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Mitochondria in neurons, in addition to their primary role in bioenergetics, also contribute to specialized functions, including regulation of synaptic transmission, Ca2+ homeostasis, neuronal excitability, and stress adaptation. However, the factors that influence mitochondrial biogenesis and function in neurons remain poorly elucidated. Here, we identify an important role for serotonin (5-HT) as a regulator of mitochondrial biogenesis and function in rodent cortical neurons, via a 5-HT2A receptor-mediated recruitment of the SIRT1- PGC-1a axis, which is relevant to the neuroprotective action of 5-HT. We found that 5-HT increasedmitochondrial biogenesis, reflected through enhanced mtDNA levels, mitotracker staining, and expression ofmitochondrial components. This resulted in higher mitochondrial respiratory capacity, oxidative phosphorylation (OXPHOS) efficiency, and a consequential increase in cellular ATP levels. Mechanistically, the effects of 5-HTweremediated via the 5-HT2A receptor and master modulators of mitochondrial biogenesis, SIRT1 and PGC- 1a. SIRT1 was required to mediate the effects of 5-HT on mitochondrial biogenesis and function in cortical neurons. In vivo studies revealed that 5-HT2A receptor stimulation increased cortical mtDNA and ATP levels in a SIRT1-dependent manner. Direct infusion of 5-HT into the neocortex and chemogenetic activation of 5-HT neurons also resulted in enhanced mitochondrial biogenesis and function in vivo. In cortical neurons, 5-HT enhanced expression of antioxidant enzymes, decreased cellular reactive oxygen species, and exhibited neuroprotection against excitotoxic and oxidative stress, an effect that required SIRT1. These findings identify 5-HT as an upstream regulator of mitochondrial biogenesis and function in cortical neurons and implicate the mitochondrial effects of 5-HT in its neuroprotective action. [ABSTRACT FROM AUTHOR]

Abstract The present study was performed to evaluate the neurobehavioural deficit induced by nonylphenol (NP), a well-known xenobiotic chemical. The neurotoxic mechanism from oxidative stress and serotonin-related progress was also investigated. Caenorhabditis elegans was exposed at different levels of NP ranging from 0 to 200 μg L−1 for 10 days. The results revealed that from a relatively low concentration (i.e., 10 μg L−1), significant effects including decreased head thrashes, body bends and forging behaviour could be observed, along with impaired learning and memory behaviour plasticity. The level of reactive oxygen species (ROS) in head was significantly elevated with the increase of NP concentrations from 10 to 200 μg L−1. Through antioxidant experiment, the oxidative damage caused by NP restored to some extent. At a NP concentration of 200 μg L−1, the significant increased expression of stress-related genes, including sod-1 , sod-3 , ctl-2 , ctl-3 and cyp-35A2 gene, was observed from integrated gene expression profiles. In addition, in comparison with wild-type N2 worms, the ROS accumulation was increased significantly with the mutation of sod-3. Tryptophan hydroxylase (TPH) in ADF and NSM neurons sharply decreased at the concentrations of 10–200 μg L−1. The transcription of TPH synthesis-related genes and serotonin-related genes were both suppressed, including tph-1 , cat-1 , cat-4 , ser-1 , and mod-5. Overall, these results indicated that NP could induce neurotoxicity on Caenorhabditis elegans through excessive induction of ROS and disturbance synthesis of serotonin. The conducted research opened up new avenues for more effective exploration of neurotoxicity caused by NP. Graphical abstract Image 1 Highlights • NP caused neurobehavioral deficit on nematodes after chronic exposure. • NP induced excessive ROS in the head of nematodes and inspired antioxidant system. • The synthesis process of serotonin was disturbed and the level of serotonin were decreased after NP exposure. • The change of ROS and serotonin contributed to NP neurotoxicity formation. This paper aimed to understand neurobehavioural deficits and changes in stress response and serotonin-related progress by NP exposure using Caenorhabditis elegans. [ABSTRACT FROM AUTHOR]

Ca 2+ plays a major role in maintaining cellular homeostasis and regulates processes including apoptotic cell death and side-effects of cancer chemotherapy including vomiting. Currently we explored the emetic mechanisms of FPL64176, an L-type Ca 2+ channel (LTCC) agonist with maximal emetogenic effect at its 10 mg/kg dose. FPL64176 evoked c-Fos immunoreactivity in shrew brainstem sections containing the vomit-associated nuclei, nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus. FPL64176 also increased phosphorylation of proteins ERK1/2, PKCα/βII and Akt in the brainstem. Moreover, their corresponding inhibitors (PD98059, GF 109203X and LY294002, respectively) reduced FPL64176-evoked vomiting. A 30 min subcutaneous (s.c.) pretreatment with the LTCC antagonist nifedipine (10 mg/kg) abolished FPL64176-elicited vomiting, c-Fos expression, and emetic effector phosphorylation. Ryanodine receptors (RyRs) and inositol trisphosphate receptors (IP 3 Rs) mediate intracellular Ca 2+ release from the sarcoplasmic/endoplasmic reticulum. The RyR antagonist dantrolene (i.p.), or a combination of low doses of nifedipine and dantrolene, but not the IP 3 R antagonist 2-APB, significantly attenuated FPL64176-induced vomiting. The serotonin type 3 receptor (5-HT 3 R) antagonist palonosetron (s.c.), the neurokinin 1 receptor (NK 1 R) antagonist netupitant (i.p.) or a combination of non-effective doses of netupitant and palonosetron showed antiemetic potential against FPL64176-evoked vomiting. Serotonin (5-HT) and substance P immunostaining revealed FPL64176-induced emesis was accompanied by an increase in 5-HT but not SP-immunoreactivity in the dorsomedial subdivision of the NTS. These findings demonstrate that Ca 2+ mobilization through LTCCs and RyRs, and subsequent emetic effector phosphorylation and 5-HT release play important roles in FPL64176-induced emesis which can be prevented by 5-HT 3 R and NK 1 R antagonists. [ABSTRACT FROM AUTHOR]

Previous studies suggested that serotonergic neurons and platelets share similarities in serotonin (5-HT) uptake by serotonin transporter (SERT), storage, metabolism and release mechanisms, indicating that platelets may be used as a reliable peripheral surrogate to measure central SERT activity in neuropsychiatric research. In this study, platelet 5-HT content and 5-HT uptake capacity of SERT in depression and anxiety patients were measured by ELISA and flow cytometry with IDT307 at baseline and after serotonin reuptake inhibitors (SSRIs) treatment for 4 weeks. Healthy persons matched with age and gender were used as reference. The clinical presentations of the patients were assessed with Hamilton Depression (HAMD) and Anxiety Rating Scales (HAMA) at the same time points. Compared to healthy subjects, anxiety and depression patients showed higher levels of platelet 5-HT and IDT307 fluorescence intensity, but the values were comparable between the patient groups. SSRIs administration for 4 weeks significantly decreased scores of HAMD (29 vs 14) and HAMA (22 vs 14) in depression and anxiety patients, respectively; while it decreased platelet 5-HT content, but did not change the IDT307 fluorescence intensity of platelets. After incubation with fluoxetine in vitro, the IDT307 fluorescence intensity of isolated platelets from both healthy subjects and patients decreased in a dose-dependent manner. These results provide further evidence supporting the employment of platelet 5-HT content and SERT as peripheral surrogates in depression and anxiety patients, and are of help in understanding the several weeks’ delay from the initiation of antidepressant medication to their full therapeutic effects in the patients. [ABSTRACT FROM AUTHOR]

Heparin-induced thrombocytopenia (HIT) is associated with clinically significant morbidity and mortality. Patients who are critically ill are commonly thrombocytopenic and exposed to heparin. Although HIT should be considered, it is not usually the cause of thrombocytopenia in the medical-surgical ICU population. A systematic approach to the patient who is critically ill who has thrombocytopenia according to clinical features, complemented by appropriate laboratory confirmation, should lead to a reduction in inappropriate laboratory testing and reduce the use of more expensive and less reliable anticoagulants. If the patient is deemed as being at intermediate or high risk for HIT or if HIT is confirmed by means of the serotonin-release assay, heparin should be stopped, heparin-bonded catheters should be removed, and a direct antithrombin or fondaparinux should be initiated to reduce the risk of thrombosis. Warfarin is absolutely contraindicated in the acute phase of HIT; if administered, its effects must be reversed by using vitamin K. [ABSTRACT FROM AUTHOR]

Background: Trypanosoma cruzi (T. cruzi) infects millions of Latin Americans each year and can induce chagasic megacolon. Little is known about how serotonin (5-HT) modulates this condition. Aim We investigated whether 5-HT synthesis alters T. cruzi infection in the colon.Materials and Methods: Forty-eight paraffin-embedded samples from normal colon and chagasic megacolon were histopathologically analyzed (173/2009). Tryptophan hydroxylase 1 (Tph1) knockout (KO) mice and c-KitW-sh mice underwent T. cruzi infection together with their wild-type counterparts. Also, mice underwent different drug treatments (16.1.1064.60.3).Results: In both humans and experimental mouse models, the serotonergic system was activated by T. cruzi infection (p < 0.05). While treating Tph1KO mice with 5-HT did not significantly increase parasitemia in the colon (p > 0.05), rescuing its synthesis promoted trypanosomiasis (p < 0.01). T. cruzi-related 5-HT release (p < 0.05) seemed not only to increase inflammatory signaling, but also to enlarge the pericryptal macrophage and mast cell populations (p < 0.01). Knocking out mast cells reduced trypanosomiasis (p < 0.01), although it did not further alter the neuroendocrine cell number and Tph1 expression (p > 0.05). Further experimentation revealed that pharmacologically inhibiting mast cell activity reduced colonic infection (p < 0.01). A similar finding was achieved when 5-HT synthesis was blocked in c-KitW-sh mice (p > 0.05). However, inhibiting mast cell activity in Tph1KO mice increased colonic trypanosomiasis (p < 0.01).Conclusion: We show that mast cells may modulate the T. cruzi-related increase of 5-HT synthesis in the intestinal colon. [ABSTRACT FROM AUTHOR]

Fetal exposure to endocrine disrupting chemicals (EDCs) has been associated with adverse neurobehavioral outcomes across the lifespan and can persist across multiple generations of offspring. However, the underlying mechanisms driving these changes are not well understood. We investigated the molecular perturbations associated with EDC-induced behavioral changes in first (F1) and second (F2) filial generations, using the model EDC bisphenol A (BPA). C57BL/6J dams were exposed to BPA from preconception until lactation through the diet at doses (10 μg/kg bw/d-lower dose or 10 mg/kg bw/d-upper dose) representative of human exposure levels. As adults, F1 male offspring exhibited increased depressive-like behavior, measured by the forced swim test, while females were unaffected. These behavioral changes were limited to the F1 generation and were not associated with altered maternal care. Transcriptome analysis by RNA-sequencing in F1 control and upper dose BPA-exposed adult male hippocampus revealed neurotransmitter systems as major pathways disrupted by developmental BPA exposure. High performance liquid chromatography demonstrated a male-specific reduction in hippocampal serotonin. Administration of the selective serotonin reuptake inhibitor fluoxetine (20 mg/kg bw) rescued the depressive-like phenotype in males exposed to lower, but not upper, dose BPA, suggesting distinct mechanisms of action for each exposure dose. Finally, high resolution mass spectrometry revealed reduced circulating levels of the neuroactive steroid dehydroepiandrosterone in BPA-exposed males, suggesting another potential mechanism underlying the depressive-like phenotype. Thus, behavioral changes associated with early life BPA exposure may be mediated by sex-specific disruptions in the serotonergic system and/or sex steroid biogenesis in male offspring. [ABSTRACT FROM AUTHOR]

The red imported fire ant, Solenopsis invicta Buren, is a dangerous invasive pest in the United States, China and other countries. Efficient division of labor is one of the main reasons for the success of this social insect. Biogenic amines are important regulators of worker division of labor in this eusocial insect, but the related molecular mechanisms are largely unknown. In this study, we identified 10 candidate biogenic amine synthetic enzyme genes and 17 candidate biogenic amine receptor genes in the genome of S. invicta . Quantitative real-time PCR results indicated that foragers had higher head transcripts levels of all the tested enzyme genes than nurses did. In the abdomen, only the rate-limiting enzyme genes for the biosynthesis of serotonin and dopamine were higher in foragers than in nurses. Among the tested serotonin receptors, only the expression of 5-HT 2A gene showed significant difference between foragers and nurses. In the head, more abundant 5-HT 2A transcripts were detected in foragers than in nurses. Foragers expressed higher Octβ4R than nurses in the head and abdomen. However, much lower mRNA levels of Dop3 receptor gene were detected in both body regions of foragers than nurses. Several other octopamine and tyramine receptor genes were also differentially expressed between foragers and nurses in the head and/or in the abdomen. Our results will improve the understanding of molecular mechanisms underlying biogenic amine modulation of the worker division of labor in S. invicta . [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH), a condition that is defined by pulmonary vasculature constriction and remodeling, involves dysfunctional signaling of the serotonin (5-HT) receptors, 5-HT 2A/2B/7 . In a rat model of monocrotaline (MCT)-induced PAH, the effectiveness of RP5063 (RP), a dopamine and 5-HT receptor modulator, was evaluated as monotherapy and as an adjunct to standard PAH treatments. After a single 60 mg/kg dose of MCT, rats received vehicle (MCT+Veh; gavage twice-daily [b.i.d.]), RP (10 mg/kg; gavage b.i.d.), bosentan (B; 100 mg/kg; gavage BID), sildenafil (S; 50 mg/kg; gavage, BID), treprostinil (T; 100 ng/kg/min over 24 h intravenous), RP+B, RP+S, and RP+T for 28 days. Single-agent RP limited the functional and structural effects of PAH seen in the MCT+Veh group, with significant improvements in pulmonary hemodynamics, right ventricular (RV) hypertrophy, SO 2 , and pulmonary blood vessel structural changes. These effects appeared comparable with those associated with B, S, and T. Adjunctive RP treatment resulted in significantly lower mean pulmonary arterial pressures, RV systolic pressure. It also improved SO 2 measurements, as compared with MCT+Veh ( P  < 0.05), and diastolic pulmonary artery pressure ( P  < 0.05), as compared with single-agent B and S therapy (Bonferroni method adjusting for multiplicity). RP+S appeared to show the most consistent and extensive effects on pulmonary hemodynamics, respiratory parameters, and histopathologic changes. These results corroborate earlier preclinical findings supporting the efficacy of single-agent RP in PAH. RP, as mono and adjunctive therapy compared with induced-control, mitigated the functional and structural effects of MCT-induced PAH. [ABSTRACT FROM AUTHOR]

In the present study, the distribution and dynamic expression of serotonin and dopamine in the nervous system and ovary of the sea cucumber, Holothuria scabra, during different ovarian stages were investigated. We found that serotonin-immunoreactivity was more intense in the neurons and neuropils of the outer ectoneural part, the inner hyponeural part, and the wall of hyponeural canal of radial nerve cord during the mature stages of ovarian cycle, whereas dopamine-immunoreactivity was detected at a higher intensity in these tissues during the early stages. Both neurotransmitters were detected in the ectoneural part of the nerve ring. In the ovary, serotonin intensity was more intense in the cytoplasm of late oocytes, while dopamine-immunoreactivity was more intense in the early stages. The changes in the levels serotonin in the radial nerve cord and oocytes are incremental towards the late stages of ovarian maturation. In contrast, dopamine levels in the nervous tissues and oocytes were more intense in early stages and became decremental towards the late stages. These findings suggest that serotonin and dopamine may have opposing effects on ovarian development in this sea cucumber species. [ABSTRACT FROM AUTHOR]

The functionally selective 5-HT2C receptor ligand SB242084 can increase motivation and have rapid onset anti-depressant-like effects. We sought to identify the specific behavioral effects of SB242084 treatment and elucidate the mechanism in female and male mice. Using a quantitative behavioral approach, we determined that SB242084 increases the vigor and persistence of goal-directed activity across different types of physical work, particularly when work requirements are demanding. We found this influence of SB242084 on effort, rather than reward to be reflected in striatal DA measured during behavior. Using in vivo fast scan cyclic voltammetry, we found that SB242084 has no effect on reward- related phasic DA release in the NAc. Using in vivo microdialysis to measure tonic changes in extracellular DA, we also found no changes in the NAc. In contrast, SB242084 treatment increases extracellular DA in the dorsomedial striatum, an area that plays a key role in response vigor. These findings have several implications. At the behavioral level, this work shows that the capacity to work in demanding situations can be increased, without a generalized increase in motor activity or reward value. At the circuit level, we identified a pathway restricted potentiation of DA release and showed that this was the reason for the increased response vigor. At the cellular level, we show that a specific serotonin receptor cross talks to the DA system. Together, this information provides promise for the development of treatments for apathy, a serious clinical condition that can afflict patients with psychiatric and neurological disorders. [ABSTRACT FROM AUTHOR]

The current study used data from two longitudinal samples to test whether self-regulation, depressive symptoms, and aggression/antisociality were mediators in the relation between a polygenic score indexing serotonin (5-HT) functioning and alcohol use in adolescence. The results from an independent genome-wide association study of 5-hydroxyindoleacetic acid in the cerebrospinal fluid were used to create 5-HT polygenic risk scores. Adolescents and/or parents reported on adolescents' self-regulation (Time 1), depressive symptoms (Time 2), aggression/antisociality (Time 2), and alcohol use (Time 3). The results showed that 5-HT polygenic risk did not predict self-regulation. However, adolescents with higher levels of 5-HT polygenic risk showed greater depression and aggression/antisociality. Adolescents' aggression/antisociality mediated the relation between 5-HT polygenic risk and later alcohol use. Deficits in self-regulation also predicted depression and aggression/antisociality, and indirectly predicted alcohol use through aggression/antisociality. Pathways to alcohol use were especially salient for males from families with low parental education in one of the two samples. The results provide insights into the longitudinal mechanisms underlying the relation between 5-HT functioning and alcohol use (i.e., earlier aggression/antisociality). There was no evidence that genetically based variation in 5-HT functioning predisposed individuals to deficits in self-regulation. Genetically based variation in 5-HT functioning and self-regulation might be separate, transdiagnostic risk factors for several types of psychopathology. [ABSTRACT FROM AUTHOR]

Serotonin (5-HT) and adrenaline acting at platelet 5-HT 2A -serotoninergic and α 2 -adrenergic receptors are involved in platelet aggregation. We have evaluated the antagonistic potency at 5-HT 2A , α 2A –, and α 2B -adrenoceptors as well as an anti-aggregation effect of aroxyalkyl derivatives of 2-methoxyphenylpiperazine and compared them with ketanserin, sarpogrelate, prazosin, yohimbine and ARC239 (2-[2-[4-(o-methoxyphenyl)-piperazin-1-yl]-ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione). Functional bioassays at cells expressing human receptors, revealed studied compounds to be moderate antagonists of 5-HT 2A and α 2 -adrenoceptors, with around 2–7 times stronger antagonistic effect at α 2B subtype than α 2A subtype. Further, studied compounds inhibited 5-HT 2A -mediated contraction in isolated rat aortic rings and 5-HT vasopressor response in rat in vivo. Studied compounds inhibited collagen stimulated whole rat blood aggregation with compound MH-77 (1-[(2,3-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride) being more potent than sarpogrelate or yohimbine. They also inhibited 5-HT/adrenaline-, amplified ADP- or collagen- induced platelet aggregation. Simultaneous, moderate blockade of 5-HT 2A serotonin and α 2 -adrenergic receptors is effective in preventing aggregation and could constitute alternative antiplatelet therapy. [ABSTRACT FROM AUTHOR]

The serotonin 2B receptor (5-HT 2B R), which was first cloned and characterized in the rat stomach fundus, is the most recent addition to the 5-HT 2 R family. While its involvement in the regulation of gastrointestinal, vascular, pulmonary and cardiac physiology has been widely investigated, its functional role within the central nervous system (CNS) has received much less attention. Nevertheless, when considering the data available in the literature with regards to the regulatory control exerted by the central 5-HT 2B R on dopamine (DA) and serotonin (5-HT) neuron activity, a very interesting picture emerges and highlights the key role of these receptors for future therapeutic strategies of DA-related neuropsychiatric disorders. Thus, the present review, by compiling molecular, biochemical, electrophysiological and behavioral findings from the literature of the past twenty years, aims at providing a sound analysis of the current knowledge supporting the interest of the central 5-HT 2B R for future therapeutic avenues. First, we recall the neuroanatomical and functional data supporting the therapeutic relevance of the 5-HT/DA interaction in the CNS. Thereafter, after a short overview of the central expression and molecular properties of the 5-HT 2B R, as well as of the 5-HT 2B R agonists and antagonists available in the market, we will focus on the functional role of this receptor in the control of 5-HT, DA and neuroglia activity in the rodent brain. Finally, the therapeutic potential of 5-HT 2B R antagonists for improved treatment of schizophrenia and drug addiction will be discussed. [ABSTRACT FROM AUTHOR]

Background: Genetic predisposition is an important factor leading to aggressive behavior. However, the relationship between genetic polymorphisms and aggressive behavior has not been elucidated.Methods: We identified candidate genes located in the dopaminergic and serotonin system (DRD3, DRD4, and FEV) that had been previously reported to be associated with aggressive behavior. We investigated 14 tag single-nucleotide polymorphisms (SNPs) using a multi-analytic strategy combining logistic regression (LR) and classification and regression tree (CART) to explore higher-order interactions between these SNPs and aggressive behavior in 318 patients and 558 controls.Results: Both LR and CART analyses suggested that the rs16859448 polymorphism is the strongest individual factor associated with aggressive behavior risk. In CART analysis, individuals carrying the combined genotypes of rs16859448TT/GT-rs11246228CT/TT-rs3773679TT had the highest risk, while rs16859448GG-rs2134655CT had the lowest risk (OR = 5.25, 95% CI: 2.53-10.86).Conclusion: This study adds to the growing evidence on the association of single- and multiple-risk variants in DRD3, DRD4, and FEV with aggressive behavior in Chinese adolescents. However, the aggressive behavior scale used to diagnose aggression in this study did not account for comorbid conditions; therefore, further studies are needed to confirm our observations. [ABSTRACT FROM AUTHOR]

Recent preclinical and clinical data suggest that low dose of caffeine enhances the effects of common antidepressants. Here we investigated the effects of chronic administration of caffeine (5 mg/kg, twice daily for 14 days) and its withdrawal on day 15th on the activity of per se ineffective doses of fluoxetine (5 mg/kg) and escitalopram (2 mg/kg) given on day 15th. We found decreased immobility time in the forced swim and tail suspension tests in mice in which caffeine was administered simultaneously with antidepressants on day 15th following a 14-day caffeine treatment and no alterations in the spontaneous locomotor activity. A decrease in the level of escitalopram and an increase in the level of caffeine in serum were observed after concomitant administration of these compounds, while the joint administration of caffeine and fluoxetine was not associated with changes in their levels in serum or brain. Caffeine withdrawal caused a decrease in Adora1 mRNA level in the cerebral cortex (Cx). Administration of escitalopram or fluoxetine followed by caffeine withdrawal caused an increase in this gene expression, whereas administration of escitalopram, but not fluoxetine, on day 15th together with caffeine caused a decrease in Adora1 mRNA level in the Cx. Furthermore, antidepressant-like activity observed after joint administration of the tested drugs with caffeine was associated with decreased Slc6a15 mRNA level in the Cx. The results show that withdrawal of caffeine after its chronic intake may change activity of antidepressants with concomitant alterations within monoamine, adenosine and glutamate systems. [ABSTRACT FROM AUTHOR]

We present a method to target voltage-sensitive fluorescent dyes to specified cells using an enzyme-catalyzed fluorogenic reaction on cell surfaces. The dye/enzyme hybrids are composed of a photoinduced electron transfer (PeT)- based fluorescent voltage indicator and a complementary enzyme expressed on the cell surface. Action of the exogenous enzyme on the dye results in fluorogenic activation of the dye, enabling fast voltage imaging in defined neurons with sensitivity surpassing those of purely genetically encoded approaches. We employ a bulky methylcyclopropylacetoxymethyl ether to diminish the fluorescence of a PeT-based voltage-sensitive dye, or VoltageFluor. The hydrolytically stable ether can be removed by the action of porcine liver esterase (PLE) to reveal the bright unmodified VoltageFluor. We established that the chemically modified VoltageFluor is a substrate for PLE in vitro and in live cells. When PLE is targeted to the external face of cell membranes, it controls the apparent staining of cells. The use of neuron-specific promoters can direct staining to mammalian neurons to provide clear detection of neuronal action potentials in single trials. All of the new VoltageFluors targeted by esterase expression (VF-EXs) report single spikes in cultured mammalian neurons. The best, VF-EX2, does so with a signal-to-noise ratio nearly double that of comparable genetically encoded voltage reporters. By targeting PLE to neurons, VF-EX2 can interrogate the neuromodulatory effects of serotonin in cultured hippocampal neurons. Taken together, our results show that a combination of synthetic chemistry and biochemistry enables bright and fast voltage imaging from genetically defined neurons in culture. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Although the notion that alcohol promotes violence is widespread, not all individuals are aggressive while intoxicated. Genetic variation could be a contributing factor to individual differences in alcohol-heightened aggression. The present study examines the effects of OPRM1C77G genotype on responses to threat in rhesus macaques under normal conditions and following alcohol administration. Prior studies have shown that a low CSF level of 5-HIAA is a trait marker for individuals prone to escalated aggression. We wanted to examine whether the predictive value for this marker on aggression was moderated by OPRM1 genotype. Animals were administered alcohol (BAC 100-200 mg%), were provoked by a human intruder, and aggressive responses were recorded. Factor analysis was performed to generate aggressive response factors, which were then used as dependent variables for ANOVA, with OPRM1 genotype and CSF 5-HIAA as independent variables. Factor analysis generated three factors ('Threatening', 'Distance Decreasing' and 'High Intensity'). We found that High Intensity aggression was increased among carriers of the OPRM1 G allele, especially among individuals with low CSF levels of 5-HIAA. Aggression in the non-intoxicated state was predicted by 5-HIAA, but not by genotype. This study demonstrates that OPRM1 genotype predicts alcohol-heightened aggression in rhesus macaques with low CSF levels of 5-HIAA. Because OPRM1 variation predicts similar effects on alcohol response and behavior in humans and macaques, this study could suggest a role for OPRM1 genotype in alcohol-heightened aggression in humans. If so, it may be that compounds that block this receptor could reduce alcohol-associated violence in selected patient populations. [ABSTRACT FROM AUTHOR]

Phytohormones or plant growth regulators play a crucial role in plant growth and developmental process. Apart from the traditional plant hormones studied so far i.e., auxin, gibberellins, cytokinin, abscisic acid, and ethylene, various other biomolecules are being reported to act as hormones. Several novel plant growth regulators discovered in the recent past includes compounds like Melatonin, Serotonin, Strigolactone, Harzianolide and Karrikins. Melatonin and Serotonin which were previously studied exclusively due to their function as neurotransmitter in animals are also being reported in plants widely. These two hormones impart specific functions during biotic and abiotic stress as well as plant growth and developmental processes. On the other hand Strigolactone previously reported as germination stimulant for weed species, also has important function in plant architecture modification. Strigolactone also imparts resistance to plants during abiotic stresses i.e. drought, salinity, heavy metal stress, temperature, nutrient starvation as well as various biotic stresses. It can be used along with the major plant hormones- auxin and cytokinin to regulate organogenesis. Reports elucidating the nature of these newly discovered biomolecules, there effects on plant growth and developmental processes as well as their interaction with other traditional hormones and other organic and inorganic molecules keep open the door for further exploration. Harzianolide isolated from Trichoderma harzianum was studied for its role in plant growth and systemic resistance. These secondary metabolites of Trichoderma promote plant growth through better root development and activation of plant defense responses. Karrikins are a group of plant growth regulators found in the smoke of burning plant materials are known to stimulate the germination of seeds. This paper reviews the literature supporting evidence on different novel plant growth regulators and their potential roles in agriculture. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic and serotoninergic signalling. A number of pathogenic mechanisms have been implicated including loss of mitochondrial function at the level of complex I, and lysosomal metabolism at the level of lysosomal glucocerebrosidase (GBA1). In order to investigate further the potential involvement of complex I and GBA1 in PD, we assessed the impact of loss of respective enzyme activities upon dopamine and serotonin turnover. Using SH-SY5Y cells, complex I deficiency was modelled by using rotenone whilst GBA1 deficiency was modelled by the use of conduritol B epoxide (CBE). Dopamine, its principal metabolites, and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the extracellular medium were quantified by HPLC. Inhibition of complex I significantly increased extracellular concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-HIAA. Comparable results were observed with CBE. These results suggest increased monoamine oxidase activity and provide evidence for involvement of impaired complex I or GBA1 activity in the dopamine/serotonin deficiency seen in PD. Use of extracellular media may also permit relatively rapid assessment of dopamine/serotonin metabolism and permit screening of novel therapeutic agents. [ABSTRACT FROM AUTHOR]

Serotonin is known to regulate energy and calcium homeostasis in several mammalian species. The objective of this study was to determine if pre-partum infusions of 5-hydroxytryptophan (5-HTP), the immediate precursor to serotonin synthesis, could modulate energy homeostasis at the level of the hepatocyte in post-partum Holstein and Jersey dairy cows. Twelve multiparous Holstein cows and twelve multiparous Jersey cows were intravenously infused daily for approximately 7 d pre-partum with either saline or 1 mg/kg bodyweight of 5-HTP. Blood was collected for 14 d post-partum and on d30 post-partum. Liver biopsies were taken on d1 and d7 post-partum. There were no changes in the circulating concentrations of glucose, insulin, glucagon, non-esterified fatty acids, or urea nitrogen in response to treatment, although there were decreased beta-hydroxybutyrate concentrations with 5-HTP treatment around d6 to d10 post-partum, particularly in Jersey cows. Cows infused with 5-HTP had increased hepatic serotonin content and increased mRNA expression of the serotonin 2B receptor on d1 and d7 post-partum. Minimal changes were seen in the hepatic mRNA expression of various gluconeogenic enzymes. There were no changes in the mRNA expression profile of cell-cycle progression marker cyclin-dependent kinase 4 or apoptotic marker caspase 3, although proliferating cell nuclear antigen expression tended to be increased in Holstein cows infused with 5-HTP on d1 post-partum. Immunofluorescence assays showed an increased number of CASP3- and Ki67-positive cells in Holstein cows infused with 5-HTP on d1 post-partum. Given the elevated hepatic serotonin content and increased mRNA abundance of 5HTR2B, 5-HTP infusions may be stimulating an autocrine-paracrine adaptation to lactation in the Holstein cow liver. [ABSTRACT FROM AUTHOR]

Tryptophan hydroxylase 2 ( TPH2) is the key enzyme in the synthesis of neuronal serotonin . Although previous studies suggest that TPH2 neuron-restrictive silencer element ( NRSE) functions as a negative regulator dependent on neuron-restrictive silencer factor ( NRSF) activity, the underlying mechanisms are yet to be fully elucidated. Here, we show a detailed analysis of the NRSE-mediated repression of the human TPH2 ( hTPH2) promoter activity in RN46A cells, a cell line derived from rat raphe neurons. Quantitative real-time RT- PCR analysis revealed the expression of serotonergic marker genes ( Mash1, Nkx2.2, Gata2, Gata3, Lmx1b, Pet-1, 5-Htt, and Vmat2) and Nrsf gene in RN46A cells. Tph1 mRNA is the prevalent form expressed in RN46A cells; Tph2 mRNA is also expressed but at a lower level. Electrophoretic mobility shift assays and reporter assays showed that hTPH2 NRSE is necessary for the efficient DNA binding of NRSF and for the NRSF-dependent repression of the hTPH2 promoter activity. The hTPH2 promoter activity was increased by knockdown of NRSF, or over-expression of the engineered NRSF (a dominant-negative mutant or a DNA-binding domain and activation domain fusion protein). MS-275, a class I histone deacetylase ( HDAC) inhibitor, was found to be more potent than MC-1568, a class II HDAC inhibitor, in enhancing the hTPH2 promoter activity. Furthermore, treatment with the ubiquitin-specific protease 7 deubiquitinase inhibitors, P-22077 or HBX 41108, increased the hTPH2 promoter activity. Collectively, our data demonstrate that the hTPH2 NRSE-mediated promoter repression via NRSF involves class I HDACs and is modulated by the ubiquitin-specific protease 7-mediated deubiquitination and stabilization of NRSF. [ABSTRACT FROM AUTHOR]

Background 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). Methods 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. Results 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. Conclusion 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. [ABSTRACT FROM AUTHOR]

There is substantial evidence for the assumption that particularly heavy cannabis usett is associated with a variety of psychopathologic conditions. Little is known about the relationship between cannabis and anxiety. Prior studies have concluded that cannabis use alone is not sufficient for the development of long-term anxiety, and it has been suggested that cannabis is simply a risk factor that operates in conjunction with other risk factors. One such risk factor may be an individuals' genetic vulnerability. The present study examines the relationship between cannabis use and symptoms of anxiety by taking a developmental molecular-genetic perspective with a focus on a polymorphism involved in the regulation of serotonin. Specifically, we concentrated on changes in cannabis use and symptoms of anxiety over time and differences herein for individuals with and without the short allele of the 5-HTTLPR genotype. Data were from 1424 adolescents over a period of 5 years. We used different statistical analyses to test co-development of cannabis use and symptoms of anxiety throughout adolescence and the possible role of the 5-HTTLPR genotype in this process. Results from different analyses showed that cannabis use is associated with an increase in symptoms of anxiety, but only in carriers of the short allele of the 5-HTTLPR genotype, not in non-carriers. The findings of the present study show first evidence that the links between cannabis use and symptoms of anxiety are conditional on the individuals' genetic make-up. [ABSTRACT FROM AUTHOR]

Recent findings have demonstrated that serotonin is an important participant in the development and progression of peripheral artery diseases. Taking this into consideration, the goals of this study were to investigate the effects of serotonin on isolated Wistar rat femoral arteries in both healthy and diabetic animals, with and without artery occlusion, with a particular focus on determining the role of calcium in this process. Contraction experiments with serotonin on intact and denuded femoral artery rings, in the presence or absence of nifedipine and ouabain (both separately, or in combination), as well as Ca2+-free Krebs-Ringer bicarbonate solution were performed. The serotonin-induced results were concentration dependent, but only in healthy animals. The endothelium-dependent contraction of the femoral artery was assessed. In healthy animals, the endothelium-reliant part of contraction was dependent on the extracellular calcium, while the smooth muscle-related part was instead dependent on the intracellular calcium. In diabetic animals, both nifedipine and ouabain influenced serotonin-induced vascular effects by blocking intracellular calcium pathways. However, this was diminished after the simultaneous administration of both blockers. [ABSTRACT FROM AUTHOR]

Tryptophan (Trp) is an essential amino-acid and the precursor of many biologically active substances such as kynurenine (KYN) and serotonin (5HT). Its metabolism is involved in different physiopathological states, such as cardiovascular diseases, cancer, immunomodulation or depression. Hence, the quantification of Trp catabolites, from both KYN and 5HT pathways, might be usefulfor the discovery of novel diagnostic and follow-up biomarkers. We have developed a simple method for quantification of Trp and 8 of its metabolites,involved in both KYN and 5HT pathways, using liquid chromatography coupled to tandem mass spectrometry. We also validated the methodin human plasma samples, according to NF EN ISO 15189 criteria. Our method shows acceptable intra- and inter-day coefficients of variation (CV) (<12% and <16% respectively). The linearity entirelycovers the human plasma range. Stabilities of whole blood and of residues weredetermined, as well as the use of 2 different types of collectiontube, enabling us to adapt our process. Matrix effects and reference values showed good agreement compared to the literature. We propose here a method allowing the simultaneous quantification of a panel of Trp catabolites, never used before to our knowledge. This method, witha quickchromatographic runtime (15 min) and simple sample preparation, has beenvalidated according to NF EN ISO 15189 criteria. The method enables the detailed analysis of these metabolic pathways, which are thought to be involved in a number of pathological conditions. [ABSTRACT FROM AUTHOR]

Background: 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.Methods: 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.Results: 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.Conclusions: Serotonin is a marker for decompensation in patients with chronic heart failure. Higher serotonin levels were associated with worse HF symptoms and systolic dysfunction. [ABSTRACT FROM AUTHOR]

Serotonin, or 5-hydroxytryptamine (5-HT), is a well-known neurotransmitter that plays vital roles in neural activities and social behaviors. Clinically, deficiency of serotonin is linked with many psychiatric disorders. Interestingly, a large proportion of serotonin is also produced outside the central nervous system (CNS). There is increasing evidence demonstrating important roles of serotonin in the peripheral tissues. Here, we will describe the multiple biological functions of serotonin in hematopoietic system, such as development of hematopoietic stem and progenitor cells (HSPCs), differentiation of hematopoietic cells, maintenance of vascular system, and relationship with hematological diseases. The roles of serotonin in inflammatory responses mediated by hematopoietic cells as well as in liver regeneration are also discussed. Our recent understandings of the impact of serotonin on hematopoietic system, immune responses, and tissue regeneration support utilization of serotonin as a potential therapeutic target for the treatment of hematological diseases and organ repair in clinic. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective 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. Study design and measurements 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 si RNA knockdown of the vitamin D receptor ( VDR) and administration of 10 n m 1,25-dihydroxyvitamin D3 on serotonin secretion in human umbilical vein endothelial cells ( HUVECs) in vitro. Results 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 D3 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. Conclusions 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. [ABSTRACT FROM AUTHOR]

In our previous work we have shown that L-Tryptophan (TrP) enriched diet prevents the age-induced decline of hippocampal Serotonin (5-HT) production. Considering that loss or reduction in 5-HT neurotransmission may contribute to age-related cognitive decline, here we have investigated the effect of such diet on passive avoidance (PA) behavior, cell death, pro- and anti- apoptotic molecules (BAX, Bcl-2 and Caspase-3) and an important transcription factor involved in synaptic plasticity and memory (CREB). The increase in 5-HT neurotransmission in the Hippocampus (Hp) of aged rats was induced by 1 month of high TrP administration. In the first phase of our study we found that high TrP diet improves PA behaviour of aged rats and this correlated with a decrease of TUNEL positive cells in all hippocampal regions tested (CA1, CA2, CA3, DG). Interestingly, the Hp of aged animals fed with high TrP diet showed a significant downregulation of proapoptotic proteins, caspase-3 and BAX, and an increase of antiapoptotic molecules Bcl-2 as indicated by Western Blot and immunohistochemical analyses. Also, high TrP diet partially rescued the age-induced inhibition of hippocampal CREB phosphorylation. Altogether, our data suggest that enhanced TrP intake, and in consequence a potential increase in 5-HT neurotransmission, might be beneficial in preventing age-related detrimental features by inhibition of hippocampal apoptosis. [ABSTRACT FROM AUTHOR]

Background Alterations in serotonin (5-HT) metabolism have been postulated to play a role in the pathogenesis of irritable bowel syndrome (IBS). However, previous reports regarding 5-HT metabolism in IBS are contradicting. Aim To compare platelet poor plasma (PPP) 5-HT and 5-hydroxyindole acetic acid (5-HIAA) levels and their ratio in a large cohort of IBS patients and healthy controls (HC), including IBS-subgroup analysis. Methods Irritable bowel syndrome patients and HC were evaluated for fasting PPP 5-HT and 5-HIAA levels. Furthermore, GI-symptom diary, GSRS, quality of life, anxiety and depression scores were assessed in the 2 weeks before blood sampling. Results One hundred and fifty four IBS patients and 137 HC were included. No differences were detected in plasma 5-HT between groups. The 5-HIAA concentrations and 5-HIAA/5-HT ratio were significantly lower in IBS compared to HC: 24.6 ± 21.9 vs. 39.0 ± 29.5 lg/L (P < 0.001) and 8.4 ± 12.2 vs. 13.5 ± 16.6 (P < 0.01), respectively. Subtype analysis for 5-HIAA showed all IBS subtypes to be significantly different from HC. The 5-HIAA/5-HT ratio was significantly lower in the IBS-M subtype vs. HC. Linear regression analysis points to an influence of gender but not of GI-symptoms, psychological scores or medication use. Conclusions We demonstrated that fasting 5-HT plasma levels are not significantly different in IBS patients compared to controls. However, decreased 5-HIAA levels and 5-HIAA/5-HT ratio in IBS patients may reflect altered serotonin metabolism in IBS. Gender affects 5-HIAA levels in IBS patients, but no effects of drugs, such as SSRIs, or higher GI-symptom or psychological scores were found. [ABSTRACT FROM AUTHOR]

Summary Serotonergic (5HT) neurons modulate diverse behaviors and physiology and are implicated in distinct clinical disorders. Corresponding diversity in 5HT neuronal phenotypes is becoming apparent and is likely rooted in molecular differences, yet a comprehensive approach characterizing molecular variation across the 5HT system is lacking, as is concomitant linkage to cellular phenotypes. Here we combine intersectional fate mapping, neuron sorting, and genome-wide RNA-seq to deconstruct the mouse 5HT system at multiple levels of granularity—from anatomy, to genetic sublineages, to single neurons. Our unbiased analyses reveal principles underlying system organization, 5HT neuron subtypes, constellations of differentially expressed genes distinguishing subtypes, and predictions of subtype-specific functions. Using electrophysiology, subtype-specific neuron silencing, and conditional gene knockout, we show that these molecularly defined 5HT neuron subtypes are functionally distinct. Collectively, this resource classifies molecular diversity across the 5HT system and discovers sertonergic subtypes, markers, organizing principles, and subtype-specific functions with potential disease relevance. [ABSTRACT FROM AUTHOR]

Although serotonin has been shown to inhibit peripheral sympathetic outflow, serotonin regulation on renal sympathetic outflow has not yet been elucidated. This study investigated which 5-HT receptor subtypes are involved. Wistar rats were anesthetized (sodium pentobarbital; 60 mg/kg, i.p.), and prepared for in situ autoperfused rat kidney, which allows continuous measurement of systemic blood pressure (SBP), heart rate (HR) and renal perfusion pressure (PP). Electrical stimulation of renal sympathetic nerves resulted in frequency-dependent increases in PP (18.3 ± 1.0, 43.7 ± 2.7 and 66.7 ± 4.0 for 2, 4 and 6 Hz, respectively), without altering SBP or HR. 5-HT, 5-carboxamidotryptamine (5-HT 1/7 agonist) (0.00000125–0.1 μg/kg each) or l -694,247 (5-HT 1D agonist; 0.0125 μg/kg) i.a. bolus inhibited vasopressor responses by renal nerve electrical stimulation, unlike i.a. bolus of agonists α-methyl-5-HT (5-HT 2 ), 1-PBG (5-HT 3 ), cisapride (5-HT 4 ), AS-19 (5-HT 7 ), CGS-12066B (5-HT 1B ) or 8-OH-DPAT (5-HT 1A ) (0.0125 μg/kg each). The effect of l -694,247 did not affect the exogenous norepinephrine-induced vasoconstrictions, whereas was abolished by antagonist LY310762 (5-HT 1D ; 1 mg/kg) or l -NAME (nitric oxide; 10 mg/kg), but not by indomethacin (COX 1/2 ; 2 mg/kg) or glibenclamide (ATP-dependent K + channel; 20 mg/kg). These results suggest that 5-HT mechanism-induced inhibition of rat vasopressor renal sympathetic outflow is mainly mediated by prejunctional 5-HT 1D receptors via nitric oxide release. [ABSTRACT FROM AUTHOR]

We have previously demonstrated that nicotine withdrawal produces depression-like behavior and that serotonin (5- HT)2A/2C receptor ligands modulate that mood-like state. In the present study we aimed to identify the mechanisms (changes in radioligand binding, transcription or RNA-editing) related to such a behavioral outcome. Rats received vehicle or nicotine (0.4 mg/kg, s.c.) for 5 days in home cages. Brain 5- HT2A/2C receptors were analyzed on day 3 of nicotine withdrawal. Nicotine withdrawal increased [3H]ketanserin binding to 5- HT2A receptors in the ventral tegmental area and ventral dentate gyrus, yet decreased binding in the nucleus accumbens shell. Reduction in [3H]mesulergine binding to 5- HT2C receptors was seen in the ventral dentate gyrus. Profound decrease in the 5- HT2A receptor transcript level was noted in the hippocampus and ventral tegmental area. Out of five 5- HT2C receptor mRNA editing sites, deep sequencing data showed a reduction in editing at the E site and a trend toward reduction at the C site in the hippocampus. In the ventral tegmental area, a reduction for the frequency of CD 5- HT2C receptor transcript was seen. These results show that the reduction in the 5- HT2A receptor transcript level may be an auto-regulatory response to the increased receptor density in the hippocampus and ventral tegmental area during nicotine withdrawal, while decreased 5- HT2C receptor mRNA editing may explain the reduction in receptor labeling in the hippocampus. [ABSTRACT FROM AUTHOR]

Background/Aims: Several disorders of the gastrointestinal tract are associated with abnormal serotonin (5-HT) signaling or metabolism where the 5-HT3 and 5-HT4 receptors are clinically relevant. The aim was to examine the distribution of 5-HT3, 5-HT4, and 5-HT7 receptors in the normal human colon and how this is associated with receptor interacting chaperone 3, G protein coupled receptor kinases, and protein LIN-7 homologs to extend previous observations limited to the sigmoid colon or the upper intestine. Methods: Samples from ascending, transverse, descending, and sigmoid human colon were dissected into 3 separate layers (mucosa, longitudinal, and circular muscles) and ileum samples were dissected into mucosa and muscle layers (n = 20). Complementary DNA was synthesized by reverse transcription from extracted RNA and expression was determined by quantitative or end point polymerase chain reaction. Results: The 5-HT3 receptor subunits were found in all tissues throughout the colon and ileum. The A subunit was detected in all samples and the C subunit was expressed at similar levels while the B subunit was expressed at lower levels and less frequently. The 5-HT3 receptor E subunit was mainly found in the mucosa layers. All splice variants of the 5-HT4 and 5-HT7 receptors were expressed throughout the colon although the 5-HT4 receptor d, g, and i variants were expressed less often. Conclusions: The major differences in 5-HT receptor distribution within the human colon are in relation to the mucosa and muscular tissue layers where the 5-HT3 receptor E subunit is predominantly found in the mucosal layer which may be of therapeutic relevance. [ABSTRACT FROM AUTHOR]

The article offers information on a diet study wherein ingested amount of serotonin leading to 5-Hydroxyindoleacetic acid elevations (5-HIAA) was monitored in blood proteins and urinary secretions to diagnose patients suffering from Neuroendocrine tumors (NCT). Topics discussed include ingestion of serotonin containing foods including banana, walnuts and pineapple; medications used in blood samples were beta-blockers, metformin and spironolactone, and distributory analysis of HIAA.

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

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) use may have long-term neurotoxic effects. In this study, positron emission tomography with the tracer alpha-[11C]methyl-Ltryptophan (11C-AMT) was used to compare human brain serotonin (5-HT) synthesis capacity in 17 currently drug-free MDMA polydrug users with that in 18 healthy matched controls. Gender differences and associations between regional 11C-AMT trapping and characteristics of MDMA use were also examined. MDMA polydrug users exhibited lower normalized 11C-AMT trapping in pre-frontal, orbitofrontal, and parietal regions, relative to controls. These differences were more widespread in males than in females. Increased normalized 11C-AMT trapping in MDMA users was also observed, mainly in the brainstem and in frontal and temporal areas. Normalized 11C-AMT trapping in the brainstem and prefrontal regions correlated positively and negatively, respectively, with greater lifetime accumulated MDMA use, longer durations of MDMA use, and shorter time elapsed since the last MDMA use. Although the possibility of pre-existing 5-HT alterations pre-disposing people to use MDMA cannot be ruled out, regionally decreased 5-HT synthesis capacity in the forebrain could be interpreted as neurotoxicity of MDMA on distal (frontal) brain regions. On the other hand, increased 5-HT synthesis capacity in the raphe and adjacent areas could be due to compensatory mechanisms. [ABSTRACT FROM AUTHOR]

The elevated T-maze (ETM) was developed to test the hypothesis that serotonin (5-HT) plays an opposing role in the regulation of defensive behaviors associated with anxiety and panic. This test allows the measurement in the same rat of inhibitory avoidance acquisition, related to generalized anxiety disorder, and of one-way escape, associated with panic disorder. The evidence so far reported with the ETM supports the above hypothesis and indicates that: (1) whereas 5-HT neurons located at the dorsal raphe nucleus are involved in the regulation of both inhibitory avoidance and escape, those of the median raphe nucleus are primarily implicated in the former task; (2) facilitation of 5-HT1A- and 5-HT2A-mediated neurotransmission in the dorsal periaqueductal gray (dPAG) is likely to mediate the panicolytic drug action; (3) stimulation of 5-HT2C receptors in the basolateral amygdala increases anxiety and is implicated in the anxiogenesis caused by short-term administration of antidepressant drugs, and (4) 5-HT1A and the μ-opioid receptors work together in the dPAG to modulate escape or panic attacks. These last results point to the possible benefits of adjunctive opioid therapy for panic patients resistant to antidepressants that act on 5-HT neurotransmission. [ABSTRACT FROM AUTHOR]

Hearing loss induces plasticity in excitatory and inhibitory neurotransmitter systems in auditory brain regions. Excitatory-inhibitory balance is also influenced by a range of neuromodulatory regulatory systems, but less is known about the effects of auditory damage on these networks. In this work, we studied the effects of acoustic trauma on neuromodulatory plasticity in the auditory midbrain of CBA/J mice. Quantitative PCR was used to measure the expression of serotonergic and GABAergic receptor genes in the inferior colliculus (IC) of mice that were unmanipulated, sham controls with no hearing loss, and experimental individuals with hearing loss induced by exposure to a 116 dB, 10 kHz pure tone for 3 h. Acoustic trauma induced substantial hearing loss that was accompanied by selective upregulation of two serotonin receptor genes in the IC. The Htr1B receptor gene was upregulated tenfold following trauma relative to shams, while the Htr1A gene was upregulated threefold. In contrast, no plasticity in serotonin receptor gene expression was found in the hippocampus, a region also innervated by serotonergic projections. Analyses in the IC demonstrated that acoustic trauma also changed the coexpression of genes in relation to each other, leading to an overexpression of Htr1B compared to other genes. These data suggest that acoustic trauma induces serotonergic plasticity in the auditory system, and that this plasticity may involve comodulation of functionally-linked receptor genes. [ABSTRACT FROM AUTHOR]

The termination of serotonin (5-hydroxytryptamine, 5-HT) neurotransmission is regulated by its uptake by the 5-HT transporter (5-HTT), as well as its degradation by monoamine oxidase (MAO)-A. MAO-A deficiency results in a wide set of behavioral alterations, including perseverative behaviors and social deficits. These anomalies are likely related to 5-HTergic homeostatic imbalances; however, the role of 5-HTT in these abnormalities remains unclear. To ascertain the role of 5-HTT in the behavioral anomalies associated to MAO-A deficiency, we tested the behavioral effects of its blocker fluoxetine on perseverative, social and aggressive behaviors in transgenic animals with hypomorphic or null-allele MAO-A mutations. Acute treatment with the 5-HTT blocker fluoxetine (10 mg/kg, i.p.) reduced aggressive behavior in MAO-A knockout (KO) mice and social deficits in hypomorphic MAO-ANeo mice. Furthermore, this treatment also reduced perseverative responses (including marble burying and water mist-induced grooming) in both MAO-A mutant genotypes. Both MAO-A mutant lines displayed significant reductions in 5-HTT expression across the prefrontal cortex, amygdala and striatum, as quantified by immunohistochemical detection; however, the down-regulation of 5-HTT in MAO-ANeo mice was more pervasive and widespread than in their KO counterparts, possibly indicating a greater ability of the hypomorphic line to enact compensatory mechanisms with respect to 5-HT homeostasis. Collectively, these findings suggest that the behavioral deficits associated with low MAO-A activity may reflect developmental alterations of 5-HTT within 5-HTergic neurons. Furthermore, the translational implications of our results highlight 5-HT reuptake inhibition as an interesting approach for the control of aggressive outbursts in MAO-A deficient individuals. [ABSTRACT FROM AUTHOR]

5-hydroxytryptamine (5-HT) reuptake inhibitors counteract the pro-thrombotic effect of elevated plasma 5-HT by down-regulating the 5-HT uptake rates of platelets. Cocaine also down-regulates the platelet 5-HT uptake rates but in contrast, the platelets of cocaine-injected mice show a much higher aggregation rate than the platelets of control mice. To examine the involvement of plasma 5-HT in cocaine-mediated platelet aggregation, we studied the function of platelets isolated from wild-type and transgenic, peripheral 5-HT knock-out (TPH1-KO) mice, and cocaine-insensitive dopamine transporter knock in (DAT-KI) mice. In cocaine-injected mice compared to the control mice, the plasma 5-HT level as well as the surface level of P-selectin was elevated; in vitro platelet aggregation in the presence of type I fibrillar collagen was enhanced. However, cocaine injection lowered the 5-HT uptake rates of platelets and increased the plasma 5-HT levels of the DAT-KI mice but did not change their platelets aggregation rates further which are already hyper-reactive. Furthermore, the in vitro studies supporting these in vivo findings suggest that cocaine mimics the effect of elevated plasma 5-HT level on platelets and in 5-HT receptor- and transporter-dependent pathways in a two-step process propagates platelet aggregation by an additive effect of 5-HT and nonserotonergic catecholamine. [ABSTRACT FROM AUTHOR]

In Drosophila, serotonin (5- HT) regulates aggression, mating behaviour and sleep/wake behaviour through different receptors. Currently, how these various receptors are themselves regulated is still not completely understood. The KCTD12-family of proteins, which have been shown to modify G-protein-coupled receptor ( GPCR) signalling in mammals, are one possibility of auxiliary proteins modulating 5- HT receptor signalling. The KCTD12-family was found to be remarkably conserved and present in species from C. elegans to humans. The Drosophila KCTD12 homologue Kctd12-like ( Ktl) was highly expressed in both the larval and adult CNS. By performing behavioural assays in male Drosophila, we now reveal that Ktl is required for proper male aggression and mating behaviour. Previously, it was shown that Ktl is in a complex with the Drosophila 5- HT receptor 5- HT7, and we observed that both Ktl and the 5- HT1A receptor are required in insulin-producing cells ( IPCs) for proper adult male behaviour, as well as for hyperaggressive activity induced by the mammalian 5- HT1A receptor agonist 8-hydroxy-2-dipropylaminotetralin-hydrobromide. Finally, we show that Ktl expression in the IPCs is necessary to regulate locomotion and normal sleep/wake patterns in Drosophila, but not the 5- HT1A receptor. Similar to what was observed with mammalian KCTD12-family members that interact physically with a GPCR receptor to regulate desensitization, in Drosophila Ktl may function in GPCR 5- HT receptor pathways to regulate their signalling, which is required for proper adult male behaviour. [ABSTRACT FROM AUTHOR]

Studies devoted to understanding locomotor control have mainly addressed the functioning of the neural circuits controlling leg movements and relatively little is known of the operation of networks that activate trunk muscles in coordination with limb movements. The aim of the present work was (1) to identify the exogenous neurotransmitter cocktail that most strongly activates postural thoracic circuitry; (2) to investigate how the biogenic amines serotonin (5-HT), dopamine (DA), and noradrenaline (NA) modulate the coordination between limb and axial motor networks. Experiments were carried out on in vitro isolated spinal cord preparations from newborn rats. We recorded from ventral roots to monitor hindlimb locomotor and axial postural network activity. Each combination of the three amines with excitatory amino acids (EAAs) elicited coordinated rhythmic motor activity at all segmental levels with specific characteristics. The variability in cycle period was similar with 5-HT and DA while it was significantly higher with NA. DA elicited motor bursts of smaller amplitude in thoracic segments compared to 5-HT and NA, while both DA and NA elicited motor bursts of higher amplitude than 5-HT in the lumbar and sacral segments.The amines modulated the phase relationships of bursts in various segments with respect to the reference lumbar segment. At the thoracic level there was a phase lag between all recorded segments in the presence of 5-HT, while DA and NA elicited synchronous bursting. At the sacral level, 5-HT and DA induced an intersegmental phase shift while relationships became phase-locked with NA. Various combinations of EAAs with two or even all three amines elicited rhythmic motor output that was more variable than with one amine alone. Our results provide new data on the coordinating processes between spinal cord networks, demonstrating that each amine has a characteristic "signature" regarding its specific effect on intersegmental phase relationships. [ABSTRACT FROM AUTHOR]

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Elevated blood serotonin (5-HT) levels were the first biomarker identified in autism research. Many studies have contrasted blood 5-HT levels in autistic patients and controls, but different measurement protocols, technologies, and biomaterials have been used through the years. We performed a systematic review and meta-analysis to provide an overall estimate of effect size and between-study heterogeneity, while verifying whether and to what extent different methodological approaches influence the strength of this association. Our literature search strategy identified 551 papers, from which 22 studies providing patient and control blood 5-HT values were selected for meta-analysis. Significantly higher 5-HT levels in autistic patients compared to controls were recorded both in whole blood (WB) [O.R.=4.6; (3.1–5.2); P=1.0×10−12], and in platelet-rich plasma (PRP) [O.R.=2.6 (1.8–3.9); P=2.7×10−7]. Predictably, studies measuring 5-HT levels in platelet-poor plasma (PPP) yielded no significant group difference [O.R.=0.54 (0.2–2–0); P=0.36]. Altogether, elevated 5-HT blood levels were recorded in 28.3% in WB and 22.5% in PRP samples of autistic individuals, as reported in 15 and 4 studies, respectively. Studies employing HPLC vs fluorometric assays yield similar cumulative effect sizes, but the former display much lower variability. In summary, despite some limitations mainly due to small study sample sizes, our results significantly reinforce the reliability of elevated 5-HT blood levels as a biomarker in ASD, providing practical indications potentially useful for its inclusion in multi-marker diagnostic panels for clinical use. [ABSTRACT FROM AUTHOR]

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

Several studies have been conducted to analyze the role of short polymorphism of serotonin transporter (5-HTTLPR) in response to psy-chosocial stress mediated by Cortisol, having found inconsistent results. In order to synthesize and analyze available information about the role of short polymorphisms of 5-HTTLPR gen in the stress response, this meta-analysis has been carried out. A meta-analysis of studies published until November 2011 without language restrictions, which analyzed the effect of the short polymorphisms of 5-HTTLPR in the Cortisol response during a stress-inducing protocol was conducted. Published F or p genotype values were collected as estimators of the difference between groups as well as the sign of this difference for analysis. The global meta-analysis showed no significant association between the presence of the short allele and a different response to psychosocial stress. After comparing the subgroups of studies where participants underwent an emotionally neutral intervention versus an emotionally negative interven-tion, significant differences were found. The subgroup of studies where pa-tients underwent an emotionally negative intervention showed a significant-ly greater Cortisol release by those individuals carrying the short allele. This association was not seen in the neutral subgroup. [ABSTRACT FROM AUTHOR]