kicking out the edges linking to nodes with large betweenness, which we called the “black sheep.” The advantages of our method are of facility and practical importance. Since the black sheep edges are very costly due to their large bandwidth, our method could decrease the cost as well as gain higher throughput of networks. Moreover, we analyze the curve of the largest betweenness on deleting more and more black sheep edges and find that there is a sharp transition at the critical point where the average degree of the nodes ⟨k⟩→2 .

High-contrast terahertz wave modulation by gated graphene enhanced by extraordinary transmission through ring apertures.

PubMed

Gao, Weilu; Shu, Jie; Reichel, Kimberly; Nickel, Daniel V; He, Xiaowei; Shi, Gang; Vajtai, Robert; Ajayan, Pulickel M; Kono, Junichiro; Mittleman, Daniel M; Xu, Qianfan

2014-03-12

Gate-controllable transmission of terahertz (THz) radiation makes graphene a promising material for making high-speed THz wave modulators. However, to date, graphene-based THz modulators have exhibited only small on/off ratios due to small THz absorption in single-layer graphene. Here we demonstrate a ∼50% amplitude modulation of THz waves with gated single-layer graphene by the use of extraordinary transmission through metallic ring apertures placed right above the graphene layer. The extraordinary transmission induced ∼7 times near-filed enhancement of THz absorption in graphene. These results promise complementary metal-oxide-semiconductor compatible THz modulators with tailored operation frequencies, large on/off ratios, and high speeds, ideal for applications in THz communications, imaging, and sensing.

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 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

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.

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.

Ethanol intake and sup 3 H-serotonin uptake I: A study in Fawn-Hooded rats

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

Daoust, M.; Compagnon, P.; Legrand, E.

1991-01-01

Ethanol intake and synaptosomal {sup 3}H-serotonin uptake were studied in male Fawn-Hooded and Sprague-Dawley rats. Fawn-Hooded rats consumed more alcohol and more water than Sprague-Dawley rats. Plasma alcohol levels of Sprague-Dawley rats were not detectable but were about 5 mg/dl in Fawn-Hooded rats. Ethanol intake increased the Vmax of serotonin uptake in Fawn-Hooded rats in hippocampus and cortex, but not in thalamus. In Fawn-Hooded rats, serotonin uptake (Vmax) was higher than in Sprague-Dawley rats cortex. Ethanol intake reduced the Vmax of serotonin uptake in Fawn-Hooded rats in hippocampus and cortex. In cortex, the carrier affinity for serotonin was increased inmore » alcoholized Fawn-Hooded rats. These results indicate that synaptosomal {sup 3}H-serotonin uptake is affected by ethanol intake. In Fawn-Hooded rats, high ethanol consumption is associated with high serotonin uptake. In rats presenting high serotonin uptake, alcoholization reduces {sup 3}H-serotonin internalization in synaptosomes, indicating a specific sensitivity to alcohol intake of serotonin uptake system.« less

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

Serotonin Affects Movement Gain Control in the Spinal Cord

PubMed Central

Glaser, Joshua I.; Deng, Linna; Thompson, Christopher K.; Stevenson, Ian H.; Wang, Qining; Hornby, Thomas George; Heckman, Charles J.; Kording, Konrad P.

2014-01-01

A fundamental challenge for the nervous system is to encode signals spanning many orders of magnitude with neurons of limited bandwidth. To meet this challenge, perceptual systems use gain control. However, whether the motor system uses an analogous mechanism is essentially unknown. Neuromodulators, such as serotonin, are prime candidates for gain control signals during force production. Serotonergic neurons project diffusely to motor pools, and, therefore, force production by one muscle should change the gain of others. Here we present behavioral and pharmaceutical evidence that serotonin modulates the input–output gain of motoneurons in humans. By selectively changing the efficacy of serotonin with drugs, we systematically modulated the amplitude of spinal reflexes. More importantly, force production in different limbs interacts systematically, as predicted by a spinal gain control mechanism. Psychophysics and pharmacology suggest that the motor system adopts gain control mechanisms, and serotonin is a primary driver for their implementation in force production. PMID:25232107

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

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

Plasma serotonin in horses undergoing surgery for small intestinal colic

PubMed Central

Torfs, Sara C.; Maes, An A.; Delesalle, Catherine J.; Pardon, Bart; Croubels, Siska M.; Deprez, Piet

2015-01-01

This study compared serotonin concentrations in platelet poor plasma (PPP) from healthy horses and horses with surgical small intestinal (SI) colic, and evaluated their association with postoperative ileus, strangulation and non-survival. Plasma samples (with EDTA) from 33 horses with surgical SI colic were collected at several pre- and post-operative time points. Serotonin concentrations were determined using liquid-chromatography tandem mass spectrometry. Results were compared with those for 24 healthy control animals. The serotonin concentrations in PPP were significantly lower (P < 0.01) in pre- and post-operative samples from surgical SI colic horses compared to controls. However, no association with postoperative ileus or non-survival could be demonstrated at any time point. In this clinical study, plasma serotonin was not a suitable prognostic factor in horses with SI surgical colic. PMID:25694668

Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice

PubMed Central

Suidan, Georgette L.; Demers, Melanie; Herr, Nadine; Carbo, Carla; Brill, Alexander; Cifuni, Stephen M.; Mauler, Maximilian; Cicko, Sanja; Bader, Michael; Idzko, Marco; Bode, Christoph

2013-01-01

The majority of peripheral serotonin is stored in platelets, which secrete it on activation. Serotonin releases Weibel-Palade bodies (WPBs) and we asked whether absence of platelet serotonin affects neutrophil recruitment in inflammatory responses. Tryptophan hydroxylase (Tph)1–deficient mice, lacking non-neuronal serotonin, showed mild leukocytosis compared with wild-type (WT), primarily driven by an elevated neutrophil count. Despite this, 50% fewer leukocytes rolled on unstimulated mesenteric venous endothelium of Tph1−/− mice. The velocity of rolling leukocytes was higher in Tph1−/− mice, indicating fewer selectin-mediated interactions with endothelium. Stimulation of endothelium with histamine, a secretagogue of WPBs, or injection of serotonin normalized the rolling in Tph1−/− mice. Diminished rolling in Tph1−/− mice resulted in reduced firm adhesion of leukocytes after lipopolysaccharide treatment. Blocking platelet serotonin uptake with fluoxetine in WT mice reduced serum serotonin by > 80% and similarly reduced leukocyte rolling and adhesion. Four hours after inflammatory stimulation, neutrophil extravasation into lung, peritoneum, and skin wounds was reduced in Tph1−/− mice, whereas in vitro neutrophil chemotaxis was independent of serotonin. Survival of lipopolysaccharide-induced endotoxic shock was improved in Tph1−/− mice. In conclusion, platelet serotonin promotes the recruitment of neutrophils in acute inflammation, supporting an important role for platelet serotonin in innate immunity. PMID:23243271

Enhanced middle-infrared light transmission through Au/SiO(x)N(y)/Au aperture arrays.

PubMed

Xiao, Gongli; Yao, Xiang; Ji, Xinming; Zhou, Jia; Bao, Zongming; Huang, Yiping

2011-12-01

The enhanced middle-infrared light transmission through Au/SiO(x)N(y)/Au aperture arrays by changing the refractive index and the thickness of a dielectric layer was studied experimentally. The results indicated that the transmission spectra was highly dependent on the refractive index and the thickness of SiO(x)N(y). We found that the transmission peaks redshifted regularly along with the refractive index from 1.6 to 1.8, owing to the role of surface plasmon polaritons (SPP) coupling in the Au/SiO(x)N(y)/Au cascaded metallic structure. Simultaneously, a higher transmission efficiency and narrower transmission peak was obtained in Au/SiO2.1N0.3/Au cascaded metallic structure with small refractive index (1.6) than in Au/SiO0.6N1/Au cascaded metallic structure with large refractive index (1.8). When the thickness of SiO(x)N(y) changes from 0.2 to 0.4 microm, the shape of transmission spectra exhibits a large change. It was found that a higher transmission efficiency and narrower transmission peak was obtained in Au/SiO(x)N(y)/Au cascaded metallic structure with a thin dielectric film (0.2 microm), with the increase of SiO(x)N(y) film's thickness, the transmission peak gradually widened and disappeared finally. This effect is useful in applications of biochemical sensing and tunable integrated plasmonic devices in the middle-infrared region.

Pharmacological characterization of RS-1259, an orally active dual inhibitor of acetylcholinesterase and serotonin transporter, in rodents: possible treatment of Alzheimer's disease.

PubMed

Abe, Yasuyuki; Aoyagi, Atsushi; Hara, Takao; Abe, Kazumi; Yamazaki, Reina; Kumagae, Yoshihiro; Naruto, Shunji; Koyama, Kazuo; Marumoto, Shinji; Tago, Keiko; Toda, Narihiro; Takami, Kazuko; Yamada, Naho; Ori, Mayuko; Kogen, Hiroshi; Kaneko, Tsugio

2003-09-01

A dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT), RS-1259 (4-[1S)-methylamino-3-(4-nitrophenoxy)]propylphenyl N,N-dimethylcarbamate (fumaric acid)(1/2)salt), was newly synthesized. RS-1259 simultaneously inhibited AChE and SERT in the brain following an oral administration in mice and rats. Actual simultaneous elevation of extracellular levels of 5-HT and ACh in the rat hippocampus was confirmed by microdialysis. The compound was as effective as SERT inhibitors such as fluoxetine and fluvoxamine in a 5-hydroxytryptophan-enhancing test in mice. Spatial memory deficits in the two-platform task of a water maze in aged rats were ameliorated by RS-1259 as well as donepezil. Both RS-1259 and donepezil increased the awake episodes in the daytime electroencephalogram of rats. Although RS-1259 was weaker than donepezil in enhancing central cholinergic transmission, as observed by ACh elevation in the hippocampus and memory enhancement in aged rats, the efficacy of RS-1259 on the consciousness level, which reflects the whole activity in the brain, was almost the same as that of donepezil. These results suggest that both cholinergic and serotonergic systems are involved in maintaining brain arousal and that a dual inhibitor of AChE and SERT may be useful for the treatment of cognitive disorders associated with reduced brain activity such as in Alzheimer's disease.

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.

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.

Enhancing action of LSD on neuronal responsiveness to serotonin in a brain structure involved in obsessive-compulsive disorder.

PubMed

Zghoul, Tarek; Blier, Pierre

2003-03-01

Potent serotonin (5-HT) reuptake inhibitors are the only drugs that consistently exert a therapeutic action in obsessive-compulsive disorder (OCD). Given that some hallucinogens were reported to exert an anti-OCD effect outlasting their psychotomimetic action, possible modifications of neuronal responsiveness to 5-HT by LSD were examined in two rat brain structures: one associated with OCD, the orbitofrontal cortex (OFC), and another linked to depression, the hippocampus. The effects of concurrent microiontophoretic application of LSD and 5-HT were examined on neuronal firing rate in the rat OFC and hippocampus under chloral hydrate anaesthesia. In order to determine whether LSD could also exert a modification of 5-HT neuronal responsiveness upon systemic administration, after a delay when hallucinosis is presumably no longer present, it was given once daily (100 microg/kg i.p.) for 4 d and the experiments were carried out 24 h after the last dose. LSD attenuated the firing activity of OFC neurons, and enhanced the inhibitory effect of 5-HT when concomitantly ejected on the same neurons. In the hippocampus, LSD also decreased firing rate by itself but decreased the inhibitory action of 5-HT. The inhibitory action of 5-HT was significantly greater in the OFC, but smaller in the hippocampus, when examined after subacute systemic administration of LSD. It is postulated that some hallucinogens could have a beneficial action in OCD by enhancing the responsiveness to 5-HT in the OFC, and not necessarily in direct relation to hallucinosis. The latter observation may have theoretical implications for the pharmacotherapy of OCD.

Antagonism of serotonin receptor 1B decreases viability and promotes apoptosis in the COS canine osteosarcoma cell line.

PubMed

Viall, A K; Goodall, C P; Stang, B; Marley, K; Chappell, P E; Bracha, S

2016-06-01

Serotonin receptor 1B (5HTR1B) traditionally exhibits anti-proliferative activity in osteoblasts. We examined the expression and function of 5HTR1B in the COS canine osteosarcoma cell line and normal canine osteoblasts. Equal levels of 5HTR1B gene and protein expression were found between normal and malignant osteoblasts. Treatment with serotonin enhanced viability of osteosarcoma cells but not normal osteoblasts. Challenge with the 5HTR1B agonist anpirtoline caused no change in cell viability. Rather incubation with the specific receptor antagonist SB224289 caused reduction in osteoblast viability, with this effect more substantial in osteosarcoma cells. Investigation of this inhibitory activity showed 5HTR1B antagonism induces apoptosis in malignant cells. Evaluation of phosphorylated levels of CREB and ERK, transcriptional regulators associated with serotonin receptor signalling in osteoblasts, revealed aberrant 5HTR1B signalling in COS. Our results confirm the presence of 5HTR1B in a canine osteosarcoma cell line and highlight this receptor as a possible novel therapeutic target. © 2014 John Wiley & Sons Ltd.

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.

A case of serotonin syndrome associated with methadone overdose.

PubMed

Martinez, Terry T; Martinez, Daniel N

2008-01-01

A chronic pain patient prescribed 20 mg of methadone per day was seen at the Emergency Department within one hour following a witnessed intentional 200 mg ingestion. In addition, he was taking the serotonin re-uptake inhibitor antidepressant drugs, sertraline and venlafaxine as prescribed. Methadone is also a serotonin re-uptake inhibitor which has been involved in serotonin toxicity reactions. Initially, no symptoms of narcotic overdose (depressed central nervous system, respiration, or blood pressure) could be distinguished, and the standard narcotic urine screen was negative. No decontamination or antagonist therapy was given, and the patient was discharged to a psychiatric unit for observation. At 5 hours post-ingestion he presented in a panic with hallucinations and elevated blood pressure, pulse, and respiration. These symptoms are characteristic of serotonin syndrome which is often described as mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. At 10 hours post-ingestion the patient was found unconscious. He had aspirated stomach contents into his lungs. His respiration, blood pressure, and pulse were all severely depressed. He never regained conciousness, and he died 5 days later. The medical examiner's finding was probable acute methadone intoxication. In this case serotonin syndrome appears to have opposed and delayed typical narcotic symptoms. Methadone has additional pharmacologic and toxicologic properties which may complicate the assessment and treatment in overdose situations.

Antidepressants differentially affect striatal amphetamine-stimulated dopamine and serotonin release in rats with high and low novelty-oriented behaviour.

PubMed

O'Leary, Aet; Kõiv, Kadri; Raudkivi, Karita; Harro, Jaanus

2016-11-01

In the studies of depression pathogenesis and antidepressant action, the monoaminergic hypothesis of depression has mainly focused on the serotonergic and noradrenergic mechanisms. However, dopaminergic neurotransmission is also linked to both depressive symptomatology as well as antidepressant effects. We have previously shown that persistent inter-individual differences in the rat behavioural activity in novel environments is associated with differences in the striatal extracellular levels of dopamine and serotonin, depressive-like behaviour and the expression of several depression-related genes. The aim of the current study was to investigate the relative potency of the tricyclic antidepressant imipramine, the selective serotonin re-uptake inhibitor fluoxetine, and the selective noradrenaline re-uptake inhibitor reboxetine (all drugs administered in the dose of 10mg/kg, i.p.) to enhance amphetamine-stimulated dopamine and serotonin release in the striatum using in vivo microdialysis in awake, freely-moving rats, categorized into high explorers (HE) and low explorers (LE) based on their spontaneous novelty-oriented behaviour. The basal extracellular dopamine and serotonin concentration in the striatum did not differ between the LE- and HE-rats. None of the antidepressants alone were able to modify baseline striatal dopamine levels, but the amphetamine-stimulated dopamine release was significantly higher in the HE-rats after acute and chronic imipramine (but not fluoxetine or reboxetine). Acute imipramine and fluoxetine, but not reboxetine, increased both the basal and amphetamine-stimulated levels of serotonin in the striatum. Again, the HE-rats had higher amphetamine-stimulated serotonin release after fluoxetine administration. These findings suggest that rats with depressive-like phenotype are less sensitive to the neurochemical effects of antidepressants in the striatum. These results may have relevance in understanding the neurobiological bases for inter

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.

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

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

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.

Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and in the determination of platelet serotonin levels.

PubMed

Coutinho, Ana M; Sousa, Inês; Martins, Madalena; Correia, Catarina; Morgadinho, Teresa; Bento, Celeste; Marques, Carla; Ataíde, Assunção; Miguel, Teresa S; Moore, Jason H; Oliveira, Guiomar; Vicente, Astrid M

2007-04-01

Autism is a neurodevelopmental disorder of unclear etiology. The consistent finding of platelet hyperserotonemia in a proportion of patients and its heritability within affected families suggest that genes involved in the serotonin system play a role in this disorder. The role in autism etiology of seven candidate genes in the serotonin metabolic and neurotransmission pathways and mapping to autism linkage regions (SLC6A4, HTR1A, HTR1D, HTR2A, HTR5A, TPH1 and ITGB3) was analyzed in a sample of 186 nuclear families. The impact of interactions among these genes in autism was assessed using the multifactor-dimensionality reduction (MDR) method in 186 patients and 181 controls. We further evaluated whether the effect of specific gene variants or gene interactions associated with autism etiology might be mediated by their influence on serotonin levels, using the quantitative transmission disequilibrium test (QTDT) and the restricted partition method (RPM), in a sample of 109 autistic children. We report a significant main effect of the HTR5A gene in autism (P = 0.0088), and a significant three-locus model comprising a synergistic interaction between the ITGB3 and SLC6A4 genes with an additive effect of HTR5A (P < 0.0010). In addition to the previously reported contribution of SLC6A4, we found significant associations of ITGB3 haplotypes with serotonin level distribution (P = 0.0163). The most significant models contributing to serotonin distribution were found for interactions between TPH1 rs4537731 and SLC6A4 haplotypes (P = 0.002) and between HTR1D rs6300 and SLC6A4 haplotypes (P = 0.013). In addition to the significant independent effects, evidence for interaction between SLC6A4 and ITGB3 markers was also found. The overall results implicate SLC6A4 and ITGB3 gene interactions in autism etiology and in serotonin level determination, providing evidence for a common underlying genetic mechanism and a molecular explanation for the association of platelet hyperserotonemia

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.

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

Hindbrain serotonin and the rapid induction of sodium appetite

NASA Technical Reports Server (NTRS)

Menani, J. V.; De Luca, L. A. Jr; Thunhorst, R. L.; Johnson, A. K.

2000-01-01

Both systemically administered furosemide and isoproterenol produce water intake (i.e., thirst). Curiously, however, in light of the endocrine and hemodynamic effects produced by these treatments, they are remarkably ineffective in eliciting intake of hypertonic saline solutions (i.e., operationally defined as sodium appetite). Recent work indicates that bilateral injections of the serotonin receptor antagonist methysergide into the lateral parabrachial nuclei (LPBN) markedly enhance a preexisting sodium appetite. The present studies establish that a de novo sodium appetite can be induced with LPBN-methysergide treatment under experimental conditions in which only water is typically ingested. The effects of bilateral LPBN injections of methysergide were studied on the intake of water and 0. 3 M NaCl following acute (beginning 1 h after treatment) diuretic (furosemide)-induced sodium and water depletion and following subcutaneous isoproterenol treatment. With vehicle injected into the LPBN, furosemide treatment and isoproterenol injection both caused water drinking but essentially no intake of hypertonic saline. In contrast, bilateral treatment of the LPBN with methysergide induced the intake of 0.3 M NaCl after subcutaneous furosemide and isoproterenol. Water intake induced by subcutaneous furosemide or isoproterenol was not changed by LPBN-methysergide injections. The results indicate that blockade of LPBN-serotonin receptors produces a marked intake of hypertonic NaCl (i.e., a de novo sodium appetite) after furosemide treatment as well as subcutaneous isoproterenol.

Transient uptake of serotonin by newborn olfactory projection neurons

PubMed Central

Beltz, Barbara S.; Benton, Jeanne L.; Sullivan, Jeremy M.

2001-01-01

A life-long turnover of sensory and interneuronal populations has been documented in the olfactory pathways of both vertebrates and invertebrates, creating a situation where the axons of new afferent and interneuronal populations must insert into a highly specialized glomerular neuropil. A dense serotonergic innervation of the primary olfactory processing areas where these neurons synapse also is a consistent feature across species. Prior studies in lobsters have shown that serotonin promotes the branching of olfactory projection neurons. This paper presents evidence that serotonin also regulates the proliferation and survival of projection neurons in lobsters, and that the serotonergic effects are associated with a transient uptake of serotonin into newborn neurons. PMID:11675504

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.

In utero exposure to venlafaxine, a serotonin-norepinephrine reuptake inhibitor, increases cardiac anomalies and alters placental and heart serotonin signaling in the rat.

PubMed

Laurent, Laetitia; Huang, Chunwei; Ernest, Sheila R; Berard, Anick; Vaillancourt, Cathy; Hales, Barbara F

2016-12-01

Human studies are inconsistent with respect to an association between treatment with selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRI/SNRIs) and an increase in the incidence of congenital heart defects. Here we tested the hypothesis that in utero exposure to venlafaxine, a highly prescribed SNRI, increases the incidence of fetal heart defects and alters placental and fetal heart serotonin signaling in the rat. Timed-pregnant Sprague Dawley rats were gavaged daily with venlafaxine hydrochloride (0, 3, 10, 30, or 100 mg/kg/day) from gestation day 8 to 20. On gestation day 21, fetuses were examined for external and internal malformations; placentas and fetal hearts were collected for the analysis of gene expression. Venlafaxine had no effect on the number of live fetuses, fetal body weights, or external morphology in the absence of maternal toxicity. However, venlafaxine significantly increased the placental index (fetal body/placental weight ratio) and the incidence of fetal cardiac anomalies. Venlafaxine exposure decreased placental expression of the serotonin transporter (SERT/Slc6a4) at the transcript and protein levels. In contrast, venlafaxine increased SERT expression in the hearts of female, but not male, fetuses. Expression of the serotonin 2B receptor (5-HT 2B /Htr2b) and of fibroblast growth factor 8 was induced in fetal hearts. In utero venlafaxine exposure altered the placental index and induced fetal cardiac anomalies in rats. We propose that the increased incidence of cardiac anomalies is mediated through alterations in serotonin signaling in the placenta and fetal heart. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:1044-1055, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

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

Brain serotonin content - Increase following ingestion of carbohydrate diet.

NASA Technical Reports Server (NTRS)

Fernstrom, J. D.; Wurtman, R. J.

1971-01-01

In the rat, the injection of insulin or the consumption of carbohydrate causes sequential increases in the concentrations of tryptophan in the plasma and the brain and of serotonin in the brain. Serotonin-containing neurons may thus participate in systems whereby the rat brain integrates information about the metabolic state in its relation to control of homeostasis and behavior.

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.

Serotonin effects on sleep and emotional disorders in adolescent migraine.

PubMed

Pakalnis, Ann; Splaingard, Mark; Splaingard, Deborah; Kring, Donna; Colvin, Andrew

2009-01-01

To determine frequency of emotional disorders and sleep disturbances in adolescent migraineurs with episodic and chronic headaches. To determine the relationship of whole blood serotonin, caffeine consumption, and frequency of sleep and mood disorders. The neurotransmitter serotonin has been implicated to play a role in the initiation and maintenance of sleep and in modulating mood. A putative role in migraine pathophysiology is also known. Adolescents from 13 to 17 years of age were identified from our headache clinic with episodic or chronic migraine (according to International Classification of Headache Disorders-Second Edition criteria) and healthy controls enrolled. Psychological rating scales were completed, including Adolescent Symptom Inventory (4th Edition) and Child Depression Inventory. Sleep questionnaires (Pediatric Sleep Questionnaire and Child Sleep Habit Questionnaire) were completed by the teenager's parents/guardian. Whole blood serotonin levels were drawn and analyzed and caffeine consumption obtained by history. A total of 18 controls (8 girls) and 15 patients each with episodic migraines (9 girls) and chronic migraine (10 girls) were studied. Patients with headache had significantly more sleep problems than controls. Patients with chronic migraines had increased daytime sleepiness and dysthymia compared with teenagers with episodic migraines. Serotonin levels were not significantly different, and no association was noted between serotonin levels and sleep abnormalities or emotional rating scales. Increased caffeine intake was related to sleep and depressive complaints. Sleep and emotional disorders were common in adolescents with migraine. Sleep disorders and dysthymia were more prevalent with increased headache frequency. No correlation was noted with whole blood serotonin levels.

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 �

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.

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

A Theoretical Study of the Conformational Landscape of Serotonin

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

Mourik, Van Tonja; Emson, Laura E.

2002-10-25

The conformational landscape of neutral serotonin has been investigated by several theoretical methods. The potential energy surface was scanned by systematically varying the three dihedral angles that determine the conformation of the alkyl side chain. In addition, the two possible conformations of the phenol hydroxyl group (anti and syn with respect to the indole NH) were considered. The OH-anti stationary points located with SCF/6-31G* have been re-optimized with B3LYP/6-31+G*, which resulted in twelve true minima. Eleven of these have a corresponding OH-syn conformer that is 1-4 kJ/mol higher in energy. IR vibrational spectra of all twenty-three serotonin conformers, computed atmore » the B3LYP/6-31+G* level f theory, are presented. The initial scan of the serotonin potential energy surface has been repeated with several computationally cheaper methods, to assess their reliability for locating the correct serotonin conformers. It is found that the semi-empirical methods AM1 and PM3 do no t yield sufficiently accurate results, due to their inability to account for subtle intramolecular interactions within the serotonin molecule. On the other hand, SCF in combination with the 3-21G* basis set is ascertained to be a good alternative to SCF/6-31G* for performing the initial scan of the potential energy surface of flexible molecules.« less

Nicotine Uses Neuron-Glia Communication to Enhance Hippocampal Synaptic Transmission and Long-term Memory

PubMed Central

López-Hidalgo, Mónica; Salgado-Puga, Karla; Alvarado-Martínez, Reynaldo; Medina, Andrea Cristina; Prado-Alcalá, Roberto A.; García-Colunga, Jesús

2012-01-01

Nicotine enhances synaptic transmission and facilitates long-term memory. Now it is known that bi-directional glia-neuron interactions play important roles in the physiology of the brain. However, the involvement of glial cells in the effects of nicotine has not been considered until now. In particular, the gliotransmitter D-serine, an endogenous co-agonist of NMDA receptors, enables different types of synaptic plasticity and memory in the hippocampus. Here, we report that hippocampal long-term synaptic plasticity induced by nicotine was annulled by an enzyme that degrades endogenous D-serine, or by an NMDA receptor antagonist that acts at the D-serine binding site. Accordingly, both effects of nicotine: the enhancement of synaptic transmission and facilitation of long-term memory were eliminated by impairing glial cells with fluoroacetate, and were restored with exogenous D-serine. Together, these results show that glial D-serine is essential for the long-term effects of nicotine on synaptic plasticity and memory, and they highlight the roles of glial cells as key participants in brain functions. PMID:23185511

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.

Structure and variation of three canine genes involved in serotonin binding and transport: the serotonin receptor 1A gene (htr1A), serotonin receptor 2A gene (htr2A), and serotonin transporter gene (slc6A4).

PubMed

van den Berg, L; Kwant, L; Hestand, M S; van Oost, B A; Leegwater, P A J

2005-01-01

Aggressive behavior is the most frequently encountered behavioral problem in dogs. Abnormalities in brain serotonin metabolism have been described in aggressive dogs. We studied canine serotonergic genes to investigate genetic factors underlying canine aggression. Here, we describe the characterization of three genes of the canine serotonergic system: the serotonin receptor 1A and 2A gene (htr1A and htr2A) and the serotonin transporter gene (slc6A4). We isolated canine bacterial artificial chromosome clones containing these genes and designed oligonucleotides for genomic sequencing of coding regions and intron-exon boundaries. Golden retrievers were analyzed for DNA sequence variations. We found two nonsynonymous single nucleotide polymorphisms (SNPs) in the coding sequence of htr1A; one SNP close to a splice site in htr2A; and two SNPs in slc6A4, one in the coding sequence and one close to a splice site. In addition, we identified a polymorphic microsatellite marker for each gene. Htr1A is a strong candidate for involvement in the domestication of the dog. We genotyped the htr1A SNPs in 41 dogs of seven breeds with diverse behavioral characteristics. At least three SNP haplotypes were found. Our results do not support involvement of the gene in domestication.

Effects of prenatal maternal stress on serotonin and fetal development.

PubMed

St-Pierre, Joey; Laurent, Laetitia; King, Suzanne; Vaillancourt, Cathy

2016-12-01

Fetuses are exposed to many environmental perturbations that can influence their development. These factors can be easily identifiable such as drugs, chronic diseases or prenatal maternal stress. Recently, it has been demonstrated that the serotonin synthetized by the placenta was crucial for fetal brain development. Moreover, many studies show the involvement of serotonin system alteration in psychiatric disease during childhood and adulthood. This review summarizes existing studies showing that prenatal maternal stress, which induces alteration of serotonin systems (placenta and fetal brain) during a critical window of early development, could lead to alteration of fetal development and increase risks of psychiatric diseases later in life. This phenomenon, termed fetal programming, could be moderated by the sex of the fetus. This review highlights the need to better understand the modification of the maternal, placental and fetal serotonin systems induced by prenatal maternal stress in order to find early biomarkers of psychiatric disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.

Halogenated naphthyl methoxy piperidines for mapping serotonin transporter sites

DOEpatents

Goodman, Mark M.; Faraj, Bahjat

1999-01-01

Halogenated naphthyl methoxy piperidines having a strong affinity for the serotonin transporter are disclosed. Those compounds can be labeled with positron-emitting and/or gamma emitting halogen isotopes by a late step synthesis that maximizes the useable lifeterm of the label. The labeled compounds are useful for localizing serotonin transporter sites by positron emission tomography and/or single photon emission computed tomography.

Halogenated naphthyl methoxy piperidines for mapping serotonin transporter sites

DOEpatents

Goodman, M.M.; Faraj, B.

1999-07-06

Halogenated naphthyl methoxy piperidines having a strong affinity for the serotonin transporter are disclosed. Those compounds can be labeled with positron-emitting and/or gamma emitting halogen isotopes by a late step synthesis that maximizes the useable lifeterm of the label. The labeled compounds are useful for localizing serotonin transporter sites by positron emission tomography and/or single photon emission computed tomography.

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.

[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.

Fluoxetine (Prozac) Binding to Serotonin Transporter Is Modulated by Chloride and Conformational Changes

PubMed Central

Tavoulari, Sotiria; Forrest, Lucy R.; Rudnick, Gary

2010-01-01

Serotonin transporter (SERT) is the main target for widely used antidepressant agents. Several of these drugs, including imipramine, citalopram, sertraline, and fluoxetine (Prozac), bound more avidly to SERT in the presence of Cl–. In contrast, Cl– did not enhance cocaine or paroxetine binding. A Cl– binding site recently identified in SERT, and shown to be important for Cl– dependent transport, was also critical for the Cl– dependence of antidepressant affinity. Mutation of the residues contributing to this site eliminated the Cl–-mediated affinity increase for imipramine and fluoxetine. Analysis of ligand docking to a single state of SERT indicated only small differences in the energy of interaction between bound ligands and Cl–. These differences in interaction energy cannot account for the affinity differences observed for Cl– dependence. However, fluoxetine binding led to a conformational change, detected by cysteine accessibility experiments, that was qualitatively different from that induced by cocaine or other ligands. Given the known Cl– requirement for serotonin-induced conformational changes, we propose that Cl– binding facilitates conformational changes required for optimal binding of fluoxetine and other antidepressant drugs. PMID:19641126

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.

Protonated serotonin: Geometry, electronic structures and photophysical properties

NASA Astrophysics Data System (ADS)

Omidyan, Reza; Amanollahi, Zohreh; Azimi, Gholamhassan

2017-07-01

The geometry and electronic structures of protonated serotonin have been investigated by the aim of MP2 and CC2 methods. The relative stabilities, transition energies and geometry of sixteen different protonated isomers of serotonin have been presented. It has been predicted that protonation does not exhibit essential alteration on the S1 ← S0 electronic transition energy of serotonin. Instead, more complicated photophysical nature in respect to its neutral analogue is suggested for protonated system owing to radiative and non-radiative deactivation pathways. In addition to hydrogen detachment (HD), hydrogen/proton transfer (H/PT) processes from ammonium to indole ring along the NH+⋯ π hydrogen bond have been predicted as the most important photophysical consequences of SERH+ at S1 excited state. The PT processes is suggested to be responsible for fluorescence of SERH+ while the HD driving coordinate is proposed for elucidation of its nonradiative deactivation mechanism.

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.

Fluorescence enhancement and nonreciprocal transmission of light waves by nanomaterial interfaces

NASA Astrophysics Data System (ADS)

Nyman, M.; Shevchenko, A.; Kaivola, M.

2017-11-01

In an optically absorbing or amplifying linear medium, the energy flow density of interfering optical waves is in general periodically modulated in space. This makes the wave transmission through a material boundary, as described by the Fresnel transmission coefficients, nonreciprocal and apparently violating the energy conservation law. The modulation has been previously described in connection to ordinary homogeneous nonmagnetic materials. In this work, we extend the description to nanomaterials with designed structural units that can be magnetic at optical frequencies. We find that in such a "metamaterial" the modulation in energy flow can be used to enhance optical far-field emission in spite of the fact that the material is highly absorbing. We also demonstrate a nanomaterial design that absorbs light, but simultaneously eliminates the power flow modulation and returns the reciprocity, which is impossible to achieve with a nonmagnetic material. We anticipate that these unusual optical effects can be used to increase the efficiency of nanostructured light emitters and absorbers, such as light-emitting diodes and solar cells.

Resonance surface plasmon spectroscopy by tunable enhanced light transmission through nanostructured gratings and thin films

NASA Astrophysics Data System (ADS)

Yeh, Wei-Hsun

Surface plasmon resonance (SPR) is a powerful tool in probing interfacial events in that any changes of effective refractive index in the interface directly impact the behavior of surface plasmons, an electromagnetic wave, travelling along the interface. Surface plasmons (SPs) are generated only if the momemtum of incident light matches that of SPs in the interface. This thesis focuses on tuning the behavior of SPs by changing the topology of diffraction gratings, monitoring the thickness of thin films by diffraction gratings, and use of dispersion images to analyze complex optical responses of SPs through diffraction gratings. Chapter 1 covers the background/principle of SPR, comprehensive literature review, sensor applications, control of SPR spectral responses, and sensitivity of SPR. In Chapter 2, we illustrate a chirped grating with varying surface topology along its spatial position. We demonstrated that the features of nanostructure such as pitch and amplitude significantly impact the behavior of enhanced transmission. In addition, we also illustrate the sensing application of chirped grating and the results indicate that the chirped grating is a sensitive and information rich SPR platform. In chapter 3, we used a commercial DVD diffraction grating as a SPR coupler. A camera-mounted microscope with Bertrend lens attachment is used to observe the enhanced transmission. We demonstrate that this system can monitor the SPR responses and track the thickness of a silicon monoxide film without using a spectrophotometer. Surface plasmons are a result of collective oscillation of free electrons in the metal/dielectric interface. Thus, the interaction of SPs with delocalized electrons from molecular resonance is complex. In chapter 4, we perform both experimental and simulation works to address this complex interaction. Detailed examination and analysis show nontypical SPR responses. For p-polarized light, a branch of dispersion curve and quenching of SPs in the Q

Role of protein kinase C in the induction and maintenance of serotonin-dependent enhancement of the glutamate response in isolated siphon motor neurons of Aplysia californica.

PubMed

Villareal, Greg; Li, Quan; Cai, Diancai; Fink, Ann E; Lim, Travis; Bougie, Joanna K; Sossin, Wayne S; Glanzman, David L

2009-04-22

Serotonin (5-HT) mediates learning-related facilitation of sensorimotor synapses in Aplysia californica. Under some circumstances 5-HT-dependent facilitation requires the activity of protein kinase C (PKC). One critical site of PKC's contribution to 5-HT-dependent synaptic facilitation is the presynaptic sensory neuron. Here, we provide evidence that postsynaptic PKC also contributes to synaptic facilitation. We investigated the contribution of PKC to enhancement of the glutamate-evoked potential (Glu-EP) in isolated siphon motor neurons in cell culture. A 10 min application of either 5-HT or phorbol ester, which activates PKC, produced persistent (> 50 min) enhancement of the Glu-EP. Chelerythrine and bisindolylmaleimide-1 (Bis), two inhibitors of PKC, both blocked the induction of 5-HT-dependent enhancement. An inhibitor of calpain, a calcium-dependent protease, also blocked 5-HT's effect. Interestingly, whereas chelerythrine blocked maintenance of the enhancement, Bis did not. Because Bis has greater selectivity for conventional and novel isoforms of PKC than for atypical isoforms, this result implicates an atypical isoform in the maintenance of 5-HT's effect. Although induction of enhancement of the Glu-EP requires protein synthesis (Villareal et al., 2007), we found that maintenance of the enhancement does not. Maintenance of 5-HT-dependent enhancement appears to be mediated by a PKM-type fragment generated by calpain-dependent proteolysis of atypical PKC. Together, our results suggest that 5-HT treatment triggers two phases of PKC activity within the motor neuron, an early phase that may involve conventional, novel or atypical isoforms of PKC, and a later phase that selectively involves an atypical isoform.

Effect of neonatal handling on serotonin 1A sub-type receptors in the rat hippocampus.

PubMed

Stamatakis, A; Mantelas, A; Papaioannou, A; Pondiki, S; Fameli, M; Stylianopoulou, F

2006-06-19

Serotonin 1A sub-type receptors play an important role in the etiopathogenesis of depression, which is known to occur more often in females than males. Early experiences can be a predisposing factor for depression; however, the underlying cellular processes remain unknown. In an effort to address such issues, we employed neonatal handling, an experimental model of early experience, which has been previously shown to render females more vulnerable to display enhanced depression-like behavior in response to chronic stress, while it increases the ability of males to cope. In rat pre-pubertal (30 days of age) and adult (90 days) hippocampus, of both males and females, the effect of neonatal handling on serotonin 1A sub-type receptor mRNA and protein levels was determined by in situ hybridization and immunohistochemistry, respectively, while the number of binding sites was determined by in vitro autoradiography using [(3)H]8-hydroxy-2(di-n-propylamino)tetralin as the ligand. Our results revealed a significant sex difference in serotonin 1A sub-type receptor mRNA, protein and binding sites, with females having higher levels than males. Handling resulted in statistically significant decreased numbers of cells positive for serotonin 1A sub-type receptor mRNA or protein, as well as [(3)H]8-hydroxy-2(di-n-propylamino)tetralin binding sites in the area 4 of Ammon's horn and dentate gyrus of both pre-pubertal males and females. In adult animals the number of serotonin 1A sub-type receptor mRNA positive cells was increased as a result of handling in the area 1 of Ammon's horn, area 4 of Ammon's horn and dentate gyrus of males, while it was decreased only in the area 4 of Ammon's horn of females. Furthermore, the number of serotonin sub-type 1A receptor immunopositive cells, as well as [(3)H]8-hydroxy-2(di-n-propylamino)tetralin binding sites was increased in the area 1 of Ammon's horn, area 4 of Ammon's horn and dentate gyrus of handled males, whereas it was decreased in these

Serotonin reuptake inhibitors and breastfeeding: a systematic review.

PubMed

Orsolini, Laura; Bellantuono, Cesario

2015-01-01

The postnatal period represents a critical phase for mothers because of physiological hormonal changes, the increase of emotional reactions and a greater susceptibility for the onset/recrudescence of psychiatric disorders. Despite the evidence of an increasing utilization of antidepressant drugs during breastfeeding, there is still few reliable information on the neonatal safety of the selective serotonin reuptake inhibitors (SSRIs) and selective noradrenergic reuptake inhibitors (SNRIs) [serotonin reuptake inhibitors (SRIs)] in nursing mothers. The aim of this study is to provide a systematic review on the neonatal safety profile of these drugs during breastfeeding, also assessing the limits of available tools. MEDLINE and PubMed databases were searched without any language restrictions by using the following set of keywords: ((SSRIs OR selective serotonin inhibitor reuptake OR SNRIs OR selective serotonin noradrenaline inhibitor reuptake) AND (breastfeeding OR lactation OR breast milk)). A separate search was also performed for each SSRIs (paroxetine, fluvoxamine, fluoxetine, sertraline, citalopram and escitalopram) and SNRIs (venlafaxine and duloxetine). Sertraline and paroxetine show a better neonatal safety profile during breastfeeding as compared with other SRIs. Less data are available for fluvoxamine, escitalopram and duloxetine. Few studies followed up infants breastfeed for assessing the neurodevelopmental outcomes. Literature review clearly indicates paroxetine and sertraline as the drugs that should be preferred as first line choice in nursing women who need an antidepressant treatment. Copyright © 2014 John Wiley & Sons, Ltd.

Childhood socioeconomic status and serotonin transporter gene polymorphism enhance cardiovascular reactivity to mental stress.

PubMed

Williams, Redford B; Marchuk, Douglas A; Siegler, Ilene C; Barefoot, John C; Helms, Michael J; Brummett, Beverly H; Surwit, Richard S; Lane, James D; Kuhn, Cynthia M; Gadde, Kishore M; Ashley-Koch, Allison; Svenson, Ingrid K; Schanberg, Saul M

2008-01-01

To test the hypothesis that low socioeconomic status (SES) and the 5HTTLPR L allele are associated with increased cardiovascular reactivity (CVR) to stress in a larger sample and that SES and 5HTTLPR genotypes interact to enhance CVR to stress. CVR to mental stress has been proposed as one mechanism linking stress to the pathogenesis of cardiovascular disease. The more transcriptionally efficient long (L) allele of a polymorphism of the serotonin transporter gene promoter (5HTTLPR) has been found associated with increased risk of myocardial infarction. We found the long allele associated with larger CVR to mental stress in a preliminary study of 54 normal volunteers. Subjects included 165 normal community volunteers stratified for race, gender, and SES, who underwent mental stress testing. Childhood SES as indexed by Father's Education Level was associated with larger systolic blood pressure (SBP) (p < .05) and diastolic blood pressure (DBP) (p = .01) responses to mental stress. The L allele was associated with larger SBP (p = .04), DBP (p < .0001), and heart rate (p = .04) responses to mental stress compared with the short (S) allele. Subjects with the SS genotype and high Father's Education exhibited smaller SBP (5.2 mm Hg) and DBP (2.9 mm Hg) responses than subjects with LL genotype and low Father's Education (SBP = 13.3 mm Hg, p = .002; DBP = 9.7 mm Hg, p < .0001). Both the 5HTTLPR long allele and low SES, particularly during childhood, are associated with increased CVR to mental stress, which could account, at least in part, for the increased cardiovascular disease risk associated with these characteristics. If confirmed in further research, these characteristics could be used to identify persons who might benefit from preventive interventions.

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.

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

Fluoxetine potentiates methylphenidate-induced gene regulation in addiction-related brain regions: Concerns for use of cognitive enhancers?

PubMed Central

Steiner, Heinz; Van Waes, Vincent; Marinelli, Michela

2009-01-01

Background There is growing use of psychostimulant cognitive enhancers such as methylphenidate (Ritalin). Methylphenidate differs from the psychostimulant cocaine because it does not enhance brain levels of serotonin. We investigated whether exposure to methylphenidate combined with a serotonin-enhancing medication, the prototypical selective serotonin reuptake inhibitor (SSRI) fluoxetine (Prozac), would produce more “cocaine-like” molecular and behavioral changes. Methods We measured the effects of fluoxetine on gene expression induced by the cognitive enhancer methylphenidate in the striatum and nucleus accumbens of rats, by in situ hybridization histochemistry. We also determined whether fluoxetine modified behavioral effects of methylphenidate. Results Fluoxetine robustly potentiated methylphenidate-induced expression of the transcription factors c-fos and zif 268 throughout the striatum and to some degree in the nucleus accumbens. Fluoxetine also enhanced methylphenidate-induced stereotypical behavior. Conclusions Both potentiated gene regulation in the striatum and the behavioral effects indicate that combining the SSRI fluoxetine with the cognitive enhancer methylphenidate mimics cocaine effects, consistent with an increased risk for substance use disorder. PMID:19931852

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.

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

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.

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.

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

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

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.

Sex Differences in Serotonin 1 Receptor Binding in Rat Brain

NASA Astrophysics Data System (ADS)

Fischette, Christine T.; Biegon, Anat; McEwen, Bruce S.

1983-10-01

Male and female rats exhibit sex differences in binding by serotonin 1 receptors in discrete areas of the brain, some of which have been implicated in the control of ovulation and of gonadotropin release. The sex-specific changes in binding, which occur in response to the same hormonal (estrogenic) stimulus, are due to changes in the number of binding sites. Castration alone also affects the number of binding sites in certain areas. The results lead to the conclusion that peripheral hormones modulate binding by serotonin 1 receptors. The status of the serotonin receptor system may affect the reproductive capacity of an organism and may be related to sex-linked emotional disturbances in humans.

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

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.

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.

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.

Serotonin receptor 1A–modulated phosphorylation of glycine receptor α3 controls breathing in mice

PubMed Central

Manzke, Till; Niebert, Marcus; Koch, Uwe R.; Caley, Alex; Vogelgesang, Steffen; Hülsmann, Swen; Ponimaskin, Evgeni; Müller, Ulrike; Smart, Trevor G.; Harvey, Robert J.; Richter, Diethelm W.

2010-01-01

Rhythmic breathing movements originate from a dispersed neuronal network in the medulla and pons. Here, we demonstrate that rhythmic activity of this respiratory network is affected by the phosphorylation status of the inhibitory glycine receptor α3 subtype (GlyRα3), which controls glutamatergic and glycinergic neuronal discharges, subject to serotonergic modulation. Serotonin receptor type 1A–specific (5-HTR1A–specific) modulation directly induced dephosphorylation of GlyRα3 receptors, which augmented inhibitory glycine-activated chloride currents in HEK293 cells coexpressing 5-HTR1A and GlyRα3. The 5-HTR1A–GlyRα3 signaling pathway was distinct from opioid receptor signaling and efficiently counteracted opioid-induced depression of breathing and consequential apnea in mice. Paradoxically, this rescue of breathing originated from enhanced glycinergic synaptic inhibition of glutamatergic and glycinergic neurons and caused disinhibition of their target neurons. Together, these effects changed respiratory phase alternations and ensured rhythmic breathing in vivo. GlyRα3-deficient mice had an irregular respiratory rhythm under baseline conditions, and systemic 5-HTR1A activation failed to remedy opioid-induced respiratory depression in these mice. Delineation of this 5-HTR1A–GlyRα3 signaling pathway offers a mechanistic basis for pharmacological treatment of opioid-induced apnea and other breathing disturbances caused by disorders of inhibitory synaptic transmission, such as hyperekplexia, hypoxia/ischemia, and brainstem infarction. PMID:20978350

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

A new Drosophila octopamine receptor responds to serotonin.

PubMed

Qi, Yi-Xiang; Xu, Gang; Gu, Gui-Xiang; Mao, Fen; Ye, Gong-Yin; Liu, Weiwei; Huang, Jia

2017-11-01

As the counterparts of the vertebrate adrenergic transmitters, octopamine and tyramine are important physiological regulators in invertebrates. They control and modulate many physiological and behavioral functions in insects. In this study, we reported the pharmacological properties of a new α2-adrenergic-like octopamine receptor (CG18208) from Drosophila melanogaster, named DmOctα2R. This new receptor gene encodes two transcripts by alternative splicing. The long isoform DmOctα2R-L differs from the short isoform DmOctα2R-S by the presence of an additional 29 amino acids within the third intracellular loop. When heterologously expressed in mammalian cell lines, both receptors were activated by octopamine, tyramine, epinephrine and norepinephrine, resulting in the inhibition of cAMP production in a dose-dependent manner. The long form is more sensitive to the above ligands than the short form. The adrenergic agonists naphazoline, tolazoline and clonidine can stimulate DmOctα2R as full agonists. Surprisingly, serotonin and serotoninergic agonists can also activate DmOctα2R. Several tested adrenergic antagonists and serotonin antagonists blocked the action of octopamine or serotonin on DmOctα2R. The data presented here reported an adrenergic-like G protein-coupled receptor activated by serotonin, suggesting that the neurotransmission and neuromodulation in the nervous system could be more complex than previously thought. Copyright © 2017 Elsevier Ltd. All rights reserved.

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.

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

The effects of serotonin manipulations on emotional information processing and mood.

PubMed

Merens, Wendelien; Willem Van der Does, A J; Spinhoven, Philip

2007-11-01

Serotonin is implicated in both mood and cognition. It has recently been shown that antidepressant treatment has immediate effects on emotional information processing, which is much faster than any clinically significant effects. This review aims to investigate whether the effects on emotional information processing are reliable, and whether these effects are related to eventual clinical outcome. Treatment-efficiency may be greatly improved if early changes in emotional information processing are found to predict clinical outcome following antidepressant treatment. Review of studies investigating the short-term effects of serotonin manipulations (including medication) on the processing of emotional information, using PubMed and PsycInfo databases. Twenty-five studies were identified. Serotonin manipulations were found to affect attentional bias, facial emotion recognition, emotional memory, dysfunctional attitudes and decision making. The sequential link between changes in emotional processing and mood remains to be further investigated. The number of studies on serotonin manipulations and emotional information processing in currently depressed subjects is small. No studies yet have directly tested the link between emotional information processing and clinical outcome during the course of antidepressant treatment. Serotonin function is related to several aspects of emotional information processing, but it is unknown whether these changes predict or have any relationship with clinical outcome. Suggestions for future research are provided.

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

Acute and constitutive increases in central serotonin levels reduce social play behaviour in peri-adolescent rats

PubMed Central

Schiepers, Olga J. G.; Schoffelmeer, Anton N. M.; Cuppen, Edwin; Vanderschuren, Louk J. M. J.

2007-01-01

Rationale Serotonin is an important modulator of social behaviour. Individual differences in serotonergic signalling are considered to be a marker of personality that is stable throughout lifetime. While a large body of evidence indicates that central serotonin levels are inversely related to aggression and sexual behaviour in adult rats, the relationship between serotonin and social behaviour during peri-adolescence has hardly been explored. Objective To study the effect of acute and constitutive increases in serotonin neurotransmission on social behaviour in peri-adolescent rats. Materials and methods Social behaviour in peri-adolesent rats (28–35 days old) was studied after genetic ablation of the serotonin transporter, causing constitutively increased extra-neuronal serotonin levels, and after acute treatment with the serotonin reuptake inhibitor fluoxetine or the serotonin releasing agent 3,4-methylenedioxymethamphetamine (MDMA). A distinction was made between social play behaviour that mainly occurs during peri-adolescence, and non-playful social interactions that are abundant during the entire lifespan of rats. Results In serotonin transporter knockout rats, social play behaviour was markedly reduced, while non-playful aspects of social interaction were unaffected. Acute treatment with fluoxetine or MDMA dose-dependently inhibited social play behaviour. MDMA also suppressed non-playful social interaction but at higher doses than those required to reduce social play. Fluoxetine did not affect non-playful social interaction. Conclusions These data show that both acute and constitutive increases in serotonergic neurotransmission reduce social play behaviour in peri-adolescent rats. Together with our previous findings of reduced aggressive and sexual behaviour in adult serotonin transporter knockout rats, these data support the notion that serotonin modulates social behaviour in a trait-like manner. PMID:17661017

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

Long-term consumption of fish oil-enriched diet impairs serotonin hypophagia in rats.

PubMed

Watanabe, Regina L H; Andrade, Iracema S; Telles, Mônica M; Albuquerque, Kelse T; Nascimento, Cláudia M O; Oyama, Lila M; Casarini, Dulce E; Ribeiro, Eliane B

2010-10-01

Hypothalamic serotonin inhibits food intake and stimulates energy expenditure. High-fat feeding is obesogenic, but the role of polyunsaturated fats is not well understood. This study examined the influence of different high-PUFA diets on serotonin-induced hypophagia, hypothalamic serotonin turnover, and hypothalamic protein levels of serotonin transporter (ST), and SR-1B and SR-2C receptors. Male Wistar rats received for 9 weeks from weaning a diet high in either soy oil or fish oil or low fat (control diet). Throughout 9 weeks, daily intake of fat diets decreased such that energy intake was similar to that of the control diet. However, the fish group developed heavier retroperitoneal and epididymal fat depots. After 12 h of either 200 or 300 μg intracerebroventricular serotonin, food intake was significantly inhibited in control group (21-25%) and soy group (37-39%) but not in the fish group. Serotonin turnover was significantly lower in the fish group than in both the control group (-13%) and the soy group (-18%). SR-2C levels of fish group were lower than those of control group (50%, P = 0.02) and soy group (37%, P = 0.09). ST levels tended to decrease in the fish group in comparison to the control group (16%, P = 0.339) and the soy group (21%, P = 0.161). Thus, unlike the soy-oil diet, the fish-oil diet decreased hypothalamic serotonin turnover and SR-2C levels and abolished serotonin-induced hypophagia. Fish-diet rats were potentially hypophagic, suggesting that, at least up to this point in its course, the serotonergic impairment was either compensated by other factors or not of a sufficient extent to affect feeding. That fat pad weight increased in the absence of hyperphagia indicates that energy expenditure was affected by the serotonergic hypofunction.

Evidence that coded-wire-tagging procedures can enhance transmission of Renibacterium salmoninarum in chinook salmon

USGS Publications Warehouse

Elliott, D.G.; Pascho, R.J.

2001-01-01

Binary coded wire tags (CWTs) are used extensively for identification and management of anadromous salmonid populations. A study of bacterial kidney disease (BKD) in two brood year groups of hatchery-reared spring chinook salmon Oncorhynchus tshawytscha provided strong evidence that horizontal transmission of Renibacterium salmoninarum, the causative agent of BKD, might be enhanced by CWT-marking procedures. About 4 months after CWTs were implanted in the snouts of juvenile fish, 14-16 different tissues were sampled from each of 60 fish per brood year group for histological analysis. Of the fish that were positive for R. salmoninarum by histological examination, 41% (7 of 17) of the 1988 brood year fish and 24% (10 of 42) of the 1989 brood year fish had BKD lesions confined to the head near the site of tag implantation. These lesions often resulted in the destruction of tissues of one or both olfactory organs. No focal snout infections were observed in fish that had not been marked with CWTs. Further data obtained from tissue analyses by use of an enzyme-linked immunosorbent assay and a fluorescent antibody test for detection of R. salmoninarum supported the hypothesis that infections of R. salmoninarum can be initiated in the snout tissues of CWT-marked fish and then spread to other organs. The tagging procedures might promote transmission of the pathogen among fish via contaminated tagging needles, by facilitating the entry of pathogens through the injection wound, or both. Limited evidence from this study suggested that implantation of passive integrated transponder tags in the peritoneal cavities of fish might also promote the transmission of R. salmoninarum or exacerbate existing infections. The results indicated a need for strict sanitary procedures during the tagging of fish in populations positive for R. salmoninarum to reduce the probability of enhanced horizontal transmission of the pathogen.

Activation of α7 nicotinic acetylcholine receptors persistently enhances hippocampal synaptic transmission and prevents Aß-mediated inhibition of LTP in the rat hippocampus.

PubMed

Ondrejcak, Tomas; Wang, Qinwen; Kew, James N C; Virley, David J; Upton, Neil; Anwyl, Roger; Rowan, Michael J

2012-02-29

Nicotinic acetylcholine receptors mediate fast cholinergic modulation of glutamatergic transmission and synaptic plasticity. Here we investigated the effects of subtype selective activation of the α7 nicotinic acetylcholine receptors on hippocampal transmission and the inhibition of synaptic long-term potentiation by the Alzheimer's disease associated amyloid ß-protein (Aß). The α7 nicotinic acetylcholine receptor agonist "compound A" ((R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl))thiophene-2-carboxamide) induced a rapid-onset persistent enhancement of synaptic transmission in the dentate gyrus in vitro. Consistent with a requirement for activation of α7 nicotinic acetylcholine receptors, the type II α7-selective positive allosteric modulator PheTQS ((3aR, 4S, 9bS)-4-(4-methylphenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) potentiated, and the antagonist methyllycaconitine (MLA) prevented the persistent enhancement. Systemic injection of the agonist also induced a similar MLA-sensitive persistent enhancement of synaptic transmission in the CA1 area in vivo. Remarkably, although compound A did not affect control long-term potentiation (LTP) in vitro, it prevented the inhibition of LTP by Aß1-42 and this effect was inhibited by MLA. These findings strongly indicate that activation of α7 nicotinic acetylcholine receptors is sufficient to persistently enhance hippocampal synaptic transmission and to overcome the inhibition of LTP by Aß. Copyright © 2011 Elsevier B.V. All rights reserved.

Enhanced infrared transmission through subwavelength hole arrays in a thin gold film mounted with dielectric micro-domes

NASA Astrophysics Data System (ADS)

Kumar, Raghwendra; Ramakrishna, S. Anantha

2018-04-01

Dielectric micro-domes were mounted on the subwavelength holes of a periodically perforated gold film such that a lens-like micro-dome covers each hole. In comparison to the extraordinary transmission through an array of bare holes in the gold film, this structure showed a further enhanced transmission over a larger range of incident angles with much larger bandwidth at mid-wave infrared wavelengths (3-4.5~μ m). The structure was fabricated using laser interference lithography, a novel back-exposure with an ultra-violet laser, and lift-off process that left behind the micro-domes of SU-8, covering each of the holes in the gold film. The measured transmittance of these perforated gold films, with and without the micro-domes, was verified by electromagnetic wave simulations. The enhanced transmittance arises from the scattered electromagnetic fields of the micro-domes, which couple the incident light efficiently via the scattered near-fields into the waveguide modes of holes in the plasmonic film. The increased transmittance and the highly enhanced and localized near-fields can be used to enhance the photo-response of infrared detectors over relevant bands, for example, the 3-4.5~μ m band that is used for thermal imaging applications.

ENHANCED 5-HT1A RECEPTOR-DEPENDENT FEEDBACK CONTROL OVER DORSAL RAPHE SEROTONIN NEURONS IN THE SERT KNOCKOUT MOUSE

PubMed Central

Soiza-Reilly, Mariano; Goodfellow, Nathalie M.; Lambe, Evelyn K.; Commons, Kathryn G.

2014-01-01

5-HT1A receptors are widely expressed in the brain and play a critical role in feedback inhibition of serotonin (5-HT) neurons through multiple mechanisms. Yet, it remains poorly understood how these feedback mechanisms, particularly those involving long-range projections, adapt in mood disorders. Here, we examined several aspects of 5-HT1A receptor function in the 5-HT transporter knockout mouse (SERT-KO), a model of vulnerability to stress and mood disorders. We found that in comparison to wild-type (WT) mice, SERT-KO mice had more passive coping in response to acute swim stress and this was accompanied by hypo-activation of medial prefrontal cortex (mPFC) Fos expression. Both of these effects were reversed by systemically blocking 5-HT1A receptors. Ex-vivo electrophysiological experiments showed that 5-HT exerted greater 5-HT1A-mediated inhibitory effects in the mPFC of SERT-KO mice compared to WT. Since 5-HT1A receptors in the mPFC provide a key feedback regulation of the dorsal raphe nucleus (DRN), we used a disinhibition strategy to examined endogenous feedback control of 5-HT neurons. Blocking 5-HT1A receptors disinhibited several fold more 5-HT neurons in the DRN of SERT-KO than in WT mice, revealing the presence of enhanced feedback inhibition of 5-HT neurons in the SERT-KO. Taken together our results indicate that increased stress sensitivity in the SERT-KO is associated with the enhanced capacity of 5-HT1A receptors to inhibit neurons in the mPFC as well as to exert feedback inhibition of DRN 5-HT neurons. PMID:25261781

Tryptophan availability modulates serotonin release from rat hypothalamic slices

NASA Technical Reports Server (NTRS)

Schaechter, Judith D.; Wurtman, Richard J.

1989-01-01

The relationship between the tryptophan availability and serononin release from rat hypothalamus was investigated using a new in vitro technique for estimating rates at which endogenous serotonin is released spontaneously or upon electrical depolarization from hypothalamic slices superfused with a solution containing various amounts of tryptophan. It was found that the spontaneous, as well as electrically induced, release of serotonin from the brain slices exhibited a dose-dependent relationship with the tryptophan concentration of the superfusion medium.

Linezolid-induced serotonin syndrome

PubMed Central

Gupta, Vishal; Karnik, Niteen D; Deshpande, Rushikesh; Patil, Meenakshi Amit

2013-01-01

A young drug abuser was admitted to our intensive care unit for organophosphorus poisoning. He required mechanical ventilation and was started empirically on linezolid for suspected nosocomial infection. The patient developed high-grade fever with altered sensorium and clonus. Serotonin syndrome was suspected and the patient was started on cyproheptadine. He recovered within 3 days of withdrawing linezolide and administering cyproheptadine. PMID:23513014

On the possible quantum role of serotonin in consciousness.

PubMed

Tonello, Lucio; Cocchi, Massimo; Gabrielli, Fabio; Tuszynski, Jack A

2015-09-01

Cell membrane's fatty acids (FAs) have been carefully investigated in neurons and platelets in order to study a possible connection to psychopathologies. An important link between the FA distribution and membrane dynamics appears to emerge with the cytoskeleton dynamics. Microtubules (MTs) in particular have been implicated in some recent quantum consciousness models and analyses. The recently proposed quantum model of Craddock et al. (2014) states that MTs possess structural and functional characteristics that are consistent with collective quantum coherent excitations in the aromatic groups of their tryptophan residues. These excitations are consistent with a clocking mechanism on a sub-nanosecond scale. This mechanism and analogous phenomena in light-harvesting complexes in plants and bacteria, are induced by photons and have been touted as evidence of quantum processes in biology. A possible source of intra-cellular photons could be membrane lipid peroxidation processes, so the FA profile could then be linked to the bio-photon emission. The model presented here suggests new ways to understand the role serotonin plays in relation to FAs. In plants, tryptophan conversion of light to exciton energy can participate in the directional orientation of leaves toward sunlight. Since serotonin is structurally similar to tryptophan, in the human brain, neurons could use tryptophan to capture photons and also use serotonin to initiate movement toward the source of light. Hence, we postulate two possible new roles for serotonin: (1) as an antioxidant, in order to counter-balance the oxidative effect of FAs, and (2) to participate in quantum interactions with MTs, in the same way as anesthetics and psychoactive compounds have been recently shown to act. In this latter case, the FA profile could provide an indirect measure of serotonin levels.

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.

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.

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

Acute serotonin depletion releases motivated inhibition of response vigour.

PubMed

den Ouden, Hanneke E M; Swart, Jennifer C; Schmidt, Kristin; Fekkes, Durk; Geurts, Dirk E M; Cools, Roshan

2015-04-01

The neurotransmitter serotonin has long been implicated in the motivational control of behaviour. Recent theories propose that the role of serotonin can be understood in terms of an interaction between a motivational and a behavioural activation axis. Experimental support for these ideas, however, has been mixed. In the current study, we aimed to investigate the role of serotonin (5HT) in behavioural vigour as a function of incentive motivation. We employed dietary acute tryptophan depletion (ATD) to lower the 5HT precursor tryptophan during the performance of a speeded visual discrimination task. Feedback valence and feedback probability were manipulated independently and cued prior to target onset. On feedback trials, fast correct responses led to either reward or avoidance of punishment, while slow or incorrect responses led to reward omission or punishment. We show that behavioural responding is inhibited under high incentive motivation (i.e. high-feedback probability) at baseline 5HT levels and that lowering these leads to behavioural disinhibition, while leaving accuracy unaffected. Surprisingly, there were no differential effects of motivational valence, with 5HT depletion releasing behavioural inhibition under both appetitive and aversive motivation. Our findings extend current theories on the role of 5HT in behavioural inhibition by showing that reductions in serotonin lead to increased behavioural vigour only if there is a motivational drive to inhibit behaviour at baseline.

Serotonin as a Biomarker: Stress Resilience among Battlefield Airmen Trainees

DTIC Science & Technology

2016-05-21

Report 3 . DATES COVERED (From – To) January 2015 – May 2016 4. TITLE AND SUBTITLE Serotonin as a Biomarker: Stress Resilience among Battlefield...failed (33.3%), and 3 (14.3%) self-initiated elimination. Discriminant analysis showed that subjects with increased serotonin levels were more likely to... 3 Table 2. p-Values for t-Tests for Differences between Graduates and Failures and p-values for F

Serotonin transporter promoter variants: Analysis in Indian autistic and control population.

PubMed

Guhathakurta, Subhrangshu; Ghosh, Sagarmoy; Sinha, Swagata; Chatterjee, Anindita; Ahmed, Shabina; Chowdhury, Susanta Roy; Gangopadhyay, Prasanta Kumar; Ghosh, Saurabh; Singh, Manoranjan; Usha, Rajamma

2006-05-30

Serotonin transporter (5-HTT) is a transmembrane protein belonging to Na+/Cl- dependent membrane transporter family and transports 5-HT across the membranes of presynaptic neurons. 5-HTT-linked polymorphic region (5-HTTLPR) gained much interest because of the differential regulation of expression and activity of 5-HTT by its various genotypes. A population-based study has been conducted on 5-HTTLPR with 358 individuals, which included 79 autistic probands, 136 parents, and 143 controls from two subpopulations of east and northeast regions of India. The genotypic frequencies of all the groups conform to Hardy-Weinberg equilibrium. With the finding of efficacy of serotonin reuptake inhibitors in ameliorating ritualistic behavior in autistic disorder, 5-HTT emerged as a putative candidate gene for autism and association studies have been carried out in different ethnic populations. But these studies were inconclusive due to conflicting results on association. Because such a study has never been performed in the Indian population, we have tested the possible involvement of 5-HTTLPR polymorphism with autism. The present study failed to establish any association or linkage of 5-HTTLPR with autism in the Indian population by case-control studies (chi2 = 1.314, P = 0.63) and family-based approaches (TDT chi2 = 0.22, P = 0.64 and HHRR-chi2 = 0.25, P = 0.61). However, when a meta-analysis of all the available TDT data, inclusive of the present study is carried out, we observed a significant preferential transmission of S-allele from parents to the affected offspring (chi2 = 7.51, P = 0.006) indicating an association of 5-HTTLPR with autism.

Serotonin projection patterns to the cochlear nucleus.

PubMed

Thompson, A M; Thompson, G C

2001-07-13

The cochlear nucleus is well known as an obligatory relay center for primary auditory nerve fibers. Perhaps not so well known is the neural input to the cochlear nucleus from cells containing serotonin that reside near the midline in the midbrain raphe region. Although the specific locations of the main, if not sole, sources of serotonin within the dorsal cochlear nucleus subdivision are known to be the dorsal and median raphe nuclei, sources of serotonin located within other cochlear nucleus subdivisions are not currently known. Anterograde tract tracing was used to label fibers originating from the dorsal and median raphe nuclei while fluorescence immunohistochemistry was used to simultaneously label specific serotonin fibers in cat. Biotinylated dextran amine was injected into the dorsal and median raphe nuclei and was visualized with Texas Red, while serotonin was visualized with fluorescein. Thus, double-labeled fibers were unequivocally identified as serotoninergic and originating from one of the labeled neurons within the dorsal and median raphe nuclei. Double-labeled fiber segments, typically of fine caliber with oval varicosities, were observed in many areas of the cochlear nucleus. They were found in the molecular layer of the dorsal cochlear nucleus, in the small cell cap region, and in the granule cell and external regions of the cochlear nuclei, bilaterally, of all cats. However, the density of these double-labeled fiber segments varied considerably depending upon the exact region in which they were found. Fiber segments were most dense in the dorsal cochlear nucleus (especially in the molecular layer) and the large spherical cell area of the anteroventral cochlear nucleus; they were moderately dense in the small cell cap region; and fiber segments were least dense in the octopus and multipolar cell regions of the posteroventral cochlear nucleus. Because of the presence of labeled fiber segments in subdivisions of the cochlear nucleus other than the

Serotonin2C receptors in the nucleus accumbens are involved in enhanced alcohol-drinking behavior

PubMed Central

Yoshimoto, Kanji; Watanabe, Yoshihisa; Tanaka, Masaki; Kimura, Minoru

2012-01-01

Dopamine and serotonin (5-HT) in the nucleus accumbens (ACC) and ventral tegmental area of the mesoaccumbens reward pathways have been implicated in the mechanisms underlying development of alcohol dependence. We used a C57BL/6J mouse model with increased voluntary alcohol-drinking behavior by exposing the mice to alcohol vapor for 20 consecutive days. In the alcohol-exposed mice, the expression of 5-HT2C receptor mRNA increased in the ACC, caudate nucleus and putamen, dorsal raphe nucleus (DRN), hippocampus and lateral hypothalamus, while the protein level of 5-HT2C receptor significantly increased in the ACC. The expression of 5-HT7 receptor mRNA increased in the ACC and DRN. Contents of 5-HT decreased in the ACC shell (ACCS) and DRN of the alcohol-exposed mice. The basal extracellular releases of dopamine (DA) and 5-HT in the ACCS increased more in the alcohol-exposed mice than in alcohol-naïve mice. The magnitude of the alcohol-induced ACCS DA and 5-HT release in the alcohol-exposed mice was increased compared with the control mice. Intraperitoneal (i.p.) administration or local injection into ACCS of the 5-HT2C receptor antagonist, SB-242084, suppressed voluntary alcohol-drinking behavior in the alcohol-exposed mice. But the i.p. administration of the 5-HT7 receptor antagonist, SB-258719, did not have significant effects on alcohol-drinking behavior in the alcohol-exposed mice. The effects of the 5-HT2C receptor antagonist were not observed in the air-exposed control mice. These results suggest that adaptations of the 5-HT system, especially the upregulation of 5-HT2C receptors in the ACCS, are involved in the development of enhanced voluntary alcohol-drinking behavior. PMID:22512261

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…

Crystal Structure of an LSD-Bound Human Serotonin Receptor

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

Wacker, Daniel; Wang, Sheng; McCorvy, John D.

The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT2B. The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD’s key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT2BR and 5-HT2AR—a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD’s slow binding kinetics may be due to a “lid” formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatlymore » accelerates LSD’s binding kinetics and selectively dampens LSD-mediated β-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD’s actions at human serotonin receptors.« less

Crystal Structure of an LSD-Bound Human Serotonin Receptor.

PubMed

Wacker, Daniel; Wang, Sheng; McCorvy, John D; Betz, Robin M; Venkatakrishnan, A J; Levit, Anat; Lansu, Katherine; Schools, Zachary L; Che, Tao; Nichols, David E; Shoichet, Brian K; Dror, Ron O; Roth, Bryan L

2017-01-26

The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT 2B . The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD's key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT 2B R and 5-HT 2A R-a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD's slow binding kinetics may be due to a "lid" formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatly accelerates LSD's binding kinetics and selectively dampens LSD-mediated β-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD's actions at human serotonin receptors. PAPERCLIP. Copyright © 2017 Elsevier Inc. All rights reserved.

Regulation of Pituitary Beta Endorphin Release: Role of Serotonin Neurons

DTIC Science & Technology

1983-12-15

degradable by peptidases , and had a molecular weight of 800-1200. Subsequently, the active factor present in extracts of pig brain was purified...argylene, a drug which prolong’s serotonin’s action at the synapse bv inhibiting enzvmatic degradation of serotonin, also ele- vated circulating...either he re-incorporated into storage granules or degraded enzymatically bv a monoamine oxidase (^tAO)/aldehyde dehydrogenase (ADH) nathvTay to 5

Enhancement of magneto-optical Faraday effects and extraordinary optical transmission in a tri-layer structure with rectangular annular arrays.

PubMed

Lei, Chengxin; Chen, Leyi; Tang, Zhixiong; Li, Daoyong; Cheng, Zhenzhi; Tang, Shaolong; Du, Youwei

2016-02-15

The properties of optics and magneto-optical Faraday effects in a metal-dielectric tri-layer structure with subwavelength rectangular annular arrays are investigated. It is noteworthy that we obtained the strongly enhanced Faraday rotation of the desired sign along with high transmittance by optimizing the parameters of the nanostructure in the visible spectral ranges. In this system, we obtained two extraordinary optical transmission (EOT) resonant peaks with enhanced Faraday rotations, whose signs are opposite, which may provide the possibility of designing multi-channel magneto-optical devices. Study results show that the maximum of the figure of merit (FOM) of the structure can be obtained between two EOT resonant peaks accompanied by an enhanced Faraday rotation. The positions of the maximum value of the FOM and resonant peaks of transmission along with a large Faraday rotation can be tailored by simply adjusting the geometric parameters of our models. These research findings are of great importance for future applications of magneto-optical devices.

Vagus nerve stimulation enhances perforant path-CA3 synaptic transmission via the activation of β-adrenergic receptors and the locus coeruleus.

PubMed

Shen, Huilian; Fuchino, Yuta; Miyamoto, Daisuke; Nomura, Hiroshi; Matsuki, Norio

2012-05-01

Vagus nerve stimulation (VNS) is an approved treatment for epilepsy and depression and has cognition-enhancing effects in patients with Alzheimer's disease. The hippocampus is widely recognized to be related to epilepsy, depression, and Alzheimer's disease. One possible mechanism of VNS involves its effect on the hippocampus; i.e. it increases the release of noradrenaline in the hippocampus. However, the effect of VNS on synaptic transmission in the hippocampus is unknown. To determine whether VNS modulates neurotransmission in the hippocampus, we examined the effects of VNS on perforant path (PP)-CA3 synaptic transmission electrophysiologically in anaesthetized rats. VNS induces a persistent enhancement of PP-CA3 field excitatory post-synaptic potentials (fEPSPs). Arc, an immediate early gene, was used to identify active brain regions after VNS. The locus coeruleus (LC), which contains the perikarya of noradrenergic projections, harboured more Arc-positive cells, as measured by in-situ hybridization, after 10-min VNS. In addition, electrical lesions of LC neurons or intraventricular administration of the β-adrenergic receptor antagonist timolol prevented the enhancement of PP-CA3 responses by VNS. In conclusion, the protracted increase in PP-CA3 synaptic transmission that is induced by VNS entails activation of the LC and β-adrenergic receptors. Our novel findings suggest that information from the periphery modulates synaptic transmission in the CA3 region of the hippocampus.

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

Tramadol: seizures, serotonin syndrome, and coadministered antidepressants.

PubMed

Sansone, Randy A; Sansone, Lori A

2009-04-01

This ongoing column is dedicated to the challenging clinical interface between psychiatry and primary care-two fields that are inexorably linked.Tramadol (Ultram(®)) is a commonly prescribed analgesic because of its relatively lower risk of addiction and better safety profile in comparison with other opiates. However, two significant adverse reactions are known to potentially occur with tramadol-seizures and serotonin syndrome. These two adverse reactions may develop during tramadol monotherapy, but appear much more likely to emerge during misuse/overdose as well as with the coadministration of other drugs, particularly antidepressants. In this article, we review the data relating to tramadol, seizures, and serotonin syndrome. This pharmacologic intersection is of clear relevance to both psychiatrists and primary care clinicians.

Enhanced synaptic transmission at the squid giant synapse by artificial seawater based on physically modified saline

PubMed Central

Choi, Soonwook; Yu, Eunah; Rabello, Guilherme; Merlo, Suelen; Zemmar, Ajmal; Walton, Kerry D.; Moreno, Herman; Moreira, Jorge E.; Sugimori, Mutsuyuki; Llinás, Rodolfo R.

2014-01-01

Superfusion of the squid giant synapse with artificial seawater (ASW) based on isotonic saline containing oxygen nanobubbles (RNS60 ASW) generates an enhancement of synaptic transmission. This was determined by examining the postsynaptic response to single and repetitive presynaptic spike activation, spontaneous transmitter release, and presynaptic voltage clamp studies. In the presence of RNS60 ASW single presynaptic stimulation elicited larger postsynaptic potentials (PSP) and more robust recovery from high frequency stimulation than in control ASW. Analysis of postsynaptic noise revealed an increase in spontaneous transmitter release with modified noise kinetics in RNS60 ASW. Presynaptic voltage clamp demonstrated an increased EPSP, without an increase in presynaptic ICa++ amplitude during RNS60 ASW superfusion. Synaptic release enhancement reached stable maxima within 5–10 min of RNS60 ASW superfusion and was maintained for the entire recording time, up to 1 h. Electronmicroscopic morphometry indicated a decrease in synaptic vesicle density and the number at active zones with an increase in the number of clathrin-coated vesicles (CCV) and large endosome-like vesicles near junctional sites. Block of mitochondrial ATP synthesis by presynaptic injection of oligomycin reduced spontaneous release and prevented the synaptic noise increase seen in RNS60 ASW. After ATP block the number of vesicles at the active zone and CCV was reduced, with an increase in large vesicles. The possibility that RNS60 ASW acts by increasing mitochondrial ATP synthesis was tested by direct determination of ATP levels in both presynaptic and postsynaptic structures. This was implemented using luciferin/luciferase photon emission, which demonstrated a marked increase in ATP synthesis following RNS60 administration. It is concluded that RNS60 positively modulates synaptic transmission by up-regulating ATP synthesis, thus leading to synaptic transmission enhancement. PMID:24575037

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.

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

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.

Enhanced serotonin response in the hippocampus of Galphaz protein knock-out mice.

PubMed

Oleskevich, Sharon; Leck, Kwong-Joo; Matthaei, Klaus; Hendry, Ian A

2005-06-21

The serotonin-1A [5-hydroxytryptamine 1A (5HT1A)] receptor is important for emotional and homeostatic processes in the central nervous system. In the hippocampus, the 5HT1A receptor couples to inhibitory Gi/o proteins to decrease pyramidal cell excitability. Here we investigate the 5HT1A receptor in a mouse deficient in the alpha-subunit of Gz protein (Galphaz knock-out). Behavioural tests showed heightened anxiety and depression-like behaviour in the Galphaz knock-out mice. Whole-cell recording in CA1 pyramidal neurons showed a significantly greater 5HT1A receptor-mediated potassium current in Galphaz knock-out mice. The effect was independent of 5HT4 receptors as the slow after-hyperpolarization was unaffected and a slow depolarization was absent in the Galphaz knock-out mice. Other receptors linked to Gi/o proteins [gamma-aminobutyric acid type B receptor (GABAB), adenosine A1 and muscarinic acetylcholine receptors] were not affected in Galphaz knock-out mice. These results suggest that the 5HT1A receptor may be linked to Galphaz protein, as reported previously in cell culture but shown here in an intact neural network.

Human tear serotonin levels correlate with symptoms and signs of dry eye

PubMed Central

Chhadva, Priyanka; Lee, Tinthu; Sarantopoulos, Constantine D.; Hackam, Abigail S.; McClellan, Allison L.; Felix, Elizabeth R.; Levitt, Roy C.; Galor, Anat

2015-01-01

Purpose Serotonin, a neurotransmitter known to be involved in nociceptor sensitization, is present in human tears. The purpose of this study was to correlate tear serotonin levels, as a marker of nociceptor sensitization, to facets of dry eye (DE) including symptoms and signs. Design Cross-sectional study Participants Sixty-two patients with normal eyelid and corneal anatomy were prospectively recruited from a Veterans Administration Ophthalmology Clinic over 11 months. Methods DE symptoms (Ocular Surface Disease Index [OSDI]), signs (tear break-up time [TBUT], corneal staining, and Schirmer’s score), and clinical descriptors of neuropathic ocular pain (NOP) (sensitivity to light and/or sensitivity to wind) were assessed. For tear analysis, each patient’s tears were collected after instilling 50µl of sterile saline to the lower cul-de-sac of each eye and using capillary action microcaps to collect the ocular wash. Tear serotonin levels were measured using enzyme-linked immunosorbent assay. Main Outcomes Measured Correlations between tear serotonin concentrations and DE symptoms and signs. Results The mean age of the population was 61±14 years and 84% (n=52) of the patients were male. Serotonin concentrations negatively correlated with Schirmer’s scores (r=−0.28; p=0.02), but did not correlate with other DE parameters, such as OSDI scores, sensitivity to light or wind, TBUT, or staining. According to our hypothesis, we divided patients into groups based on both DE symptoms and aqueous tear production; serotonin concentrations were found to be significantly higher in DE group 1 (OSDI≥6 and Schirmer’s<8) compared to both DE group 2 (OSDI≥6 and Schirmer’s≥8) and controls (OSDI<6 and Schirmer’s≥8). Patients in the DE group 2 more frequently complained of sensitivity to light (64%) and wind (67%) compared to the DE group 1 (40% and 60%, respectively) and controls (8% and 17%, respectively). Conclusion Patients with DE symptoms and aqueous tear

Enhancement of transmission of laser and other radiation by soft turbid physical and biological media

NASA Astrophysics Data System (ADS)

Askar'yan, G. A.

1982-07-01

An analysis is made and experimental results are reported of studies of the transmission of laser and other radiation by turbid physical and biological media, such as layers of a scattering medium or human tissue of thickness much greater than the characteristic attenuation length. It is reported that the transmission increases strongly as a result of depression and piercing of soft scattering media. A local pressure applied to a biological tissue produces a transmission enhancement considerably greater than compression of a layer of a physically turbid medium: this is due to the displacement of blood and of muscle out of the compressed region. A reduction in the scattering and absorption is expected to occur also in the case of rf and ionizing radiations, such as charged particles, x rays, gamma rays, etc. It is pointed out that this could be useful in deep irradiation carried out with the aim of inhibiting internal morbid processes (for example, in the spinal cord) and in treatment of neuroinfectious diseases (amyotrophic lateral sclerosis, multiple sclerosis, poliomyelitis, etc.), as well as in oncological conditions, ulcers, etc.

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.

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

The impact of peripheral serotonin on leptin-brain serotonin axis, bone metabolism and strength in growing rats with experimental chronic kidney disease.

PubMed

Pawlak, Dariusz; Domaniewski, Tomasz; Znorko, Beata; Oksztulska-Kolanek, Ewa; Lipowicz, Paweł; Doroszko, Michał; Karbowska, Malgorzata; Pawlak, Krystyna

2017-12-01

Chronic kidney disease (CKD) results in decreased bone strength. Serotonin (5-HT) is one of the critical regulators of bone health, fulfilling distinct functions depending on its synthesis site: brain-derived serotonin (BDS) favors osteoblast proliferation, whereas gut-derived serotonin (GDS) inhibits it. We assessed the role of BDS and peripheral leptin in the regulation of bone metabolism and strength in young rats with 5/6 nephrectomy. BDS synthesis was accelerated during CKD progression. Decreased peripheral leptin in CKD rats was inversely related to BDS content in the hypothalamus, brainstem and frontal cortex. Serotonin in these brain regions affected bone strength and metabolism in the studied animals. The direct effect of circulating leptin on bone was not shown in uremia. At the molecular level, there was an inverse association between elevated GDS and the expression of cAMP responsive element-binding protein (Creb) gene in bone of CKD animals. In contrast, increased expression of activating transcription factor 4 (Atf4) was shown, which was associated with GDS-dependent transcription factor 1 (Foxo1), clock gene - Cry-1, cell cycle genes: c-Myc, cyclins, and osteoblast differentiation genes. These results identified a previously unknown molecular pathway, by which elevated GDS can shift in Foxo1 target genes from Creb to Atf4-dependent response, disrupting the leptin-BDS - dependent gene pathway in the bone of uremic rats. Thus, in the condition of CKD the effect of BDS and GDS on bone metabolism and strength can't be distinguished. Copyright © 2017 Elsevier Inc. All rights reserved.

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

PubMed

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

2014-05-01

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

Tributyltin impaired reproductive success in female zebrafish through disrupting oogenesis, reproductive behaviors and serotonin synthesis.

PubMed

Xiao, Wei-Yang; Li, Ying-Wen; Chen, Qi-Liang; Liu, Zhi-Hao

2018-07-01

Tributyltin (TBT), an organotin acting as aromatase (Cyp19a1) inhibitor, has been found to disrupt gametogenesis and reproductive behaviors in several fish species. However, few studies addressing the mechanisms underlying the impaired gametogenesis and reproduction have been reported. In this study, female adults of zebrafish (Danio rerio) were continuously exposed to two nominal concentrations of TBT (100 and 500 ng/L, actual concentrations: 90.8 ± 1.3 ng/L and 470.3 ± 2.7 ng/L, respectively) for 28 days. After exposures, TBT decreased the total egg number, reduced the hatchability and elevated the mortality of the larvae. Decreased gonadosomatic index (GSI) and altered percentages of follicles in different developmental stages (increased early-stage follicles and reduced mid/late-stage follicles) were also observed in the ovary of TBT-treated fish. TBT also lowered the plasma level of 17β-estradiol and suppressed the expressions of cyp19a1a in the ovary. In treated fish, up-regulated expressions of aldhla2, sycp3 and dmc1 were present in the ovary, indicating an enhanced level of meiosis. The mRNA level of vtg1 was dramatically suppressed in the liver of TBT-treated fish, suggesting an insufficient synthesis of Vtg protein, consistent with the decreased percentage of mid/late-stage follicles in the ovaries. Moreover, TBT significantly suppressed the reproductive behaviors of the female fish (duration of both sexes simultaneously in spawning area, the frequency of meeting and the visit in spawning area) and down-regulated the mRNA levels of genes involved in the regulation of reproductive behaviors (cyp19a1b, gnrh-3 and kiss 2) in the brain. In addition, TBT significantly suppressed the expressions of serotonin-related genes, such as tph2 (encoding serotonin synthase), pet1 (marker of serotonin neuron) and kiss 1 (the modulator of serotonin synthesis), suggesting that TBT might disrupt the non-reproductive behaviors of zebrafish. The present

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.

Interaction between serotonin transporter and serotonin receptor 1 B genes polymorphisms may be associated with antisocial alcoholism.

PubMed

Wang, Tzu-Yun; Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chen, Shih-Heng; Chu, Chun-Hsien; Huang, San-Yuan; Tzeng, Nian-Sheng; Wang, Chen-Lin; Lee, I Hui; Yeh, Tzung Lieh; Yang, Yen Kuang; Lu, Ru-Band

2012-07-11

Several studies have hypothesized that genes regulating the components of the serotonin system, including serotonin transporter (5-HTTLPR) and serotonin 1 B receptor (5-HT1B), may be associated with alcoholism, but their results are contradictory because of alcoholism's heterogeneity. Therefore, we examined whether the 5-HTTLPR gene and 5-HT1B gene G861C polymorphism are susceptibility factors for a specific subtype of alcoholism, antisocial alcoholism in Han Chinese in Taiwan. We recruited 273 Han Chinese male inmates with antisocial personality disorder (ASPD) [antisocial alcoholism (AS-ALC) group (n=120) and antisocial non-alcoholism (AS-N-ALC) group (n=153)] and 191 healthy male controls from the community. Genotyping was done using PCR-RFLP. There were no significant differences in the genotypic frequency of the 5-HT1B G861C polymorphism between the 3 groups. Although AS-ALC group members more frequently carried the 5-HTTLPR S/S, S/LG, and LG/LG genotypes than controls, the difference became non-significant after controlling for the covarying effects of age. However, the 5-HTTLPR S/S, S/LG, and LG/LG genotypes may have interacted with the 5-HT1B G861C C/C polymorphism and increased the risk of becoming antisocial alcoholism. Our study suggests that neither the 5-HTTLPR gene nor the 5-HT1B G861C polymorphism alone is a risk factor for antisocial alcoholism in Taiwan's Han Chinese population, but that the interaction between both genes may increase susceptibility to antisocial alcoholism.

Mechanisms and environmental factors that underlying the intensification of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced serotonin syndrome in rats

PubMed Central

Tao, Rui; Shokry, Ibrahim M.; Callanan, John J.; Adams, H. Daniel; Ma, Zhiyuan

2014-01-01

Rationale Illicit use of MDMA (3,4-methylenedioxymethamphetamine; Ecstasy) may cause a mild or severe form of the serotonin syndrome. The syndrome intensity is not just influenced by drug doses but also by environmental factors. Objectives Warm environmental temperatures and physical activity are features of raves. The purpose of this study was to assess how these two factors can potentially intensify the syndrome. Methods Rats were administered MDMA at doses of 0.3, 1 or 3 mg/kg, and examined in the absence or presence of warm temperature and physical activity. The syndrome intensity was estimated by visual scoring for behavioral syndrome and also instrumentally measuring changes in symptoms of the syndrome. Results Our results showed that MDMA at 3 mg/kg, but not 0.3 or 1 mg/kg, caused a mild serotonin syndrome in rats. Each environmental factor alone moderately intensified the syndrome. When the two factors were combined, the intensification became more severe than each factor alone highlighting a synergistic effect. This intensification was blocked by the 5-HT2A receptor antagonist M100907, competitive NMDA receptor antagonist CGS19755, autonomic ganglionic blocker hexamethonium, and the benzodiazepine-GABAA receptor agonist midazolam, but not by the 5-HT1A receptor antagonist WAY100635 or nicotinic receptor antagonist methyllycaconitine. Conclusions Our data suggest that, in the absence of environmental factors, the MDMA-induced syndrome is mainly mediated through the serotonergic transmission (5HT-dependent mechanism), and therefore, is relatively mild. Warm temperature and physical activity facilitate serotonergic and other neural systems such as glutamatergic and autonomic transmissions, resulting in intensification of the syndrome (non-5HT mechanisms). PMID:25300903

Synthesis of graphene oxide grafted poly(lactic acid) with palladium nanoparticles and its application to serotonin sensing

NASA Astrophysics Data System (ADS)

Han, Hyoung Soon; You, Jung-Min; Jeong, Haesang; Jeon, Seungwon

2013-11-01

Graphene oxide (GO) has treated with methylene diphenyl diisocyanate (MDI) and subsequent 1,4-butanediol (BD) to create an anchoring OH site on the surface of GO (GO-MDI-OH). The OH groups of GO-MDI-OH were the initiators of the polymerization of poly(lactic acid) (PLA). The subsequent GO-g-PLA was synthesized by the polymerization reaction in the presence of GO-MDI-OH and PLA. The synthesized materials were characterized via 1H-NMR, Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), thermal analysis (differential scanning calorimeter (DSC), and thermogravimetric analysis (TGA)). The surface morphologies and degree of dispersions at G-g-PLA-metals were observed using a field emission scanning electron microscope (FE-SEM) and a transmission electron microscopy (TEM). The electrical conductivity of G-g-PLA-Pd was largely enhanced compared with those of GO and GO-g-PLA. G-g-PLA-Pd was used for the electrochemical detection of serotonin. Electrocatalytic activities were verified from the cyclic voltammetry (CV) and amperometric response in a 0.1 M phosphate buffer solution (PBS). A significantly higher concentration range (0.1-100.0 μM) and a lower detection limit (8.0 × 10-8 M, where s/n = 3) were found at the G-g-PLA-Pd modified glassy carbon electrode (GCE).

Docosahexaenoyl serotonin emerges as most potent inhibitor of IL-17 and CCL-20 released by blood mononuclear cells from a series of N-acyl serotonins identified in human intestinal tissue.

PubMed

Wang, Ya; Balvers, Michiel G J; Hendriks, Henk F J; Wilpshaar, Tessa; van Heek, Tjarda; Witkamp, Renger F; Meijerink, Jocelijn

2017-09-01

Fatty acid amides (FAAs), conjugates of fatty acids with ethanolamine, mono-amine neurotransmitters or amino acids are a class of molecules that display diverse functional roles in different cells and tissues. Recently we reported that one of the serotonin-fatty acid conjugates, docosahexaenoyl serotonin (DHA-5-HT), previously found in gut tissue of mouse and pig, attenuates the IL-23-IL-17 signaling axis in LPS-stimulated mice macrophages. However, its presence and effects in humans remained to be elucidated. Here, we report for the first time its identification in human intestinal (colon) tissue, along with a series of related N-acyl serotonins. Furthermore, we tested these fatty acid conjugates for their ability to inhibit the release of IL-17 and CCL-20 by stimulated human peripheral blood mononuclear cells (PBMCs). Serotonin conjugates with palmitic acid (PA-5-HT), stearic acid (SA-5-HT) and oleic acid (OA-5-HT) were detected in higher levels than arachidonoyl serotonin (AA-5-HT) and DHA-5-HT, while eicosapentaenoyl serotonin (EPA-5-HT) could not be quantified. Among these, DHA-5-HT was the most potent in inhibiting IL-17 and CCL-20, typical Th17 pro-inflammatory mediators, by Concanavalin A (ConA)-stimulated human PBMCs. These results underline the idea that DHA-5-HT is a gut-specific endogenously produced mediator with the capacity to modulate the IL-17/Th17 signaling response. Our findings may be of relevance in relation to intestinal inflammatory diseases like Crohn's disease and Ulcerative colitis. Copyright © 2017. Published by Elsevier B.V.

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

The Protective Action Encoding of Serotonin Transients in the Human Brain.

PubMed

Moran, Rosalyn J; Kishida, Kenneth T; Lohrenz, Terry; Saez, Ignacio; Laxton, Adrian W; Witcher, Mark R; Tatter, Stephen B; Ellis, Thomas L; Phillips, Paul Em; Dayan, Peter; Montague, P Read

2018-05-01

The role of serotonin in human brain function remains elusive due, at least in part, to our inability to measure rapidly the local concentration of this neurotransmitter. We used fast-scan cyclic voltammetry to infer serotonergic signaling from the striatum of 14 brains of human patients with Parkinson's disease. Here we report these novel measurements and show that they correlate with outcomes and decisions in a sequential investment game. We find that serotonergic concentrations transiently increase as a whole following negative reward prediction errors, while reversing when counterfactual losses predominate. This provides initial evidence that the serotonergic system acts as an opponent to dopamine signaling, as anticipated by theoretical models. Serotonin transients on one trial were also associated with actions on the next trial in a manner that correlated with decreased exposure to poor outcomes. Thus, the fluctuations observed for serotonin appear to correlate with the inhibition of over-reactions and promote persistence of ongoing strategies in the face of short-term environmental changes. Together these findings elucidate a role for serotonin in the striatum, suggesting it encodes a protective action strategy that mitigates risk and modulates choice selection particularly following negative environmental events.

Serotonin transporter gene polymorphism and psychiatric disorders: Is there a link?

PubMed Central

Margoob, Mushtaq A.; Mushtaq, Dhuha

2011-01-01

Though still in infancy, the field of psychiatric genetics holds great potential to contribute to the development of new diagnostic and therapeutic options to treat these disorders. Among a large number of existing neurotransmitter systems, the serotonin system dysfunction has been implicated in many psychiatric disorders and therapeutic efficacy of many drugs is also thought to be based on modulation of serotonin. Serotonin transporter gene polymorphism is one of the most extensively studied polymorphisms in psychiatric behavioral genetics. In this article, we review the status of evidence for association between the serotonin gene polymorphism and some common mental disorders like affective disorders, post-traumatic stress disorder, obsessive-compulsive disorder, suicide, autism, and other anxiety and personality disorders. Going beyond traditional association studies, gene-environment interaction, currently gaining momentum, is also discussed in the review. While the existing information of psychiatric genetics is inadequate for putting into practice genetic testing in the diagnostic work-up of the psychiatric patient, if consistent in future research attempts, such results can be of great help to improve the clinical care of a vast majority of patients suffering from such disorders. PMID:22303036

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

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.

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.

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

Fatal serotonin toxicity caused by moclobemide and fluoxetine overdose.

PubMed

Wu, Ming-Ling; Deng, Jou-Fang

2011-01-01

Both moclobemide and fluoxetine are used in the treatment of depression, and have been shown to produce fewer side effects than conventional tricyclic antidepressants. A combination of moclobemide and fluoxetine has been used in refractory depression, however there is potential for severe serotonin toxicity. We describe a lethal case of serotonin toxicity in a 36 year-old woman after she ingested multiple drugs, including moclobemide 4500 mg, fluoxetine 200 mg, propranolol 300 mg and several benzodiazepines. The clinical features included coma, mydriasis, hyperthermia, tremor, hyperreflexia, rhabdomyolysis, renal failure and respiratory insufficiency. Eventually, the patient died of disseminated intravascular coagulation and circulatory collapse at 22.5 h postingestion. Toxicological analysis of the patient's blood confirmed high levels of moclobemide 150 μg/mL (therapeutic 1-3 μg/mL), fluoxetine 3750 ng/mL (therapeutic 47-469 ng/mL) and several benzodiazepines. In conclusion, a combination of moclobemide and fluoxetine should be avoided in depressed patients with high suicidal tendencies. Moreover, early recognition and aggressive intervention are the mainstays in the management of potentially life-threatening serotonin toxicity.

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.

Ethanol produces corticotropin releasing factor receptor-dependent enhancement of spontaneous glutamatergic transmission in the mouse central amygdala

PubMed Central

Silberman, Yuval; Fetterly, Tracy L.; Awad, Elias K.; Milano, Elana J.; Usdin, Ted B.; Winder, Danny G.

2015-01-01

Background Ethanol modulation of Central Amygdala (CeA) neurocircuitry plays a key role in the development of alcoholism via activation of the corticotropin releasing factor (CRF) receptor system. Previous work has predominantly focused on ethanol/CRF interactions on the CeA GABA circuitry; however our lab recently showed that CRF enhances CeA glutamatergic transmission. Therefore, this study sought to determine if ethanol modulates CeA glutamate transmission via activation of CRF signaling. Methods The effects of ethanol on spontaneous excitatory postsynaptic currents (sEPSCs) and basal resting membrane potentials were examined via standard electrophysiology methods in adult male C57BL/6J mice. Local ablation of CeA CRF neurons (CRFCeAhDTR) was achieved by targeting the human diphtheria toxin receptor (hDTR) to CeA CRF neurons with an adeno-associated virus. Ablation was quantified post-hoc with confocal microscopy. Genetic targeting of the diphtheria toxin active subunit to CRF neurons (CRFDTA mice) ablated CRF neurons throughout the CNS, as assessed by qRT-PCR quantification of CRF mRNA. Results Acute bath application of ethanol significantly increased sEPSC frequency in a concentration dependent manner in CeA neurons, and this effect was blocked by pretreatment of co-applied CRF receptor 1 and CRF receptor 2 antagonists. In experiments utilizing a CRF-tomato reporter mouse, ethanol did not significantly alter the basal membrane potential of CeA CRF neurons. The ability of ethanol to enhance CeA sEPSC frequency was not altered in CRFCeAhDTR mice despite a ~78% reduction in CeA CRF cell counts. The ability of ethanol to enhance CeA sEPSC frequency was also not altered in the CRFDTA mice despite a three-fold reduction in CRF mRNA levels. Conclusion These findings demonstrate that ethanol enhances spontaneous glutamatergic transmission in the CeA via a CRF receptor dependent mechanism. Surprisingly, our data suggest that this action may not require endogenous CRF

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.

Serotonin depletion induces pessimistic-like behavior in a cognitive bias paradigm in pigs.

PubMed

Stracke, Jenny; Otten, Winfried; Tuchscherer, Armin; Puppe, Birger; Düpjan, Sandra

2017-05-15

Cognitive and affective processes are highly interrelated. This has implications for neuropsychiatric disorders such as major depressive disorder in humans but also for the welfare of non-human animals. The brain serotonergic system might play a key role in mediating the relationship between cognitive functions and affective regulation. The aim of our study was to examine the influence of serotonin depletion on the affective state and cognitive processing in pigs, an important farm animal species but also a potential model species for biomedical research in humans. For this purpose, we modified a serotonin depletion model using para-chlorophenylalanine (pCPA) to decrease serotonin levels in brain areas involved in cognitive and affective processing (part 1). The consequences of serotonin depletion were then measured in two behavioral tests (part 2): the spatial judgement task (SJT), providing information about the effects of the affective state on cognitive processing, and the open field/novel object (OFNO) test, which measures behavioral reactions to novelty that are assumed to reflect affective state. In part 1, 40 pigs were treated with either pCPA or saline for six consecutive days. Serotonin levels were assessed in seven different brain regions 4, 5, 6, 11 and 13days after the first injection. Serotonin was significantly depleted in all analyzed brain regions up to 13days after the first application. In part 2, the pCPA model was applied to 48 animals in behavioral testing. Behavioral tests, the OFNO test and the SJT, were conducted both before and after pCPA/saline injections. While results from the OFNO tests were inconclusive, an effect of treatment as well as an effect of the phase (before and after treatment) was observed in the SJT. Animals treated with pCPA showed more pessimistic-like behavior, suggesting a more negative affective state due to serotonin depletion. Thus, our results confirm that the serotonergic system is a key player in cognitive

Characterization of the Caenorhabditis elegans G protein-coupled serotonin receptors.

PubMed

Carre-Pierrat, Maïté; Baillie, David; Johnsen, Robert; Hyde, Rhonda; Hart, Anne; Granger, Laure; Ségalat, Laurent

2006-12-01

Serotonin (5-HT) regulates a wide range of behaviors in Caenorhabditis elegans, including egg laying, male mating, locomotion and pharyngeal pumping. So far, four serotonin receptors have been described in the nematode C. elegans, three of which are G protein-coupled receptors (GPCR), (SER-1, SER-4 and SER-7), and one is an ion channel (MOD-1). By searching the C. elegans genome for additional 5-HT GPCR genes, we identified five further genes which encode putative 5-HT receptors, based on sequence similarities to 5-HT receptors from other species. Using loss-of-function mutants and RNAi, we performed a systematic study of the role of the eight GPCR genes in serotonin-modulated behaviors of C. elegans (F59C12.2, Y22D7AR.13, K02F2.6, C09B7.1, M03F4.3, F16D3.7, T02E9.3, C24A8.1). We also examined their expression patterns. Finally, we tested whether the most likely candidate receptors were able to modulate adenylate cyclase activity in transfected cells in a 5-HT-dependent manner. This paper is the first comprehensive study of G protein-coupled serotonin receptors of C. elegans. It provides a direct comparison of the expression patterns and functional roles for 5-HT receptors in C. elegans.

Serotonin depletion increases seizure susceptibility and worsens neuropathological outcomes in kainate model of epilepsy.

PubMed

Maia, Gisela H; Brazete, Cátia S; Soares, Joana I; Luz, Liliana L; Lukoyanov, Nikolai V

2017-09-01

Serotonin is implicated in the regulation of seizures, but whether or not it can potentiate the effects of epileptogenic factors is not fully established. Using the kainic acid model of epilepsy in rats, we tested the effects of serotonin depletion on (1) susceptibility to acute seizures, (2) development of spontaneous recurrent seizures and (3) behavioral and neuroanatomical sequelae of kainic acid treatment. Serotonin was depleted by pretreating rats with p-chlorophenylalanine. In different groups, kainic acid was injected at 3 different doses: 6.5mg/kg, 9.0mg/kg or 12.5mg/kg. A single dose of 6.5mg/kg of kainic acid reliably induced status epilepticus in p-chlorophenylalanine-pretreated rats, but not in saline-pretreated rats. The neuroexcitatory effects of kainic acid in the p-chlorophenylalanine-pretreated rats, but not in saline-pretreated rats, were associated with the presence of tonic-clonic convulsions and high lethality. Compared to controls, a greater portion of serotonin-depleted rats showed spontaneous recurrent seizures after kainic acid injections. Loss of hippocampal neurons and spatial memory deficits associated with kainic acid treatment were exacerbated by prior depletion of serotonin. The present findings are of particular importance because they suggest that low serotonin activity may represent one of the major risk factors for epilepsy and, thus, offer potentially relevant targets for prevention of epileptogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

Serotonin in Autism and Pediatric Epilepsies

ERIC Educational Resources Information Center

Chugani, Diane C.

2004-01-01

Serotonergic abnormalities have been reported in both autism and epilepsy. This association may provide insights into underlying mechanisms of these disorders because serotonin plays an important neurotrophic role during brain development--and there is evidence for abnormal cortical development in both autism and some forms of epilepsy. This…

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 toxicity as a consequence of linezolid use in revision hip arthroplasty.

PubMed

Mason, Lyndon W; Randhawa, Kiran S; Carpenter, Eleanor C

2008-11-01

Linezolid is the first in a new group of antibiotics called oxazolidinones. As a potent antimicrobial, it has activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus, penicillin-resistant Streptococcus pneumoniae, and macrolide-resistant streptococci. There are several documented case reports of serotonin toxicity when used with selective serotonin reuptake inhibitors. The symptoms of serotonin syndrome are alteration of mental state, autonomic dysfunction, and neuromuscular disorders. This article presents a case of an interaction of the serotonin reuptake inhibitor venlafaxine and linezolid and the possible diagnostic problems that can occur. A 58-year-old woman presented with signs of systemic infection. Her medical history included bladder resection for transitional cell carcinoma, bilateral total hip arthroplasty (THA), and depression, for which she was on venlafaxine. Serological and imaging investigations revealed MRSA infection of the bilateral THA. The patient was started on vancomycin and rifampicin intravenously. As intravenous access was becoming problematic and long-term antibiotics were needed, treatment was changed to oral linezolid and oral rifampicin. Four days after the commencement of linezolid, the patient was acutely disorientated with generalized cerebellar signs and no autonomic dysfunction. A computed tomography scan of the head and lumbar puncture revealed no abnormal findings. A diagnosis of serotonin toxicity was made. The patient recovered when linezolid and venlafaxine were discontinued and supportive measures were provided. Linezolid is a popular choice of antibiotic, especially for the treatment of orthopedic-related MRSA infections. Patients who commonly require linezolid as an antimicrobial are those with complex infections where other antibiotic treatment has failed. It is therefore important to be vigilant with linezolid use. Physicians should be aware of the nonspecific presentation

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

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

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

1987-01-01

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

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

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.

TRIENNIAL LACTATION SYMPOSIUM/BOLFA: Serotonin and the regulation of calcium transport in dairy cows.

PubMed

Hernandez, L L

2017-12-01

The mammary gland regulates maternal metabolism during lactation. Numerous factors within the tissue send signals to shift nutrients to the mammary gland for milk synthesis. Serotonin is a monoamine that has been well documented to regulate several aspects of lactation among species. Maintenance of maternal calcium homeostasis during lactation is a highly evolved process that is elegantly regulated by the interaction of the mammary gland with the bone, gut, and kidney tissues. It is well documented that dietary calcium is insufficient to maintain maternal calcium concentrations during lactation, and mammals must rely on bone resorption to maintain normocalcemia. Our recent work focused on the ability of the mammary gland to function as an accessory parathyroid gland during lactation. It was demonstrated that serotonin acts to stimulate parathyroid hormone-related protein (PTHrP) in the mammary gland during lactation. The main role of mammary-derived PTHrP during mammalian lactation is to stimulate bone resorption to maintain maternal calcium homeostasis during lactation. In addition to regulating PTHrP, it was shown that serotonin appears to directly affect calcium transporters and pumps in the mammary gland. Our current working hypothesis regarding the control of calcium during lactation is as follows: serotonin directly stimulates PTHrP production in the mammary gland through interaction with the sonic hedgehog signaling pathway. Simultaneously, serotonin directly increases calcium movement into the mammary gland and, subsequently, milk. These 2 direct actions of serotonin combine to induce a transient maternal hypocalcemia required to further stimulate PTHrP production and calcium mobilization from bone. Through these 2 routes, serotonin is able to improve maternal calcium concentrations. Furthermore, we have shown that Holstein and Jersey cows appear to regulate calcium in different manners and also respond differently to serotonergic stimulation of the calcium

Serotonin, neural markers, and memory

PubMed Central

Meneses, Alfredo

2015-01-01

Diverse neuropsychiatric disorders present dysfunctional memory and no effective treatment exits for them; likely as result of the absence of neural markers associated to memory. Neurotransmitter systems and signaling pathways have been implicated in memory and dysfunctional memory; however, their role is poorly understood. Hence, neural markers and cerebral functions and dysfunctions are revised. To our knowledge no previous systematic works have been published addressing these issues. The interactions among behavioral tasks, control groups and molecular changes and/or pharmacological effects are mentioned. Neurotransmitter receptors and signaling pathways, during normal and abnormally functioning memory with an emphasis on the behavioral aspects of memory are revised. With focus on serotonin, since as it is a well characterized neurotransmitter, with multiple pharmacological tools, and well characterized downstream signaling in mammals' species. 5-HT1A, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 receptors as well as SERT (serotonin transporter) seem to be useful neural markers and/or therapeutic targets. Certainly, if the mentioned evidence is replicated, then the translatability from preclinical and clinical studies to neural changes might be confirmed. Hypothesis and theories might provide appropriate limits and perspectives of evidence. PMID:26257650

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.

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.

Serotonin 6 receptor controls Alzheimer's disease and depression.

PubMed

Yun, Hyung-Mun; Park, Kyung-Ran; Kim, Eun-Cheol; Kim, Sanghyeon; Hong, Jin Tae

2015-09-29

Alzheimer's disease (AD) and depression in late life are one of the most severe health problems in the world disorders. Serotonin 6 receptor (5-HT6R) has caused much interest for potential roles in AD and depression. However, a causative role of perturbed 5-HT6R function between two diseases was poorly defined. In the present study, we found that a 5-HT6R antagonist, SB271036 rescued memory impairment by attenuating the generation of Aβ via the inhibition of γ-secretase activity and the inactivation of astrocytes and microglia in the AD mouse model. It was found that the reduction of serotonin level was significantly recovered by SB271036, which was mediated by an indirect regulation of serotonergic neurons via GABA. Selective serotonin reuptake inhibitor (SSRI), fluoxetine significantly improved cognitive impairment and behavioral changes. In human brain of depression patients, we then identified the potential genes, amyloid beta (A4) precursor protein-binding, family A, member 2 (APBA2), well known AD modulators by integrating datasets from neuropathology, microarray, and RNA seq. studies with correlation analysis tools. And also, it was demonstrated in mouse models and patients of AD. These data indicate functional network of 5-HT6R between AD and depression.

Serotonin in the solitary tract nucleus shortens the laryngeal chemoreflex in anaesthetized neonatal rats.

PubMed

Donnelly, William T; Bartlett, Donald; Leiter, J C

2016-07-01

What is the central question of this study? Failure to terminate apnoea and arouse is likely to contribute to sudden infant death syndrome (SIDS). Serotonin is deficient in the brainstems of babies who died of SIDS. Therefore, we tested the hypothesis that serotonin in the nucleus of the solitary tract (NTS) would shorten reflex apnoea. What is the main finding and its importance? Serotonin microinjected into the NTS shortened the apnoea and respiratory inhibition associated with the laryngeal chemoreflex. Moreover, this effect was achieved through a 5-HT3 receptor. This is a new insight that is likely to be relevant to the pathogenesis of SIDS. The laryngeal chemoreflex (LCR), an airway-protective reflex that causes apnoea and bradycardia, has long been suspected as an initiating event in the sudden infant death syndrome. Serotonin (5-HT) and 5-HT receptors may be deficient in the brainstems of babies who die of sudden infant death syndrome, and 5-HT seems to be important in terminating apnoeas directly or in causing arousals or as part of the process of autoresuscitation. We hypothesized that 5-HT in the brainstem would limit the duration of the LCR. We studied anaesthetized rat pups between 7 and 21 days of age and made microinjections into the cisterna magna or into the nucleus of the solitary tract (NTS). Focal, bilateral microinjections of 5-HT into the caudal NTS significantly shortened the LCR. The 5-HT1a receptor antagonist, WAY 100635, did not affect the LCR consistently, nor did a 5-HT2 receptor antagonist, ketanserin, alter the duration of the LCR. The 5-HT3 specific agonist, 1-(3-chlorophenyl)-biguanide, microinjected bilaterally into the caudal NTS significantly shortened the LCR. Thus, endogenous 5-HT released within the NTS may curtail the respiratory depression that is part of the LCR, and serotonergic shortening of the LCR may be attributed to activation of 5-HT3 receptors within the NTS. 5-HT3 receptors are expressed presynaptically on C�

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.

Serotonin Signaling in Schistosoma mansoni: A Serotonin–Activated G Protein-Coupled Receptor Controls Parasite Movement

PubMed Central

Rashid, Mohammed; Ribeiro, Paula

2014-01-01

Serotonin is an important neuroactive substance in all the parasitic helminths. In Schistosoma mansoni, serotonin is strongly myoexcitatory; it potentiates contraction of the body wall muscles and stimulates motor activity. This is considered to be a critical mechanism of motor control in the parasite, but the mode of action of serotonin is poorly understood. Here we provide the first molecular evidence of a functional serotonin receptor (Sm5HTR) in S. mansoni. The schistosome receptor belongs to the G protein-coupled receptor (GPCR) superfamily and is distantly related to serotonergic type 7 (5HT7) receptors from other species. Functional expression studies in transfected HEK 293 cells showed that Sm5HTR is a specific serotonin receptor and it signals through an increase in intracellular cAMP, consistent with a 5HT7 signaling mechanism. Immunolocalization studies with a specific anti-Sm5HTR antibody revealed that the receptor is abundantly distributed in the worm's nervous system, including the cerebral ganglia and main nerve cords of the central nervous system and the peripheral innervation of the body wall muscles and tegument. RNA interference (RNAi) was performed both in schistosomulae and adult worms to test whether the receptor is required for parasite motility. The RNAi-suppressed adults and larvae were markedly hypoactive compared to the corresponding controls and they were also resistant to exogenous serotonin treatment. These results show that Sm5HTR is at least one of the receptors responsible for the motor effects of serotonin in S. mansoni. The fact that Sm5HTR is expressed in nerve tissue further suggests that serotonin stimulates movement via this receptor by modulating neuronal output to the musculature. Together, the evidence identifies Sm5HTR as an important neuronal protein and a key component of the motor control apparatus in S. mansoni. PMID:24453972

Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity

PubMed Central

Isbister, Geoffrey K; Hackett, L P; Dawson, Andrew H; Whyte, Ian M; Smith, Anthony J

2003-01-01

Aims To investigate the spectrum of toxicity of moclobemide overdose, the occurrence of serotonin toxicity, and to estimate toxicokinetic parameters. Methods All moclobemide overdoses presenting over a 10-year period to the Hunter Area Toxicology Service were reviewed. Clinical features, complications, length of stay (LOS) and intensive care (ICU) admission rate were extracted from a standardized, prospectively collected database. Comparisons were made between moclobemide alone and moclobemide with a serotonergic coingestant poisoning. Serotonin toxicity was defined by a combination of Sternbach's criteria and a clinical toxicologist's diagnosis. In five patients serial moclobemide concentrations were measured. Time to maximal plasma concentration (Tmax), peak plasma concentration (Cmax) and terminal elimination half-lives were estimated. Results Of 106 included patients, 33 ingested moclobemide alone, 21 ingested moclobemide with another serotonergic agent (in some cases in therapeutic doses) and 52 ingested moclobemide with a nonserotonergic agent. Eleven (55%) of 21 patients coingesting a serotonergic drug developed serotonin toxicity, which was significantly more than one (3%) of 33 moclobemide-alone overdoses (odds ratio 35, 95% confidence inteval 4, 307; P < 0.0001). In six of these 21 cases severe serotonin toxicity developed with temperature> 38.5 °C and muscle rigidity requiring intubation and paralysis. The 21 patients had a significantly increased LOS (34 h) compared with moclobemide alone overdoses (12 h) (P < 0.0001) and a significantly increased ICU admission rate of 57% vs. 3% (P < 0.0001). Time to peak plasma concentration was delayed in two patients where prepeak samples were obtained. Cmax increased slightly with dose, but all three patients ingesting ≥ 6 g vomited or had charcoal. The mean elimination half-life of moclobemide in the five patients in whom serial moclobemide concentrations were measured was 6.3 h and elimination was first order

Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity.

PubMed

Isbister, Geoffrey K; Hackett, L P; Dawson, Andrew H; Whyte, Ian M; Smith, Anthony J

2003-10-01

To investigate the spectrum of toxicity of moclobemide overdose, the occurrence of serotonin toxicity, and to estimate toxicokinetic parameters. All moclobemide overdoses presenting over a 10-year period to the Hunter Area Toxicology Service were reviewed. Clinical features, complications, length of stay (LOS) and intensive care (ICU) admission rate were extracted from a standardized, prospectively collected database. Comparisons were made between moclobemide alone and moclobemide with a serotonergic coingestant poisoning. Serotonin toxicity was defined by a combination of Sternbach's criteria and a clinical toxicologist's diagnosis. In five patients serial moclobemide concentrations were measured. Time to maximal plasma concentration (Tmax), peak plasma concentration (Cmax) and terminal elimination half-lives were estimated. Of 106 included patients, 33 ingested moclobemide alone, 21 ingested moclobemide with another serotonergic agent (in some cases in therapeutic doses) and 52 ingested moclobemide with a nonserotonergic agent. Eleven (55%) of 21 patients coingesting a serotonergic drug developed serotonin toxicity, which was significantly more than one (3%) of 33 moclobemide-alone overdoses (odds ratio 35, 95% confidence interval 4, 307; P < 0.0001). In six of these 21 cases severe serotonin toxicity developed with temperature >38.5 degrees C and muscle rigidity requiring intubation and paralysis. The 21 patients had a significantly increased LOS (34 h) compared with moclobemide alone overdoses (12 h) (P < 0.0001) and a significantly increased ICU admission rate of 57% vs. 3% (P < 0.0001). Time to peak plasma concentration was delayed in two patients where prepeak samples were obtained. Cmax increased slightly with dose, but all three patients ingesting > or = 6 g vomited or had charcoal. The mean elimination half-life of moclobemide in the five patients in whom serial moclobemide concentrations were measured was 6.3 h and elimination was first order in all

Interaction between Serotonin Transporter and Serotonin Receptor 1 B genes polymorphisms may be associated with antisocial alcoholism

PubMed Central

2012-01-01

Background Several studies have hypothesized that genes regulating the components of the serotonin system, including serotonin transporter (5-HTTLPR) and serotonin 1 B receptor (5-HT1B), may be associated with alcoholism, but their results are contradictory because of alcoholism’s heterogeneity. Therefore, we examined whether the 5-HTTLPR gene and 5-HT1B gene G861C polymorphism are susceptibility factors for a specific subtype of alcoholism, antisocial alcoholism in Han Chinese in Taiwan. Methods We recruited 273 Han Chinese male inmates with antisocial personality disorder (ASPD) [antisocial alcoholism (AS-ALC) group (n = 120) and antisocial non-alcoholism (AS-N-ALC) group (n = 153)] and 191 healthy male controls from the community. Genotyping was done using PCR-RFLP. Results There were no significant differences in the genotypic frequency of the 5-HT1B G861C polymorphism between the 3 groups. Although AS-ALC group members more frequently carried the 5-HTTLPR S/S, S/LG, and LG/LG genotypes than controls, the difference became non-significant after controlling for the covarying effects of age. However, the 5-HTTLPR S/S, S/LG, and LG/LG genotypes may have interacted with the 5-HT1B G861C C/C polymorphism and increased the risk of becoming antisocial alcoholism. Conclusion Our study suggests that neither the 5-HTTLPR gene nor the 5-HT1B G861C polymorphism alone is a risk factor for antisocial alcoholism in Taiwan’s Han Chinese population, but that the interaction between both genes may increase susceptibility to antisocial alcoholism. PMID:22550993

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.

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.

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.

Reboxetine Enhances the Olanzapine-Induced Antipsychotic-Like Effect, Cortical Dopamine Outflow and NMDA Receptor-Mediated Transmission

PubMed Central

Marcus, Monica M; Jardemark, Kent; Malmerfelt, Anna; Björkholm, Carl; Svensson, Torgny H

2010-01-01

Preclinical data have shown that addition of the selective norepinephrine transporter (NET) inhibitor reboxetine increases the antipsychotic-like effect of the D2/3 antagonist raclopride and, in parallel, enhances cortical dopamine output. Subsequent clinical results suggested that adding reboxetine to stable treatments with various antipsychotic drugs (APDs) may improve positive, negative and depressive symptoms in schizophrenia. In this study, we investigated in rats the effects of adding reboxetine to the second-generation APD olanzapine on: (i) antipsychotic efficacy, using the conditioned avoidance response (CAR) test, (ii) extrapyramidal side effect (EPS) liability, using a catalepsy test, (iii) dopamine efflux in the medial prefrontal cortex and the nucleus accumbens, using in vivo microdialysis in freely moving animals and (iv) cortical N-methyl--aspartate (NMDA) receptor-mediated transmission, using intracellular electrophysiological recording in vitro. Reboxetine (6 mg/kg) enhanced the suppression of CAR induced by a suboptimal dose (1.25 mg/kg), but not an optimal (2.5 mg/kg) dose of olanzapine without any concomitant catalepsy. Addition of reboxetine to the low dose of olanzapine also markedly increased cortical dopamine outflow and facilitated prefrontal NMDA receptor-mediated transmission. Our data suggest that adjunctive treatment with a NET inhibitor may enhance the therapeutic effect of low-dose olanzapine in schizophrenia without increasing EPS liability and add an antidepressant action, thus in principle allowing for a dose reduction of olanzapine with a concomitant reduction of dose-related side effects, such as EPS and weight gain. PMID:20463659

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

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

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.

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

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

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.

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.

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.

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

Association Study of Serotonin Transporter Gene Polymorphisms with Obstructive Sleep Apnea Syndrome in Chinese Han Population

PubMed Central

Yue, Weihua; Liu, Huiguo; Zhang, Jishui; Zhang, Xianghui; Wang, Xiaoping; Liu, Tieqiao; Liu, Pozi; Hao, Wei

2008-01-01

Background: Since the serotonin (5-HT) is associated with circadian rhythm and breathing regulation, the serotonin transporter (5-HTT), which plays an important role in serotoninergic transmission, might be a strong candidate gene in the pathogenesis of obstructive sleep apnea syndrome (OSAS). Objective: To investigate the association of 5-HTT gene polymorphisms with OSAS and clinical characteristics. Methods: We genotyped the 5-HTT gene linked polymorphic region (5-HTTLPR) and a variable number of tandem repeats at intron 2 (STin2.VNTR) in 254 OSAS patients and 338 healthy controls in Chinese Han population. Results: In total sample, the 10-repeat allele of STin2.VNTR was significantly associated with OSAS (P = 0.007, OR = 1.72, 95% CI = 1.15~2.58), but no association was found in 5-HTTLPR. In male subjects, both polymorphisms showed significant association with OSAS (Allele L: P = 0.005, OR = 1.44, 95% CI = 1.11 to 1.87; Allele 10: P = 0.002, OR = 1.94, 95% CI = 1.26 to 3.00). Two haplotypes, S-12 and L-10, constructed by the above polymorphisms also revealed significant associations with OSAS (global P-values were 0.020 for total sample and 0.0006 for male subjects, respectively). Male patients carrying the haplotype S-12 showed a significantly lower apnea / hypopnea index (AHI), depressive factor, plasma 5-HT level and 5-hydroxyindolacetic acid (5-HIAA) levels, but higher episodic memory, when compared with non-S-12 carriers (P < 0.05). However, no significant differences were found in excessive daytime sleepiness or other psychological function across haplotype carriers (P > 0.05). Conclusions: These findings support that 5-HTT gene may be involved in susceptibility to OSAS, especially with sex-dependent effect. Citation: Yue W; Liu H; Zhang J; Zhang X; Wang X; Liu T; Liu P; Hao W. Association study of serotonin transporter gene polymorphisms with obstructive sleep apnea syndrome in chinese han population. SLEEP 2008;31(11):1535–1541. PMID:19014073

Parameters optimization for magnetic resonance coupling wireless power transmission.

PubMed

Li, Changsheng; Zhang, He; Jiang, Xiaohua

2014-01-01

Taking maximum power transmission and power stable transmission as research objectives, optimal design for the wireless power transmission system based on magnetic resonance coupling is carried out in this paper. Firstly, based on the mutual coupling model, mathematical expressions of optimal coupling coefficients for the maximum power transmission target are deduced. Whereafter, methods of enhancing power transmission stability based on parameters optimal design are investigated. It is found that the sensitivity of the load power to the transmission parameters can be reduced and the power transmission stability can be enhanced by improving the system resonance frequency or coupling coefficient between the driving/pick-up coil and the transmission/receiving coil. Experiment results are well conformed to the theoretical analysis conclusions.

Serotonin Receptor 6 Mediates Defective Brain Development in Monoamine Oxidase A-deficient Mouse Embryos

PubMed Central

Wang, Chi Chiu; Man, Gene Chi Wai; Chu, Ching Yan; Borchert, Astrid; Ugun-Klusek, Aslihan; Billett, E. Ellen; Kühn, Hartmut; Ufer, Christoph

2014-01-01

Monoamine oxidases A and B (MAO-A and MAO-B) are enzymes of the outer mitochondrial membrane that metabolize biogenic amines. In the adult central nervous system, MAOs have important functions for neurotransmitter homeostasis. Expression of MAO isoforms has been detected in the developing embryo. However, suppression of MAO-B does not induce developmental alterations. In contrast, targeted inhibition and knockdown of MAO-A expression (E7.5–E10.5) caused structural abnormalities in the brain. Here we explored the molecular mechanisms underlying defective brain development induced by MAO-A knockdown during in vitro embryogenesis. The developmental alterations were paralleled by diminished apoptotic activity in the affected neuronal structures. Moreover, dysfunctional MAO-A expression led to elevated levels of embryonic serotonin (5-hydroxytryptamine (5-HT)), and we found that knockdown of serotonin receptor-6 (5-Htr6) expression or pharmacologic inhibition of 5-Htr6 activity rescued the MAO-A knockdown phenotype and restored apoptotic activity in the developing brain. Our data suggest that excessive 5-Htr6 activation reduces activation of caspase-3 and -9 of the intrinsic apoptotic pathway and enhances expression of antiapoptotic proteins Bcl-2 and Bcl-XL. Moreover, we found that elevated 5-HT levels in MAO-A knockdown embryos coincided with an enhanced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and a reduction of proliferating cell numbers. In summary, our findings suggest that excessive 5-HT in MAO-A-deficient mouse embryos triggers cellular signaling cascades via 5-Htr6, which suppresses developmental apoptosis in the brain and thus induces developmental retardations. PMID:24497636

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

Hypoxia directly increases serotonin transport by porcine pulmonary artery endothelial cell (PAEC) plasma membrane vesicles

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

Bhat, G.B.; Block, E.R.

1990-02-26

Alterations in the physical state and composition of membrane lipids have been shown to interfere with a number of critical cellular and membrane functions including transmembrane transport. The authors have reported that hypoxia has profound effects upon the physical state and lipid composition of the PAEC plasma membrane bilayer and have suggested that this is responsible for increased serotonin uptake by these cells. In order to determine whether hypoxia has a direct effect on the plasma membrane transport of serotonin, they measured serotonin transport activity (1) in plasma membrane vesicles isolated from normoxic (20% O{sub 2}-5% CO{sub 2}) and hypoxicmore » (0% O{sub 2}-5% CO{sub 2}) PAEC and (2) in PAEC plasma membrane vesicles that were exposed directly to normoxia or hypoxia. A 24-h exposure of PAEC to hypoxia resulted in a 40% increase in specific serotonin transport by plasma membrane vesicles derived from these cells. When plasma membrane vesicles were isolated and then directly exposed to normoxia or hypoxia for 1 h at 37C, a 31% increase in specific 5-HT transport was observed in hypoxic vesicles. Hypoxia did not alter the Km of serotonin transport (normoxia = 3.47 {mu}M versus hypoxia = 3.76 {mu}M) but markedly increased the maximal rate of transport (V{sup max}) (normoxia = 202.4 pmol/min/mg protein versus hypoxia = 317.9 pmol/min/mg protein). These results indicate that hypoxia increases serotonin transport in PAEC by a direct effect on the plasma membrane leading to an increase in the effective number of transporter molecules without alteration in transporter affinity for serotonin.« less

Characterization, solubilization and partial purification of serotonin 5-HT1C receptors

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

Yagaloff, K.A.

1986-01-01

/sup 125/I-Lysergic acid diethylamide (/sup 125/I-LSD) binds with high affinity to a unique serotonergic site on rat choroid plexus. These sites were localized to choroid plexus epithelial cells using a novel high resolution autoradiographic technique. In membrane preparations, the serotonergic site density was 3100 fmol/mg protein, which is 10 fold higher than the density of any other serotonergic site in brain homogenates. The pharmacology of this site, termed the 5-HT1c site, does not match that of 5-Ht1a, 5-HT1b or 5HT2 serotonergic sites. 5-Ht1c sites were solubilized from pig choroid plexus using the zwitterionic detergent, CHAPS. High affinity labelling of themore » solubilized site was obtained using the serotonergic radioligand, N1-methyl-2-(/sup 125/I)lysergic acid diethylamide (/sup 125/I-MIL). Choroid plexus tumors obtained from transgenic mice were examined for the presence of serotonin 5-HT1c receptors. /sup 125/I-LSD binding to choroid plexus tumors displays a pharmacological profile that matches the properties of 5-HT1c receptors in normal choroid plexus. The tumor exhibits the highest site density of serotonin receptors (6600 fmol/mg protein) found in any tissue. /sup 125/I-LSD autoradiography of brain sections from transgenic mice shows high levels of specific labelling over the tumor. The affinities of various indolealkyl, phenlakyl and beta-carboline derivatives for the serotonin 5-HT1c receptor were measured in pig choroid plexus using /sup 125/I-MIL. Serotonin precursors and metabolites were all very weak inhibitors of specific /sup 125/I-MIL binding. Structure-affinity relationships were determined for a number of indolealkylamine analogues. Only serotonin is present in cerebrospinal fluid at concentrations near its 5-HT1c inhibition constant, suggesting that serotonin is the natural 5-HT1c agonist.« less

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

Variation in the serotonin transporter gene modulates selective attention to threat.

PubMed

Osinsky, Roman; Reuter, Martin; Küpper, Yvonne; Schmitz, Anja; Kozyra, Eva; Alexander, Nina; Hennig, Jürgen

2008-08-01

The 5-HTTLPR is an insertion/deletion polymorphism in the promoter region of the serotonin transporter gene. Prior research has revealed associations between the short-allele variant of this polymorphism, enhanced self-reported negative emotionality, and hypersensitivity of fear relevant neural circuits. In a sample of 50 healthy women we examined the role of 5-HTTLPR for cognitive-affective processing of phylogenetical fear-relevant stimuli (spiders) in a dot probe task. In contrast to homozygote long-allele carriers (ll), participants carrying at least 1 short allele (ss and sl) selectively shifted attention toward pictures of spiders, when these were presented for a duration of 2,000 ms. These results argue for an involvement of 5-HTTLPR in cognitive processing of threatening stimuli and thus, underpin its general role for individual differences in negative affect.

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

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

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

PubMed

Angoa-Pérez, Mariana; Kuhn, Donald M

2015-09-01

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

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

PubMed Central

Angoa-Pérez, Mariana; Kuhn, Donald M.

2016-01-01

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

Brief Report: Whole Blood Serotonin Levels and Gastrointestinal Symptoms in Autism Spectrum Disorder

ERIC Educational Resources Information Center

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

2016-01-01

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,…

Examination of association of genes in the serotonin system to autism.

PubMed

Anderson, B M; Schnetz-Boutaud, N C; Bartlett, J; Wotawa, A M; Wright, H H; Abramson, R K; Cuccaro, M L; Gilbert, J R; Pericak-Vance, M A; Haines, J L

2009-07-01

Autism is characterized as one of the pervasive developmental disorders, a spectrum of often severe behavioral and cognitive disturbances of early development. The high heritability of autism has driven multiple efforts to identify genetic variation that increases autism susceptibility. Numerous studies have suggested that variation in peripheral and central metabolism of serotonin (5-hydroxytryptamine) may play a role in the pathophysiology of autism. We screened 403 autism families for 45 single nucleotide polymorphisms in ten serotonin pathway candidate genes. Although genome-wide linkage scans in autism have provided support for linkage to various loci located within the serotonin pathway, our study does not provide strong evidence for linkage to any specific gene within the pathway. The most significant association (p = 0.0002; p = 0.02 after correcting for multiple comparisons) was found at rs1150220 (HTR3A) located on chromosome 11 ( approximately 113 Mb). To test specifically for multilocus effects, multifactor dimensionality reduction was employed, and a significant two-way interaction (p value = 0.01) was found between rs10830962, near MTNR1B (chromosome11; 92,338,075 bp), and rs1007631, near SLC7A5 (chromosome16; 86,413,596 bp). These data suggest that variation within genes on the serotonin pathway, particularly HTR3A, may have modest effects on autism risk.

Long-term enhancement of synaptic transmission between antennal lobe and mushroom body in cultured Drosophila brain.

PubMed

Ueno, Kohei; Naganos, Shintaro; Hirano, Yukinori; Horiuchi, Junjiro; Saitoe, Minoru

2013-01-01

In Drosophila, the mushroom body (MB) is a critical brain structure for olfactory associative learning. During aversive conditioning, the MBs are thought to associate odour signals, conveyed by projection neurons (PNs) from the antennal lobe (AL), with shock signals conveyed through ascending fibres of the ventral nerve cord (AFV). Although synaptic transmission between AL and MB might play a crucial role for olfactory associative learning, its physiological properties have not been examined directly. Using a cultured Drosophila brain expressing a Ca(2+) indicator in the MBs, we investigated synaptic transmission and plasticity at the AL-MB synapse. Following stimulation with a glass micro-electrode, AL-induced Ca(2+) responses in the MBs were mediated through Drosophila nicotinic acetylcholine receptors (dnAChRs), while AFV-induced Ca(2+) responses were mediated through Drosophila NMDA receptors (dNRs). AL-MB synaptic transmission was enhanced more than 2 h after the simultaneous 'associative-stimulation' of AL and AFV, and such long-term enhancement (LTE) was specifically formed at the AL-MB synapses but not at the AFV-MB synapses. AL-MB LTE was not induced by intense stimulation of the AL alone, and the LTE decays within 60 min after subsequent repetitive AL stimulation. These phenotypes of associativity, input specificity and persistence of AL-MB LTE are highly reminiscent of olfactory memory. Furthermore, similar to olfactory aversive memory, AL-MB LTE formation required activation of the Drosophila D1 dopamine receptor, DopR, along with dnAChR and dNR during associative stimulations. These physiological and genetic analogies indicate that AL-MB LTE might be a relevant cellular model for olfactory memory.

Long-term enhancement of synaptic transmission between antennal lobe and mushroom body in cultured Drosophila brain

PubMed Central

Ueno, Kohei; Naganos, Shintaro; Hirano, Yukinori; Horiuchi, Junjiro; Saitoe, Minoru

2013-01-01

In Drosophila, the mushroom body (MB) is a critical brain structure for olfactory associative learning. During aversive conditioning, the MBs are thought to associate odour signals, conveyed by projection neurons (PNs) from the antennal lobe (AL), with shock signals conveyed through ascending fibres of the ventral nerve cord (AFV). Although synaptic transmission between AL and MB might play a crucial role for olfactory associative learning, its physiological properties have not been examined directly. Using a cultured Drosophila brain expressing a Ca2+ indicator in the MBs, we investigated synaptic transmission and plasticity at the AL–MB synapse. Following stimulation with a glass micro-electrode, AL-induced Ca2+ responses in the MBs were mediated through Drosophila nicotinic acetylcholine receptors (dnAChRs), while AFV-induced Ca2+ responses were mediated through Drosophila NMDA receptors (dNRs). AL–MB synaptic transmission was enhanced more than 2 h after the simultaneous ‘associative-stimulation’ of AL and AFV, and such long-term enhancement (LTE) was specifically formed at the AL–MB synapses but not at the AFV–MB synapses. AL–MB LTE was not induced by intense stimulation of the AL alone, and the LTE decays within 60 min after subsequent repetitive AL stimulation. These phenotypes of associativity, input specificity and persistence of AL–MB LTE are highly reminiscent of olfactory memory. Furthermore, similar to olfactory aversive memory, AL–MB LTE formation required activation of the Drosophila D1 dopamine receptor, DopR, along with dnAChR and dNR during associative stimulations. These physiological and genetic analogies indicate that AL–MB LTE might be a relevant cellular model for olfactory memory. PMID:23027817

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 receptor 5-HT5A in rat hippocampus decrease by leptin treatment.

PubMed

García-Alcocer, Guadalupe; Rodríguez, Angelina; Moreno-Layseca, Paulina; Berumen, Laura C; Escobar, Jesica; Miledi, Ricardo

2010-12-17

5-Hydroxytryptamine (5-HT) is involved in a variety of different physiological processes and behaviors through the activation of equally diverse receptors subtypes. In this work we studied the changes on the expression of 5-HT(5A) receptors in rat hippocampus induced by leptin, an adipocyte-derived hormone that has been reported to participate in the modulation of food intake and in adult hippocampal neurogenesis. To study the effect of leptin on the 5-HT(5A) receptor gene expression a qRT-PCR was used and the distribution of those receptors in the hippocampus was visualized by immunohistochemistry. Rats were separated in four groups: control (untreated rats), leptin-treated, serotonin-treated and leptin+serotonin treated. The results showed that even though the 5-HT(5A) gene expression did not change in the hippocampus of any of the treated groups, in the rats treated with leptin and serotonin, the specific immunostaining for the 5-HT(5A) serotonin receptor decreased significantly in the dentate gyrus. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

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.

Equalization enhanced phase noise in Nyquist-spaced superchannel transmission systems using multi-channel digital back-propagation

PubMed Central

Xu, Tianhua; Liga, Gabriele; Lavery, Domaniç; Thomsen, Benn C.; Savory, Seb J.; Killey, Robert I.; Bayvel, Polina

2015-01-01

Superchannel transmission spaced at the symbol rate, known as Nyquist spacing, has been demonstrated for effectively maximizing the optical communication channel capacity and spectral efficiency. However, the achievable capacity and reach of transmission systems using advanced modulation formats are affected by fibre nonlinearities and equalization enhanced phase noise (EEPN). Fibre nonlinearities can be effectively compensated using digital back-propagation (DBP). However EEPN which arises from the interaction between laser phase noise and dispersion cannot be efficiently mitigated, and can significantly degrade the performance of transmission systems. Here we report the first investigation of the origin and the impact of EEPN in Nyquist-spaced superchannel system, employing electronic dispersion compensation (EDC) and multi-channel DBP (MC-DBP). Analysis was carried out in a Nyquist-spaced 9-channel 32-Gbaud DP-64QAM transmission system. Results confirm that EEPN significantly degrades the performance of all sub-channels of the superchannel system and that the distortions are more severe for the outer sub-channels, both using EDC and MC-DBP. It is also found that the origin of EEPN depends on the relative position between the carrier phase recovery module and the EDC (or MC-DBP) module. Considering EEPN, diverse coding techniques and modulation formats have to be applied for optimizing different sub-channels in superchannel systems. PMID:26365422

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.

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.

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.

Rationality and emotionality: serotonin transporter genotype influences reasoning bias

PubMed Central

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

2013-01-01

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

Rationality and emotionality: serotonin transporter genotype influences reasoning bias.

PubMed

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

2013-04-01

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

Serotonin mediated immunoregulation and neural functions: Complicity in the aetiology of autism spectrum disorders.

PubMed

Jaiswal, Preeti; Mohanakumar, Kochupurackal P; Rajamma, Usha

2015-08-01

Serotonergic system has long been implicated in the aetiology of autism spectrum disorders (ASD), since platelet hyperserotonemia is consistently observed in a subset of autistic patients, who respond well to selective serotonin reuptake inhibitors. Apart from being a neurotransmitter, serotonin functions as a neurotrophic factor directing brain development and as an immunoregulator modulating immune responses. Serotonin transporter (SERT) regulates serotonin level in lymphoid tissues to ensure its proper functioning in innate and adaptive responses. Immunological molecules such as cytokines in turn regulate the transcription and activity of SERT. Dysregulation of serotonergic system could trigger signalling cascades that affect normal neural-immune interactions culminating in neurodevelopmental and neural connectivity defects precipitating behavioural abnormalities, or the disease phenotypes. Therefore, we suggest that a better understanding of the cross talk between serotonergic genes, immune systems and serotonergic neurotransmission will open wider avenues to develop pharmacological leads for addressing the core ASD behavioural deficits. Copyright © 2015 Elsevier Ltd. All rights reserved.

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.

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

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

Serotonin neurons in the dorsal raphe mediate the anticataplectic action of orexin neurons by reducing amygdala activity.

PubMed

Hasegawa, Emi; Maejima, Takashi; Yoshida, Takayuki; Masseck, Olivia A; Herlitze, Stefan; Yoshioka, Mitsuhiro; Sakurai, Takeshi; Mieda, Michihiro

2017-04-25

Narcolepsy is a sleep disorder caused by the loss of orexin (hypocretin)-producing neurons and marked by excessive daytime sleepiness and a sudden weakening of muscle tone, or cataplexy, often triggered by strong emotions. In a mouse model for narcolepsy, we previously demonstrated that serotonin neurons of the dorsal raphe nucleus (DRN) mediate the suppression of cataplexy-like episodes (CLEs) by orexin neurons. Using an optogenetic tool, in this paper we show that the acute activation of DRN serotonin neuron terminals in the amygdala, but not in nuclei involved in regulating rapid eye-movement sleep and atonia, suppressed CLEs. Not only did stimulating serotonin nerve terminals reduce amygdala activity, but the chemogenetic inhibition of the amygdala using designer receptors exclusively activated by designer drugs also drastically decreased CLEs, whereas chemogenetic activation increased them. Moreover, the optogenetic inhibition of serotonin nerve terminals in the amygdala blocked the anticataplectic effects of orexin signaling in DRN serotonin neurons. Taken together, the results suggest that DRN serotonin neurons, as a downstream target of orexin neurons, inhibit cataplexy by reducing the activity of amygdala as a center for emotional processing.

Serotonin neurons in the dorsal raphe mediate the anticataplectic action of orexin neurons by reducing amygdala activity

PubMed Central

Hasegawa, Emi; Maejima, Takashi; Yoshida, Takayuki; Herlitze, Stefan; Yoshioka, Mitsuhiro; Sakurai, Takeshi; Mieda, Michihiro

2017-01-01

Narcolepsy is a sleep disorder caused by the loss of orexin (hypocretin)-producing neurons and marked by excessive daytime sleepiness and a sudden weakening of muscle tone, or cataplexy, often triggered by strong emotions. In a mouse model for narcolepsy, we previously demonstrated that serotonin neurons of the dorsal raphe nucleus (DRN) mediate the suppression of cataplexy-like episodes (CLEs) by orexin neurons. Using an optogenetic tool, in this paper we show that the acute activation of DRN serotonin neuron terminals in the amygdala, but not in nuclei involved in regulating rapid eye-movement sleep and atonia, suppressed CLEs. Not only did stimulating serotonin nerve terminals reduce amygdala activity, but the chemogenetic inhibition of the amygdala using designer receptors exclusively activated by designer drugs also drastically decreased CLEs, whereas chemogenetic activation increased them. Moreover, the optogenetic inhibition of serotonin nerve terminals in the amygdala blocked the anticataplectic effects of orexin signaling in DRN serotonin neurons. Taken together, the results suggest that DRN serotonin neurons, as a downstream target of orexin neurons, inhibit cataplexy by reducing the activity of amygdala as a center for emotional processing. PMID:28396432

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