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Sample records for 5-hydroxytryptamine 5-ht signaling

  1. 5-hydroxytryptamine receptor (5-HT1DR) promotes colorectal cancer metastasis by regulating Axin1/β-catenin/MMP-7 signaling pathway

    PubMed Central

    Ji, Qing; Liu, Xuan; Zhou, Lihong; Song, Haiyan; Zhou, Xiqiu; Xu, Yangxian; Chen, Zhesheng; Cai, Jianfeng; Ji, Guang; Li, Qi

    2015-01-01

    Overexpression of 5-hydroxytryptamine (5-HT) in human cancer contributes to tumor metastasis, but the role of 5-HT receptor family in cancer has not been thoroughly explored. Here, we report overexpression of 5-HT1D receptor (5-HT1DR) was associated with Wnt signaling pathway and advanced tumor stage. The underlying mechanism of 5-HT1DR-promoted tumor invasion was through its activation on the Axin1/β-catenin/MMP-7 pathway. In an orthotopic colorectal cancer mouse model, we demonstrated that a 5-HT1DR antagonist (GR127935) effectively inhibited tumor metastasis through targeting Axin1. Furthermore, in intestinal epithelium cells, we observed that 5-HT1DR played an important role in cell invasion via Axin1/β-catenin/MMP-7 pathway. Together, our findings reveal an essential role of the physiologic level of 5-HT1DR in pulmonary metastasis of colorectal cancer. PMID:26214021

  2. 5-hydroxytryptamine receptor (5-HT1DR) promotes colorectal cancer metastasis by regulating Axin1/β-catenin/MMP-7 signaling pathway.

    PubMed

    Sui, Hua; Xu, Hanchen; Ji, Qing; Liu, Xuan; Zhou, Lihong; Song, Haiyan; Zhou, Xiqiu; Xu, Yangxian; Chen, Zhesheng; Cai, Jianfeng; Ji, Guang; Li, Qi

    2015-09-22

    Overexpression of 5-hydroxytryptamine (5-HT) in human cancer contributes to tumor metastasis, but the role of 5-HT receptor family in cancer has not been thoroughly explored. Here, we report overexpression of 5-HT(1D) receptor (5-HT(1D)R) was associated with Wnt signaling pathway and advanced tumor stage. The underlying mechanism of 5-HT(1D)R-promoted tumor invasion was through its activation on the Axin1/β-catenin/MMP-7 pathway. In an orthotopic colorectal cancer mouse model, we demonstrated that a 5-HT(1D)R antagonist (GR127935) effectively inhibited tumor metastasis through targeting Axin1. Furthermore, in intestinal epithelium cells, we observed that 5-HT(1D)R played an important role in cell invasion via Axin1/β-catenin/MMP-7 pathway. Together, our findings reveal an essential role of the physiologic level of 5-HT(1D)R in pulmonary metastasis of colorectal cancer. PMID:26214021

  3. Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors.

    PubMed

    Cubeddu, L X; Bönisch, H; Göthert, M; Molderings, G; Racké, K; Ramadori, G; Miller, K J; Schwörer, H

    2000-01-01

    Nearly 30% of patients treated with metformin experience gastrointestinal side effects. Since release of 5-hydroxytryptamine (5-HT) from the intestine is associated with nausea, vomiting, and diarrhea, we examined whether metformin induces 5-HT release from the intestinal mucosa. In 40% of tissue biopsy specimens of human duodenal mucosa, metformin (1, 10, and 30 microM) caused an increase in 5-HT outflow by 35, 70, and 98%, respectively. Peak increases in 5-HT outflow were observed after 10-15 min exposure to metformin, returning to baseline levels after 25 min. Tetrodotoxin (1 microM) reduced by about 50% the metformin-evoked increase in 5-HT outflow (P<0.05). Metformin-evoked release was not affected by scopolamine + hexamethonium, propranolol, the 5-HT3 receptor antagonist dolasetron, naloxone, or the NK1 receptor antagonist L703606. In the presence of tetrodotoxin (1 microM), somatostatin (1 microM) further reduced metformin-induced 5-HT release by 15-20%. In view of the 5-HT releasing effects of selective 5-HT3 receptor agonists to which metformin (N-N-dimethylbiguanide) is structurally related, we investigated whether metformin directly interacts with 5-HT3 receptors. Receptor binding (inhibition of [3H]-GR65630 binding) and agonist effects (stimulation of [14C]-guanidinium influx) at 5-HT3 receptors were studied in murine neuroblastoma N1E-115 cells, which express functional 5-HT3 receptors. Metformin up to 0.3 mM failed to inhibit [3H]-GR65630 binding and to modify displacement of [3H]-GR65630 binding induced by 5-HT. 5-HT (3 microM) stimulated the influx of [14C]-guanidinium in intact N1E-115 cells. Metformin up to 1 mM failed to modify basal influx, 5-HT-induced influx, and 5-HT+ substance P-induced influx of [14C]-guanidinium. Our results indicate that metformin induces 5-HT3 receptor-independent release of 5-HT from human duodenal mucosa via neuronal and non-neuronal mechanisms. Part of the gastrointestinal side effects observed during treatment with

  4. 5-Hydroxytryptamine (5-HT) Cellular Sequestration during Chronic Exposure Delays 5-HT3 Receptor Resensitization due to Its Subsequent Release*

    PubMed Central

    Hothersall, J. Daniel; Alexander, Amy; Samson, Andrew J.; Moffat, Christopher; Bollan, Karen A.; Connolly, Christopher N.

    2014-01-01

    The serotonergic synapse is dynamically regulated by serotonin (5-hydroxytryptamine (5-HT)) with elevated levels leading to the down-regulation of the serotonin transporter and a variety of 5-HT receptors, including the 5-HT type-3 (5-HT3) receptors. We report that recombinantly expressed 5-HT3 receptor binding sites are reduced by chronic exposure to 5-HT (IC50 of 154.0 ± 45.7 μm, t½ = 28.6 min). This is confirmed for 5-HT3 receptor-induced contractions in the guinea pig ileum, which are down-regulated after chronic, but not acute, exposure to 5-HT. The loss of receptor function does not involve endocytosis, and surface receptor levels are unaltered. The rate and extent of down-regulation is potentiated by serotonin transporter function (IC50 of 2.3 ± 1.0 μm, t½ = 3.4 min). Interestingly, the level of 5-HT uptake correlates with the extent of down-regulation. Using TX-114 extraction, we find that accumulated 5-HT remains soluble and not membrane-bound. This cytoplasmically sequestered 5-HT is readily releasable from both COS-7 cells and the guinea pig ileum. Moreover, the 5-HT level released is sufficient to prevent recovery from receptor desensitization in the guinea pig ileum. Together, these findings suggest the existence of a novel mechanism of down-regulation where the chronic release of sequestered 5-HT prolongs receptor desensitization. PMID:25281748

  5. Functional selectivity of hallucinogenic phenethylamine and phenylisopropylamine derivatives at human 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors.

    PubMed

    Moya, Pablo R; Berg, Kelly A; Gutiérrez-Hernandez, Manuel A; Sáez-Briones, Patricio; Reyes-Parada, Miguel; Cassels, Bruce K; Clarke, William P

    2007-06-01

    2,5-Dimethoxy-4-substituted phenylisopropylamines and phenethylamines are 5-hydroxytryptamine (serotonin) (5-HT)(2A/2C) agonists. The former are partial to full agonists, whereas the latter are partial to weak agonists. However, most data come from studies analyzing phospholipase C (PLC)-mediated responses, although additional effectors [e.g., phospholipase A(2) (PLA(2))] are associated with these receptors. We compared two homologous series of phenylisopropylamines and phenethylamines measuring both PLA(2) and PLC responses in Chinese hamster ovary-K1 cells expressing human 5-HT(2A) or 5-HT(2C) receptors. In addition, we assayed both groups of compounds as head shake inducers in rats. At the 5-HT(2C) receptor, most compounds were partial agonists for both pathways. Relative efficacy of some phenylisopropylamines was higher for both responses compared with their phenethylamine counterparts, whereas for others, no differences were found. At the 5-HT(2A) receptor, most compounds behaved as partial agonists, but unlike findings at 5-HT(2C) receptors, all phenylisopropylamines were more efficacious than their phenethylamine counterparts. 2,5-Dimethoxyphenylisopropylamine activated only the PLC pathway at both receptor subtypes, 2,5-dimethoxyphenethylamine was selective for PLC at the 5-HT(2C) receptor, and 2,5-dimethoxy-4-nitrophenethylamine was PLA(2)-specific at the 5-HT(2A) receptor. For both receptors, the rank order of efficacy of compounds differed depending upon which response was measured. The phenylisopropylamines were strong head shake inducers, whereas their phenethylamine congeners were not, in agreement with in vitro results and the involvement of 5-HT(2A) receptors in the head shake response. Our results support the concept of functional selectivity and indicate that subtle changes in ligand structure can result in significant differences in the cellular signaling profile. PMID:17337633

  6. 5-Hydroxytryptamine-induced bladder hyperactivity via the 5-HT2A receptor in partial bladder outlet obstruction in rats.

    PubMed

    Sakai, Takumi; Kasahara, Ken-ichi; Tomita, Ken-ichi; Ikegaki, Ichiro; Kuriyama, Hiroshi

    2013-04-01

    We investigated the effects of partial bladder outlet obstruction (BOO) on the function and gene expression of 5-hydroxytryptamine (5-HT) receptor subtypes in rat bladder. Isometric contractions of the isolated bladders from sham-operated control and BOO rats were examined. The contractile responses to 5-HT were significantly increased in BOO rat bladder strips, while the responses to KCl, carbachol, or phenylephrine were not different from the control. The 5-HT-induced hypercontraction in BOO rat bladder strips was inhibited by ketanserin, a 5-HT(2A) receptor antagonist. The contractile responses to 5-HT in bladder strips were not affected by urothelium removal from the intact bladder. The gene expression of 5-HT receptor subtypes in the bladders was analyzed by RT-PCR. The mRNA expression of the 5-HT(2A), 5-HT(2B), 5-HT(2C), 5-HT(4), and 5-HT(7) receptors was detected in both the control and BOO rat bladders. Quantitative RT-PCR analysis showed there was a significant increase of 5-HT(2A) receptor mRNA in the BOO rat bladder compared with the control bladder. On the other hand, the gene expression of the 5-HT(4) receptor was not changed in the BOO rat bladder. These results suggest that the increased contractile responses to 5-HT in BOO rat bladder may be partly caused by 5-HT(2A) receptor upregulation in the detrusor smooth muscles. PMID:23344575

  7. 5-hydroxytryptamine (5-HT) reduces total peripheral resistance during chronic infusion: direct arterial mesenteric relaxation is not involved

    PubMed Central

    2012-01-01

    Serotonin (5-hydroxytryptamine; 5-HT) delivered over 1 week results in a sustained fall in blood pressure in the sham and deoxycorticosterone acetate (DOCA)-salt rat. We hypothesized 5-HT lowers blood pressure through direct receptor-mediated vascular relaxation. In vivo, 5-HT reduced mean arterial pressure (MAP), increased heart rate, stroke volume, cardiac index, and reduced total peripheral resistance during a 1 week infusion of 5-HT (25 µg/kg/min) in the normotensive Sprague Dawley rat. The mesenteric vasculature was chosen as an ideal candidate for the site of 5-HT receptor mediated vascular relaxation given the high percentage of cardiac output the site receives. Real-time RT-PCR demonstrated that mRNA transcripts for the 5-HT2B, 5-HT1B, and 5-HT7 receptors are present in sham and DOCA-salt superior mesenteric arteries. Immunohistochemistry and Western blot validated the presence of the 5-HT2B, 5- HT1B and 5-HT7 receptor protein in sham and DOCA-salt superior mesenteric artery. Isometric contractile force was measured in endothelium-intact superior mesenteric artery and mesenteric resistance arteries in which the contractile 5- HT2A receptor was antagonized. Maximum concentrations of BW-723C86 (5- HT2B agonist), CP 93129 (5-HT1B agonist) or LP-44 (5-HT7 agonist) did not relax the superior mesenteric artery from DOCA-salt rats vs. vehicle. Additionally, 5-HT (10–9 M to 10–5 M) did not cause relaxation in either contracted mesenteric resistance arteries or superior mesenteric arteries from normotensive Sprague- Dawley rats. Thus, although 5-HT receptors known to mediate vascular relaxation are present in the superior mesenteric artery, they are not functional, and are therefore not likely involved in a 5-HT-induced fall in total peripheral resistance and MAP. PMID:22559843

  8. The action of SDZ 205,557 at 5-hydroxytryptamine (5-HT3 and 5-HT4) receptors.

    PubMed Central

    Eglen, R. M.; Alvarez, R.; Johnson, L. G.; Leung, E.; Wong, E. H.

    1993-01-01

    1. The interaction of the novel antagonist, SDZ 205,557 (2-methoxy-4-amino-5-chloro benzoic acid 2-(diethylamino) ethyl ester), at 5-HT3 and 5-HT4 receptors has been assessed in vitro and in vivo. 2. In guinea-pig hippocampus and in the presence of 0.4 microM 5-carboxamidotryptamine, 5-HT4-mediated stimulation of adenylyl cyclase was competitively antagonized by SDZ 205,557, with a pA2 value of 7.5, and a Schild slope of 0.81. In rat carbachol-contracted oesophagus, 5-HT4-receptor mediated relaxations were surmountably antagonized by SDZ 205,557 with a similar pA2 value (7.3). This value was agonist-independent with the exception of (R)-zacopride, against which a significantly lower value (6.4) was observed. 3. In functional studies of 5-HT3 receptors, SDZ 205,557 exhibited an affinity of 6.2 in guinea-pig ileum compared with 6.9 at binding sites labelled by [3H]-quipazine in NG108-15 cells. In the anaesthetized, vagotomized micropig, SDZ 205,557 produced only a transient blockade of 5-HT4-mediated tachycardia. This contrasted with tropisetron, which was active for over 60 min after administration. The half-lives for the inhibitory responses of SDZ 205,557 and tropisetron were 23 and 116 min, respectively. 4. In conclusion, SDZ 205,557 has similar affinity for 5-HT3 and 5-HT4 receptors. The apparent selectivity observed in guinea-pig is due to the atypical nature of the 5-HT3 receptor in this species. The short duration of action of this novel antagonist may complicate its use in vivo. SDZ 205,557 should, therefore, be used with appropriate caution in studies defining the 5-HT4 receptor. PMID:8448587

  9. Medial hypothalamic 5-hydroxytryptamine (5-HT)1A receptors regulate neuroendocrine responses to stress and exploratory locomotor activity: application of recombinant adenovirus containing 5-HT1A sequences.

    PubMed

    Li, Qian; Holmes, Andrew; Ma, Li; Van de Kar, Louis D; Garcia, Francisca; Murphy, Dennis L

    2004-12-01

    Our previous studies found that serotonin transporter (SERT) knock-out mice showed increased sensitivity to minor stress and increased anxiety-like behavior but reduced locomotor activity. These mice also showed decreased density of 5-hydroxytryptamine (5-HT1A) receptors in the hypothalamus, amygdala, and dorsal raphe. To evaluate the contribution of hypothalamic 5-HT1A receptors to these phenotypes of SERT knock-out mice, two studies were conducted. Recombinant adenoviruses containing 5-HT1A sense and antisense sequences (Ad-1AP-sense and Ad-1AP-antisense) were used to manipulate 5-HT1A receptors in the hypothalamus. The expression of the 5-HT1A genes is controlled by the 5-HT1A promoter, so that they are only expressed in 5-HT1A receptor-containing cells. (1) Injection of Ad-1AP-sense into the hypothalamus of SERT knock-out mice restored 5-HT1A receptors in the medial hypothalamus; this effect was accompanied by elimination of the exaggerated adrenocorticotropin responses to a saline injection (minor stress) and reduced locomotor activity but not by a change in increased exploratory anxiety-like behavior. (2) To further confirm the observation in SERT-/- mice, Ad-1AP-antisense was injected into the hypothalamus of normal mice. The density and the function of 5-HT1A receptors in the medial hypothalamus were significantly reduced in Ad-1AP-antisense-treated mice. Compared with the control group (injected with Ad-track), Ad-1A-antisense-treated mice showed a significant reduction in locomotor activity, but again no changes in exploratory anxiety-like behaviors, tested by elevated plus-maze and open-field tests. Thus, the present results demonstrate that medial hypothalamic 5-HT1A receptors regulate stress responses and locomotor activity but may not regulate exploratory anxiety-like behaviors. PMID:15574737

  10. Enhanced 5-hydroxytryptamine (5-HT) release from vascular adrenergic nerves in spontaneously hypertensive rats

    SciTech Connect

    Kawasaki, H.; Urabe, M.; Takasaki, K.

    1986-03-01

    The release of 5-HT from vascular adrenergic nerves was compared between normotensive Wistar Kyoto rats (WKY) and SHR. The mesenteric vascular bed isolated from WKY and SHR was perfused with Krebs solution at a constant flow rate of 5 ml/min. Periarterial nerve stimulation (PNS) was delivered at 4 to 16 Hz for 30 sec. In the SHR preparation, the pressor response to PNS, previously decreased by prazonsin (50 nM), was greatly potentiated after treatment with 5-HT(1 ..mu..M) for 15 min and a frequency-dependent pressor response to PNS reappeared, whereas the 5-HT treatment did not alter the pressor response to exogenous norepinephrine (1 nmol) previously reduced by prazonsin. The potentiation of pressor response to PNS after 5-HT treatment was small in the WKY preparation. This potentiation in both WKY and SHR did not occur in the presence of ketanserin (10 nM). In the preparation labeled with (/sup 3/H)-5-HT, PNS (4-16 Hz) evoked a frequency-dependent increase of (/sup 3/H)-efflux, which was abolished by treatment with tetrodotoxin (100 nM) or 6-hydroxydopamine (50 mg/kg i.p. x 2) and in calcium-free Krebs solution. The PNS evoked-(/sup 3/H)-efflux was much greater in SHR than WKY. These results suggest that the release of 5-HT from vascular adrenergic nerves by PNS is enhanced in the SHR preparation.

  11. Molecular modelling of human 5-hydroxytryptamine receptor (5-HT2A) and virtual screening studies towards the identification of agonist and antagonist molecules.

    PubMed

    Gandhimathi, A; Sowdhamini, R

    2016-05-01

    The serotonin receptors, also known as 5-hydroxytryptamine (5-HT) receptors, are a group of G protein-coupled receptors (GPCRs) and ligand-gated ion channels found in the central and peripheral nervous systems. GPCRs have a characteristic feature of activating different signalling pathways upon ligand binding and these ligands display several efficacy levels to differentially activate the receptor. GPCRs are primary drug targets due to their central role in several signal transduction pathways. Drug design for GPCRs is also most challenging due to their inherent promiscuity in ligand recognition, which gives rise to several side effects of existing drugs. Here, we have performed the ligand interaction study using the two prominent states of GPCR, namely the active and inactive state of the 5-HT2A receptor. Active state of 5-HT2A receptor model enhances the understanding of conformational difference which influences the ligand-binding site. A 5-HT2A receptor active state model was constructed by homology modelling using active state β2-adrenergic receptor (β2-AR). In addition, virtual screening and docking studies with both active and inactive state models reveal potential small molecule hits which could be considered as agonist-like and antagonist-like molecules. The results from the all-atom molecular dynamics simulations further confirmed that agonists and antagonists interact in different modes with the receptor. PMID:26327576

  12. Circadian 5-HT production regulated by adrenergic signaling

    PubMed Central

    Sun, Xing; Deng, Jie; Liu, Tiecheng; Borjigin, Jimo

    2002-01-01

    Using on-line microdialysis, we have characterized in vivo dynamics of pineal 5-hydroxytryptamine (5-HT; serotonin) release. Daily pineal 5-HT output is triphasic: (i) 5-HT levels are constant and high during the day; (ii) early in the night, there is a novel sharp rise in 5-HT synthesis and release, which precedes the nocturnal rise in melatonin synthesis; and (iii) late in the night, levels are low. This triphasic 5-HT production persists in constant darkness and is influenced strongly by intrusion of light at night. We demonstrate that both diurnal 5-HT synthesis and 5-HT release are activated by sympathetic innervation from the superior cervical ganglion and show that these processes are controlled by distinct receptors. The increase in 5-HT synthesis is controlled by β-adrenergic receptors, whereas the increase in 5-HT release is mediated by α-adrenergic signaling. On the other hand, the marked decrease in 5-HT content and release late at night is a passive process, influenced by the extent of melatonin synthesis. In the absence of melatonin synthesis, the late-night decline in 5-HT release is prevented, reaching levels roughly twice as high as that of the day value. In summary, our results demonstrate that 5-HT levels display marked circadian rhythms that depend on adrenergic signaling. PMID:11917109

  13. Upregulation of 5-Hydroxytryptamine Receptor Signaling in Coronary Arteries after Organ Culture

    PubMed Central

    Rao, Fang; Xue, Yu-Mei; Zhou, Zhi-Ling; Liu, Xiao-Ying; Shan, Zhi-Xin; Li, Xiao-Hong; Lin, Qiu-Xiong; Wu, Shu-Lin; Yu, Xi-Yong

    2014-01-01

    Background 5-Hydroxytryptamine (5-HT) is a powerful constrictor of coronary arteries and is considered to be involved in the pathophysiological mechanisms of coronary-artery spasm. However, the mechanism of enhancement of coronary-artery constriction to 5-HT during the development of coronary artery disease remains to be elucidated. Organ culture of intact blood-vessel segments has been suggested as a model for the phenotypic changes of smooth muscle cells in cardiovascular disease. Methodology/Principal Findings We wished to characterize 5-HT receptor-induced vasoconstriction and quantify expression of 5-HT receptor signaling in cultured rat coronary arteries. Cumulative application of 5-HT produced a concentration-dependent vasoconstriction in fresh and 24 h-cultured rat coronary arteries without endothelia. 5-HT induced greater constriction in cultured coronary arteries than in fresh coronary arteries. U46619- and CaCl2-induced constriction in the two groups was comparable. 5-HT stimulates the 5-HT2A receptor and cascade of phospholipase C to induce coronary vasoconstriction. Calcium influx through L-type calcium channels and non-L-type calcium channels contributed to the coronary-artery constrictions induced by 5-HT. The contractions mediated by non-L-type calcium channels were significantly enhanced in cultured coronary arteries compared with fresh coronary arteries. The vasoconstriction induced by thapsigargin was also augmented in cultured coronary arteries. The decrease in Orai1 expression significantly inhibited 5-HT-evoked entry of Ca2+ in coronary artery cells. Expression of the 5-HT2A receptor, Orai1 and STIM1 were augmented in cultured coronary arteries compared with fresh coronary arteries. Conclusions An increased contraction in response to 5-HT was mediated by the upregulation of 5-HT2A receptors and downstream signaling in cultured coronary arteries. PMID:25202989

  14. Dorsal Raphe Neurons Signal Reward through 5-HT and Glutamate

    PubMed Central

    Liu, Zhixiang; Zhou, Jingfeng; Li, Yi; Hu, Fei; Lu, Yao; Ma, Ming; Feng, Qiru; Zhang, Ju-en; Wang, Daqing; Zeng, Jiawei; Bao, Junhong; Kim, Ji-Young; Chen, Zhou-Feng; Mestikawy, Salah El; Luo, Minmin

    2015-01-01

    Summary The dorsal raphe nucleus (DRN) in the midbrain is a key center for serotonin (5-hydroxytryptamine; 5-HT) expressing neurons. Serotonergic neurons in the DRN have been theorized to encode punishment by opposing the reward signaling of dopamine neurons. Here, we show that DRN neurons encode reward, but not punishment, through 5-HT and glutamate. Optogenetic stimulation of DRN Pet-1 neurons reinforces mice to explore the stimulation-coupled spatial region, shifts sucrose preference, drives optical self-stimulation, and directs sensory discrimination learning. DRN Pet-1 neurons increase their firing activity during reward tasks and this activation can be used to rapidly change neuronal activity patterns in the cortnassociated with 5-HT, they also release glutamate, and both neurotransmitters contribute to reward signaling. These experiments demonstrate the ability of DRN neurons to organize reward behaviors and might provide insights into the underlying mechanisms of learning facilitation and anhedonia treatment. PMID:24656254

  15. Participation of 5-HT1-like and 5-HT2A receptors in the contraction of human temporal artery by 5-hydroxytryptamine and related drugs.

    PubMed Central

    Verheggen, R.; Freudenthaler, S.; Meyer-Dulheuer, F.; Kaumann, A. J.

    1996-01-01

    1. We investigated the hypothesis that, as in some other large human arteries, 5-HT-induced contraction of the temporal artery is mediated through two co-existing receptor populations, 5-HT1-like- and 5-HT2A. Temporal arterial segments were obtained from patients undergoing brain surgery and rings prepared set up to contract with 5-HT and related agents. Fractions of maximal 5-HT responses mediated through 5-HT1-like and 5-HT2A receptors, f1 and f2 = 1-f1, were estimated by use of the 5-HT2A-selective antagonist ketanserin. 2. In rings with intact endothelium 5-HT evoked contractions with a -log EC50, M of 7.0. Ketanserin (10-1000 nM) antagonized part of the 5-HT-induced contractions. Ketanserin-resistant components of 5-HT-induced contractions were found with -log EC50, M of 6.9 and f1 of 0.17 (100 nM ketanserin) and -log EC50, M of 6.4 and f1 of 0.20 (1000 nM ketanserin). 3. In rings with endothelial function attenuated by enzymatic treatment, 5-HT caused contractions with a -log EC50, M of 7.2 that were partially blocked by ketanserin. Ketanserin-resistant components of 5-HT-induced contractions were found with -log EC50, M 7.4 and f1 of 0.16 (100 nM ketanserin) and -log EC50, M of 7.5 and f1 of 0.14 (1000 nM ketanserin). 4. The ketanserin-resistant component of 5-HT-evoked contraction was blocked by methiothepin (100-1000 nM) consistent with mediation through 5-HT1-like receptors. 5. In rings with intact endothelium the 5-HT1-like-selective agonist, sumatriptan, caused small contractions with a -log EC50, M of 6.5 and intrinsic activity of 0.21 with respect to 5-HT that were resistant to blockade by 1000 nM ketanserin but antagonized by 100 nM methiothepin. 6. In rings with intact endothelium the 5-HT2A receptor partial agonist SK&F 103829 (2,3,4,5-tetrahydro-8[methyl sulphonyl]-1H3-benzazepin-7-ol methensulphonate) contracted rings with a -log EC50, M of 5.0 and an intrinsic activity of 0.49 with respect to 5-HT; the effects were antagonized by ketanserin 1000

  16. Pharmacological characterization of a rat 5-hydroxytryptamine type3 receptor subunit (r5-HT3A(b)) expressed in Xenopus laevis oocytes

    PubMed Central

    Mair, Ian D; Lambert, Jeremy J; Yang, Jay; Dempster, John; Peters, John A

    1998-01-01

    The present study has utilized the two electrode voltage-clamp technique to examine the pharmacological profile of a splice variant of the rat orthologue of the 5-hydroxytryptamine type 3A subunit (5-HT3A(b)) heterologously expressed in Xenopus laevis oocytes. At negative holding potentials, bath applied 5-HT (300 nM–10 μM) evoked a transient, concentration-dependent (EC50=1.1±0.1 μM), inward current. The response reversed in sign at a holding potential of −2.1±1.6 mV. The response to 5-HT was mimicked by the 5-HT3 receptor selective agonists 2-methyl-5-HT (EC50=4.1±0.2 μM), 1-phenylbiguanide (EC50=3.0±0.1 μM), 3-chlorophenylbiguanide (EC50=140± 10 nM), 3,5-dichlorophenylbiguanide (EC50=14.5±0.4 nM) and 2,5-dichlorophenylbiguanide (EC50= 10.2±0.6 nM). With the exception of 2-methyl-5-HT, all of the agonists tested elicited maximal current responses comparable to those produced by a saturating concentration (10 μM) of 5-HT. Responses evoked by 5-HT at EC50 were blocked by the 5-HT3 receptor selective antagonist ondansetron (IC50=231±22 pM) and by the less selective agents (+)-tubocurarine (IC50=31.9± 0.01 nM) and cocaine (IC50=2.1±0.2 μM). The data are discussed in the context of results previously obtained with the human and mouse orthologues of the 5-HT3A subunit. Overall, the study reinforces the conclusion that species differences detected for native 5-HT3 receptors extend to, and appear largely explained by, differences in the properties of homo-oligomeric receptors formed from 5-HT3A subunit orthologues. PMID:9756382

  17. 5-Hydroxytryptamine

    PubMed Central

    Curzon, G.; Fernando, J.C.R.; Marsden, C.A.

    1978-01-01

    1 Control rats given L-tryptophan (100 mg/kg) showed a smaller increase of brain 5-hydroxytryptamine (5-HT) than its metabolite 5-hydroxyindoleacetic acid (5-HIAA). However, when brain 5-HT concentrations were depleted by 40-50% after treatment with the synthesis inhibitor p-chlorophenylalanine (PCPA) (150 mg/kg) L-tryptophan caused a considerable increase in 5-HT but no change in 5-HIAA. Similar results were obtained following depletion of brain 5-HT by pretreatment with p-chloroamphetamine (10 mg/kg). 2 Electrical stimulation of the median raphe nucleus of control rats significantly increased 5-HIAA in the hypothalamus, hippocampus and striatum. However, stimulation of PCPA (200 mg/kg) pretreated animals did not significantly increase 5-H1AA either 24 or 72 h after administration of the drug. 3 Pretreatment of rats with PCPA (200 mg/kg) increased striatal synaptosomal uptake of [3H]-5HT by 30% and reduced 5-HT concentration in the rest of the brain by 62%. 4 PCPA (150 mg/kg) markedly reduced the acute behavioural response (-76%) to p-chloroamphetamine (10 mg/kg) although brain 5-HT was only moderately reduced (-36%). L-Tryptophan (100 mg/kg) given 15 min before p-chloroamphetamine restored both brain 5-HT and the behavioural effects of p-chloroamphetamine in PCPA pretreated rats and enhanced the behavioural response to p-chloroamphetamine in control rats. 5 The results suggest that newly synthesized 5-HT is less rapidly metabolized in rats with low brain 5-HT. The possible reasons for this and the relevance of the results to the use of L-tryptophan in the treatment of depressive illness are discussed. PMID:80243

  18. Comparison of the performance of different DFT methods in the calculations of the molecular structure and vibration spectra of serotonin (5-hydroxytryptamine, 5-HT)

    NASA Astrophysics Data System (ADS)

    Yang, Yue; Gao, Hongwei

    2012-04-01

    Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine neurotransmitter which plays an important role in treating acute or clinical stress. The comparative performance of different density functional theory (DFT) methods at various basis sets in predicting the molecular structure and vibration spectra of serotonin was reported. The calculation results of different methods including mPW1PW91, HCTH, SVWN, PBEPBE, B3PW91 and B3LYP with various basis sets including LANL2DZ, SDD, LANL2MB, 6-31G, 6-311++G and 6-311+G* were compared with the experimental data. It is remarkable that the SVWN/6-311++G and SVWN/6-311+G* levels afford the best quality to predict the structure of serotonin. The results also indicate that PBEPBE/LANL2DZ level show better performance in the vibration spectra prediction of serotonin than other DFT methods.

  19. Regulation of Oligomeric Organization of the Serotonin 5-Hydroxytryptamine 2C (5-HT2C) Receptor Observed by Spatial Intensity Distribution Analysis*

    PubMed Central

    Ward, Richard J.; Pediani, John D.; Godin, Antoine G.; Milligan, Graeme

    2015-01-01

    The questions of whether G protein-coupled receptors exist as monomers, dimers, and/or oligomers and if these species interconvert in a ligand-dependent manner are among the most contentious current issues in biology. When employing spatial intensity distribution analysis to laser scanning confocal microscope images of cells stably expressing either a plasma membrane-associated form of monomeric enhanced green fluorescent protein (eGFP) or a tandem version of this fluorophore, the eGFP tandem was identified as a dimer. Similar studies on cells stably expressing an eGFP-tagged form of the epidermal growth factor receptor demonstrated that, although largely a monomer in the basal state, this receptor rapidly became predominantly dimeric upon the addition of its ligand epidermal growth factor. In cells induced to express an eGFP-tagged form of the serotonin 5-hydroxytryptamine 2C (5-HT2C) receptor, global analysis of construct quantal brightness was consistent with the predominant form of the receptor being dimeric. However, detailed spatial intensity distribution analysis demonstrated the presence of multiple forms ranging from monomers to higher-order oligomers. Furthermore, treatment with chemically distinct 5-HT2C receptor antagonists resulted in a time-dependent change in the quaternary organization to one in which there was a preponderance of receptor monomers. This antagonist-mediated effect was reversible, because washout of the ligand resulted in the regeneration of many of the oligomeric forms of the receptor. PMID:25825490

  20. The Role of 5-HT3 Receptors in Signaling from Taste Buds to Nerves

    PubMed Central

    Vandenbeuch, Aurelie; Voigt, Anja; Meyerhof, Wolfgang; Kinnamon, Sue C.; Finger, Thomas E.

    2015-01-01

    Activation of taste buds triggers the release of several neurotransmitters, including ATP and serotonin (5-hydroxytryptamine; 5-HT). Type III taste cells release 5-HT directly in response to acidic (sour) stimuli and indirectly in response to bitter and sweet tasting stimuli. Although ATP is necessary for activation of nerve fibers for all taste stimuli, the role of 5-HT is unclear. We investigated whether gustatory afferents express functional 5-HT3 receptors and, if so, whether these receptors play a role in transmission of taste information from taste buds to nerves. In mice expressing GFP under the control of the 5-HT3A promoter, a subset of cells in the geniculate ganglion and nerve fibers in taste buds are GFP-positive. RT-PCR and in situ hybridization confirmed the presence of 5-HT3A mRNA in the geniculate ganglion. Functional studies show that only those geniculate ganglion cells expressing 5-HT3A-driven GFP respond to 10 μm 5-HT and this response is blocked by 1 μm ondansetron, a 5-HT3 antagonist, and mimicked by application of 10 μm m-chlorophenylbiguanide, a 5-HT3 agonist. Pharmacological blockade of 5-HT3 receptors in vivo or genetic deletion of the 5-HT3 receptors reduces taste nerve responses to acids and other taste stimuli compared with controls, but only when urethane was used as the anesthetic. We find that anesthetic levels of pentobarbital reduce taste nerve responses apparently by blocking the 5-HT3 receptors. Our results suggest that 5-HT released from type III cells activates gustatory nerve fibers via 5-HT3 receptors, accounting for a significant proportion of the neural taste response. SIGNIFICANCE STATEMENT Historically, serotonin (5-hydroxytryptamine; 5-HT) has been described as a candidate neurotransmitter in the gustatory system and recent studies show that type III taste receptor cells release 5-HT in response to various taste stimuli. In the present study, we demonstrate that a subset of gustatory sensory neurons express functional

  1. Oligomer size of the serotonin 5-hydroxytryptamine 2C (5-HT2C) receptor revealed by fluorescence correlation spectroscopy with photon counting histogram analysis: evidence for homodimers without monomers or tetramers.

    PubMed

    Herrick-Davis, Katharine; Grinde, Ellinor; Lindsley, Tara; Cowan, Ann; Mazurkiewicz, Joseph E

    2012-07-01

    Fluorescence correlation spectroscopy (FCS) and photon counting histogram (PCH) are techniques with single molecule sensitivity that are well suited for examining the biophysical properties of protein complexes in living cells. In the present study, FCS and PCH were applied to determine the diffusion coefficient and oligomeric size of G-protein-coupled receptors. FCS was used to record fluctuations in fluorescence intensity arising from fluorescence-tagged 5-hydroxytryptamine 2C (5-HT(2C)) receptors diffusing within the plasma membrane of HEK293 cells and rat hippocampal neurons. Autocorrelation analysis yielded diffusion coefficients ranging from 0.8 to 1.2 μm(2)/s for fluorescence-tagged receptors. Because the molecular brightness of a fluorescent protein is directly proportional to the number of fluorescent proteins traveling together within a protein complex, it can be used to determine the oligomeric size of the protein complex. FCS and PCH analysis of fluorescence-tagged 5-HT(2C) receptors provided molecular brightness values that were twice that of GFP and YFP monomeric controls, similar to a dimeric GFP control, and unaltered by 5-HT. Bimolecular fluorescence complementation of the N- and C-terminal halves of YFP attached to 5-HT(2C) receptors was observed in endoplasmic reticulum/Golgi and plasma membranes with a brightness equal to monomeric YFP. When GFP-tagged 5-HT(2C) receptors were co-expressed with a large excess of untagged, non-fluorescent 5-HT(2C) receptors, the molecular brightness was reduced by half. PCH analysis of the FCS data were best described by a one-component dimer model without monomers or tetramers. Therefore, it is concluded that 5-HT(2C) receptors freely diffusing within the plasma membrane are dimeric. PMID:22593582

  2. Neuropharmacology of 5-hydroxytryptamine

    PubMed Central

    Richard Green, A

    2006-01-01

    This review outlines the history of our knowledge of the neuropharmacology of 5-hydroxytryptamine (5-HT; serotonin), focusing primarily on the work of U.K. scientists. The existence of a vasoconstrictive substance in the blood has been known for over 135 years. The substance was named serotonin and finally identified as 5-HT in 1949. The presence of 5-HT in the brain was reported by Gaddum in 1954 and it was Gaddum who also demonstrated that the action of 5-HT (in the gut) was antagonised by the potent hallucinogen lysergic acid diethylamide. This provoked the notion that 5-HT played a pivotal role in the control of mood and subsequent investigations have generally confirmed this hypothesis. Over the last 50 years a good understanding has been gained of the mechanisms involved in control of the storage, synthesis and degradation of 5-HT in the brain. Knowledge has also been gained on control of the functional activity of this monoamine, often by the use of behavioural models. A considerable literature also now exists on the mechanisms by which many of the drugs used to treat psychiatric illness alter the functional activity of 5-HT, particularly the drugs used to treat depression. Over the last 20 years the number of identified 5-HT receptor subtypes has increased from 2 to 14, or possibly more. A major challenge now is to utilise this knowledge to develop receptor-specific drugs and use the information gained to better treat central nervous system disorders. PMID:16402098

  3. Insights into the complex influence of 5-HT signaling on thalamocortical axonal system development.

    PubMed

    van Kleef, Esmee S B; Gaspar, Patricia; Bonnin, Alexandre

    2012-05-01

    The topographic organization of the thalamocortical axons (TCAs) in the barrel field (BF) in the rodent primary somatosensory cortex results from a succession of temporally and spatially precise developmental events. Prenatally, growth and guidance mechanisms enable TCAs to navigate through the forebrain and reach the cortex. Postnatally, TCAs grow into the cortex, and the refinement of their terminal arborization pattern in layer IV creates barrel-like structures. The combined results of studies performed over the past 20 years clearly show that serotonin (5-hydroxytryptamine; 5-HT) signaling modulates these pre- and early postnatal developmental processes. In this context, 5-HT signaling can purposely be described as 'modulating' rather than 'controlling' because developmental alterations of 5-HT synthesis, uptake or degradation either have a dramatic, moderate or no effect at all on TCA pathway and BF formation. In this review we summarize and compare the outcomes of diverse pharmacological and genetic manipulations of 5-HT signaling on TCA pathway and BF formation, in an attempt to understand these discrepancies. PMID:22607002

  4. 5-hydroxytryptamine1A (5-HT1A) receptor agonists: A decade of empirical evidence supports their use as an efficacious therapeutic strategy for brain trauma.

    PubMed

    Cheng, Jeffrey P; Leary, Jacob B; Sembhi, Aerin; Edwards, Clarice M; Bondi, Corina O; Kline, Anthony E

    2016-06-01

    Traumatic brain injury (TBI) is a significant and enduring health care issue with limited treatment options. While several pre-clinical therapeutic approaches have led to enhanced motor and/or cognitive performance, the benefits of these treatments have not translated to the clinic. One plausible explanation is that the therapies may not have been rigorously evaluated, thus rendering the bench-to-bedside leap premature and subsequently unsuccessful. An approach that has undergone considerable empirical research after TBI is pharmacological targeting of 5-HT1A receptors with agonists such as repinotan HCl, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), and buspirone. The goal of this review is to integrate and interpret the findings from a series of studies that evaluated the efficacy of 5-HT1A receptor agonists on functional, histological, and molecular outcome after acquired brain injury. The overwhelming consensus of this exhaustive review is that a decade of empirical evidence supports their use as an efficacious therapeutic strategy for brain trauma. This article is part of a Special Issue entitled SI:Brain injury and recovery. PMID:26612522

  5. SIGNALING MECHANISMS INVOLVED IN THE ACUTE EFFECTS OF ESTRADIOL ON 5-HT CLEARANCE

    PubMed Central

    Benmansour, Saloua; Privratsky, Anthony A.; Adeniji, Opeyemi S.; Frazer, Alan

    2014-01-01

    Estradiol was found previously to have an antidepressant-like effect and to block the ability of selective serotonin reuptake inhibitors (SSRIs) to have an antidepressant-like effect. The antidepressant-like effect of estradiol was due to estrogen receptor β (ERβ) and/or GPR30 activation whereas estradiol’s blockade of the effect of an SSRI was mediated by ERα. This study focuses on investigating signaling pathways as well as interacting receptors associated with these two effects of estradiol. In vivo chronoamperometry was used to measure serotonin transporter (SERT) function. The effect of local application of estradiol or selective agonists for ERα (PPT) or ERβ (DPN) into the CA3 region of the hippocampus of ovariectomized (OVX) rats on 5-hydroxytryptamine (5-HT, serotonin) clearance as well as on the ability of fluvoxamine to slow 5-HT clearance was examined after selective blockade of signaling pathways or that of interacting receptors. Estradiol- or DPN-induced slowing of 5-HT clearance mediated by ERβ was blocked after inhibition of MAPK/ERK1/2 but not of PI3K/Akt signaling pathways. This effect also involved interactions with TrkB, and IGF-1 receptors. Estradiol’s or PPT’s inhibition of the fluvoxamine-induced slowing of 5-HT clearance mediated by ERα, was blocked after inhibition of either MAPK/ERK1/2 or PI3K/Akt signaling pathways. This effect involved interactions with the IGF-1 receptor and with the metabotropic glutamate receptor 1 but not with TrkB. This study illustrates some of the signaling pathways required for the effects of estradiol on SERT function and particularly shows that ER subtypes elicit different as well as common signaling pathways for their actions. PMID:24423185

  6. Signaling mechanisms involved in the acute effects of estradiol on 5-HT clearance.

    PubMed

    Benmansour, Saloua; Privratsky, Anthony A; Adeniji, Opeyemi S; Frazer, Alan

    2014-05-01

    Estradiol was found previously to have an antidepressant-like effect and to block the ability of selective serotonin reuptake inhibitors (SSRIs) to have an antidepressant-like effect. The antidepressant-like effect of estradiol was due to estrogen receptor β (ERβ) and/or GPR30 activation, whereas estradiol's blockade of the effect of an SSRI was mediated by ERα. This study focuses on investigating signaling pathways as well as interacting receptors associated with these two effects of estradiol. In vivo chronoamperometry was used to measure serotonin transporter (SERT) function. The effect of local application of estradiol or selective agonists for ERα (PPT) or ERβ (DPN) into the CA3 region of the hippocampus of ovariectomized (OVX) rats on 5-hydroxytryptamine (5-HT) clearance as well as on the ability of fluvoxamine to slow 5-HT clearance was examined after selective blockade of signaling pathways or that of interacting receptors. Estradiol- or DPN-induced slowing of 5-HT clearance mediated by ERβ was blocked after inhibition of MAPK/ERK1/2 but not of PI3K/Akt signaling pathways. This effect also involved interactions with TrkB, and IGF-1 receptors. Estradiol's or PPT's inhibition of the fluvoxamine-induced slowing of 5-HT clearance mediated by ERα, was blocked after inhibition of either MAPK/ERK1/2 or PI3K/Akt signaling pathways. This effect involved interactions with the IGF-1 receptor and with the metabotropic glutamate receptor 1, but not with TrkB. This study illustrates some of the signaling pathways required for the effects of estradiol on SERT function, and particularly shows that ER subtypes elicit different as well as common signaling pathways for their actions. PMID:24423185

  7. Convergence of melatonin and serotonin (5-HT) signaling at MT2/5-HT2C receptor heteromers.

    PubMed

    Kamal, Maud; Gbahou, Florence; Guillaume, Jean-Luc; Daulat, Avais M; Benleulmi-Chaachoua, Abla; Luka, Marine; Chen, Patty; Kalbasi Anaraki, Dina; Baroncini, Marc; Mannoury la Cour, Clotilde; Millan, Mark J; Prevot, Vincent; Delagrange, Philippe; Jockers, Ralf

    2015-05-01

    Inasmuch as the neurohormone melatonin is synthetically derived from serotonin (5-HT), a close interrelationship between both has long been suspected. The present study reveals a hitherto unrecognized cross-talk mediated via physical association of melatonin MT2 and 5-HT2C receptors into functional heteromers. This is of particular interest in light of the "synergistic" melatonin agonist/5-HT2C antagonist profile of the novel antidepressant agomelatine. A suite of co-immunoprecipitation, bioluminescence resonance energy transfer, and pharmacological techniques was exploited to demonstrate formation of functional MT2 and 5-HT2C receptor heteromers both in transfected cells and in human cortex and hippocampus. MT2/5-HT2C heteromers amplified the 5-HT-mediated Gq/phospholipase C response and triggered melatonin-induced unidirectional transactivation of the 5-HT2C protomer of MT2/5-HT2C heteromers. Pharmacological studies revealed distinct functional properties for agomelatine, which shows "biased signaling." These observations demonstrate the existence of functionally unique MT2/5-HT2C heteromers and suggest that the antidepressant agomelatine has a distinctive profile at these sites potentially involved in its therapeutic effects on major depression and generalized anxiety disorder. Finally, MT2/5-HT2C heteromers provide a new strategy for the discovery of novel agents for the treatment of psychiatric disorders. PMID:25770211

  8. Peptide Inhibitors Disrupt the Serotonin 5-HT2C Receptor Interaction with Phosphatase and Tensin Homolog to Allosterically Modulate Cellular Signaling and Behavior

    PubMed Central

    Anastasio, Noelle C.; Gilbertson, Scott R.; Bubar, Marcy J.; Agarkov, Anton; Stutz, Sonja J.; Jeng, Yowjiun; Bremer, Nicole M.; Smith, Thressa D.; Fox, Robert G.; Swinford, Sarah E.; Seitz, Patricia K.; Charendoff, Marc N.; Craft, John W.; Laezza, Fernanda M.; Watson, Cheryl S.; Briggs, James M.; Cunningham, Kathryn A.

    2013-01-01

    Serotonin (5-hydroxytryptamine; 5-HT) signaling through the 5-HT2C receptor (5-HT2CR) is essential in normal physiology, whereas aberrant 5-HT2CR function is thought to contribute to the pathogenesis of multiple neural disorders. The 5-HT2CR interacts with specific protein partners, but the impact of such interactions on 5-HT2CR function is poorly understood. Here, we report convergent cellular and behavioral data that the interaction between the 5-HT2CR and protein phosphatase and tensin homolog (PTEN) serves as a regulatory mechanism to control 5-HT2CR-mediated biology but not that of the closely homologous 5-HT2AR. A peptide derived from the third intracellular loop of the human 5-HT2CR [3L4F (third loop, fourth fragment)] disrupted the association, allosterically augmented 5-HT2CR-mediated signaling in live cells, and acted as a positive allosteric modulator in rats in vivo. We identified the critical residues within an 8 aa fragment of the 3L4F peptide that maintained efficacy (within the picomolar range) in live cells similar to that of the 3L4F peptide. Last, molecular modeling identified key structural features and potential interaction sites of the active 3L4F peptides against PTEN. These compelling data demonstrate the specificity and importance of this protein assembly in cellular events and behaviors mediated by 5-HT2CR signaling and provide a chemical guidepost to the future development of drug-like peptide or small-molecule inhibitors as neuroprobes to study 5-HT2CR allostery and therapeutics for 5-HT2CR-mediated disorders. PMID:23345234

  9. The Role of 5-HT3 Receptors in Signaling from Taste Buds to Nerves.

    PubMed

    Larson, Eric D; Vandenbeuch, Aurelie; Voigt, Anja; Meyerhof, Wolfgang; Kinnamon, Sue C; Finger, Thomas E

    2015-12-01

    Activation of taste buds triggers the release of several neurotransmitters, including ATP and serotonin (5-hydroxytryptamine; 5-HT). Type III taste cells release 5-HT directly in response to acidic (sour) stimuli and indirectly in response to bitter and sweet tasting stimuli. Although ATP is necessary for activation of nerve fibers for all taste stimuli, the role of 5-HT is unclear. We investigated whether gustatory afferents express functional 5-HT3 receptors and, if so, whether these receptors play a role in transmission of taste information from taste buds to nerves. In mice expressing GFP under the control of the 5-HT(3A) promoter, a subset of cells in the geniculate ganglion and nerve fibers in taste buds are GFP-positive. RT-PCR and in situ hybridization confirmed the presence of 5-HT(3A) mRNA in the geniculate ganglion. Functional studies show that only those geniculate ganglion cells expressing 5-HT3A-driven GFP respond to 10 μM 5-HT and this response is blocked by 1 μM ondansetron, a 5-HT3 antagonist, and mimicked by application of 10 μM m-chlorophenylbiguanide, a 5-HT3 agonist. Pharmacological blockade of 5-HT3 receptors in vivo or genetic deletion of the 5-HT3 receptors reduces taste nerve responses to acids and other taste stimuli compared with controls, but only when urethane was used as the anesthetic. We find that anesthetic levels of pentobarbital reduce taste nerve responses apparently by blocking the 5-HT3 receptors. Our results suggest that 5-HT released from type III cells activates gustatory nerve fibers via 5-HT3 receptors, accounting for a significant proportion of the neural taste response. PMID:26631478

  10. 5-Hydroxytryptamine-induced calcium-channel gating in rainbow trout (Oncorhynchus mykiss) peripheral blood lymphocytes.

    PubMed Central

    Ferriere, F; Khan, N A; Meyniel, J P; Deschaux, P

    1997-01-01

    The present study was conducted on peripheral blood lympho-cytes of rainbow trout (Oncorhynchus mykiss) to assess the role of 5-hydroxytryptamine (5-HT; 'serotonin') in calcium signalling. 5-HT-induced increases in intracellular free calcium concentrations, [Ca2+]i, and its action was mediated by 5-HT receptor subtype 3 (5-HT3), but not by 5-HT receptor subtype 1A (5-HT1A) or subtype 2 (5-HT2) in these cells. In Ca2+-containing medium (1 mM CaCl2), 5-HT and 2-methyl-5-HT (5-HT3 receptor agonist) induced increases in [Ca2+]i, whereas in Ca2+-free medium (0 Ca2+, 1 mM EGTA), these two agents failed to evoke increases in [Ca2+]i in these cells, demonstrating that 5-HT mobilizes Ca2+ from the extracellular environment. Furthermore, 5-HT-induced increases in [Ca2+]i are not contributed to by the intracellular endoplasmic reticulum (ER) pool, as thapsigargin, an agent that recruits Ca2+ from ER stores, had additive effects on 5-HT-induced [Ca2+]i responses in fish peripheral lymphocytes. 5-HT-induced increases in [Ca2+]i were mediated by 5-HT3 receptors via gating the calcium through L-type, but not N-type, calcium channels in trout lymphocytes. PMID:9173890

  11. 5-Hydroxytryptamine Receptor Subtypes and their Modulators with Therapeutic Potentials

    PubMed Central

    Pithadia, Anand B.; Jain, Sunita M.

    2009-01-01

    5-hydroxytryptamine (5-HT) has become one of the most investigated and complex biogenic amines. The main receptors and their subtypes, e.g., 5-HTI (5-HT1A, 5-HT1B, 5-HTID, 5-HTIE and 5-HT1F), 5-HT2 (5-HT2A, 5-HT2B and 5-HT2C), 5-HT3, 5-HT4, 5-HT5 (5-HT5A, 5-HT5B), 5-HT6 and 5-HT7 have been identified. Specific drugs which are capable of either selectively stimulating or inhibiting these receptor subtypes are being designed. This has generated therapeutic potentials of 5-HT receptor modulators in a variety of disease conditions. Conditions where 5-HT receptor modulators have established their use with distinct efficacy and advantages include migraine, anxiety, psychosis, obesity and cancer therapy-induced vomiting by cytotoxic drugs and radiation. Discovery of 5-HT, its biosynthesis, metabolism, physiological role and the potential of 5-HT receptor modulators in various nervous, cardiovascular and gastrointestinal tract disorders, bone growth and micturition have been discussed in this article. Keywords 5-hydroxytryptamine (5-HT) receptors; Modulators; Biogenic amines PMID:22505971

  12. 5-hydroxytryptamine medications for the treatment of obesity.

    PubMed

    Burke, L K; Heisler, L K

    2015-06-01

    The central 5-hydroxytryptamine (5-HT; serotonin) system represents a fundamental component of the brain's control of energy homeostasis. Medications targeting the 5-HT pathway have been at the forefront of obesity treatment for the past 15 years. Pharmacological agents targeting 5-HT receptors (5-HTR), in combination with genetic models of 5-HTR manipulation, have uncovered a role for specific 5-HTRs in energy balance and reveal the 5-HT2 C R as the principal 5-HTR mediating this homeostatic process. Capitalising on this neurophysiological machinery, 5-HT2 C R agonists improve obesity and glycaemic control in patient populations. The underlying therapeutic mechanism has been probed using model systems and appears to be achieved primarily through 5-HT2 C R modulation of the brain melanocortin circuit via activation of pro-opiomelanocortin neurones signalling at melanocortin4 receptors. Thus, 5-HT2 C R agonists offer a means to improve obesity and type 2 diabetes, which are conditions that now represent global challenges to human health. PMID:25925636

  13. Voltammetric detection of 5-hydroxytryptamine release in the rat brain.

    PubMed

    Hashemi, Parastoo; Dankoski, Elyse C; Petrovic, Jelena; Keithley, Richard B; Wightman, R M

    2009-11-15

    5-Hydroxytryptamine (5-HT) is an important molecule in the brain that is implicated in mood and emotional processes. In vivo, its dynamic release and uptake kinetics are poorly understood due to a lack of analytical techniques for its rapid measurement. Whereas fast-scan cyclic voltammetry with carbon fiber microelectrodes is used frequently to monitor subsecond dopamine release in freely moving and anesthetized rats, the electrooxidation of 5-HT forms products that quickly polymerize and irreversibly coat the carbon electrode surface. Previously described modifications of the electrochemical waveform allow stable and sensitive 5-HT measurements in mammalian tissue slice preparations and in the brain of fruit fly larvae. For in vivo applications in mammals, however, the problem of electrode deterioration persists. We identify the root of this problem to be fouling by extracellular metabolites such as 5-hydoxyindole acetic acid (5-HIAA), which is present in 200-1000 times the concentration of 5-HT and displays similar electrochemical properties, including filming of the electrode surface. To impede access of the 5-HIAA to the electrode surface, a thin layer of Nafion, a cation exchange polymer, has been electrodeposited onto cylindrical carbon-fiber microelectrodes. The presence of the Nafion film was confirmed with environmental scanning electron microscopy and was demonstrated by the diminution of the voltammetric signals for 5-HIAA as well as other common anionic species. The modified microelectrodes also display increased sensitivity to 5-HT, yielding a characteristic cyclic voltammogram that is easily distinguishable from other common electroactive brain species. The thickness of the Nafion coating and a diffusion coefficient (D) in the film for 5-HT were evaluated by measuring permeation through Nafion. In vivo, we used physiological, anatomical, and pharmacological evidence to validate the signal as 5-HT. Using Nafion-modified microelectrodes, we present the

  14. Comparative biochemical and pharmacological characterization of the mouse 5HT5A 5-hydroxytryptamine receptor and the human beta2-adrenergic receptor produced in the methylotrophic yeast Pichia pastoris.

    PubMed

    Weiss, H M; Haase, W; Michel, H; Reiländer, H

    1998-03-15

    Over the last few years, Pichia pastoris has been developed into a powerful expression system for a multitude of foreign genes. Here, we demonstrate that the P. pastoris expression system has similar power to the baculovirus expression system in high-level production of two G-protein-coupled receptors, the mouse 5HT5A 5-hydroxtryptamine receptor and the human beta2-adrenergic receptor. Different expression plasmids were constructed in which the cDNAs of the two receptors were cloned under the transcriptional control of the highly inducible promoter of the P. pastoris alcohol oxidase 1 (AOX1) gene. In three expression plasmids, the receptors were fused to the Saccharomyces cerevisiae alpha-factor prepropeptide and also to the c-myc tag or the FLAG tag to permit immunological detection of the receptors. After transformation into P. pastoris strains KM71 and SMD 1163, recombinant clones were selected and tested for the production of the 5HT5A receptor and the beta2-adrenergic receptor by radioligand binding using [N-methyl-3H]lysergic acid diethylamide and [5,7-3H](-)CGP-12177 respectively. The production level of the 5HT5A receptor was improved by a factor of three by fusion with the alpha-factor prepropeptide. Also, the higher gene dosage resulting from multiple insertions of the expression cassette led to an improvement in production by a factor of two for both receptors. The addition of the adrenergic antagonist alprenolol to the culture medium had a positive effect on the number of specific binding sites detectable in clones producing the beta2-adrenergic receptor. For the 5HT5A receptor the addition of yohimbine resulted in a similar but smaller effect. Binding assays revealed that approx. 25 pmol of beta2-adrenergic receptor and approx. 40 pmol of 5HT5A receptor per mg of membrane protein in crude membrane preparations were produced. The pharmacological profiles for the heterologously produced receptors, estimated by ligand-displacement analysis using certain

  15. Spinal 5-HT7 receptors induce phrenic motor facilitation via EPAC-mTORC1 signaling.

    PubMed

    Fields, D P; Springborn, S R; Mitchell, G S

    2015-09-01

    Spinal serotonin type 7 (5-HT7) receptors elicit complex effects on motor activity. Whereas 5-HT7 receptor activation gives rise to long-lasting phrenic motor facilitation (pMF), it also constrains 5-HT2 receptor-induced pMF via "cross-talk inhibition." We hypothesized that divergent cAMP-dependent signaling pathways give rise to these distinct 5-HT7 receptor actions. Specifically, we hypothesized that protein kinase A (PKA) mediates cross-talk inhibition of 5-HT2 receptor-induced pMF whereas 5-HT7 receptor-induced pMF results from exchange protein activated by cAMP (EPAC) signaling. Anesthetized, paralyzed, and ventilated rats receiving intrathecal (C4) 5-HT7 receptor agonist (AS-19) injections expressed pMF for >90 min, an effect abolished by pretreatment with a selective EPAC inhibitor (ESI-05) but not a selective PKA inhibitor (KT-5720). Furthermore, intrathecal injections of a selective EPAC activator (8-pCPT-2'-Me-cAMP) were sufficient to elicit pMF. Finally, spinal mammalian target of rapamycin complex-1 (mTORC1) inhibition via intrathecal rapamycin abolished 5-HT7 receptor- and EPAC-induced pMF, demonstrating that spinal 5-HT7 receptors elicit pMF by an EPAC-mTORC1 signaling pathway. Thus 5-HT7 receptors elicit and constrain spinal phrenic motor plasticity via distinct signaling mechanisms that diverge at cAMP (EPAC vs. PKA). Selective manipulation of these molecules may enable refined regulation of serotonin-dependent spinal motor plasticity for therapeutic advantage. PMID:26269554

  16. Anticonvulsant compounds and 5-hydroxytryptamine in rat brain

    PubMed Central

    Bonnycastle, D. D.; Giarman, N. J.; Paasonen, M. K.

    1957-01-01

    In rats, a series of anticonvulsant compounds have been shown to cause a significant elevation of brain 5-hydroxytryptamine (5-HT) levels in comparison with control values. This increase in 5-HT only occurred in brain tissue and was not observed in spleen, upper small intestine or blood. Elevation of brain levels of 5-HT by iproniazid (Marsilid) or 5-hydroxytryptophan failed to give protection against the convulsant or lethal action of lept zol (75 mg./kg.). PMID:13446378

  17. Synergism Between a Serotonin 5-HT2A Receptor (5-HT2AR) Antagonist and 5-HT2CR Agonist Suggests New Pharmacotherapeutics for Cocaine Addiction

    PubMed Central

    2012-01-01

    Relapse to cocaine dependence, even after extended abstinence, involves a number of liability factors including impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) and cue reactivity (sensitivity to cues associated with cocaine-taking which can promote cocaine-seeking). These factors have been mechanistically linked to serotonin (5-hydroxytryptamine, 5-HT) signaling through the 5-HT2A receptor (5-HT2AR) and 5-HT2CR; either a selective 5-HT2AR antagonist or a 5-HT2CR agonist suppresses impulsivity and cocaine-seeking in preclinical models. We conducted proof-of-concept analyses to evaluate whether a combination of 5-HT2AR antagonist plus 5-HT2CR agonist would have synergistic effects over these liability factors for relapse as measured in a 1-choice serial reaction time task and cocaine self-administration/reinstatement assay. Combined administration of a dose of the selective 5-HT2AR antagonist M100907 plus the 5-HT2CR agonist WAY163909, each ineffective alone, synergistically suppressed cocaine-induced hyperactivity, inherent and cocaine-evoked impulsive action, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. The identification of synergism between a 5-HT2AR antagonist plus a 5-HT2CR agonist to attenuate these factors important in relapse indicates the promise of a bifunctional ligand as an anti-addiction pharmacotherapeutic, setting the stage to develop new ligands with improved efficacy, potency, selectivity, and in vivo profiles over the individual molecules. PMID:23336050

  18. Synergism between a serotonin 5-HT2A receptor (5-HT2AR) antagonist and 5-HT2CR agonist suggests new pharmacotherapeutics for cocaine addiction.

    PubMed

    Cunningham, Kathryn A; Anastasio, Noelle C; Fox, Robert G; Stutz, Sonja J; Bubar, Marcy J; Swinford, Sarah E; Watson, Cheryl S; Gilbertson, Scott R; Rice, Kenner C; Rosenzweig-Lipson, Sharon; Moeller, F Gerard

    2013-01-16

    Relapse to cocaine dependence, even after extended abstinence, involves a number of liability factors including impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) and cue reactivity (sensitivity to cues associated with cocaine-taking which can promote cocaine-seeking). These factors have been mechanistically linked to serotonin (5-hydroxytryptamine, 5-HT) signaling through the 5-HT(2A) receptor (5-HT(2A)R) and 5-HT(2C)R; either a selective 5-HT(2A)R antagonist or a 5-HT(2C)R agonist suppresses impulsivity and cocaine-seeking in preclinical models. We conducted proof-of-concept analyses to evaluate whether a combination of 5-HT(2A)R antagonist plus 5-HT(2C)R agonist would have synergistic effects over these liability factors for relapse as measured in a 1-choice serial reaction time task and cocaine self-administration/reinstatement assay. Combined administration of a dose of the selective 5-HT(2A)R antagonist M100907 plus the 5-HT(2C)R agonist WAY163909, each ineffective alone, synergistically suppressed cocaine-induced hyperactivity, inherent and cocaine-evoked impulsive action, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. The identification of synergism between a 5-HT(2A)R antagonist plus a 5-HT(2C)R agonist to attenuate these factors important in relapse indicates the promise of a bifunctional ligand as an anti-addiction pharmacotherapeutic, setting the stage to develop new ligands with improved efficacy, potency, selectivity, and in vivo profiles over the individual molecules. PMID:23336050

  19. 5-Hydroxytryptamine promotes hepatocellular carcinoma proliferation by influencing β-catenin.

    PubMed

    Fatima, Sarwat; Shi, Xiaoke; Lin, Zesi; Chen, Guo-Qing; Pan, Xiao-Hua; Wu, Justin Che-Yuen; Ho, John W; Lee, Nikki P; Gao, Hengjun; Zhang, Ge; Lu, Aiping; Bian, Zhao Xiang

    2016-02-01

    5-Hydroxytryptamine (5-HT), a neurotransmitter and vasoactive factor, has been reported to promote proliferation of serum-deprived hepatocellular carcinoma (HCC) cells but the detailed intracellular mechanism is unknown. As Wnt/β-catenin signalling is highly dysregulated in a majority of HCC, this study explored the regulation of Wnt/β-catenin signalling by 5-HT. The expression of various 5-HT receptors was studied by quantitative real-time polymerase chain reaction (qPCR) in HCC cell lines as well as in 33 pairs of HCC tumours and corresponding adjacent non-tumour tissues. Receptors 5-HT1D (21/33, 63.6%), 5-HT2B (12/33, 36.4%) and 5-HT7 (15/33, 45.4%) were overexpressed whereas receptors 5-HT2A (17/33, 51.5%) and 5-HT5 (30/33, 90.1%) were reduced in HCC tumour tissues. In vitro data suggests 5-HT increased total β-catenin, active β-catenin and decreased phosphorylated β-catenin protein levels in serum deprived HuH-7 and HepG2 cells compared to control cells under serum free medium without 5-HT. Activation of Wnt/β-catenin signalling was evidenced by increased expression of β-catenin downstream target genes, Axin2, cyclin D1, dickoppf-1 (DKK1) and glutamine synthetase (GS) by qPCR in serum-deprived HCC cell lines treated with 5-HT. Additionally, biochemical analysis revealed 5-HT disrupted Axin1/β-catenin interaction, a critical step in β-catenin phosphorylation. Increased Wnt/β-catenin activity was attenuated by antagonist of receptor 5-HT7 (SB-258719) in HCC cell lines and patient-derived primary tumour tissues in the presence of 5-HT. SB-258719 also reduced tumour growth in vivo. This study provides evidence of Wnt/β-catenin signalling activation by 5-HT and may represent a potential therapeutic target for hepatocarcinogenesis. PMID:26474915

  20. 5-hydroxytryptamine induced relaxation in the pig urinary bladder neck

    PubMed Central

    Recio, Paz; Barahona, María Victoria; Orensanz, Luis M; Bustamante, Salvador; Martínez, Ana Cristina; Benedito, Sara; García-Sacristán, Albino; Prieto, Dolores; Hernández, Medardo

    2009-01-01

    Background and purpose 5-Hydroxytryptamine (5-HT) is one of the inhibitory mediators in the urinary bladder outlet region. Here we investigated mechanisms involved in 5-HT-induced relaxations of the pig bladder neck. Experimental approach Urothelium-denuded strips of pig bladder were mounted in organ baths for isometric force recordings of responses to 5-HT and electrical field stimulation (EFS). Key results After phenylephrine-induced contraction, 5-HT and 5-HT receptor agonists concentration-dependently relaxed the preparations, with the potency order: 5-carboxamidotryptamine (5-CT) > 5-HT = RS67333 > (±)-8-hydroxy-2-dipropylaminotetralinhydrobromide > m-chlorophenylbiguanide > α-methyl-5-HT > ergotamine. 5-HT and 5-CT relaxations were reduced by the 5-HT7 receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulphonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride and potentiated by (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenylpropanamide dihydrochloride (WAY 100135) and cyanopindolol, 5-HT1A and 5-HT1A/1B receptor antagonists respectively. Inhibitors of 5-HT1B/1D, 5-HT2, 5-HT2B/2C, 5-HT3, 5-HT4, 5-HT5A and 5-HT6 receptors failed to modify 5-HT responses. Blockade of monoamine oxidase A/B, noradrenergic neurotransmission, α-adrenoceptors, muscarinic and purinergic receptors, nitric oxide synthase, guanylate cyclase and prostanoid synthesis did not alter relaxations to 5-HT. Inhibitors of Ca2+-activated K+ and ATP-dependent K+ channels failed to modify 5-HT responses but blockade of neuronal voltage-gated Na+-, Ca2+-and voltage-gated K+ (Kv)-channels potentiated these relaxations. Adenylyl cyclase activation and cAMP-dependent protein kinase (PKA) inhibition potentiated and reduced, respectively, 5-HT-induced responses. Under non-adrenergic, non-cholinergic, non-nitrergic conditions, EFS induced neurogenic, frequency-dependent, relaxations which were resistant to WAY 100135 and cyanopindolol. Conclusions and implications 5-HT relaxed

  1. Pharmacological Characterization of a 5-HT1-Type Serotonin Receptor in the Red Flour Beetle, Tribolium castaneum

    PubMed Central

    Vleugels, Rut; Lenaerts, Cynthia; Baumann, Arnd; Vanden Broeck, Jozef; Verlinden, Heleen

    2013-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) is known for its key role in modulating diverse physiological processes and behaviors by binding various 5-HT receptors. However, a lack of pharmacological knowledge impedes studies on invertebrate 5-HT receptors. Moreover, pharmacological information is urgently needed in order to establish a reliable classification system for invertebrate 5-HT receptors. In this study we report on the molecular cloning and pharmacological characterization of a 5-HT1 receptor from the red flour beetle, Tribolium castaneum (Trica5-HT1). The Trica5-HT1 receptor encoding cDNA shows considerable sequence similarity with members of the 5-HT1 receptor class. Real time PCR showed high expression in the brain (without optic lobes) and the optic lobes, consistent with the role of 5-HT as neurotransmitter. Activation of Trica5-HT1 in mammalian cells decreased NKH-477-stimulated cyclic AMP levels in a dose-dependent manner, but did not influence intracellular Ca2+ signaling. We studied the pharmacological profile of the 5-HT1 receptor and demonstrated that α-methylserotonin, 5-methoxytryptamine and 5-carboxamidotryptamine acted as agonists. Prazosin, methiothepin and methysergide were the most potent antagonists and showed competitive inhibition in presence of 5-HT. This study offers important information on a 5-HT1 receptor from T. castaneum facilitating functional research of 5-HT receptors in insects and other invertebrates. The pharmacological profiles may contribute to establish a reliable classification scheme for invertebrate 5-HT receptors. PMID:23741451

  2. 5-Hydroxytryptamine 4(a) receptor expressed in Sf9 cells is palmitoylated in an agonist-dependent manner.

    PubMed Central

    Ponimaskin, E G; Schmidt, M F; Heine, M; Bickmeyer, U; Richter, D W

    2001-01-01

    The mouse 5-hydroxytryptamine 4(a) receptor [5-HT(4(a))] was expressed with a baculovirus system in insect cells and analysed for acylation. [(3)H]Palmitic acid was effectively incorporated into 5-HT(4(a)) and label was sensitive to the treatment with reducing agents indicating a thioester-type bond. Analysis of protein-bound fatty acids revealed that 5-HT(4(a)) contains predominantly palmitic acid. Treatment of infected Sf9 (Spodoptera frugiperda) cells with BIMU8 [(endo-N-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dehydro-2-oxo-3-(prop-2-yl)-1H-benzimid-azole-1-carboxamide], a 5-HT(4) receptor-selective agonist, generated a dose-dependent increase in [(3)H]palmitate incorporation into 5-HT(4(a)) with an EC(50) of approx. 10 nM. The change in receptor labelling after stimulation with agonist was receptor-specific and did not result from general metabolic effects. We also used both pulse labelling and pulse-chase labelling to address the dynamics of 5-HT(4(a)) palmitoylation. Incorporation studies revealed that the rate of palmitate incorporation was increased approx. 3-fold after stimulation with agonist. Results of pulse-chase experiments show that activation with BIMU8 promoted the release of radiolabel from 5-HT(4(a)), thereby reducing the levels of receptor-bound palmitate to approximately one-half. Taken together, our results demonstrate that palmitoylation of 5-HT(4(a)) is a reversible process and that stimulation of 5-HT(4(a)) with agonist increases the turnover rate for receptor-bound palmitate. This provides evidence for a regulated cycling of receptor-bound palmitate and suggests a functional role for palmitoylation/depalmitoylation in 5-hydroxytryptamine-mediated signalling. PMID:11171060

  3. The role of the 5-hydroxytryptamine pathway in reflux-induced esophageal mucosal injury in rats

    PubMed Central

    2012-01-01

    Background Dysfunction of the 5-hydroxytryptamine (5-HT) signaling pathway can lead to gastrointestinal motility and secretion abnormalities and to visceral hypersensitivity. The aim of this study is to investigate the role of 5-HT in reflux-induced esophageal mucosal injury. Methods Fifty 8-week-old male Sprague-Dawley (SD) rats were randomly divided into a gastroesophageal reflux (GER) model group (30 rats) and a sham surgery control group (20 rats). Four weeks after surgery, the esophageal mucosa was collected for histological evaluation, 5-HT concentrations, and 5-HT selective reuptake transporter (SERT) mRNA and 5-HT4 receptor (5-HT4R) protein expressions. Results Twenty-seven rats in the GER model group survived, and three rats died. Histologically, in the GER model group, 20 rats had reflux esophagitis (RE group), and 7 rats had non-erosive reflux disease (NERD group). The 5-HT levels in the esophageal tissue from the RE group were significantly higher than those from the control and NERD groups. Both the RE and NERD groups showed significant increases in SERT mRNA expression of the esophageal mucosa than that of the controls, and the SERT mRNA level in the RE group was significantly higher than that in the NERD group. The 5-HT4R protein level of the esophageal mucosa in the RE group was significantly lower than that in the controls and the NERD group. Conclusions We conclude that a 5-HT signaling pathway disorder could be a major factor in the pathogenesis of GER and RE. PMID:23092450

  4. Antagonism of 5-hydroxytryptamine2A Receptor Results in Decreased Contractile Response of Bovine Lateral Saphenous Vein to Tall Fescue Alkaloids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pharmacologic profiling of 5-hydroxytryptamine (5HT) receptors of bovine lateral saphenous vein has shown that cattle grazing endophyte-infected (Neotyphodium coenophialum) tall fescue (Lolium arundinaceum) have altered responses to ergovaline (ERV), 5HT, 5HT2A and 5HT7 agonists. To determine if 5HT...

  5. Modulation of cannabinoid signaling by hippocampal 5-HT4 serotonergic system in fear conditioning.

    PubMed

    Nasehi, Mohammad; Farrahizadeh, Maryam; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

    2016-09-01

    Behavioral studies have suggested a key role for the cannabinoid system in the modulation of conditioned fear memory. Likewise, much of the literature has revealed that the serotonergic system affects Pavlovian fear conditioning and extinction. A high level of functional overlap between the serotonin and cannabinoid systems has also been reported. To clarify the interaction between the hippocampal serotonin (5-HT4) receptor and the cannabinoid CB1 receptor in the acquisition of fear memory, the effects of 5-HT4 agents, arachidonylcyclopropylamide (ACPA; CB1 receptor agonist), and the combined use of these drugs on fear learning were studied in a fear conditioning task in adult male NMRI mice. Pre-training intraperitoneal administration of ACPA (0.1 mg/kg) decreased the percentage of freezing time in both context- and tone-dependent fear conditions, suggesting impairment of the acquisition of fear memory. Pre-training, intra-hippocampal (CA1) microinjection of RS67333, a 5-HT4 receptor agonist, at doses of 0.1 and 0.2 or 0.2 µg/mouse impaired contextual and tone fear memory, respectively. A subthreshold dose of RS67333 (0.005 µg/mouse) did not alter the ACPA response in either condition. Moreover, intra-CA1 microinjection of RS23597 as a 5-HT4 receptor antagonist did not alter context-dependent fear memory acquisition, but it did impair tone-dependent fear memory acquisition. However, a subthreshold dose of the RS23597 (0.01 µg/mouse) potentiated ACPA-induced fear memory impairment in both conditions. Therefore, we suggest that the blockade of hippocampal 5-HT4 serotonergic system modulates cannabinoid signaling induced by the activation of CB1 receptors in conditioned fear. PMID:27296273

  6. Naftopidil inhibits 5-hydroxytryptamine-induced bladder contraction in rats.

    PubMed

    Sakai, Takumi; Kasahara, Ken-ichi; Tomita, Ken-ichi; Ikegaki, Ichiro; Kuriyama, Hiroshi

    2013-01-30

    Naftopidil is an α(1D) and α(1A) subtype-selective α(1)-adrenoceptor antagonist that has been used to treat lower urinary tract symptoms of benign prostatic hyperplasia. In this study, we investigated the effects of naftopidil on 5-hydroxytryptamine (5-HT)-induced rat bladder contraction (10(-8)-10(-4) M). Naftopidil (0.3, 1, and 3 μM) inhibited 5-HT-induced bladder contraction in a concentration-dependent manner. On the other hand, other α(1)-adrenoceptor antagonists, tamsulosin, silodosin or prazosin, did not inhibit 5-HT-induced bladder contraction. The 5-HT-induced bladder contraction was inhibited by both ketanserin and 4-(4-fluoronaphthalen-1-yl)-6-propan-2-ylpyrimidin-2-amine (RS127445), serotonin 5-HT(2A) and 5-HT(2B) receptor antagonists, respectively. In addition, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and α-methyl-5-HT, 5-HT(2A) and 5-HT(2) receptor agonists, respectively, induced bladder contraction. The 5-HT-induced bladder contraction was not inhibited by N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-pyridin-2-yl-cyclohexanecarboxamide (WAY-100635), [1-[2[(methylsulfonyl)amino]ethyl]-4-piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate (GR113808) or (R)-3-[2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulphonyl]phenol (SB269970), 5-HT(1A), 5-HT(4) and 5-HT(7) receptor antagonists, respectively. Naftopidil inhibited both the 5-HT(2A) and 5-HT(2) receptor agonists-induced bladder contractions. Naftopidil binds to the human 5-HT(2A) and 5-HT(2B) receptors with pKi values of 6.55 and 7.82, respectively. These results suggest that naftopidil inhibits 5-HT-induced bladder contraction via blockade of the 5-HT(2A) and 5-HT(2B) receptors in rats. Furthermore, 5-HT-induced bladder contraction was enhanced in bladder strips obtained from bladder outlet obstructed rats, with this contraction inhibited by naftopidil. The beneficial effects of naftopidil on storage symptoms such as urinary frequency and nocturia in patients with benign

  7. Allergic sensitization modifies the pulmonary expression of 5-hydroxytryptamine receptors in guinea pigs.

    PubMed

    Córdoba-Rodríguez, Guadalupe; Vargas, Mario H; Ruiz, Víctor; Carbajal, Verónica; Campos-Bedolla, Patricia; Mercadillo-Herrera, Paulina; Arreola-Ramírez, José Luis; Segura-Medina, Patricia

    2016-03-01

    There is mounting evidence that 5-hydroxytryptamine (5-HT) plays a role in asthma. However, scarce information exists about the pulmonary expression of 5-HT receptors and its modification after allergic sensitization. In the present work, we explored the expression of 5-HT1A, 5-HT2A, 5-HT3, 5-HT4, 5-ht5a, 5-HT6, and 5-HT7 receptors in lungs from control and sensitized guinea pigs through qPCR and Western blot. In control animals, mRNA from all receptors was detectable in lung homogenates, especially from 5-HT2A and 5-HT4 receptors. Sensitized animals had decreased mRNA expression of 5-HT2A and 5-HT4 receptors and increased that of 5-HT7 receptor. In contrast, they had increased protein expression of 5-HT2A receptor in bronchial epithelium and of 5-HT4 receptor in lung parenchyma. The degree of airway response to the allergic challenge was inversely correlated with mRNA expression of the 5-HT1A receptor. In summary, our results showed that major 5-HT receptor subtypes are constitutively expressed in the guinea pig lung, and that allergic sensitization modifies the expression of 5-HT2A, 5-HT4, and 5-HT7 receptors. PMID:26657047

  8. Chronic 5-HT transporter blockade reduces DA signaling to elicit basal ganglia dysfunction.

    PubMed

    Morelli, Emanuela; Moore, Holly; Rebello, Tahilia J; Gray, Neil; Steele, Kelly; Esposito, Ennio; Gingrich, Jay A; Ansorge, Mark S

    2011-11-01

    Serotonin (5-HT)-selective reuptake inhibitors (SSRIs) are widely administered for the treatment of depression, anxiety, and other neuropsychiatric disorders, but response rates are low, and side effects often lead to discontinuation. Side effect profiles suggest that SSRIs inhibit dopaminergic activity, but mechanistic insight remains scarce. Here we show that in mice, chronic 5-HT transporter (5-HTT) blockade during adulthood but not during development impairs basal ganglia-dependent behaviors in a dose-dependent and reversible fashion. Furthermore, chronic 5-HTT blockade reduces striatal dopamine (DA) content and metabolism. A causal relationship between reduced DA signaling and impaired basal ganglia-dependent behavior is indicated by the reversal of behavioral deficits through L-DOPA administration. Our data suggest that augmentation of DA signaling would reduce side effects and increase efficacies of SSRI-based therapy. PMID:22049417

  9. Opposing actions of 5HT1A and 5HT2-like serotonin receptors on modulations of the electric signal waveform in the electric fish Brachyhypopomus pinnicaudatus

    PubMed Central

    Allee, Susan J.; Markham, Michael R.; Salazar, Vielka L.; Stoddard, Philip K.

    2008-01-01

    Serotonin (5-HT) is an indirect modulator of the electric organ discharge (EOD) in the weakly electric gymnotiform fish, Brachyhypopomus pinnicaudatus. Injections of 5-HT enhance EOD waveform “masculinity”, increasing both waveform amplitude and the duration of the second phase. This study investigated the pharmacological identity of 5-HT receptors that regulate the electric waveform and their effects on EOD amplitude and duration. We present evidence that two sets of serotonin receptors modulate the EOD in opposite directions. We found that the 5HT1AR agonist 8-OH-DPAT diminishes EOD duration and amplitude while the 5HT1AR antagonist WAY100635 increases these parameters. In contrast, the 5HT2R agonist α-Me-5-HT increases EOD amplitude but not duration, yet 5-HT-induced increases in EOD duration can be inhibited by blocking 5HT2A/2C-like receptors with ketanserin. These results show that 5-HT exerts bi-directional control of EOD modulations in B. pinnicaudatus via action at receptors similar to mammalian 5HT1A and 5HT2 receptors. The discordant amplitude and duration response suggests separate mechanisms for modulating these waveform parameters. PMID:18206154

  10. The arylpiperazine derivatives N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide and N-benzyl-4-(2-diphenyl)-1-piperazinehexanamide exert a long-lasting inhibition of human serotonin 5-HT7 receptor binding and cAMP signaling.

    PubMed

    Atanes, Patricio; Lacivita, Enza; Rodríguez, Javier; Brea, José; Burgueño, Javier; Vela, José Miguel; Cadavid, María Isabel; Loza, María Isabel; Leopoldo, Marcello; Castro, Marián

    2013-12-01

    We performed a detailed in vitro pharmacological characterization of two arylpiperazine derivatives, compound N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211) previously identified as a high-affinity brain penetrant ligand for 5-hydroxytryptamine (serotonin) type 7 (5-HT7) receptors, and its analog N-benzyl-4-(2-diphenyl)-1-piperazinehexanamide (MEL-9). Both ligands exhibited competitive displacement of [(3)H]-(2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine ([(3)H]-SB-269970) radioligand binding and insurmountable antagonism of 5-carboxamidotryptamine (5-CT)-stimulated cyclic adenosine monophosphate (cAMP) signaling in human embryonic kidney (HEK293) cells stably expressing human 5-HT7 receptors. They also inhibited forskolin-stimulated adenylate cyclase activity in 5-HT7-expressing HEK293 cells but not in the parental cell line. The compounds elicited long-lasting (at least 24 h) concentration-dependent inhibition of radioligand binding at 5-HT7-binding sites in whole-cell radioligand binding assays, after pretreatment of the cells with the compounds and subsequent compound removal. In cAMP assays, pretreatment of cells with the compounds rendered 5-HT7 receptors unresponsive to 5-CT and also rendered 5-HT7-expressing HEK293 cells unresponsive to forskolin. Compound 1-(2-biphenyl)piperazine (RA-7), a known active metabolite of LP-211 present in vivo, was able to partially inhibit 5-HT7 radioligand binding in a long-lasting irreversible manner. Hence, LP-211 and MEL-9 were identified as high-affinity long-acting inhibitors of human 5-HT7 receptor binding and function in cell lines. The detailed in vitro characterization of these two pharmacological tools targeting 5-HT7 receptors may benefit the study of 5-HT7 receptor function and it may lead to the development of novel selective pharmacological tools with defined functional properties at 5-HT7 receptors. PMID:25505568

  11. Endogenous 5-HT outflow from chicken aorta by 5-HT uptake inhibitors and amphetamine derivatives

    PubMed Central

    DELGERMURUN, Dugar; ITO, Shigeo; OHTA, Toshio; YAMAGUCHI, Soichiro; OTSUGURO, Ken-ichi

    2015-01-01

    Chemoreceptor cells aggregating in clusters in the chicken thoracic aorta contain 5-hydroxytryptamine (5-HT) and have voltage-dependent ion channels and nicotinic acetylcholine receptors, which are characteristics typically associated with neurons. The aim of the present study was to investigate the effects of 5-HT uptake inhibitors, fluvoxamine, fluoxetine and clomipramine (CLM), and amphetamine derivatives, p-chloroamphetamine (PCA) and methamphetamine (MET), on endogenous 5-HT outflow from the isolated chick thoracic aorta in vitro. 5-HT was measured by using a HPLC system with electrochemical detection. The amphetamine derivatives and 5-HT uptake inhibitors caused concentration-dependent increases in endogenous 5-HT outflow. PCA was about ten times more effective in eliciting 5-HT outflow than MET. The 5-HT uptake inhibitors examined had similar potency for 5-HT outflow. PCA and CLM increased 5-HT outflow in a temperature-dependent manner. The outflow of 5-HT induced by PCA or 5-HT uptake inhibitors was independent of extracellular Ca2+ concentration. The 5-HT outflow induced by CLM, but not that by PCA, was dependent on the extracellular NaCl concentration. These results suggest that the 5-HT uptake system of 5-HT-containing chemoreceptor cells in the chicken thoracic aorta has characteristics similar to those of 5-HT-containing neurons in the mammalian central nervous system (CNS). PMID:26321443

  12. Endogenous 5-HT outflow from chicken aorta by 5-HT uptake inhibitors and amphetamine derivatives.

    PubMed

    Delgermurun, Dugar; Ito, Shigeo; Ohta, Toshio; Yamaguchi, Soichiro; Otsuguro, Ken-ichi

    2016-01-01

    Chemoreceptor cells aggregating in clusters in the chicken thoracic aorta contain 5-hydroxytryptamine (5-HT) and have voltage-dependent ion channels and nicotinic acetylcholine receptors, which are characteristics typically associated with neurons. The aim of the present study was to investigate the effects of 5-HT uptake inhibitors, fluvoxamine, fluoxetine and clomipramine (CLM), and amphetamine derivatives, p-chloroamphetamine (PCA) and methamphetamine (MET), on endogenous 5-HT outflow from the isolated chick thoracic aorta in vitro. 5-HT was measured by using a HPLC system with electrochemical detection. The amphetamine derivatives and 5-HT uptake inhibitors caused concentration-dependent increases in endogenous 5-HT outflow. PCA was about ten times more effective in eliciting 5-HT outflow than MET. The 5-HT uptake inhibitors examined had similar potency for 5-HT outflow. PCA and CLM increased 5-HT outflow in a temperature-dependent manner. The outflow of 5-HT induced by PCA or 5-HT uptake inhibitors was independent of extracellular Ca(2+) concentration. The 5-HT outflow induced by CLM, but not that by PCA, was dependent on the extracellular NaCl concentration. These results suggest that the 5-HT uptake system of 5-HT-containing chemoreceptor cells in the chicken thoracic aorta has characteristics similar to those of 5-HT-containing neurons in the mammalian central nervous system (CNS). PMID:26321443

  13. Release of ( sup 14 C)5-hydroxytryptamine from human platelets by red wine

    SciTech Connect

    Jarman, J.; Glover, V.; Sandler, M. )

    1991-01-01

    Red wine, at a final dilution of 1/50, caused released of ({sup 14}C)5-hydroxytryptamine (5-HT) from preloaded platelets, an effect which was not observed with any white wines or beers tested. Since 5-HT, is probably released from body stores during migraine attacks and red wine is known to provoke migraine episodes in susceptible individuals, release of 5-HT, possibly from central stores, could represent a plausible mechanism for its mode of action.

  14. Cloning, expression and pharmacology of a truncated splice variant of the human 5-HT7 receptor (h5-HT7(b))

    PubMed Central

    Jasper, J R; Kosaka, A; To, Z P; Chang, D J; Eglen, R M

    1997-01-01

    The rat 5-hydroxytryptamine (5-HT)7 receptor displays two splice variations, a long form, and a truncated splice isoform, arising from the introduction of a stop codon near the carboxy-terminus. The human 5-HT7 receptor gene contains at least two introns and encodes a 445 amino acid 5-HT receptor. A truncated splice variation in the human 5-HT7 receptor was isolated from a human placental cDNA library. In accordance with current NC-IUPHAR nomenclature guidelines, it is suggested that this receptor be denoted as the h5-HT7(b) receptor and the long form of the receptor as h5-HT7(a). The h5-HT7(b) receptor was stably expressed in HEK 293 cells and ligand affinities were determined by displacement of [3H]-5-carboxyamidotryptamine (5-CT; Kd=0.28±0.06 nM, Bmax=7.3±1.7 pmol mg−1 protein). The rank order of affinities (pKi) for a series of ligands was: 5-carboxamidotryptamine (5-CT, 9.65)>5-hydroxytryptamine (5-HT, 9.41)>methiothepin (8.87)>mesulergine (7.87)>8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT, 6.85)>ketanserin (6.44). The h5-HT7(b) receptor coupled positively to adenylyl cyclase in HEK 293 cells. This response was elicited by a number of agonists with the following order of potency (pEC50): 5-CT (8.7±0.11)>5-MeOT (5-methoxytryptamine; 8.1±0.20)>5-HT (7.5±0.13)>tryptamine (5.6±0.36)>8-OH-DPAT (5.3±0.28)>5-methoxytryptamine (5.0±0.06). This rank order was comparable to that observed in the radioligand binding studies. In a similar fashion to that described for the 5-HT7(a) receptor, PCR studies suggested that the 5-HT7(b) receptor mRNA is found in great abundance throughout the brain, in the small intestine and aorta. It is concluded that the h5-HT7 receptor, like the rat receptor, exists as splice variants exhibiting similar pharmacology, signal transduction and distribution. It is thus likely that there exists a complex physiological role for alternate splicing products of the 5-HT7 receptor gene. PMID:9298538

  15. Functional Status of the Serotonin 5-HT2C Receptor (5-HT2CR) Drives Interlocked Phenotypes that Precipitate Relapse-Like Behaviors in Cocaine Dependence

    PubMed Central

    Anastasio, Noelle C; Stutz, Sonja J; Fox, Robert G; Sears, Robert M; Emeson, Ronald B; DiLeone, Ralph J; O'Neil, Richard T; Fink, Latham H; Li, Dingge; Green, Thomas A; Gerard Moeller, F; Cunningham, Kathryn A

    2014-01-01

    Relapse vulnerability in cocaine dependence is rooted in genetic and environmental determinants, and propelled by both impulsivity and the responsivity to cocaine-linked cues (‘cue reactivity'). The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2C receptor (5-HT2CR) within the medial prefrontal cortex (mPFC) is uniquely poised to serve as a strategic nexus to mechanistically control these behaviors. The 5-HT2CR functional capacity is regulated by a number of factors including availability of active membrane receptor pools, the composition of the 5-HT2CR macromolecular protein complex, and editing of the 5-HT2CR pre-mRNA. The one-choice serial reaction time (1-CSRT) task was used to identify impulsive action phenotypes in an outbred rat population before cocaine self-administration and assessment of cue reactivity in the form of lever presses reinforced by the cocaine-associated discrete cue complex during forced abstinence. The 1-CSRT task reliably and reproducibly identified high impulsive (HI) and low impulsive (LI) action phenotypes; HI action predicted high cue reactivity. Lower cortical 5-HT2CR membrane protein levels concomitant with higher levels of 5-HT2CR:postsynaptic density 95 complex distinguished HI rats from LI rats. The frequency of edited 5-HT2CR mRNA variants was elevated with the prediction that the protein population in HI rats favors those isoforms linked to reduced signaling capacity. Genetic loss of the mPFC 5-HT2CR induced aggregate impulsive action/cue reactivity, suggesting that depressed cortical 5-HT2CR tone confers vulnerability to these interlocked behaviors. Thus, impulsive action and cue reactivity appear to neuromechanistically overlap in rodents, with the 5-HT2CR functional status acting as a neural rheostat to regulate, in part, the intersection between these vulnerability behaviors. PMID:23939424

  16. Delineation of the functional properties and the mechanism of action of TMPPAA, an allosteric agonist and positive allosteric modulator of 5-HT3 receptors.

    PubMed

    Gasiorek, Agnes; Trattnig, Sarah M; Ahring, Philip K; Kristiansen, Uffe; Frølund, Bente; Frederiksen, Kristen; Jensen, Anders A

    2016-06-15

    We have previously identified a novel class of 5-hydroxytryptamine type 3 receptor (5-HT3R) agonists sharing little structural similarity with orthosteric 5-HT3R ligands (Jørgensen et al., 2011). In the present study we have elucidated the functional characteristics and the mechanism of action of one of these compounds, trans-3-(4-methoxyphenyl)-N-(pentan-3-yl)acrylamide (TMPPAA). In electrophysiological recordings TMPPAA was found to be a highly-efficacious partial agonist equipotent with 5-HT at the 5-HT3A receptor (5-HT3AR) expressed in COS-7 cells and somewhat less potent at the receptor expressed in Xenopus oocytes. The desensitization kinetics of TMPPAA-evoked currents were very different from those mediated by 5-HT. Moreover, repeated TMPPAA applications resulted in progressive current run-down and persistent non-responsiveness of the receptor to TMPPAA, but not to 5-HT. In addition to its direct activation, TMPPAA potentiated 5-HT-mediated 5-HT3AR signalling, and the allosteric link between the two binding sites was corroborated by the analogous ability of 5-HT to potentiate TMPPAA-evoked responses. The agonism and potentiation exerted by TMPPAA at a chimeric α7-nACh/5-HT3A receptor suggested that the ligand acts through the transmembrane domain of 5-HT3AR, a notion further substantiated by its functional properties at chimeric and mutant human/murine 5-HT3ARs. A residue in the transmembrane helix 4 of 5-HT3A was identified as an important molecular determinant for the different agonist potencies exhibited by TMPPAA at human and murine 5-HT3ARs. In conclusion, TMPPAA is a novel allosteric agonist and positive allosteric modulator of 5-HT3Rs, and its aberrant signalling characteristics compared to 5-HT at the 5-HT3AR underline the potential in Cys-loop receptor modulation and activation through allosteric sites. PMID:27086281

  17. Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior.

    PubMed

    González-Maeso, Javier; Weisstaub, Noelia V; Zhou, Mingming; Chan, Pokman; Ivic, Lidija; Ang, Rosalind; Lira, Alena; Bradley-Moore, Maria; Ge, Yongchao; Zhou, Qiang; Sealfon, Stuart C; Gingrich, Jay A

    2007-02-01

    Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect perception, cognition, and mood. All known drugs of this class are 5-HT(2A) receptor (2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactive properties. Why only certain 2AR agonists are hallucinogens and which neural circuits mediate their effects are poorly understood. By genetically expressing 2AR only in cortex, we show that 2AR-regulated pathways on cortical neurons are sufficient to mediate the signaling pattern and behavioral response to hallucinogens. Hallucinogenic and nonhallucinogenic 2AR agonists both regulate signaling in the same 2AR-expressing cortical neurons. However, the signaling and behavioral responses to the hallucinogens are distinct. While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric G(i/o) proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens. PMID:17270739

  18. Role of 5-hydroxytryptamine in platelet thrombus formation and mechanisms of inhibition of thrombus formation by 5-hydroxytryptamine2A antagonists in rabbits.

    PubMed

    Takano, S

    1995-01-01

    The role of 5-hydroxytryptamine (5-HT) in platelet thrombus formation and in the mechanisms of inhibition of thrombus formation by 5-HT2A antagonists was investigated using a turbidimetric method. Collagen-induced platelet aggregation occurred simultaneously with a release of 5-HT from the platelets. The supernatant of collagen-aggregated platelets induced a further aggregation volume-dependently. This supernatant-induced aggregation was inhibited by either 5-HT2A antagonists or adenosine-diphosphate (ADP) scavenging. 5-Hydroxytryptamine and a small amount of the supernatant shifted the dose-response curves of collagen to the left. The aggregation velocity and the onset of aggregation by collagen were significantly increased by the supernatant, but not by 5-HT. The 5-HT2A antagonists, ketanserin and MCI-9042, returned the dose-response curves of the maximum aggregation and of the aggregation velocity of collagen, which were already amplified by the supernatant, to the original values. The onset of aggregation was delayed by the antagonists, but was not completely returned to the original points. There were distinct differences between the effects of endogenous 5-HT, derived from platelets which were stimulated by collagen, and those of exogenous 5-HT on both extensive platelet activation and amplification of the collagen-induced aggregation. These findings suggest that endogenous 5-HT activates platelets in synergism with ADP. The 5-HT2A antagonists used, block the synergism via 5-HT2A receptors and lead to inhibition of a positive feedback loop of thrombus formation. PMID:8836449

  19. 5-HT spatial distribution imaging with multiphoton excitation of 5-HT correlative visible fluorescence in live cells

    NASA Astrophysics Data System (ADS)

    Zhang, Zhihong; Zeng, Shaoqun; Liu, Yafeng; Zhou, Wei; Chen, Tongsheng; Luo, Qingming

    2002-04-01

    The autofluorescence of 5-Hydroxytryptamine (5-HT) loaded rat mucosal mast cells (RBL-2H3 cells) is imaged with multiphoton excitation laser scanning microscope (MPELSM). 5-HT correlative visible fluorescence (Fco-vis) excited with 740-nm multiphoton excitation is observed in live cells for the first time, and the generating mechanism of 5-HT Fco-vis is studied. The spatial distribution of 5-HT in live cells is imaged at high spatial resolution in our experiment, which provides a new way to study the correlation between 5-HT spatial distribution and content, and the cellular functional state in live tissue or cells.

  20. Role of central vagal 5-HT3 receptors in gastrointestinal physiology and pathophysiology

    PubMed Central

    Browning, Kirsteen N.

    2015-01-01

    Vagal neurocircuits are vitally important in the co-ordination and modulation of GI reflexes and homeostatic functions. 5-hydroxytryptamine (5-HT; serotonin) is critically important in the regulation of several of these autonomic gastrointestinal (GI) functions including motility, secretion and visceral sensitivity. While several 5-HT receptors are involved in these physiological responses, the ligand-gated 5-HT3 receptor appears intimately involved in gut-brain signaling, particularly via the afferent (sensory) vagus nerve. 5-HT is released from enterochromaffin cells in response to mechanical or chemical stimulation of the GI tract which leads to activation of 5-HT3 receptors on the terminals of vagal afferents. 5-HT3 receptors are also present on the soma of vagal afferent neurons, including GI vagal afferent neurons, where they can be activated by circulating 5-HT. The central terminals of vagal afferents also exhibit 5-HT3 receptors that function to increase glutamatergic synaptic transmission to second order neurons of the nucleus tractus solitarius within the brainstem. While activation of central brainstem 5-HT3 receptors modulates visceral functions, it is still unclear whether central vagal neurons, i.e., nucleus of the tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMV) neurons themselves also display functional 5-HT3 receptors. Thus, activation of 5-HT3 receptors may modulate the excitability and activity of gastrointestinal vagal afferents at multiple sites and may be involved in several physiological and pathophysiological conditions, including distention- and chemical-evoked vagal reflexes, nausea, and vomiting, as well as visceral hypersensitivity. PMID:26578870

  1. Excitation and depression of cortical neurones by 5-hydroxytryptamine

    PubMed Central

    Roberts, M. H. T.; Straughan, D. W.

    1967-01-01

    1. 5-Hydroxytryptamine (5-HT) and various 5-HT antagonists have been applied micro-electrophoretically from multibarrelled micropipettes into the environment of single neurones in the post-sigmoid and suprasylvian gyri of the cat cerebral cortex. 2. In unanaesthetized animals (encéphale isolé) a high proportion of neurones (30%) were excited by 5-HT. This excitation usually had a rapid onset and was seen both in spontaneously active neurones and in otherwise quiescent neurones in which firing was induced by L-glutamate. Some neurones were so sensitive that the uncontrolled diffusion from micropipettes was sufficient to excite them. More cells were excited by 5-HT applied as a cation from solutions of the bimaleate salt than when solutions of the creatinine sulphate salt were used. 3. In a high proportion of cells (33%) spontaneous firing or amino acid excitation was depressed by 5-HT. 4. A mixed effect was seen in a small proportion (6%) of the cells tested; usually 5-HT caused an excitation initially which was followed by a depression. In other cells, desensitization occurred, and the excitatory effect of 5-HT was diminished or lost. 5. When glutamate was used to excite otherwise quiescent cells, there was a significant increase in the number of cells excited by 5-HT and a significant decrease in the number of cells unaffected compared with spontaneously active cells. 6. The micro-electrophoretic application of D-lysergic diethylamide (LSD 25), 2-brom LSD (BOL 148), methysergide (UML 491), or 2′- (3-dimethylaminopropylthio)cinnamanilide (SQ 10643) temporarily prevented excitation by 5-HT in half the cells tested. LSD and SQ 10643 were particularly potent in this respect. This antagonism of 5-HT excitation could still be seen when excitation of the cell by L-glutamate or acetylcholine (ACh) was unaffected. 7. The depression induced by 5-HT was not prevented by the application of known 5-HT antagonists in the majority of the cells tested (93%). In two cells

  2. Characterization of the 5-hydroxytryptamine receptors mediating contraction in the pig isolated intravesical ureter

    PubMed Central

    Hernández, Medardo; Barahona, María Victoria; Simonsen, Ulf; Recio, Paz; Rivera, Luis; Martínez, Ana Cristina; García-Sacristán, Albino; Orensanz, Luis M; Prieto, Dolores

    2003-01-01

    This study was designed to investigate the effect of 5-hydroxytryptamine (5-HT) and to characterize the 5-HT receptors involved in 5-HT responses in the pig intravesical ureter. 5-HT (0.01–10 μM) concentration-dependently increased the tone of intravesical ureteral strips, whereas the increases in phasic contractions were concentration-independent. The 5-HT2 receptor agonist α-methyl 5-HT, mimicked the effect on tone whereas weak or no response was obtained with 5-CT, 8-OH-DPAT, m-chlorophenylbiguanide and RS 67333, 5-HT1, 5-HT1A, 5-HT3 and 5-HT4 receptor agonists, respectively. 5-HT did not induce relaxation of U46619-contracted ureteral preparations. Pargyline (100 μM), a monoaminooxidase A/B activity inhibitor, produced leftward displacements of the concentration-response curves for 5-HT. 5-HT-induced tone was reduced by the 5-HT2 and 5-HT2A receptor antagonists ritanserine (0.1 μM) and spiperone (0.2 μM), respectively. However, 5-HT contraction was not antagonized by cyanopindolol (2 μM), SDZ–SER 082 (1 μM), Y-25130 (1 μM) and GR 113808 (0.1 μM), which are respectively, 5-HT1A/1B, 5-HT2B/2C, 5-HT3, and 5-HT4 selective receptor antagonists. Removal of the urothelium did not modify 5-HT-induced contractions. Blockade of neuronal voltage-activated sodium channels, α-adrenergic receptors and adrenergic neurotransmission with tetrodotoxin (1 μM), phentolamine (0.3 μM) and guanethidine (10 μM), respectively, reduced the contractions to 5-HT. However, physostigmine (1 μM), atropine (0.1 μM) and suramin (30 μM), inhibitors of cholinesterase activity, muscarinic- and purinergic P2-receptors, respectively, failed to modify the contractions to 5-HT. These results suggest that 5-HT increases the tone of the pig intravesical ureter through 5-HT2A receptors located at the smooth muscle. Part of the 5-HT contraction is indirectly mediated via noradrenaline release from sympathetic nerves. PMID:12522083

  3. Repeated lysergic acid diethylamide in an animal model of depression: Normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling.

    PubMed

    Buchborn, Tobias; Schröder, Helmut; Höllt, Volker; Grecksch, Gisela

    2014-06-01

    A re-balance of postsynaptic serotonin (5-HT) receptor signalling, with an increase in 5-HT1A and a decrease in 5-HT2A signalling, is a final common pathway multiple antidepressants share. Given that the 5-HT1A/2A agonist lysergic acid diethylamide (LSD), when repeatedly applied, selectively downregulates 5-HT2A, but not 5-HT1A receptors, one might expect LSD to similarly re-balance the postsynaptic 5-HT signalling. Challenging this idea, we use an animal model of depression specifically responding to repeated antidepressant treatment (olfactory bulbectomy), and test the antidepressant-like properties of repeated LSD treatment (0.13 mg/kg/d, 11 d). In line with former findings, we observe that bulbectomised rats show marked deficits in active avoidance learning. These deficits, similarly as we earlier noted with imipramine, are largely reversed by repeated LSD administration. Additionally, bulbectomised rats exhibit distinct anomalies of monoamine receptor signalling in hippocampus and/or frontal cortex; from these, only the hippocampal decrease in 5-HT2 related [(35)S]-GTP-gamma-S binding is normalised by LSD. Importantly, the sham-operated rats do not profit from LSD, and exhibit reduced hippocampal 5-HT2 signalling. As behavioural deficits after bulbectomy respond to agents classified as antidepressants only, we conclude that the effect of LSD in this model can be considered antidepressant-like, and discuss it in terms of a re-balance of hippocampal 5-HT2/5-HT1A signalling. PMID:24785760

  4. Differential interactions of dimethyltryptamine (DMT) with 5-HT1A and 5-HT2 receptors.

    PubMed

    Deliganis, A V; Pierce, P A; Peroutka, S J

    1991-06-01

    The interactions of the indolealkylamine N,N-dimethyltryptamine (DMT) with 5-hydroxytryptamine1A (5-HT1A) and 5-HT2 receptors in rat brain were analyzed using radioligand binding techniques and biochemical functional assays. The affinity of DMT for 5-HT1A sites labeled by [3H]-8-hydroxy-2-(di-n-propylamino)tetralin ([3H]-8-OH-DPAT) was decreased in the presence of 10(-4) M GTP, suggesting agonist activity of DMT at this receptor. Adenylate cyclase studies in rat hippocampi showed that DMT inhibited forskolin-stimulated cyclase activity, a 5-HT1A agonist effect. DMT displayed full agonist activity with an EC50 of 4 x 10(-6) M in the cyclase assay. In contrast to the agonist actions of DMT at 5-HT1A receptors, DMT appeared to have antagonistic properties at 5-HT2 receptors. The ability of DMT to compete for [3H]-ketanserin-labeled 5-HT2 receptors was not affected by the presence of 10(-4) M GTP, suggesting antagonist activity of DMT at 5-HT2 receptors. In addition, DMT antagonized 5-HT2-receptor-mediated phosphatidylinositol (PI) turnover in rat cortex at concentrations above 10(-7) M, with 70% of the 5-HT-induced PI response inhibited at 10(-4) M DMT. Micromolar concentrations of DMT produced a slight PI stimulation that was not blocked by the 5-HT2 antagonist ketanserin. These studies suggest that DMT has opposing actions on 5-HT receptor subtypes, displaying agonist activity at 5-HT1A receptors and antagonist activity at 5-HT2 receptors. PMID:1828347

  5. Posttranslational regulation of TPH1 is responsible for the nightly surge of 5-HT output in the rat pineal gland

    PubMed Central

    Huang, Zheping; Liu, Tiecheng; Chattoraj, Asamanja; Ahmed, Samreen; Wang, Michael M.; Deng, Jie; Sun, Xing; Borjigin, Jimo

    2009-01-01

    Serotonin (5-hydroxytryptamine, 5-HT), a precursor for melatonin production, is produced abundantly in the pineal gland of all vertebrate animals. The synthesis of 5-HT in the pineal gland is rate limited by tryptophan hydroxylase 1 (TPH1) whose activity displays a twofold increase at night. Earlier studies from our laboratory demonstrate that pineal 5-HT secretion exhibits dynamic circadian rhythms with elevated levels during the early night, and that the increase is controlled by adrenergic signaling at night. In this study, we report that (a) 5-HT total output from the pineal gland and TPH1 protein levels both display diurnal rhythms with a twofold increase at night; (b) stimulation of cAMP signaling elevates 5-HT output in vivo; (c) 5-HT total output and TPH1 protein content in rat pineal gland are both acutely inhibited by light exposure at night. Consistent with these findings, molecular analysis of TPH1 protein revealed that (a) TPH1 is phosphorylated at the serine 58 in vitro and in the night pineal gland; and (b) phosphorylation of TPH1 at this residue is required for cAMP-enhanced TPH1 protein stability. These data support the model that increased nocturnal 5-HT synthesis in the pineal gland is mediated by the phosphorylation of TPH1 at the serine 58, which elevates the TPH1 protein content and activity at night. PMID:18705647

  6. Spinal 5-HT3 receptors mediate descending facilitation and contribute to behavioral hypersensitivity via a reciprocal neuron-glial signaling cascade

    PubMed Central

    2014-01-01

    Background It has been recently recognized that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in the brainstem and the 5-HT3 receptor subtype in the spinal dorsal horn are involved in enhanced descending pain facilitation after tissue and nerve injury. However, the mechanisms underlying the activation of the 5-HT3 receptor and its contribution to facilitation of pain remain unclear. Results In the present study, activation of spinal 5-HT3 receptors by intrathecal injection of a selective 5-HT3 receptor agonist SR 57227 induced spinal glial hyperactivity, neuronal hyperexcitability and pain hypersensitivity in rats. We found that there was neuron-to-microglia signaling via the chemokine fractalkine, microglia to astrocyte signaling via cytokine IL-18, astrocyte to neuronal signaling by IL-1β, and enhanced activation of NMDA receptors in the spinal dorsal horn. Glial hyperactivation in spinal dorsal horn after hindpaw inflammation was also attenuated by molecular depletion of the descending 5-HT system by intra-RVM Tph-2 shRNA interference. Conclusions These findings offer new insights into the cellular and molecular mechanisms at the spinal level responsible for descending 5-HT-mediated pain facilitation during the development of persistent pain after tissue and nerve injury. New pain therapies should focus on prime targets of descending facilitation-induced glial involvement, and in particular the blocking of intercellular signaling transduction between neurons and glia. PMID:24913307

  7. Intrathecal 5-methoxy-N,N-dimethyltryptamine in mice modulates 5-HT1 and 5-HT3 receptors.

    PubMed

    Alhaider, A A; Hamon, M; Wilcox, G L

    1993-11-01

    The antinociceptive effects of intrathecally administered 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a potent 5-HT receptor agonist, were studied in three behavioral tests in mice: the tail-flick test and the intrathecal substance P and N-methyl-D-aspartic acid (NMDA) assays. Intrathecal administration of 5-MeO-DMT (4.6-92 nmol/mouse) produced a significant prolongation of the tail-flick latency. This action was blocked by 5-HT3 and gamma-aminobutyric acidA (GABAA) receptor antagonists but not by 5-HT2, 5-HT1A, 5-HT1B or 5-HT1S receptor antagonists. Binding studies indicated that 5-MeO-DMT had very low affinity for 5-HT3 receptors. 5-MeO-DMT inhibited biting behavior while increasing scratching behavior induced by intrathecally administered substance P. The inhibition of biting behavior was antagonized by intrathecal co-administration of 5-HT1B and GABAA receptor antagonists while 5-HT1A, 5-HT1S, 5-HT2 and 5-HT3 receptor antagonists had no effect. 5-MeO-DMT-enhanced scratching behavior was inhibited by all the antagonists used except ketanserin and bicuculline, suggesting the involvement of 5-HT1A, 5-HT1B, 5-HT1S, 5-HT3 and GABAA receptors. NMDA-induced biting behavior was inhibited by 5-MeO-DMT pretreatment; this action was antagonized by 5-HT1B, 5-HT3 and GABAA receptor antagonists. The involvement of these receptors in 5-MeO-DMT action suggests that it may promote release of 5-HT (5-hydroxytryptamine, serotonin). PMID:7507056

  8. Selective Recognition of 5-Hydroxytryptamine and Dopamine on a Multi-Walled Carbon Nanotube-Chitosan Hybrid Film-Modified Microelectrode Array

    PubMed Central

    Xu, Huiren; Wang, Li; Luo, Jinping; Song, Yilin; Liu, Juntao; Zhang, Song; Cai, Xinxia

    2015-01-01

    It is difficult to determine dopamine (DA) and 5-hydroxytryptamine (5-HT) accurately because of the interference of ascorbic acid (AA) in vitro, which has a high concentration and can be oxidized at a potential close to DA and 5-HT at a conventional electrode, combined with the overlapping voltammetric signal of DA and 5-HT at a bare electrode. Herein, chitosan (CS) was used as a stabilizing matrix by electrochemical reaction, and multi-walled carbon nanotubes (MWCNTs) were modified onto the microelectrode array (MEA). The CS-MWCNT hybrid film-modified MEA was quite effective at simultaneously recognizing these species in a mixture and resolved the overlapping anodic peaks of AA, DA and 5-HT into three well-defined oxidation peaks in differential pulse voltammetry (DPV) at −80 mV, 105 mV and 300 mV (versus Ag|AgCl), respectively. The linear responses were obtained in the range of 5 × 10−6 M to 2 × 10−4 M for DA (r = 0.996) and in the range of 1 × 10−5 M to 3 × 10−4 M for 5-HT (r = 0.999) using the DPV under the presence of a single substance. While DA coexisted with 5-HT in the interference of 3 × 10−4 M AA, the linear responses were obtained in the range of 1 × 10−5 M to 3 × 10−4 M for selective molecular recognition of DA (r = 0.997) and 5-HT (r = 0.997) using the DPV. Therefore, this proposed MEA was successfully used for selective molecular recognition and determination of DA and 5-HT using the DPV, which has a potential application for real-time determination in vitro experiments. PMID:25580900

  9. 5-HT4 and 5-HT2 receptors antagonistically influence gap junctional coupling between rat auricular myocytes.

    PubMed

    Derangeon, Mickaël; Bozon, Véronique; Defamie, Norah; Peineau, Nicolas; Bourmeyster, Nicolas; Sarrouilhe, Denis; Argibay, Jorge A; Hervé, Jean-Claude

    2010-01-01

    5-hydroxytryptamine-4 (5-HT(4)) receptors have been proposed to contribute to the generation of atrial fibrillation in human atrial myocytes, but it is unclear if these receptors are present in the hearts of small laboratory animals (e.g. rat). In this study, we examined presence and functionality of 5-HT(4) receptors in auricular myocytes of newborn rats and their possible involvement in regulation of gap junctional intercellular communication (GJIC, responsible for the cell-to-cell propagation of the cardiac excitation). Western-blotting assays showed that 5-HT(4) receptors were present and real-time RT-PCR analysis revealed that 5-HT(4b) was the predominant isoform. Serotonin (1 microM) significantly reduced cAMP concentration unless a selective 5-HT(4) inhibitor (GR113808 or ML10375, both 1 microM) was present. Serotonin also reduced the amplitude of L-type calcium currents and influenced the strength of GJIC without modifying the phosphorylation profiles of the different channel-forming proteins or connexins (Cxs), namely Cx40, Cx43 and Cx45. GJIC was markedly increased when serotonin exposure occurred in presence of a 5-HT(4) inhibitor but strongly reduced when 5-HT(2A) and 5-HT(2B) receptors were inhibited, showing that activation of these receptors antagonistically regulated GJIC. The serotoninergic response was completely abolished when 5-HT(4), 5-HT(2A) and 5-HT(2B) were simultaneously inhibited. A 24 h serotonin exposure strongly reduced Cx40 expression whereas Cx45 was less affected and Cx43 still less. In conclusion, this study revealed that 5-HT(4) (mainly 5-HT(4b)), 5-HT(2A) and 5-HT(2B) receptors coexisted in auricular myocytes of newborn rat, that 5-HT(4) activation reduced cAMP concentration, I(Ca)(L) and intercellular coupling whereas 5-HT(2A) or 5-HT(2B) activation conversely enhanced GJIC. PMID:19615378

  10. Anorexia induced by activation of serotonin 5-HT4 receptors is mediated by increases in CART in the nucleus accumbens

    PubMed Central

    Jean, Alexandra; Conductier, Grégory; Manrique, Christine; Bouras, Constantin; Berta, Philippe; Hen, René; Charnay, Yves; Bockaert, Joël; Compan, Valérie

    2007-01-01

    Anorexia nervosa is a growing concern in mental health, often inducing death. The potential neuronal deficits that may underlie abnormal inhibitions of food intake, however, remain largely unexplored. We hypothesized that anorexia may involve altered signaling events within the nucleus accumbens (NAc), a brain structure involved in reward. We show here that direct stimulation of serotonin (5-hydroxytryptamine, 5-HT) 4 receptors (5-HT4R) in the NAc reduces the physiological drive to eat and increases CART (cocaine- and amphetamine-regulated transcript) mRNA levels in fed and food-deprived mice. It further shows that injecting 5-HT4R antagonist or siRNA-mediated 5-HT4R knockdown into the NAc induced hyperphagia only in fed mice. This hyperphagia was not associated with changes in CART mRNA expression in the NAc in fed and food-deprived mice. Results include that 5-HT4R control CART mRNA expression into the NAc via a cAMP/PKA signaling pathway. Considering that CART may interfere with food- and drug-related rewards, we tested whether the appetite suppressant properties of 3,4-N-methylenedioxymethamphetamine (MDMA, ecstasy) involve the 5-HT4R. Using 5-HT4R knockout mice, we demonstrate that 5-HT4R are required for the anorectic effect of MDMA as well as for the MDMA-induced enhancement of CART mRNA expression in the NAc. Directly injecting CART peptide or CART siRNA into the NAc reduces or increases food consumption, respectively. Finally, stimulating 5-HT4R- and MDMA-induced anorexia were both reduced by injecting CART siRNA into the NAc. Collectively, these results demonstrate that 5-HT4R-mediated up-regulation of CART in the NAc triggers the appetite-suppressant effects of ecstasy. PMID:17913892

  11. TREK1 channel blockade induces an antidepressant-like response synergizing with 5-HT1A receptor signaling.

    PubMed

    Ye, Dongqing; Li, Yang; Zhang, Xiangrong; Guo, Fei; Geng, Leiyu; Zhang, Qi; Zhang, Zhijun

    2015-12-01

    Current antidepressants often remain the inadequate efficacy for many depressive patients, which warrant the necessary endeavor to develop the new molecules and targets for treating depression. Recently, the two-pore domain potassium channel TREK1 has been implicated in mood regulation and TREK-1 antagonists could be the promising antidepressant. This study has screened a TREK1 blocker (SID1900) with a satisfactory blood-brain barrier permeation and bioavailability. Electrophysiological research has shown that SID1900 and the previously reported TREK1 blocker (spadin) efficiently blocked TREK-1 current in HEK293 cells and specifically blocked two-pore domain potassium channels in primary-cultured rat hippocampal neurons. SID1900 and spadin induced a significant antidepressant-like response in the rat model of chronic unpredictable mild stress (CUMS). Both two TREK1 blockers substantially increased the firing rate of 5-HT-ergic neurons in the dorsal raphe nuclei (DRN) and PFC of CUMS rats. SID1900 and spadin significantly up-regulated the expression of PKA-pCREB-BDNF signaling in DRN, hippocampus and PFC of CUMS rats, which were enhanced and reversed by a 5-HTR1A agonist (8-OH-DPAT) and antagonist (WAY100635) respectively. The present findings suggested that TREK1 channel blockers posses the substantial antidepressant-like effect and have the potential synergistic effect with 5-HT1A receptor activation through the common CREB-BDNF signal transduction. PMID:26441141

  12. 5-Hydroxytryptamine does not reduce sympathetic nerve activity or neuroeffector function in the splanchnic circulation.

    PubMed

    Darios, Emma S; Barman, Susan M; Orer, Hakan S; Morrison, Shaun F; Davis, Robert P; Seitz, Bridget M; Burnett, Robert; Watts, Stephanie W

    2015-05-01

    Infusion of 5-hydroxytryptamine (5-HT) in conscious rats results in a sustained (up to 30 days) fall in blood pressure. This is accompanied by an increase in splanchnic blood flow. Because the splanchnic circulation is regulated by the sympathetic nervous system, we hypothesized that 5-HT would: 1) directly reduce sympathetic nerve activity in the splanchnic region; and/or 2) inhibit sympathetic neuroeffector function in splanchnic blood vessels. Moreover, removal of the sympathetic innervation of the splanchnic circulation (celiac ganglionectomy) would reduce 5-HT-induced hypotension. In anaesthetized Sprague-Dawley rats, mean blood pressure was reduced from 101±4 to 63±3mm Hg during slow infusion of 5-HT (25μg/kg/min, i.v.). Pre- and postganglionic splanchnic sympathetic nerve activity were unaffected during 5-HT infusion. In superior mesenteric arterial rings prepared for electrical field stimulation, neither 5-HT (3, 10, 30nM), the 5-HT1B receptor agonist CP 93129 nor 5-HT1/7 receptor agonist 5-carboxamidotryptamine inhibited neurogenic contraction compared to vehicle. 5-HT did not inhibit neurogenic contraction in superior mesenteric venous rings. Finally, celiac ganglionectomy did not modify the magnitude of fall or time course of 5-HT-induced hypotension when compared to animals receiving sham ganglionectomy. We conclude it is unlikely 5-HT interacts with the sympathetic nervous system at the level of the splanchnic preganglionic or postganglionic nerve, as well as at the neuroeffector junction, to reduce blood pressure. These important studies allow us to rule out a direct interaction of 5-HT with the splanchnic sympathetic nervous system as a cause of the 5-HT-induced fall in blood pressure. PMID:25732865

  13. Activation of human 5-hydroxytryptamine type 3 receptors via an allosteric transmembrane site.

    PubMed

    Lansdell, Stuart J; Sathyaprakash, Chaitra; Doward, Anne; Millar, Neil S

    2015-01-01

    In common with other members of the Cys-loop family of pentameric ligand-gated ion channels, 5-hydroxytryptamine type 3 receptors (5-HT3Rs) are activated by the binding of a neurotransmitter to an extracellular orthosteric site, located at the interface of two adjacent receptor subunits. In addition, a variety of compounds have been identified that modulate agonist-evoked responses of 5-HT3Rs, and other Cys-loop receptors, by binding to distinct allosteric sites. In this study, we examined the pharmacological effects of a group of monoterpene compounds on recombinant 5-HT3Rs expressed in Xenopus oocytes. Two phenolic monoterpenes (carvacrol and thymol) display allosteric agonist activity on human homomeric 5-HT3ARs (64 ± 7% and 80 ± 4% of the maximum response evoked by the endogenous orthosteric agonist 5-HT, respectively). In addition, at lower concentrations, where agonist effects are less apparent, carvacrol and thymol act as potentiators of responses evoked by submaximal concentrations of 5-HT. By contrast, carvacrol and thymol have no agonist or potentiating activity on the closely related mouse 5-HT3ARs. Using subunit chimeras containing regions of the human and mouse 5-HT3A subunits, and by use of site-directed mutagenesis, we have identified transmembrane amino acids that either abolish the agonist activity of carvacrol and thymol on human 5-HT3ARs or are able to confer this property on mouse 5-HT3ARs. By contrast, these mutations have no significant effect on orthosteric activation of 5-HT3ARs by 5-HT. We conclude that 5-HT3ARs can be activated by the binding of ligands to an allosteric transmembrane site, a conclusion that is supported by computer docking studies. PMID:25338672

  14. 5-Hydroxytryptamine does not reduce sympathetic nerve activity or neuroeffector function in the splanchnic circulation

    PubMed Central

    Darios, Emma S.; Barman, Susan M.; Orer, Hakan S.; Morrison, Shaun F.; Davis, Robert P.; Seitz, Bridget M.; Burnett, Robert; Watts, Stephanie W.

    2015-01-01

    Infusion of 5-hydroxytryptamine (5-HT) in conscious rats results in a sustained (up to 30 days) fall in blood pressure. This is accompanied by an increase in splanchnic blood flow. Because the splanchnic circulation is regulated by the sympathetic nervous system, we hypothesized that 5-HT would: 1) directly reduce sympathetic nerve activity in the splanchnic region; and/or 2) inhibit sympathetic neuroeffector function in splanchnic blood vessels. Moreover, removal of the sympathetic innervation of the splanchnic circulation (celiac ganglionectomy) would reduce 5-HT-induced hypotension. In anaesthetized Sprague-Dawley rats, mean blood pressure was reduced from 101 ± 4 to 63 ± 3 mm Hg during slow infusion of 5-HT (25 μg/kg/min, i.v.). Pre- and postganglionic splanchnic sympathetic nerve activity was unaffected during 5-HT infusion. In superior mesenteric arterial rings prepared for electrical field stimulation, neither 5-HT (3, 10, 30 nM), the 5-HT1B receptor agonist CP 93129 nor 5-HT1/7 receptor agonist 5-carboxamidotryptamine inhibited neurogenic contraction compared to vehicle. 5-HT did not inhibit neurogenic contraction in superior mesenteric venous rings. Finally, celiac ganglionectomy did not modify the magnitude of fall or time course of 5-HT-induced hypotension when compared to animals receiving sham ganglionectomy. We conclude it is unlikely 5-HT interacts with the sympathetic nervous system at the level of the splanchnic preganglionic or postganglionic nerve, as well as at the neuroeffector junction, to reduce blood pressure. These important studies allow us to rule out a direct interaction of 5-HT with the splanchnic sympathetic nervous system as a cause of the 5-HT-induced fall in blood pressure. PMID:25732865

  15. Arterial expression of 5-HT2B and 5-HT1B receptors during development of DOCA-salt hypertension

    PubMed Central

    Banes, Amy KL; Watts, Stephanie W

    2003-01-01

    Background 5-hydroxytryptamine (5-HT)2B and 5-HT1B receptors are upregulated in arteries from hypertensive DOCA-salt rats and directly by mineralocorticoids. We hypothesized that increased 5-HT2B and 5-HT1B receptor density and contractile function would precede increased blood pressure in DOCA-high salt rats. We performed DOCA-salt time course (days 1, 3, 5 and 7) studies using treatment groups of: DOCA-high salt, DOCA-low salt, Sham and Sham-high salt rats. Results In isolated-tissue baths, DOCA-high salt aorta contracted to the 5-HT2B receptor agonist BW723C86 on day 1; Sham aorta did not contract. The 5-HT1B receptor agonist CP93129 had no effect in arteries from any group. On days 3, 5 and 7 CP93129 and BW723C86 contracted DOCA-high salt and Sham-high salt aorta; Sham and DOCA-low salt aorta did not respond. Western analysis of DOCA-high salt aortic homogenates revealed increased 5-HT2B receptor levels by day 3; 5-HT1B receptor density was unchanged. Aortic homogenates from the other groups showed unchanged 5-HT2B and 5-HT1B receptor levels. Conclusion These data suggest that functional changes of 5-HT2B but not 5-HT1B receptors may play a role in the development of DOCA-salt hypertension. PMID:12974983

  16. GPER1 stimulation alters posttranslational modification of RGSz1 and induces desensitization of 5-HT1A receptor signaling in the rat hypothalamus

    PubMed Central

    McAllister, Carrie E; Mi, Zhen; Mure, Minae; Li, Qian; Muma, Nancy A

    2014-01-01

    Hyperactivity of the hypothalamic-pituitary-adrenal axis is a consistent biological characteristic of depression and response normalization coincides with clinical responsiveness to antidepressant medications. Desensitization of serotonin 1A receptor (5-HT1AR) signaling in the hypothalamic paraventricular nucleus (PVN) follows selective serotonin reuptake inhibitor (SSRI) antidepressant treatment and contributes to the antidepressant response. Estradiol alone produces a partial desensitization of 5-HT1AR signaling, and synergizes with SSRIs to result in a complete and more rapid desensitization than with SSRIs alone as measured by a decrease in the oxytocin and adrenocorticotrophic hormone(ACTH) responses to 5-HT1AR stimulation. G protein-coupled estrogen receptor1 (GPER1) is necessary for estradiol-induced desensitization of 5-HT1AR signaling, although the underlying mechanisms are still unclear. We now find that stimulation of GPER1 with the selective agonist G-1 and non-selective stimulation of estrogen receptors dramatically alter isoform expression of a key component of the 5-HT1AR signaling pathway, RGSz1, a GTPase activating protein selective for Gαz, the Gα subunit necessary for 5-HT1AR-mediated hormone release. RGSz1 isoforms are differentially glycosylated, SUMOylated, and phosphorylated, and differentially distributed in subcellular organelles. High molecular weight RGSz1 is SUMOylated and glycosylated, localized to the detergent-resistant microdomain (DRM) of the cell membrane, and increased by estradiol and G-1 treatment. Because activated Gαz also localizes to the DRM, increased DRM-localized RGSz1 by estradiol and G-1could reduce Gαz activity, functionally uncoupling 5-HT1AR signaling. Peripheral G-1 treatment produced partial reduction in oxytocin and ACTH responses to 5-HT1AR-stimulation similar to direct injections into the PVN. Together, these results identify GPER1 and RGSz1 as novel targets for the treatment of depression. PMID:25402859

  17. Constitutively Active 5-HT Receptors: An Explanation of How 5-HT Antagonists Inhibit Gut Motility in Species Where 5-HT is Not an Enteric Neurotransmitter?

    PubMed Central

    Spencer, Nick J.

    2015-01-01

    Antagonists of 5-Hydroxytryptamine (5-HT) receptors are well known to inhibit gastrointestinal (GI)-motility and transit in a variety of mammals, including humans. Originally, these observations had been interpreted by many investigators (including us) as evidence that endogenous 5-HT plays a major role in GI motility. This seemed a logical assumption. However, the story changed dramatically after recent studies revealed that 5-HT antagonists still blocked major GI motility patterns (peristalsis and colonic migrating motor complexes) in segments of intestine depleted of all 5-HT. Then, these results were further supported by Dr. Gershons' laboratory, which showed that genetic deletion of all genes that synthesizes 5-HT had minor, or no inhibitory effects on GI transit in vivo. If 5-HT was essential for GI motility patterns and transit, then one would expect major disruptions in motility and transit when 5-HT synthesis was genetically ablated. This does not occur. The inhibitory effects of 5-HT antagonists on GI motility clearly occur independently of any 5-HT in the gut. Evidence now suggests that 5-HT antagonists act on 5-HT receptors in the gut which are constitutively active, and don't require 5-HT for their activation. This would explain a long-standing mystery of how 5-HT antagonists inhibit gut motility in species like mice, rats, and humans where 5-HT is not an enteric neurotransmitter. Studies are now increasingly demonstrating that the presence of a neurochemical in enteric neurons does not mean they function as neurotransmitters. Caution should be exercised when interpreting any inhibitory effects of 5-HT antagonists on GI motility. PMID:26732863

  18. Emotional memory impairments in a genetic rat model of depression: involvement of 5-HT/MEK/Arc signaling in restoration.

    PubMed

    Eriksson, T M; Delagrange, P; Spedding, M; Popoli, M; Mathé, A A; Ögren, S O; Svenningsson, P

    2012-02-01

    Cognitive dysfunctions are common in major depressive disorder, but have been difficult to recapitulate in animal models. This study shows that Flinders sensitive line (FSL) rats, a genetic rat model of depression, display a pronounced impairment of emotional memory function in the passive avoidance (PA) task, accompanied by reduced transcription of Arc in prefrontal cortex and hippocampus. At the cellular level, FSL rats have selective reductions in levels of NMDA receptor subunits, serotonin 5-HT(1A) receptors and MEK activity. Treatment with chronic escitalopram, but not with an antidepressant regimen of nortriptyline, restored memory performance and increased Arc transcription in FSL rats. Multiple pharmacological manipulations demonstrated that procognitive effects could also be achieved by either disinhibition of 5-HT(1A)R/MEK/Arc or stimulation of 5-HT₄R/MEK/Arc signaling cascades. Taken together, studies of FSL rats in the PA task revealed reversible deficits in emotional memory processing, providing a potential model with predictive and construct validity for assessments of procognitive actions of antidepressant drug therapies. PMID:21242991

  19. Uptake of 5-hydroxytryptamine in different parts of the brain of the rabbit after intraventricular injection.

    PubMed Central

    Dow, R C; Laszlo, I

    1976-01-01

    1 The uptake of 5-hydroxytryptamine (5-HT) was investigated in different areas of the rabbit brain (anterior hypothalamus, the raphe, the region of the substantia nigra, several cortical areas and the medulla oblongata) after intraventricular injection in pargyline pretreated animals by the formaldehyde-induced histochemical fluorescence method. 2 The distribution of fluorescence showed that the uptake of 5-HT, after circulation in the cerebrospinal fluid, caused a general increase in intensity of green yellow to yellow background fluorescence. There was an increased fluorescence in the nerve terminals, but no uptake occurred either in the cell bodies of neurones or in the glial cells. Images Figure 1 Figure 2 PMID:1260225

  20. Influence of 5-hydroxytryptamine (serotonin) on blood flow in the dog pulp

    SciTech Connect

    Kim, S.; Trowbridge, H.O.; Dorscher-Kim, J.E.

    1986-05-01

    The effect of intra-arterial injection of 5-hydroxytryptamine (5-HT) on pulpal blood flow of the dog was determined using the 15-micron radioisotope-labeled microsphere injection method. Pulpal blood flow was significantly reduced following the 5-HT injection. This decrease in blood flow appeared to be due to vasoconstriction as determined by an increase in pulpal vascular hindrance. However, our findings do not preclude the possibility that blood flow was reduced as a result of passive compression of venules produced by vasodilation in a low-compliance environment.

  1. The effect of altered 5-hydroxytryptamine levels on beta-endorphin

    NASA Technical Reports Server (NTRS)

    Soliman, Karam F. A.; Mash, Deborah C.; Walker, Charles A.

    1986-01-01

    The purpose of the present study was to examine the effect of altering the concentration of 5-hydroxytryptamine (5-HT) on beta-endorphin (beta-Ep) content in the hypothalamus, thalamus, and periaqueductal gray (PAG)-rostral pons regions of the rat brain. The selective 5-HT reuptake inhibitor, fluoxetine (10 mg/kg), significantly lowered beta-Ep content in the hypothalamus and the PAG. Parachlorophenylalanine, which inhibits 5-HT synthesis, significantly elevated beta-Ep in all brain parts studied. Intracisternal injections of the neurotoxin 5-prime, 7-prime-dihydroxytryptamine with desmethylimipramine pretreatment significantly increased beta-Ep content in the hypothalamus and the PAG. In adrenalectomized rats, fluoxetine significantly decreased beta-Ep levels in the hypothalamus and increased the levels in the PAG. The results indicate that 5-HT may modulate the levels of brain beta-Ep.

  2. Toward Selective Drug Development for the Human 5-Hydroxytryptamine 1E Receptor: A Comparison of 5-Hydroxytryptamine 1E and 1F Receptor Structure-Affinity RelationshipsS⃞

    PubMed Central

    Klein, Michael T.; Dukat, Małgorzata; Glennon, Richard A.

    2011-01-01

    The 5-hydroxytryptamine (5-HT) 1E receptor is highly expressed in the human frontal cortex and hippocampus, and this distribution suggests the function of 5-HT1E receptors might be linked to memory. To test this hypothesis, behavioral experiments are needed. Because rats and mice lack a 5-HT1E receptor gene, knockout strategies cannot be used to elucidate this receptor's functions. Thus, selective pharmacological tools must be developed. The tryptamine-related agonist BRL54443 [5-hydroxy-3-(1-methylpiperidin-4-yl)-1H-indole] is one of the few agents that binds 5-HT1E receptors with high affinity and some selectively; unfortunately, it binds equally well to 5-HT1F receptors (Ki ≈ 1 nM). The differences between tryptamine binding requirements of these two receptor populations have never been extensively explored; this must be done to guide the design of analogs with greater selectivity for 5-HT1E receptors versus 5-HT1F receptors. Previously, we determined the receptor binding affinities of a large series of tryptamine analogs at the 5-HT1E receptor; we now examine the affinities of this same series of compounds at 5-HT1F receptors. The affinities of these compounds at 5-HT1E and 5-HT1F receptors were found to be highly correlated (r = 0.81). All high-affinity compounds were full agonists at both receptor populations. We identified 5-N-butyryloxy-N,N-dimethyltryptamine as a novel 5-HT1F receptor agonist with >60-fold selectivity versus 5-HT1E receptors. There is significant overlap between 5-HT1E and 5-HT1F receptor orthosteric binding properties; thus, identification of 5-HT1E-selective orthosteric ligands will be difficult. The insights generated from this study will inform future drug development and molecular modeling studies for both 5-HT1E and 5-HT1F receptors. PMID:21422162

  3. Norepinephrine triggers Ca2+-dependent exocytosis of 5-hydroxytryptamine from rat pinealocytes in culture.

    PubMed

    Yamada, Hiroshi; Hayashi, Mitsuko; Uehara, Shunsuke; Kinoshita, Mika; Muroyama, Akiko; Watanabe, Masami; Takei, Koji; Moriyama, Yoshinori

    2002-05-01

    5-hydroxytryptamine (5-HT) is a precursor and a putative modulator for melatonin synthesis in mammalian pinealocytes. 5-HT is present in organelles distinct from l-glutamate-containing synaptic-like microvesicles as well as in the cytoplasm of pinealocytes, and is secreted upon stimulation by norepinephrine (NE) to enhance serotonin N-acetyltransferase activity via the 5-HT2 receptor. However, the mechanism underlying the secretion of 5-HT from pinealocytes is unknown. In this study, we show that NE-evoked release of 5-HT is largely dependent on Ca2+ in rat pinealocytes in culture. Omission of Ca2+ from the medium and incubation of pineal cells with EGTA-tetraacetoxymethyl-ester inhibited by 59 and 97% the NE-evoked 5-HT release, respectively. Phenylephrine also triggered the Ca2+-dependent release of 5-HT, which was blocked by phentolamine, an alpha antagonist, but not by propranolol, a beta antagonist. Botulinum neurotoxin type E cleaved 25 kDa synaptosomal-associated protein and inhibited by 50% of the NE-evoked 5-HT release. Bafilomycin A1, an inhibitor of vacuolar H+-ATPase, and reserpine and tetrabenazine, inhibitors of vesicular monoamine transporter, all decreased the storage of vesicular 5-HT followed by inhibition of the NE-evoked 5-HT release. Agents that trigger L-glutamte exocytosis such as acetylcholine did not trigger any Ca2+-dependent 5-HT release. Vice versa neither NE nor phenylephrine caused synaptic-like microvesicle-mediated l-glutamate exocytosis. These results indicated that upon stimulation of a adrenoceptors pinealocytes secrete 5-HT through a Ca2+-dependent exocytotic mechanism, which is distinct from the exocytosis of synaptic-like microvesicles. PMID:12065661

  4. Two cases of mild serotonin toxicity via 5-hydroxytryptamine 1A receptor stimulation

    PubMed Central

    Nakayama, Hiroto; Umeda, Sumiyo; Nibuya, Masashi; Terao, Takeshi; Nisijima, Koichi; Nomura, Soichiro

    2014-01-01

    We propose the possibility of 5-hydroxytryptamine (5-HT)1A receptor involvement in mild serotonin toxicity. A 64-year-old woman who experienced hallucinations was treated with perospirone (8 mg/day). She also complained of depressed mood and was prescribed paroxetine (10 mg/day). She exhibited finger tremors, sweating, coarse shivering, hyperactive knee jerks, vomiting, diarrhea, tachycardia, and psychomotor agitation. After the discontinuation of paroxetine and perospirone, the symptoms disappeared. Another 81-year-old woman, who experienced delusions, was treated with perospirone (8 mg/day). Depressive symptoms appeared and paroxetine (10 mg/day) was added. She exhibited tachycardia, finger tremors, anxiety, agitation, and hyperactive knee jerks. The symptoms disappeared after the cessation of paroxetine and perospirone. Recently, the effectiveness of coadministrating 5-HT1A agonistic psychotropics with selective serotonin reuptake inhibitors (SSRIs) has been reported, and SSRIs with 5-HT1A agonistic activity have been newly approved in the treatment of depression. Perospirone is a serotonin–dopamine antagonist and agonistic on the 5-HT1A receptors. Animal studies have indicated that mild serotonin excess induces low body temperature through 5-HT1A, whereas severe serotonin excess induces high body temperature through 5-HT2A activation. Therefore, it could be hypothesized that mild serotonin excess induces side effects through 5-HT1A, and severe serotonin excess induces lethal side effects with hyperthermia through 5-HT2A. Serotonin toxicity via a low dose of paroxetine that is coadministered with perospirone, which acts agonistically on the 5-HT1A receptor and antagonistically on the 5-HT2A receptor, clearly indicated 5-HT1A receptor involvement in mild serotonin toxicity. Careful measures should be adopted to avoid serotonin toxicity following the combined use of SSRIs and 5-HT1A agonists. PMID:24627634

  5. The 5-HT1-like receptors mediating inhibition of sympathetic vasopressor outflow in the pithed rat: operational correlation with the 5-HT1A, 5-HT1B and 5-HT1D subtypes

    PubMed Central

    Villalón, Carlos M; Centurión, David; Rabelo, Gonzalo; de Vries, Peter; Saxena, Pramod R; Sánchez-López, Araceli

    1998-01-01

    It has been suggested that the inhibition of sympathetically-induced vasopressor responses produced by 5-hydroxytryptamine (5-HT) in pithed rats is mediated by 5-HT1-like receptors. The present study has re-analysed this suggestion with regard to the classification schemes recently proposed by the NC-IUPHAR subcommittee on 5-HT receptors.Intravenous (i.v.) continuous infusions of 5-HT and the 5-HT1 receptor agonists, 8-OH-DPAT (5-HT1A), indorenate (5-HT1A), CP 93,129 (5-HT1B) and sumatriptan (5-HT1B/1D), resulted in a dose-dependent inhibition of sympathetically-induced vasopressor responses.The sympatho-inhibitory responses induced by 5-HT, 8-OH-DPAT, indorenate, CP 93,129 or sumatriptan were analysed before and after i.v. treatment with blocking doses of the putative 5-HT receptor antagonists, WAY 100635 (5-HT1A), cyanopindolol (5-HT1A/1B) or GR 127935 (5-HT1B/1D). Thus, after WAY 100635, the responses to 5-HT and indorenate, but not to 8-OH-DPAT, CP 93,129 and sumatriptan, were blocked. After cyanopindolol, the responses to 5-HT, indorenate and CP 93,129 were abolished, whilst those to 8-OH-DPAT and sumatriptan (except at the lowest frequency of stimulation) remained unaltered. In contrast, after GR 127935, the responses to 5-HT, CP 93,129 and sumatriptan, but not to 8-OH-DPAT and indorenate, were abolished.In additional experiments, the inhibition induced by 5-HT was not modified after 5-HT7 receptor blocking doses of mesulergine.The above results suggest that the 5-HT1-like receptors, which inhibit the sympathetic vasopressor outflow in pithed rats, display the pharmacological profile of the 5-HT1A, 5-HT1B and 5-HT1D, but not that of 5-HT7, receptors. PMID:9692787

  6. 5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats.

    PubMed

    Martin-Gronert, Malgorzata S; Stocker, Claire J; Wargent, Edward T; Cripps, Roselle L; Garfield, Alastair S; Jovanovic, Zorica; D'Agostino, Giuseppe; Yeo, Giles S H; Cawthorne, Michael A; Arch, Jonathan R S; Heisler, Lora K; Ozanne, Susan E

    2016-04-01

    Although obesity is a global epidemic, the physiological mechanisms involved are not well understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low-protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and an increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT) is nutritionally regulated and 5-HT is a trophic factor, we hypothesised that maternal diet influences fetal 5-HT exposure, which then influences development of the central appetite network and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant rats fed a low-protein diet exhibited elevated serum levels of 5-HT, which was also evident in the placenta and fetal brains at embryonic day 16.5. This increase was associated with reduced levels of 5-HT2CR, the primary 5-HT receptor influencing appetite, in the fetal, neonatal and adult hypothalamus. As expected, a reduction of 5-HT2CR was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 5-HT primarily achieves effects on appetite by 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We show that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC neurons and that mRNA encoding 5-HT2AR is increased in the hypothalamus ofin uterogrowth-restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals at 3 months of age are more sensitive to appetite suppression induced by 5-HT2AR agonists. These findings not only reveal a 5-HT-mediated mechanism underlying the programming of susceptibility to obesity, but also provide a promising means to correct it, by treatment with a 5-HT2AR agonist. PMID:26769798

  7. 5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats

    PubMed Central

    Martin-Gronert, Malgorzata S.; Stocker, Claire J.; Wargent, Edward T.; Cripps, Roselle L.; Garfield, Alastair S.; Jovanovic, Zorica; D'Agostino, Giuseppe; Yeo, Giles S. H.; Cawthorne, Michael A.; Arch, Jonathan R. S.; Heisler, Lora K.; Ozanne, Susan E.

    2016-01-01

    ABSTRACT Although obesity is a global epidemic, the physiological mechanisms involved are not well understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low-protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and an increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT) is nutritionally regulated and 5-HT is a trophic factor, we hypothesised that maternal diet influences fetal 5-HT exposure, which then influences development of the central appetite network and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant rats fed a low-protein diet exhibited elevated serum levels of 5-HT, which was also evident in the placenta and fetal brains at embryonic day 16.5. This increase was associated with reduced levels of 5-HT2CR, the primary 5-HT receptor influencing appetite, in the fetal, neonatal and adult hypothalamus. As expected, a reduction of 5-HT2CR was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 5-HT primarily achieves effects on appetite by 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We show that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC neurons and that mRNA encoding 5-HT2AR is increased in the hypothalamus of in utero growth-restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals at 3 months of age are more sensitive to appetite suppression induced by 5-HT2AR agonists. These findings not only reveal a 5-HT-mediated mechanism underlying the programming of susceptibility to obesity, but also provide a promising means to correct it, by treatment with a 5-HT2AR agonist. PMID:26769798

  8. Spinal 5-HT1A, not the 5-HT1B or 5-HT3 receptors, mediates descending serotonergic inhibition for late-phase mechanical allodynia of carrageenan-induced peripheral inflammation.

    PubMed

    Kim, Joung Min; Jeong, Seong Wook; Yang, Jihoon; Lee, Seong Heon; Kim, Woon Mo; Jeong, Seongtae; Bae, Hong Beom; Yoon, Myung Ha; Choi, Jeong Il

    2015-07-23

    Previous electrophysiological studies demonstrated a limited role of 5-hydroxytryptamine 3 receptor (5-HT3R), but facilitatory role of 5-HT1AR and 5-HT1BR in spinal nociceptive processing of carrageenan-induced inflammatory pain. The release of spinal 5-HT was shown to peak in early-phase and return to baseline in late-phase of carrageenan inflammation. We examined the role of the descending serotonergic projections involving 5-HT1AR, 5-HT1BR, and 5-HT3R in mechanical allodynia of early- (first 4h) and late-phase (24h after) carrageenan-induced inflammation. Intrathecal administration of 5-HT produced a significant anti-allodynic effect in late-phase, but not in early-phase. Similarly, intrathecal 5-HT1AR agonist (8-OH-DPAT) attenuated the intensity of late-phase allodynia in a dose dependent fashion which was antagonized by 5-HT1AR antagonist (WAY-100635), but produced no effect on the early-phase allodynia. However, other agonists or antagonists of 5-HT1BR (CP-93129, SB-224289) and 5-HT3R (m-CPBG, ondansetron) did not produce any anti- or pro-allodynic effect in both early- and late- phase allodynia. These results suggest that spinal 5-HT1A, but not 5-HT1B or 5-HT3 receptors mediate descending serotonergic inhibition on nociceptive processing of late-phase mechanical allodynia in carrageenan-induced inflammation. PMID:26037417

  9. Interferon-γ Attenuates 5-Hydroxytryptamine-Induced Melanogenesis in Primary Melanocyte.

    PubMed

    Zhou, Jia; Ling, Jingjing; Ping, Fengfeng

    2016-01-01

    Interferon-γ (IFN-γ) is an important cytokine which can be secreted by keratinocytes or macrophages induced by UVB irradiation in skin. Mammalian skin cells have the capability to produce and metabolize 5-hydroxytryptamine (5-HT) whose cutaneous effects are mediated by the interactions with 5-HT receptors. Treatment with 5-HT resulted in a dose-dependent increase of tyrosinase (TYR) activity and melanin contents in normal human foreskin-derived epidermal melanocytes (NHEM), while with IFN-γ a decreased effect resulted. These regulatory results were due to changes of the expression levels of microphthalmia-associated transcription factor (MITF) and its downstream TYR, tyrosinase-related protein 1 (TRP-1) and dopachrome tautomerase (DCT). We proved here that 5-HTR1A/2A participated in the regulation of melanogenesis. IFN-γ could offset the pro-melanogenesis effect of 5-HT in NHEM and the intensity of this neutralization was unanticipated below the baseline level. IFN-γ neutralized the up-regulation effect of 5-HT on MITF and downstream TYR, TRP-1 and DCT. Though functioning as 5-HT1A/2A receptor during the melanogenesis process, IFN-γ played no role in 5-HT1A/2A receptor expressions. Our results also demonstrated that the inhibition of IFN-γ was reversible after its removal. Confusingly, the effect of cross-talk between 5-HT and IFN-γ on NHEM melanogenesis was irreversible. Whether treated with 5-HT for 5 d or 12 d, the pigmentation level neither recovered after displacing the IFN-γ-containing medium. In addition, IFN-γ was able to inhibit the inductive effect of 5-HT on NHEM migration. Taken together, the suppression of IFN-γ on 5-HT-induced melanogenesis further suggests the negative role of IFN-γ in inflammation-associated pigmentary changes. PMID:27374284

  10. 5-HT obesity medication efficacy via POMC activation is maintained during aging.

    PubMed

    Burke, Luke K; Doslikova, Barbora; D'Agostino, Giuseppe; Garfield, Alastair S; Farooq, Gala; Burdakov, Denis; Low, Malcolm J; Rubinstein, Marcelo; Evans, Mark L; Billups, Brian; Heisler, Lora K

    2014-10-01

    The phenomenon commonly described as the middle-age spread is the result of elevated adiposity accumulation throughout adulthood until late middle-age. It is a clinical imperative to gain a greater understanding of the underpinnings of age-dependent obesity and, in turn, how these mechanisms may impact the efficacy of obesity treatments. In particular, both obesity and aging are associated with rewiring of a principal brain pathway modulating energy homeostasis, promoting reduced activity of satiety pro-opiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus (ARC). Using a selective ARC-deficient POMC mouse line, here we report that former obesity medications augmenting endogenous 5-hydroxytryptamine (5-HT) activity d-fenfluramine and sibutramine require ARC POMC neurons to elicit therapeutic appetite-suppressive effects. We next investigated whether age-related diminished ARC POMC activity therefore impacts the potency of 5-HT obesity pharmacotherapies, lorcaserin, d-fenfluramine, and sibutramine and report that all compounds reduced food intake to a comparable extent in both chow-fed young lean (3-5 months old) and middle-aged obese (12-14 months old) male and female mice. We provide a mechanism through which 5-HT anorectic potency is maintained with age, via preserved 5-HT-POMC appetitive anatomical machinery. Specifically, the abundance and signaling of the primary 5-HT receptor influencing appetite via POMC activation, the 5-HT2CR, is not perturbed with age. These data reveal that although 5-HT obesity medications require ARC POMC neurons to achieve appetitive effects, the anorectic efficacy is maintained with aging, findings of clinical significance to the global aging obese population. PMID:25051442

  11. Role of the 5-HT7 receptor in the central nervous system: from current status to future perspectives.

    PubMed

    Matthys, Anne; Haegeman, Guy; Van Craenenbroeck, Kathleen; Vanhoenacker, Peter

    2011-06-01

    Pharmacological and genetic tools targeting the 5-hydroxytryptamine (5-HT)7 receptor in preclinical animal models have implicated this receptor in diverse (patho)physiological processes of the central nervous system (CNS). Some data obtained with 5-HT7 receptor knockout mice, selective antagonists, and, to a lesser extent, agonists, however, are quite contradictory. In this review, we not only discuss in detail the role of the 5-HT7 receptor in the CNS but also propose some hypothetical models, which could explain the observed inconsistencies. These models are based on two novel concepts within the field of G protein-coupled receptors (GPCR), namely biphasic signaling and G protein-independent signaling, which both have been shown to be mediated by GPCR dimerization. This led us to suggest that the 5-HT7 receptor could reside in different dimeric contexts and initiate different signaling pathways, depending on the neuronal circuitry and/or brain region. In conclusion, we highlight GPCR dimerization and G protein-independent signaling as two promising future directions in 5-HT7 receptor research, which ultimately might lead to the development of more efficient dimer- and/or pathway-specific therapeutics. PMID:21424680

  12. Involvement of 5-HT1B receptors in triptan-induced contractile responses in guinea-pig isolated iliac artery.

    PubMed

    Jähnichen, S; Radtke, O A; Pertz, H H

    2004-07-01

    Using a series of triptans we characterized in vitro the 5-hydroxytryptamine (5-HT) receptor that mediates the contraction in guinea-pig iliac arteries moderately precontracted by prostaglandin F2alpha (PGF2alpha). Additionally, we investigated by reverse-transcriptase polymerase chain reaction (RT-PCR) which triptan-sensitive receptor is present in this tissue. Frovatriptan, zolmitriptan, rizatriptan, naratriptan, sumatriptan, and almotriptan contracted guinea-pig iliac arteries with pD2 values of 7.52+/-0.04, 6.72+/-0.03, 6.38+/-0.06, 6.22+/-0.05, 5.86+/-0.05 and 5.26+/-0.04 respectively. For comparison, the pD2 values for 5-HT and 5-carboxamidotryptamine (5-CT) were 7.52+/-0.02 and 7.55+/-0.03 respectively. In contrast to all other triptans tested, the concentration-response curve for eletriptan was biphasic (first phase: 0.01-3 microM, pD2 approximately 6.6; second phase: > or = 10 microM). Contractions to 5-HT, 5-CT, frovatriptan, zolmitriptan, rizatriptan, naratriptan, sumatriptan, almotriptan, and eletriptan (first phase) were antagonized by the 5-HT1B/1D receptor antagonist GR127935 (10 nM) and the 5-HT1B receptor antagonist SB216641 (10 nM). RT-PCR studies in guinea-pig iliac arteries showed a strong signal for the 5-HT1B receptor while expression of 5-HT1D and 5-HT1F receptors was not detected in any sample. The present results demonstrate that triptan-induced contraction in guinea-pig iliac arteries is mediated by the 5-HT1B receptor. The guinea-pig iliac artery may be used as a convenient in vitro model to study the (cardio)vascular side-effect potential of anti-migraine drugs of the triptan family. PMID:15185063

  13. Moderate differences in circulating corticosterone alter receptor-mediated regulation of 5-hydroxytryptamine neuronal activity.

    PubMed

    Judge, Sarah J; Ingram, Colin D; Gartside, Sarah E

    2004-12-01

    Circulating glucocorticoid levels vary with stress and psychiatric illness and play a potentially important role in regulating transmitter systems that regulate mood. To determine whether chronic variation in corticosterone levels within the normal diurnal range altered the control of 5-hydroxytryptamine (5-HT) neuronal activity, male rats were adrenalectomized and implanted with either a 2% or 70% corticosterone/cholesterol pellet (100 mg). Two weeks later, the regulation of 5-HT neuronal activity in the dorsal raphe nucleus was studied by in vitro electrophysiology. At this time, serum corticosterone levels approximated the low-point (2%) and mid-point (70%) of the diurnal range. The excitatory response of 5-HT neurones to the alpha1-adrenoceptor agonist phenylephrine (1-11 microM) was significantly greater in the 2% group compared to the 70% group. By contrast, the inhibitory response to 5-HT (10-50 microM) was significantly lower in the 2% group compared to the 70% group. Thus, chronic variation in circulating corticosterone over a narrow part of the normal diurnal range causes a shift in the balance of positive and negative regulation of 5-HT neurones, with increased alpha 1-adrenoceptor-mediated excitation and reduced 5-HT-mediated autoinhibition at lower corticosterone levels. This shift would have a major impact on control of 5-HT neuronal activity. PMID:15582914

  14. Ethanol induced adaptations in 5-HT2c receptor signaling in the bed nucleus of the stria terminalis: implications for anxiety during ethanol withdrawal.

    PubMed

    Marcinkiewcz, Catherine A; Dorrier, Cayce E; Lopez, Alberto J; Kash, Thomas L

    2015-02-01

    One of the hallmarks of alcohol dependence is the presence of a withdrawal syndrome during abstinence, which manifests as physical craving for alcohol accompanied by subjective feelings of anxiety. Using a model of chronic intermittent ethanol (CIE) vapor in mice, we investigated the role of serotonin2c receptor (5HT2c-R) signaling in the BNST as a neural substrate underlying ethanol-induced anxiety during withdrawal. Mice were subjected to a 5-day CIE regimen of 16 h of ethanol vapor exposure followed by an 8 h "withdrawal" period between exposures. After the 5th and final exposure, mice were withdrawn for 24 h or 1 week before experiments began. Anxiety-like behavior was assessed in the social approach, light dark, and open field tests with mice showing deficits in social, but not general anxiety-like behavior that was alleviated by pretreatment with the 5HT2c-R antagonist SB 242,084 (3 mg/kg, i.p.) 24 h and 1 week post-CIE. Using immunohistochemistry and whole cell patch clamp electrophysiology, we also found that CIE increased FOS-IR and enhanced neuronal excitability in the ventral BNST (vBNST) 24 h into withdrawal in a 5HT2c-R dependent manner. This enhanced excitability persisted for 1 week post-CIE. We also found that mCPP, a 5HT2c/b agonist, induced a more robust depolarization in cells of the vBNST in CIE mice, confirming that 5HT2c-R signaling is upregulated in the vBNST following CIE. Taken together, these results suggest that CIE upregulates 5HT2c-R signaling in the vBNST, leading to increased excitability. This enhanced excitability of the vBNST may drive increased anxiety-like behavior during ethanol withdrawal. PMID:25229718

  15. Postnatal day 2 to 11 constitutes a 5-HT-sensitive period impacting adult mPFC function.

    PubMed

    Rebello, Tahilia J; Yu, Qinghui; Goodfellow, Nathalie M; Caffrey Cagliostro, Martha K; Teissier, Anne; Morelli, Emanuela; Demireva, Elena Y; Chemiakine, Alexei; Rosoklija, Gorazd B; Dwork, Andrew J; Lambe, Evelyn K; Gingrich, Jay A; Ansorge, Mark S

    2014-09-10

    Early-life serotonin [5-hydroxytryptamine (5-HT)] signaling modulates brain development, which impacts adult behavior, but 5-HT-sensitive periods, neural substrates, and behavioral consequences remain poorly understood. Here we identify the period ranging from postnatal day 2 (P2) to P11 as 5-HT sensitive, with 5-HT transporter (5-HTT) blockade increasing anxiety- and depression-like behavior, and impairing fear extinction learning and memory in adult mice. Concomitantly, P2-P11 5-HTT blockade causes dendritic hypotrophy and reduced excitability of infralimbic (IL) cortex pyramidal neurons that normally promote fear extinction. By contrast, the neighboring prelimbic (PL) pyramidal neurons, which normally inhibit fear extinction, become more excitable. Excitotoxic IL but not PL lesions in adult control mice reproduce the anxiety-related phenotypes. These findings suggest that increased 5-HT signaling during P2-P11 alters adult mPFC function to increase anxiety and impair fear extinction, and imply a differential role for IL and PL neurons in regulating affective behaviors. Together, our results support a developmental mechanism for the etiology and pathophysiology of affective disorders and fear-related behaviors. PMID:25209278

  16. Postnatal Day 2 to 11 Constitutes a 5-HT-Sensitive Period Impacting Adult mPFC Function

    PubMed Central

    Rebello, Tahilia J.; Yu, Qinghui; Goodfellow, Nathalie M.; Caffrey Cagliostro, Martha K.; Teissier, Anne; Morelli, Emanuela; Demireva, Elena Y.; Chemiakine, Alexei; Rosoklija, Gorazd B.; Dwork, Andrew J.; Lambe, Evelyn K.; Ansorge, Mark S.

    2014-01-01

    Early-life serotonin [5-hydroxytryptamine (5-HT)] signaling modulates brain development, which impacts adult behavior, but 5-HT-sensitive periods, neural substrates, and behavioral consequences remain poorly understood. Here we identify the period ranging from postnatal day 2 (P2) to P11 as 5-HT sensitive, with 5-HT transporter (5-HTT) blockade increasing anxiety- and depression-like behavior, and impairing fear extinction learning and memory in adult mice. Concomitantly, P2–P11 5-HTT blockade causes dendritic hypotrophy and reduced excitability of infralimbic (IL) cortex pyramidal neurons that normally promote fear extinction. By contrast, the neighboring prelimbic (PL) pyramidal neurons, which normally inhibit fear extinction, become more excitable. Excitotoxic IL but not PL lesions in adult control mice reproduce the anxiety-related phenotypes. These findings suggest that increased 5-HT signaling during P2–P11 alters adult mPFC function to increase anxiety and impair fear extinction, and imply a differential role for IL and PL neurons in regulating affective behaviors. Together, our results support a developmental mechanism for the etiology and pathophysiology of affective disorders and fear-related behaviors. PMID:25209278

  17. 3,4-methylenedioxymethamphetamine increases excitability in the dentate gyrus: role of 5HT2A receptor-induced PGE2 signaling.

    PubMed

    Collins, Stuart A; Huff, Courtney; Chiaia, Nicolas; Gudelsky, Gary A; Yamamoto, Bryan K

    2016-03-01

    3,4-methylenedioxymethamphetamine (MDMA) is a widely abused psychostimulant, which causes release of serotonin in various forebrain regions. Recently, we reported that MDMA increases extracellular glutamate concentrations in the dentate gyrus, via activation of 5HT2A receptors. We examined the role of prostaglandin signaling in mediating the effects of 5HT2A receptor activation on the increases in extracellular glutamate and the subsequent long-term loss of parvalbumin interneurons in the dentate gyrus caused by MDMA. Administration of MDMA into the dentate gyrus of rats increased PGE2 concentrations which was prevented by coadministration of MDL100907, a 5HT2A receptor antagonist. MDMA-induced increases in extracellular glutamate were inhibited by local administration of SC-51089, an inhibitor of the EP1 prostaglandin receptor. Systemic administration of SC-51089 during injections of MDMA prevented the decreases in parvalbumin interneurons observed 10 days later. The loss of parvalbumin immunoreactivity after MDMA exposure coincided with a decrease in paired-pulse inhibition and afterdischarge threshold in the dentate gyrus. These changes were prevented by inhibition of EP1 and 5HT2A receptors during MDMA. Additional experiments revealed an increased susceptibility to kainic acid-induced seizures in MDMA-treated rats, which could be prevented with SC51089 treatments during MDMA exposure. Overall, these findings suggest that 5HT2A receptors mediate MDMA-induced PGE2 signaling and subsequent increases in glutamate. This signaling mediates parvalbumin cell losses as well as physiologic changes in the dentate gyrus, suggesting that the lack of the inhibition provided by these neurons increases the excitability within the dentate gyrus of MDMA-treated rats. We hypothesized that the widely abused psychostimulant MDMA causes a loss of parvalbumin (PV) cells and increases excitability in the dentate gyrus. MDMA increases serotonin (5HT) release and activates 5HT2A

  18. 5-HT Obesity Medication Efficacy via POMC Activation is Maintained During Aging

    PubMed Central

    Burke, Luke K.; Doslikova, Barbora; D'Agostino, Giuseppe; Garfield, Alastair S.; Farooq, Gala; Burdakov, Denis; Low, Malcolm J.; Rubinstein, Marcelo; Evans, Mark L.; Billups, Brian

    2014-01-01

    The phenomenon commonly described as the middle-age spread is the result of elevated adiposity accumulation throughout adulthood until late middle-age. It is a clinical imperative to gain a greater understanding of the underpinnings of age-dependent obesity and, in turn, how these mechanisms may impact the efficacy of obesity treatments. In particular, both obesity and aging are associated with rewiring of a principal brain pathway modulating energy homeostasis, promoting reduced activity of satiety pro-opiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus (ARC). Using a selective ARC-deficient POMC mouse line, here we report that former obesity medications augmenting endogenous 5-hydroxytryptamine (5-HT) activity d-fenfluramine and sibutramine require ARC POMC neurons to elicit therapeutic appetite-suppressive effects. We next investigated whether age-related diminished ARC POMC activity therefore impacts the potency of 5-HT obesity pharmacotherapies, lorcaserin, d-fenfluramine, and sibutramine and report that all compounds reduced food intake to a comparable extent in both chow-fed young lean (3–5 months old) and middle-aged obese (12–14 months old) male and female mice. We provide a mechanism through which 5-HT anorectic potency is maintained with age, via preserved 5-HT–POMC appetitive anatomical machinery. Specifically, the abundance and signaling of the primary 5-HT receptor influencing appetite via POMC activation, the 5-HT2CR, is not perturbed with age. These data reveal that although 5-HT obesity medications require ARC POMC neurons to achieve appetitive effects, the anorectic efficacy is maintained with aging, findings of clinical significance to the global aging obese population. PMID:25051442

  19. Therapeutic Potential of 5-HT6 Receptor Agonists.

    PubMed

    Karila, Delphine; Freret, Thomas; Bouet, Valentine; Boulouard, Michel; Dallemagne, Patrick; Rochais, Christophe

    2015-10-22

    Given its predominant expression in the central nervous system (CNS), 5-hydroxytryptamine (5-HT: serotonin) subtype 6 receptor (5-HT6R) has been considered as a valuable target for the development of CNS drugs with limited side effects. After 2 decades of intense research, numerous selective ligands have been developed to target this receptor; this holds potential interest for the treatment of neuropathological disorders. In fact, some agents (mainly antagonists) are currently undergoing clinical trial. More recently, a series of potent and selective agonists have been developed, and preclinical studies have been conducted that suggest the therapeutic interest of 5-HT6R agonists. This review details the medicinal chemistry of these agonists, highlights their activities, and discusses their potential for treating cognitive issues associated with Alzheimer's disease (AD), depression, or obesity. Surprisingly, some studies have shown that both 5-HT6R agonists and antagonists exert similar procognitive activities. This article summarizes the hypotheses that could explain this paradox. PMID:26099069

  20. Functional properties of a cloned 5-hydroxytryptamine ionotropic receptor subunit: comparison with native mouse receptors.

    PubMed

    Hussy, N; Lukas, W; Jones, K A

    1994-12-01

    1. A comparative study of the whole-cell and single-channel properties of cloned and native mouse 5-hydroxytryptamine ionotropic receptors (5-HT3) was undertaken using mammalian cell lines expressing the cloned 5-HT3 receptor subunit A (5-HT3R-A), superior cervical ganglia (SCG) neurones and N1E-115 cells. 2. No pharmacological difference was found in the sensitivity to the agonists 5-HT and 2-methyl-5-HT, or to the antagonists d-tubocurare and 3-tropanyl-3,5-dichlorobenzoate (MDL-72222). 3. Current-voltage (I-V) relationships of whole-cell currents showed inward rectification in the three preparations. Rectification was stronger both in cells expressing the 5-HT3R-A subunit and in N1E-115 cells when compared with SCG neurones. 4. No clear openings could be resolved in 5-HT-activated currents in patches excised from cells expressing the 5-HT3R-A subunit or N1E-115 cells. Current fluctuation analysis of whole-cell and excised-patch records revealed a slope conductance of 0.4-0.6 pS in both preparations. Current-voltage relationships of these channels showed strong rectification that fully accounted for the whole-cell voltage dependence. 5. In contrast, single channels of about 10 pS were activated by 5-HT in patches excised from SCG neurones. The weak voltage dependence of their conductance did not account completely for the rectification of whole-cell currents. A lower unitary conductance (3.4 pS) was inferred from whole-cell noise analysis. 6. We conclude that the receptor expressed from the cloned cDNA is indistinguishable from the 5-HT3 receptor of N1E-115 cells, suggesting an identical structure for these two receptors. The higher conductance and different voltage dependence of the 5-HT3 receptor in SCG neurones might indicate the participation of an additional subunit in the structure of native ganglionic 5-HT3 receptors. Homo-oligomeric 5-HT3R-A channels may also be present as suggested by the lower conductance estimated by whole-cell noise analysis. PMID

  1. Cellular resilience: 5-HT neurons in Tph2(-/-) mice retain normal firing behavior despite the lack of brain 5-HT.

    PubMed

    Montalbano, Alberto; Waider, Jonas; Barbieri, Mario; Baytas, Ozan; Lesch, Klaus-Peter; Corradetti, Renato; Mlinar, Boris

    2015-11-01

    Considerable evidence links dysfunction of serotonin (5-hydroxytryptamine, 5-HT) transmission to neurodevelopmental and psychiatric disorders characterized by compromised "social" cognition and emotion regulation. It is well established that the brain 5-HT system is under autoregulatory control by its principal transmitter 5-HT via its effects on activity and expression of 5-HT system-related proteins. To examine whether 5-HT itself also has a crucial role in the acquisition and maintenance of characteristic rhythmic firing of 5-HT neurons, we compared their intrinsic electrophysiological properties in mice lacking brain 5-HT, i.e. tryptophan hydroxylase-2 null mice (Tph2(-/-)) and their littermates, Tph2(+/-) and Tph2(+/+), by using whole-cell patch-clamp recordings in a brainstem slice preparation and single unit recording in anesthetized animals. We report that the active properties of dorsal raphe nucleus (DRN) 5-HT neurons in vivo (firing rate magnitude and variability; the presence of spike doublets) and in vitro (firing in response to depolarizing current pulses; action potential shape) as well as the resting membrane potential remained essentially unchanged across Tph2 genotypes. However, there were subtle differences in subthreshold properties, most notably, an approximately 25% higher input conductance in Tph2(-/-) mice compared with Tph2(+/-) and Tph2(+/+) littermates (p<0.0001). This difference may at least in part be a consequence of slightly bigger size of the DRN 5-HT neurons in Tph2(-/-) mice (approximately 10%, p<0.0001). Taken together, these findings show that 5-HT neurons acquire and maintain their signature firing properties independently of the presence of their principal neurotransmitter 5-HT, displaying an unexpected functional resilience to complete brain 5-HT deficiency. PMID:26409296

  2. Effects of p-chlorophenylalanine on the sensitivity of rat intestine to agonists and on intestinal 5-hydroxytryptamine levels during Nippostrongylus brasiliensis infection.

    PubMed Central

    Farmer, S. G.; Laniyonu, A. A.

    1984-01-01

    Infection of rats with the nematode N. brasiliensis caused non-specific increases in maximum response of isolated intestine to acetylcholine and 5-hydroxytryptamine (5-HT), and a specific subsensitivity to 5-HT. Intestinal levels of 5-HT, measured fluorimetrically, increased approximately 2 fold during infection. Treatment of infected rats with parachlorophenylalanine (PCPA) depleted the gut of 5-HT, and prevented the specific subsensitivity to the amine but not the increases in maximum response. Depletion of intestinal 5-HT did not prevent the immune expulsion of the parasites. It is concluded that the specific subsensitivity of the gut is due to the elevated levels of 5-HT during infection, but that the increased maximum responses are due to some other factor. Further, the lack of effect of PCPA on parasite rejection casts doubt on the proposed role of 5-HT in this process. PMID:6236863

  3. Water-soluble jack-knife prawn extract inhibits 5-hydroxytryptamine-induced vasoconstriction and platelet aggregation in humans.

    PubMed

    Gamoh, Shuji; Kanai, Tasuku; Tanaka-Totoribe, Naoko; Ohkura, Masamichi; Kuwabara, Masachika; Nakamura, Eisaku; Yokota, Atsuko; Yamasaki, Tetsuo; Watanabe, Akiko; Hayashi, Masahiro; Fujimoto, Shouichi; Yamamoto, Ryuichi

    2015-02-01

    Coronary artery spasm plays an important role in the pathogenesis of various ischemic heart diseases or serious arrhythmia. The aim of this study is to look for functional foods which have physiologically active substances preventing 5-hydroxytryptamine (5-HT)-related vasospastic diseases including peri- and postoperative ischemic complications of coronary artery bypass grafting (CABG) from ocean resources in Japanese coastal waters. First, we evaluated the effect of water-soluble ocean resource extracts on the response to 5-HT in HEK293 cells which have forcibly expressed cyan fluorescent protein-fused 5-HT2A receptors (5-HT2A-CFP). Among 5 different water-soluble extracts of ocean resources, the crude water-soluble jack-knife prawn extract (WJPE) significantly reduced maximal Ca(2+) influx induced by 0.1 μM 5-HT in a concentration-dependent manner. The Crude WJPE significantly inhibited, in a concentration-dependent manner, 5-HT-induced constriction of human saphenous vein. 5-HT released from activated platelets plays a crucial roles in the constriction of coronary artery. Next the WJPE was purified for applying the experiment of 5-HT-induced human platelet aggregation. The purified WJPE significantly inhibited 5-HT-induced human platelet aggregation also in a concentration-dependent manner. Based on our findings, jack-knife prawn could be one of a functional food with health-promoting benefits for most people with vasospastic diseases including patients who have gone CABG. PMID:25464143

  4. Peptide displacement of ( sup 3 H)5-hydroxytryptamine binding to bovine cortical membranes

    SciTech Connect

    Takeuchi, Y.; Root-Bernstein, R.S.; Shih, J.C. )

    1990-12-01

    Chemical studies have demonstrated that peptides such as the encephalitogenic (EAE) peptide of myelin basic protein (MBP) and luteinizing hormone-releasing hormone (LHRH) can bind serotonin (5-hydroxytryptamine, 5-HT) in vitro. The present research was undertaken to determine whether such binding interferes with 5-HT binding to its 5-HT1 receptors on bovine cerebral cortical membranes. EAE peptide and LHRH displaced ({sup 3}H)5-HT with IC50s of 4.0 x 10(-4) and 1.8 x 10(-3) M respectively. MBP itself also showed apparent displacing ability with an IC50 of 6.0 x 10(-5) M, though it also caused aggregation of cortical membranes that might have interfered with normal receptor binding. These results support previous suggestions that the tryptophan peptide region of MBP may act as a 5-HT receptor in the neural system. We also tested the effects of muramyl dipeptide (N-acetyl-muramyl-L-Ala-D-isoGln, MD), a bacterial cell-wall breakdown product that acts as a slow-wave sleep promoter, binds to LHRH and EAE peptide, and competes for 5-HT binding sites on macrophages. It showed no significant displacement of 5-HT binding to cortical membranes (IC50 greater than 10(-1) M), but its D-Ala analogue did (IC50 = 1.7 x 10(-3) M). Thus, it seems likely that the 5-HT-related effects of naturally occurring muramyl peptides are physiologically limited by receptor types.

  5. 5-Hydroxytryptamine and dopamine transport by rat and human blood platelets

    PubMed Central

    Gordon, J.L.; Olverman, H.J.

    1978-01-01

    1 Uptake of 5-hydroxytryptamine (5-HT) by rat platelets in plasma was very rapid and diffusion did not contribute significantly at substrate concentrations that did not saturate the active transport. 2 Under conditions which allowed measurement of initial rates of uptake, kinetic analysis revealed a high affinity uptake mechanism for 5-HT (Km = 0.7 μM). 3 Uptake of dopamine was relatively slow and involved a lower affinity (Km = 70 μM) active transport process. Diffusion contributed significantly at concentrations that did not saturate the active transport. 4 5-HT competitively inhibited uptake of dopamine, and vice versa; Ki values for both amines were similar to their respective Km values for uptake. 5 Chlorimipramine, desmethylimipramine and benztropine were tested as uptake inhibitors. Each was equipotent against 5-HT and dopamine, although the absolute potency of the drugs varied greatly. Chlorimipramine was the most potent (Ki## 100 nM), and kinetic analysis revealed that the inhibition was competitive against both 5-HT and dopamine. 6 Similar results were obtained in studies with human platelets: Km values for 5-HT and dopamine were about 1 μM and 100 μM respectively. Activity profiles of inhibitors were also similar: each compound tested was equipotent against 5-HT and dopamine, and the two amines each competitively inhibited uptake of the other. 7 We conclude that dopamine is actively transported by platelets via the 5-HT uptake mechanism, but with a much lower affinity. There is no high-affinity dopamine-specific mechanism corresponding to that in the corpus striatum. Consequently although platelets may be valid models of transport in 5-hydroxytryptaminergic neurones, they should not be regarded as models for the dopamine transport mechanism found in dopaminergic neurones. PMID:623937

  6. Third Trimester Equivalent Alcohol Exposure Reduces Modulation of Glutamatergic Synaptic Transmission by 5-HT1A Receptors in the Rat Hippocampal CA3 Region

    PubMed Central

    Morton, Russell A.; Valenzuela, C. Fernando

    2016-01-01

    Fetal alcohol exposure has been associated with many neuropsychiatric disorders that have been linked to altered serotonin (5-hydroxytryptamine; 5-HT) signaling, including depression and anxiety. During the first 2 weeks of postnatal life in rodents (equivalent to the third trimester of human pregnancy) 5-HT neurons undergo significant functional maturation and their axons reach target regions in the forebrain (e.g., cortex and hippocampus). The objective of this study was to identify the effects of third trimester ethanol (EtOH) exposure on hippocampal 5-HT signaling. Using EtOH vapor inhalation chambers, we exposed rat pups to EtOH for 4 h/day from postnatal day (P) 2 to P12. The average serum EtOH concentration in the pups was 0.13 ± 0.04 g/dl (legal intoxication limit in humans = 0.08 g/dl). We used brain slices to assess the modulatory actions of 5-HT on field excitatory postsynaptic potentials in the hippocampal CA3 region at P13-P15. Application of the GABAA/glycine receptor antagonist, picrotoxin, caused broadening of field excitatory postsynaptic potentials (fEPSPs), an effect that was reversed by application of 5-HT in slices from air exposed rats. However, this effect of 5-HT was absent in EtOH exposed animals. In slices from naïve animals, application of a 5-HT1A receptor antagonist blocked the effect of 5-HT on the fEPSPs recorded in presence of picrotoxin, suggesting that third trimester ethanol exposure acts by inhibiting the function of these receptors. Studies indicate that 5-HT1A receptors play a critical role in the development of hippocampal circuits. Therefore, inhibition of these receptors by third trimester ethanol exposure could contribute to the pathophysiology of fetal alcohol spectrum disorders. PMID:27375424

  7. Third Trimester Equivalent Alcohol Exposure Reduces Modulation of Glutamatergic Synaptic Transmission by 5-HT1A Receptors in the Rat Hippocampal CA3 Region.

    PubMed

    Morton, Russell A; Valenzuela, C Fernando

    2016-01-01

    Fetal alcohol exposure has been associated with many neuropsychiatric disorders that have been linked to altered serotonin (5-hydroxytryptamine; 5-HT) signaling, including depression and anxiety. During the first 2 weeks of postnatal life in rodents (equivalent to the third trimester of human pregnancy) 5-HT neurons undergo significant functional maturation and their axons reach target regions in the forebrain (e.g., cortex and hippocampus). The objective of this study was to identify the effects of third trimester ethanol (EtOH) exposure on hippocampal 5-HT signaling. Using EtOH vapor inhalation chambers, we exposed rat pups to EtOH for 4 h/day from postnatal day (P) 2 to P12. The average serum EtOH concentration in the pups was 0.13 ± 0.04 g/dl (legal intoxication limit in humans = 0.08 g/dl). We used brain slices to assess the modulatory actions of 5-HT on field excitatory postsynaptic potentials in the hippocampal CA3 region at P13-P15. Application of the GABAA/glycine receptor antagonist, picrotoxin, caused broadening of field excitatory postsynaptic potentials (fEPSPs), an effect that was reversed by application of 5-HT in slices from air exposed rats. However, this effect of 5-HT was absent in EtOH exposed animals. In slices from naïve animals, application of a 5-HT1A receptor antagonist blocked the effect of 5-HT on the fEPSPs recorded in presence of picrotoxin, suggesting that third trimester ethanol exposure acts by inhibiting the function of these receptors. Studies indicate that 5-HT1A receptors play a critical role in the development of hippocampal circuits. Therefore, inhibition of these receptors by third trimester ethanol exposure could contribute to the pathophysiology of fetal alcohol spectrum disorders. PMID:27375424

  8. 5-HT3 Receptors

    PubMed Central

    Thompson, A. J.; Lummis, S. C. R.

    2009-01-01

    The 5-HT3 receptor is a member of the Cys-loop family of ligand-gated ion channels. These receptors are located in both the peripheral and central nervous systems, where functional receptors are constructed from five subunits. These subunits may be the same (homopentameric 5-HT3A receptors) or different (heteropentameric receptors, usually comprising of 5-HT3A and 5-HT3B receptor subunits), with the latter having a number of distinct properties. The 5-HT3 receptor binding site is comprised of six loops from two adjacent subunits, and critical ligand binding amino acids in these loops have been largely identified. There are a range of selective agonists and antagonists for these receptors and the pharmacophore is reasonably well understood. There are also a wide range of compounds that can modulate receptor activity. Studies have suggested many diverse potential disease targets that might be amenable to alleviation by 5-HT3 receptor selective compounds but to date only two applications have been fully realised in the clinic: the treatment of emesis and irritable-bowel syndrome. PMID:17073663

  9. 5-HT2B receptor-mediated calcium release from ryanodine-sensitive intracellular stores in human pulmonary artery endothelial cells.

    PubMed Central

    Ullmer, C.; Boddeke, H. G.; Schmuck, K.; Lübbert, H.

    1996-01-01

    1. We have characterized the 5-hydroxytryptamine (5-HT)-induced calcium signalling in endothelial cells from the human pulmonary artery. Using RT-PCR we show, that of all cloned G-protein coupled 5-HT receptors, these cells express only 5-HT1D beta, 5-HT2B and little 5-HT4 receptor mRNA. 2. In endothelial cells 5-HT inhibits the formation of adenosine 3':5'-cyclic monophosphate (cyclic AMP) via 5-HT1D beta receptors but fails to activate phosphoinositide (PI) turnover. However, the latter pathway is strongly activated by histamine. 3. Despite the lack of detectable inositol phosphate (IP) formation in human pulmonary artery endothelial cells, 5-HT (pD2 = 5.82 +/- 0.06, n = 6) or the selective 5-HT2 agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (pD2 = 5.66 +/- 0.03, n = 7) elicited transient calcium signals comparable to those evoked by histamine (pD2 = 6.44 +/- 0.01, n = 7). Since 5-HT2A and 5-HT2C receptor mRNAs are not detectable in pulmonary artery endothelial cells, activation of 5-HT2B receptors is responsible for the transient calcium release. The calcium transients are independent of the inhibition of adenylate cyclase, since DOI does not stimulate 5-HT1D beta receptors. 4. Both, the 5-HT- and histamine-stimulated calcium signals were also observed when the cells were placed in calcium-free medium. This indicates that 5-HT triggers calcium release from intracellular stores. 5. Heparin is an inhibitor of the IP3-activated calcium release channels on the endoplasmic reticulum. Intracellular infusion of heparin through patch pipettes in voltage clamp experiments failed to block 5-HT-induced calcium signals, whereas it abolished the histamine response. This supports the conclusion that the 5-HT-induced calcium release is independent of IP3 formation. 6. Unlike the histamine response, the 5-HT response was sensitive to micromolar concentrations of ryanodine and, to a lesser extent, ruthenium red. This implies that 5-HT2B receptors trigger calcium

  10. Pharmacological Characterization of 5-HT1A Autoreceptor-Coupled GIRK Channels in Rat Dorsal Raphe 5-HT Neurons

    PubMed Central

    Montalbano, Alberto; Corradetti, Renato; Mlinar, Boris

    2015-01-01

    G protein-activated inwardly rectifying potassium (GIRK) channels in 5-HT neurons are assumed to be principal effectors of 5-hydroxytryptamine 1A (5-HT1A) autoreceptors, but their pharmacology, subunit composition and the role in regulation of 5-HT neuron activity have not been fully elucidated. We sought for a pharmacological tool for assessing the functional role of GIRK channels in 5-HT neurons by characterizing the effects of drugs known to block GIRK channels in the submicromolar range of concentrations. Whole-cell voltage-clamp recording in brainstem slices were used to determine concentration-response relationships for the selected GIRK channel blockers on 5-HT1A autoreceptor-activated inwardly rectifying K+ conductance in rat dorsal raphe 5-HT neurons. 5-HT1A autoreceptor-activated GIRK conductance was completely blocked by the nonselective inwardly rectifying potassium channels blocker Ba2+ (EC50 = 9.4 μM, full block with 100 μM) and by SCH23390 (EC50 = 1.95 μM, full block with 30 μM). GIRK-specific blocker tertiapin-Q blocked 5-HT1A autoreceptor-activated GIRK conductance with high potency (EC50 = 33.6 nM), but incompletely, i.e. ~16% of total conductance resulted to be tertiapin-Q-resistant. U73343 and SCH28080, reported to block GIRK channels with submicromolar EC50s, were essentially ineffective in 5-HT neurons. Our data show that inwardly rectifying K+ channels coupled to 5-HT1A autoreceptors display pharmacological properties generally expected for neuronal GIRK channels, but different from GIRK1-GIRK2 heteromers, the predominant form of brain GIRK channels. Distinct pharmacological properties of GIRK channels in 5-HT neurons should be explored for the development of new therapeutic agents for mood disorders. PMID:26460748

  11. Recombinant saphenous vein 5-HT1B receptors of the rabbit: comparative pharmacology with human 5-HT1B receptors.

    PubMed

    Wurch, T; Palmier, C; Colpaert, F C; Pauwels, P J

    1997-01-01

    1. The rabbit recombinant saphenous vein 5-hydroxytryptamine1B (r 5-HT1B) receptor stably transfected in rat C6-glial cells was characterized by measuring adenosine 3':5'-cyclic monophosphate (cycle AMP) formation upon exposure to various 5-HT receptor ligands. The effects of agonists and antagonists were compared with their effects determined previously at the human cloned 5-HT1B (h 5-HT1B) receptor under similar experimental conditions. 2. Intact C6-glial cells expressing rb HT1B receptors exhibited [3H]-5-carboxamidotryptamine (5-CT) binding sites with a Kd of 0.80 +/- 0.13 nM and a Bmax between 225 to 570 fmol mg-1 protein. The binding affinities of a series of 5-HT receptor ligands determined in a membrane preparation with [3H]-5-CT or [3H]-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(-4 -pyridyl) benzamide (GR 125,743) were similar. With the exception of ketanserin, ligand affinities were comparable to those determined at the clones h 5-HT1B receptor site. 3. rb 5-HT1B receptors were negatively coupled to cyclic AMP formation upon stimulation with 5-HT agonists. Of the several 5-HT agonists tested, 5-CT was the most potent, the potency rank order being: 5-CT > 5-HT > zolmitriptan > naratriptan > rizatriptan > sumatriptan > R (+)-8-(hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The maximal responses of these agonists were similar to those induced by 5-HT. The potency of these agonists showed a positive correlation (r2 = 0.87; P < 0.002) with their potency at the cloned h 5-HT1B receptor subtype. 4. 2'-Methyl-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-e-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127,935), methiothepin and ketanserin each behaved as silent, competitive antagonists at rb 5HT1B receptors; pKB values were 8.41, 8.32 and 7.05, respectively when naratriptan was used as an agonist. These estimates accorded with their binding affinities and the potencies found on 5-HT and/or sumatriptan

  12. Interaction of tryptamine and ergoline compounds with threonine 196 in the ligand binding site of the 5-hydroxytryptamine6 receptor.

    PubMed

    Boess, F G; Monsma, F J; Meyer, V; Zwingelstein, C; Sleight, A J

    1997-09-01

    We examined the ligand-binding site of the 5-hydroxytryptamine6 (5-HT6) receptor using site-directed mutagenesis. Interactions with residues in two characteristic positions of trans-membrane region V are important for ligand binding in several bioamine receptors. In the 5-HT6 receptor, one of these residues is a threonine (Thr196), whereas in most other mammalian 5-HT receptors, the corresponding residue is alanine. After transient expression in human embryonic kidney 293 cells, we determined the effects of the mutation T196A on [3H]d-lysergic acid diethylamide (LSD) binding and adenylyl cyclase stimulation. This mutation produced a receptor with a 10-fold reduced affinity for [3H]LSD and a 6-fold reduced affinity for 5-HT. The potency of both LSD and 5-HT for stimulation of adenylyl cyclase was also reduced by 18- and 7-fold, respectively. The affinity of other N1-unsubstituted ergolines (e.g., ergotamine, lisuride) was reduced 10-30 fold, whereas the affinity of N1-methylated ergolines (e.g., metergoline, methysergide, mesulergine) and other ligands, such as methiothepine, clozapine, ritanserin, amitriptyline, and mainserin, changed very little or increased. This indicates that in wild-type 5-HT6 receptor, Thr196 interacts with the N1 of N1-unsubstituted ergolines and tryptamines, probably forming a hydrogen bond. Based on molecular modeling, a serine residue in transmembrane region IV of the 5-HT2A receptor has previously been proposed to interact with the N1-position of 5-HT. When the corresponding residue of the 5-HT6 receptor (Ala154) was converted to serine, no change in the affinity of twelve 5-HT6 receptor ligands or in the potency of 5-HT and LSD could be detected, suggesting that this position does not contribute to the ligand binding site of the 5-HT6 receptor. PMID:9284367

  13. Evidence for 5-HT1-like receptor-mediated vasoconstriction in human pulmonary artery.

    PubMed Central

    MacLean, M. R.; Clayton, R. A.; Templeton, A. G.; Morecroft, I.

    1996-01-01

    1. The 5-hydroxytryptamine (5-HT) receptors mediating contraction of human isolated pulmonary artery rings were investigated. Responses to the agonists 5-carboximidotryptamine (5-CT, non-selective 5-HT1 agonist), sumatriptan (5-HT1D-like receptor agonist), 5-HT and 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, 5-HT1A receptor agonist) were studied. Responses to 5-HT and sumatriptan in the presence of the antagonists, methiothepin (non-selective 5-HT1+2-receptor antagonist), ketanserin (5-HT2A receptor antagonist) and the novel antagonist, GR55562 (5-HT1D receptor antagonist) were also studied. 2. All agonists contracted human pulmonary artery ring preparations in the following order of potency 5-CT > 5-HT = sumatriptan > 8-OH-DPAT. Maximum responses to 5-HT, 5-CT and sumatriptan were not significantly different. 3. Methiothepin 1 nM and 10 nM, but not 0.1 nM reduced the maximum contractile responses to 5-HT but did not alter tissue sensitivity to 5-HT. Methiothepin 0.1 nM, 1 nM and 10 nM had a similar effect on responses to sumatriptan. 4. The 5-HT2A receptor antagonist ketanserin (10 nM, 100 nM and 1 microM) also reduced the maximum contractile response to both 5-HT and sumatriptan without affecting tissue sensitivity to these agonists. 5. The novel 5-HT1D receptor antagonist, GR55562, inhibited responses to 5-HT and sumatriptan in a true competitive fashion. 6. The results suggest that the human pulmonary artery has a functional population of 5-HT1D-like receptors which are involved in the contractile response to 5-HT. PMID:8886409

  14. Cinitapride protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds.

    PubMed

    Alarcón-de-la-Lastra Romero, C; López, A; Martín, M J; la Casa, C; Motilva, V

    1997-04-01

    This study was designed to determine the gastroprotective properties of cinitapride (CNT), a novel prokinetic benzamide derivative agonist of 5-HT4 and 5-HT1 receptors and 5-HT2 antagonist, on mucosal injury produced by 50% (v/v) ethanol. Results were compared with those for 5-hydroxytryptamine (5-HT: 10 mg kg-1). The possible involvements of gastric mucus secretion, endogenous prostaglandins (PGs) and sulfhydryl compounds (SH) in the protection mediated by CNT were also examined. Intraperitoneal administration of CNT (0.50 and 1 mg kg-1), 30 min before ethanol, significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus. CNT (1 mg kg-1) also produced a significant increase in gastric mucosal levels of PGE2, but did not induce any significant changes in SH values. On the contrary, pretreatment with 5-HT worsened ethanol-induced erosions, however, did not affect gastric mucus secretion, glycoprotein content or PGE2 levels, although the non-protein SH fraction was significantly decreased. The present results demonstrate that the gastroprotective effects of CNT could be partly explained by a complex PG dependent mechanism. We suggest that 5-HT dependent mechanisms through 5-HT2 receptor blockade and 5-HT1 receptor activation could be also involved. PMID:9211565

  15. Hippocampal 5-HT1A Receptor and Spatial Learning and Memory

    PubMed Central

    Glikmann-Johnston, Yifat; Saling, Michael M.; Reutens, David C.; Stout, Julie C.

    2015-01-01

    Spatial cognition is fundamental for survival in the topographically complex environments inhabited by humans and other animals. The hippocampus, which has a central role in spatial cognition, is characterized by high concentration of serotonin (5-hydroxytryptamine; 5-HT) receptor binding sites, particularly of the 1A receptor (5-HT1A) subtype. This review highlights converging evidence for the role of hippocampal 5-HT1A receptors in spatial learning and memory. We consider studies showing that activation or blockade of the 5-HT1A receptors using agonists or antagonists, respectively, lead to changes in spatial learning and memory. For example, pharmacological manipulation to induce 5-HT release, or to block 5-HT uptake, have indicated that increased extracellular 5-HT concentrations maintain or improve memory performance. In contrast, reduced levels of 5-HT have been shown to impair spatial memory. Furthermore, the lack of 5-HT1A receptor subtype in single gene knockout mice is specifically associated with spatial memory impairments. These findings, along with evidence from recent cognitive imaging studies using positron emission tomography (PET) with 5-HT1A receptor ligands, and studies of individual genetic variance in 5-HT1A receptor availability, strongly suggests that 5-HT, mediated by the 5-HT1A receptor subtype, plays a key role in spatial learning and memory. PMID:26696889

  16. Physiologically identified 5-HT2-like receptors at the crayfish neuromuscular junction.

    PubMed

    Tabor, Jami N; Cooper, Robin L

    2002-04-01

    The model synaptic preparation of the crayfish opener neuromuscular junction is known to be responsive to exogenous application of 5-HT. The primary effect of 5-HT is an enhancement of vesicular release from the presynaptic motor nerve terminal. 5-HT is known to act through an IP(3) cascade which suggests the presence of a 5-HT(2) receptor subtype; however, this is based on vertebrate 5-HT receptor classification. We examined this possibility by using a selective agonist and two antagonists of the vertebrate 5-HT(2) receptor subtypes. The antagonist ketanserin and spiperone reduce the responsiveness of 5-HT in a dose-dependent manner. The broad 5-HT(2) receptor agonist, alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT) enhances synaptic transmission, in a concentration-dependent manner, but it is not as potent as 5-HT. These results support the notion that a 5-HT(2) receptor subtype is present presynaptically on the crayfish motor nerve terminals. By knowing the types of 5-HT receptors present on the presynaptic motor nerve terminals in this model synaptic preparation, a better understanding of the mechanisms of action of 5-HT on vesicular release will be forthcoming. PMID:11911865

  17. Evaluation of the ocular hypotensive response of serotonin 5-HT1A and 5-HT2 receptor ligands in conscious ocular hypertensive cynomolgus monkeys.

    PubMed

    May, Jesse A; McLaughlin, Marsha A; Sharif, Najam A; Hellberg, Mark R; Dean, Thomas R

    2003-07-01

    Published investigations of serotonin-1A (5-hydroxytryptamine1A; 5-HT1A) receptor agonists and serotonin-2A (5-hydroxytryptamine2A; 5-HT2A) receptor antagonists in nonprimate species provide conflicting results with regard to their intraocular pressure-lowering efficacy. Thus, their therapeutic utility in the treatment of human glaucoma has been confusing. We evaluated the effect of selected 5-HT1A agonists and 5-HT2A receptor antagonists on intraocular pressure in a nonhuman primate model, the conscious cynomolgus monkey with laser-induced ocular hypertension. Neither selective 5-HT1A agonists [e.g., R-8-hydroxy-2-(di-n-propylamino)tetralin and flesinoxan] nor selective 5-HT2 receptor antagonists [e.g., R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (M-100907) and 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxamide (SB-242084)] lowered intraocular pressure in the primate model following topical ocular administration. However, compounds that function as agonists at both the 5-HT1A and 5-HT2 receptors were found to effectively lower intraocular pressure in the model: 5-hydroxy-alpha-methyltryptamine, 5-methoxy-alpha-methyltryptamine, 5-hydroxy-N,N-dimethyltryptamine (bufotenine), and 5-methoxy-N,N-dimethyltryptamine. Furthermore, the selective 5-HT2 receptor agonist R-(-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane lowered intraocular pressure in the primate model, demonstrating a pharmacological response associated with activation of the 5-HT2 receptor. These observations suggest that compounds that function as efficient agonists at 5-HT2 receptors should be considered as potential agents for the control of intraocular pressure in the treatment of ocular hypertension and glaucoma in humans. PMID:12676887

  18. Loss of 5-hydroxytryptamine from mammalian circulating labelled platelets

    PubMed Central

    Osim, E. E.; Wyllie, J. H.

    1983-01-01

    1. Platelets were obtained from three species of animal: rats, rabbits and dogs. They were labelled with 111In oxine to tag individual platelets and with 14C-labelled 5-hydroxytryptamine (5-HT). Doubly labelled platelets from rabbits and dogs were returned to their donors; in the case of rats the platelets were injected intravenously into other, identical rats. At time intervals from 2 to 64 hr, blood samples were drawn and platelets were collected. 111In and 14C were separately counted. In some experiments animals received the 5-HT precursor, 5-hydroxytryptophan (5-HTP) I.P. (for rats and rabbits) or subcutaneously (for dogs) in a dose of 20 mg/kg daily to accelerate synthesis of 5-HT. 2. 111In disappeared in approximately an exponential fashion in all experiments and the rate of disappearance was not affected by treatment with 5-HTP. The half-life for 111In in four control rats was 18·7 hr and in five rats treated with 5-HTP was 17·8 hr. In rabbits the half-life was 20·4 hr for eight control and 21·2 hr for seven treated with 5-HTP. In the dogs the half-life was 21·0 hr for control and 27·7 hr for experiments with 5-HTP. In control rats, the 14C behaved like the 111In. However, in control rabbits the half-life for 14C was 38·0 hr which is significantly longer than for 111In (P < 0·005). 14C also disappeared more slowly than the 111In in the dogs. 3. In all species treatment with 5-HTP accelerated the disappearance of the 14C approximately three-fold. This was not a reserpine-like effect because the platelets contained more, not less 5-HT than usual. 4. In an attempt to discover the fate of 5-HT disappearing from circulating platelets, experiments were made in which platelets from one rat were doubly labelled, and were then injected into two other rats from the identical strain; one of the recipients received daily I.P. injections of 20 mg/kg of 5-HTP. The other rat in each pair acted as a control. 5. Results from twelve control rats showed that the 14C

  19. Anxiolytic effect and memory improvement in rats by antisense oligodeoxynucleotide to 5-hydroxytryptamine-2A precursor protein.

    PubMed

    Cohen, Hagit

    2005-01-01

    Serotonergic (5-hydroxytryptamine; 5-HT) mechanisms have been implicated in a number of physiological and pathophysiological processes including mood, anxiety, and cognitive functioning. Among the many 5-HT receptor subtypes, the 5-HT2A receptors (5-HT2A-R) seem to be of particular importance in mediating these effects, and they are prime targets for a variety of psychoactive substances-from hallucinogenic drugs, through atypical antipsychotics, to anxiolytics and antidepressants. Various selective 5-HT2A-R ligands induce different behavioral responses. To determine whether receptor downregulation is an essential part of anxiolytic action, levels of 5-HT2A receptors were manipulated in rats using a nonpharmacological approach-by the administration of an antisense oligodeoxynucleotide (ASODN) to 5-HT2A-R. Each ASODN was injected icv between two and five times at 24-hr intervals. Control rats received injections of either a scrambled oligodeoxynucleotide (ScrODN) or the vehicle only. On Day 6, anxiety-related behavior was assessed in the elevated plus maze paradigm and performance of memory tasks in the Morris water maze. Gene transcripts were measured by quantitative reverse transcription polymerase chain reaction (PCR). The results show that compared to vehicle and ScrODN control animals, icv 5-HT2A-R-ASODN administrations for 4 consecutive days (but not less) significantly decreased anxietylike behavior and improved memory retention performance. The reduction in anxiety-related behavior in 5-HT2A-R-ASODN rats was accompanied by a decrease in 5-HT2A-R-mRNA expression in the frontal cortex and in the hippocampus. Receptor downregulation has been proposed as one of the central mechanisms for anxiolytic drug actions. Antisense-mediated downmanipulation of receptors in this study, especially of 5-HT2A, supports this theory. PMID:16149040

  20. 5-Hydroxytryptamine antagonists and the 5-methoxy-N,N-dimethyltryptamine-induced changes of postdecapitation convulsions.

    PubMed

    Archer, T

    1987-01-01

    The ability of various compounds to antagonise the 5-MeODMT induced prolongations of latency and duration of postdecapitation convulsions (PDCs) were compared. The 5-hydroxytryptamine (5-HT) receptor antagonists, mianserin, methergoline, cinanserin and methysergide antagonised the 5-MeODMT (0.5 to 4.0 mg/kg) induced prolongations of latency to onset of convulsions substantially and to a lesser extent the prolongation of duration. The efficacy of the 5-HT antagonists for blocking 5-MeODMT changes of PDCs was roughly of the order mianserin greater than cinanserin greater than methysergide greater than methergoline. Pirenperone, the 5-HT2 antagonist, and pimozide, the dopamine receptor antagonist did not antagonise the 5-MeODMT induced changes. Mianserin, methergoline, cinanserin and methysergide, by themselves, prolonged the duration of PDCs but did not affect latency. Pirenperone (0.25 mg/kg) prolonged both the latency and duration of the PDCs while pimozide (0.5-2.0 mg/kg) had no effect upon PDCs. This evidence suggests that 5-MeODMT induced changes of PDCs are mediated via 5-HT1 receptors and thus a reliable model to combine with other measures of spinal function is suggested. PMID:3562388

  1. Inhibitory effect of 5-hydroxytryptamine on penile erectile function in the rat.

    PubMed Central

    Finberg, J. P.; Vardi, Y.

    1990-01-01

    1. An increase in corporal pressure was elicited in pithed rats by stimulation of the sacral part of the spinal cord. This response was inhibited by intravenous injection of 5-hydroxytryptamine (5-HT) (ED50 = 28.5 +/- 2.2 micrograms kg-1). 2. The inhibitory effect of 5-HT was blocked by methysergide and methiothepin (each 1 mg kg-1), but not by ketanserin (0.02 mg kg-1), MDL 72222 (1 mg kg-1) or prazosin (0.1 mg kg-1). 3. An inhibitory effect on the corporal pressure response to spinal stimulation was also produced by 5-carboxyamidotryptamine (ED50 = 5.6 +/- 2.8 micrograms kg-1), but not by m-chlorophenylpiperazine (mCPP), RU 24969, 8-hydroxy-2-[di-n-propyl-amino]-tetralin (8-OH-DPAT) or fenfluramine (doses up to 1-2 mg kg-1). 4. Neither methiothepin (1 mg kg-1) nor clomipramine (1 mg kg-1) had any effect on the frequency-response curve for increase in corporal pressure by spinal stimulation. 5. The results indicate that 5-HT exerts an inhibitory action on penile erection by a peripheral mechanism. This effect may be mediated by vasoconstriction in cavernosal vessels, or inhibition of release of a vasodilator neurotransmitter. From the spectrum of agonist and antagonist responses, the receptor involved may be of the 5-HT1D subtype. PMID:2076486

  2. Role of 5-hydroxytryptamine in the regulation of brain neuropeptides in normal and diabetic rat

    NASA Technical Reports Server (NTRS)

    Kolta, Malak G.; Williams, Byron B.; Soliman, Karam F. A.

    1986-01-01

    The effect of 5-hydroxytryptamine (5-HT) alteration on brain dopamine (DA), norepinephrine (NE), beta-endorphin (beta-E), and immunoreactive insulin was studied in Sprague-Dawley diabetic and control rats. Diabetes was induced using alloxan (45 mg/kg), 15 days prior to sacrificing. Both control and diabetic animals were treated with either p-chlorophenylalanine (PCPA, 300 mg/kg) three days prior to sacrificing or fluoxetine (10 mg/kg) twice daily for three days. PCPA treatment significantly decreased brain content of 5-HT and 5-hydroxyindolel acetic acid, while it caused significant increase and decrease in brain beta-E and insulin levels, respectively, in both normal and diabetic rat. Meanwhile, the administration of fluoxetine resulted in significant increase in brain content of 5-HT, DA, NE and insulin but significant decline of beta-E in diabetic and saline control rats. The results of this experiment indicate that 5-HT may be regulating both beta-E and insulin regardless of the availability of pancreatic insulin.

  3. Prevention of 5-hydroxytryptamine2C receptor RNA editing and alternate splicing in C57BL/6 mice activates the hypothalamic-pituitary-adrenal axis and alters mood

    PubMed Central

    Bombail, Vincent; Qing, Wei; Chapman, Karen E; Holmes, Megan C

    2014-01-01

    The 5-hydroxytryptamine2C (5-HT)2C receptor is widely implicated in the aetiology of affective and eating disorders as well as regulation of the hypothalamo-pituitary-adrenal axis. Signalling through this receptor is regulated by A-to-I RNA editing, affecting three amino acids in the protein sequence, with unedited transcripts encoding a receptor (INI) that, in vitro, is hyperactive compared with edited isoforms. Targeted alteration (knock-in) of the Htr2c gene to generate ‘INI’ mice with no alternate splicing, solely expressing the full-length unedited isoform, did not produce an overt metabolic phenotype or altered anxiety behaviour, but did display reduced depressive-like and fear-associated behaviours. INI mice exhibited a hyperactive hypothalamo-pituitary-adrenal axis, with increased nadir plasma corticosterone and corticotrophin-releasing hormone expression in the hypothalamus but responded normally to chronic stress and showed normal circadian activity and activity in a novel environment. The circadian patterns of 5-HT2C receptor mRNA and mbii52, a snoRNA known to regulate RNA editing and RNA splicing of 5-HT2C receptor pre-mRNA, were altered in INI mice compared with wild-type control mice. Moreover, levels of 5-HT1A receptor mRNA were increased in the hippocampus of INI mice. These gene expression changes may underpin the neuroendocrine and behavioural changes observed in INI mice. However, the phenotype of INI mice was not consistent with a globally hyperactive INI receptor encoded by the unedited transcript in the absence of alternate splicing. Hence, the in vivo outcome of RNA editing may be neuronal cell type specific. PMID:25257581

  4. Reduced sensitivity to both positive and negative reinforcement in mice over-expressing the 5-hydroxytryptamine transporter.

    PubMed

    Line, Samantha J; Barkus, Chris; Rawlings, Nancy; Jennings, Katie; McHugh, Stephen; Sharp, Trevor; Bannerman, David M

    2014-12-01

    The 5-hydroxytryptamine (5-HT) transporter (5-HTT) is believed to play a key role in both normal and pathological psychological states. Much previous data suggest that the s allele of the polymorphic regulatory region of the 5-HTT gene promoter is associated with reduced 5-HTT expression and vulnerability to psychiatric disorders, including anxiety and depression. In comparison, the l allele, which increases 5-HTT expression, is generally considered protective. However, recent data link this allele to both abnormal 5-HT signalling and psychopathic traits. Here, we studied the processing of aversive and rewarding cues in transgenic mice that over-express the 5-HTT (5-HTTOE mice). Compared with wild-type mice, 5-HTTOE mice froze less in response to both a tone that had previously been paired with footshock, and the conditioning context. In addition, on a decision-making T-maze task, 5-HTTOE mice displayed reduced preference for a larger, delayed reward and increased preference for a smaller, immediate reward, suggesting increased impulsiveness compared with wild-type mice. However, further inspection of the data revealed that 5-HTTOE mice displayed a relative insensitivity to reward magnitude, irrespective of delay. In contrast, 5-HTTOE mice appeared normal on tests of spatial working and reference memory, which required an absolute choice between options associated with either reward or no reward. Overall, the present findings suggest that 5-HTT over-expression results in a reduced sensitivity to both positive and negative reinforcers. Thus, these data show that increased 5-HTT expression has some maladaptive effects, supporting recent suggestions that l allele homozygosity may be a potential risk factor for disabling psychiatric traits. PMID:25283165

  5. Circadian variation in sensitivity of suprachiasmatic and lateral geniculate neurones to 5-hydroxytryptamine in the rat.

    PubMed Central

    Mason, R

    1986-01-01

    Extracellular single-unit recordings were obtained from neurones in the suprachiasmatic nuclei (s.c.n.) of the rat (a putative circadian pace-maker), the ventral lateral geniculate nucleus (v.l.g.n.) and the hippocampus. These areas receive a 5-hydroxytryptamine (5-HT) innervation from the raphe nuclei. Recording of neuronal activity in the s.c.n., v.l.g.n. and the hippocampus revealed a diurnal variation in the response to the ionophoresis of 5-HT. This variation was manifest as a 2-3-fold increase in post-synaptic sensitivity to 5-HT during the subjective dark (active) phase of the circadian cycle. In contrast there was no apparent circadian variation in the sensitivity of s.c.n., v.l.g.n. or hippocampal neurones to ionophoresed gamma-aminobutyric acid (GABA). Neuronal activity recorded in the s.c.n., v.l.g.n. and hippocampus also exhibited a circadian variation in the recovery from 5-HT-induced suppression of firing. This may reflect reuptake processes as recovery can be prolonged by ionophoresis of uptake blockers (imipramine or fluoxetine). Rats (n = 15) expressing circadian arrhythmicity in their rest-activity behaviour induced by long-term continuous illumination (150-200 lx) showed no apparent circadian variation in 5-HT sensitivity. This loss was accompanied by either the development of a 5-6-fold subsensitivity to ionophoresed 5-HT (eleven out of fifteen rats) or a 2-3-fold supersensitivity to ionophoresed 5-HT (four out of fifteen rats). A similar loss of circadian variation and the development of a subsensitivity to ionophoresed 5-HT was also found in three rats sustaining complete electrolytic lesions of the s.c.n. These changes were not found in rats (n = 4) with partial s.c.n. lesions. These results implicate the s.c.n., or fibres passing through it, in the circadian modulation of 5-HT sensitivity in neurones both intrinsic to the s.c.n. circadian pace-maker itself and in the hippocampus and lateral geniculate nucleus (regions remote from the s

  6. Modulation of 5-hydroxytryptamine efflux from rat cortical synaptosomes by opioids and nociceptin

    PubMed Central

    Sbrenna, S; Marti, M; Morari, M; Calo', G; Guerrini, R; Beani, L; Bianchi, C

    2000-01-01

    The modulation of [3H]-5-hydroxytryptamine ([3H]-5-HT) efflux from superfused rat cortical synaptosomes by delta, kappa, mu and ORL1 opioid receptor agonists and antagonists was studied. Spontaneous [3H]-5-HT efflux was reduced (20% inhibition) by either 0.5 μM tetrodotoxin or Ca2+-omission. Ten mM K+-evoked [3H]-5-HT overflow was largely Ca2+-dependent (90%) and tetrodotoxin-sensitive (50%). The delta receptor agonist, deltorphin-I, failed to modulate the K+-evoked neurotransmitter efflux up to 0.3 μM. The kappa and the mu receptor agonists, U-50,488 and endomorphin-1, inhibited K+-evoked [3H]-5-HT overflow (EC50=112 and 7 nM, respectively; Emax=28 and 29% inhibition, respectively) in a norBinaltorphimine- (0.3 μM) and naloxone- (1 μM) sensitive manner, respectively. None of these agonists significantly affected spontaneous [3H]-5-HT efflux. The ORL1 receptor agonist nociceptin inhibited both spontaneous (EC50=67 nM) and K+-evoked (EC50=13 nM; Emax=52% inhibition) [3H]-5-HT efflux. The effect of NC was insensitive to naloxone (up to 10 μM), but was antagonized by [Nphe1]nociceptin(1-13)NH2 (a novel selective ORL1 receptor antagonist; pA2=6.7) and by naloxone benzoylhydrazone (pA2=6.3). The ORL1 ligand [Phe1ψ(CH2-NH)Gly2]nociceptin(1-13)NH2 also inhibited K+ stimulated [3H]-5-HT overflow (EC50=64 nM; Emax=31% inhibition), but its effect was partially antagonized by 10 μM naloxone. It is concluded that the ORL1 receptor is the most important presynaptic modulator of neocortical 5-HT release within the opioid receptor family. This suggests that the ORL1/nociceptin system may have a powerful role in the control of cerebral 5-HT-mediated biological functions. PMID:10807682

  7. Distribution of cells responsive to 5-HT6 receptor antagonist-induced hypophagia

    PubMed Central

    Garfield, Alastair S.; Burke, Luke K.; Shaw, Jill; Evans, Mark L.; Heisler, Lora K.

    2014-01-01

    The central 5-hydroxytryptamine (5-HT; serotonin) system is well established as an important regulator of appetite and continues to remain a focus of obesity research. While much emphasis has focussed on the 5-HT2C receptor (5-HT2CR) in 5-HT's anorectic effect, pharmacological manipulation of the 5-HT6 receptor (5-HT6R) also reduces appetite and body weight and may be amenable to obesity treatment. However, the neurological circuits that underlie 5-HT6R-induced hypophagia remain to be identified. Using c-fos immunoreactivity (FOS-IR) as a marker of neuronal activation, here we mapped the neuroanatomical targets activated by an anorectic dose of the 5-HT6R antagonist SB-399885 throughout the brain. Furthermore, we quantified SB-399855 activated cells within brain appetitive nuclei, the hypothalamus, dorsal raphe nucleus (DRN) and nucleus of the solitary tract (NTS). Our results reveal that 5-HT6R antagonist-induced hypophagia is associated with significantly increased neuronal activation in two nuclei with an established role in the central control of appetite, the paraventricular nucleus of the hypothalamus (PVH) and the NTS. In contrast, no changes in FOS-IR were observed between treatment groups within other hypothalamic nuclei or DRN. The data presented here provide a first insight into the neural circuitry underlying 5-HT6R antagonist-induced appetite suppression and highlight the PVH and NTS in the coordination of 5-HT6R hypophagia. PMID:24566060

  8. Ascorbic acid prevents nonreceptor specific binding of (/sup 3/H)-5-hydroxytryptamine to bovine cerebral cortex membranes

    SciTech Connect

    Hamblin, M.W.; Adriaenssens, P.I.; Ariani, K.; Cawthon, R.M.; Stratford, C.A.; Tan, G.L.; Ciaranello, R.D.

    1987-03-01

    (/sup 3/H)-5-Hydroxytryptamine ((/sup 3/H)-5-HT) decomposes rapidly when exposed to air in solution at physiological pH if antioxidants are not present. The decomposition products appear to bind to two saturable sites on brain membranes (apparent Kd values = 1-2 and 100-1000 nM). This binding mimics ''specific'' ligand/receptor binding in that it is inhibited by 10 microM unlabeled 5-HT. This inhibition is not competitive, but rather is due to the prevention of (/sup 3/H)-5-HT breakdown by excess unlabeled 5-HT. Unlike genuine ligand/receptor binding, the binding of (/sup 3/H)-5-HT breakdown products is essentially irreversible and does not display a tissue distribution consistent with binding to authentic 5-HT receptors. (/sup 3/H)-5-HT decomposition can be eliminated by the inclusion of 0.05 to 5 mM ascorbic acid. At these concentrations ascorbic acid is not deleterious to reversible (/sup 3/H)-5-HT binding. When (/sup 3/H) 5-HT exposure to air occurs in the presence of brain membranes, the apparent antioxidant activity of brain membranes themselves affords protection against (/sup 3/H)-5-HT degradation equal to ascorbic acid. This protection is effective below final (/sup 3/H)-5-HT concentrations of 10 nM. Above 10 nM (/sup 3/H)-5-HT, addition of ascorbic acid or other antioxidants is necessary to avoid the occurrence of additional low affinity (apparent Kd = 15-2000 nM) binding sites that are specific but nonetheless irreversible. When care is taken to limit (/sup 3/H)-5-HT oxidation, the only reversible and saturable specific binding sites observed are of the 5-HT1 high affinity (Kd = 1-2 nM) type. Radioligand oxidation artifacts may be involved in previous reports of low affinity (Kd = 15-250 nM) (/sup 3/H)-5-HT binding sites in brain membrane preparations.

  9. Long-term Stress with Hyperglucocorticoidemia-induced Hepatic Steatosis with VLDL Overproduction Is Dependent on both 5-HT2 Receptor and 5-HT Synthesis in Liver

    PubMed Central

    Fu, Jihua; Ma, Shaoxin; Li, Xin; An, Shanshan; Li, Tao; Guo, Keke; Lin, Min; Qu, Wei; Wang, Shanshan; Dong, Xinyue; Han, Xiaoyu; Fu, Ting; Huang, Xinping; Wang, Tianying; He, Siyu

    2016-01-01

    Hepatic triglycerides production and adipose lipolysis are pivotal for long-term stress (LTS) or hyperglucocorticoidemia-induced insulin resistance. 5-hydroxytryptamine (5-HT) has been demonstrated to induce hepatic lipid metabolic abnormality by activating mammalian target of rapamycin (mTOR). In present study, we explored whether 5-HT is involved in LTS effects in liver using restraint stress-exposed rats and cultured primary rat hepatocytes and HepG2 cells. LTS with hyperglucocorticoidemia induced hepatic 5-HT synthetic increase with tryptophan hydroxylase 1 (Tph1) up-regulation, and 5-HT2 receptor (5-HT2R, including 5-HT2A, 2B receptor) up-regulation in liver and visceral adipose, as well as hepatic mTOR activation with triglycerides and VLDL overproduction with steatosis, and visceral adipose lipolytic increase with high blood free fatty acids (FFAs) level. 5-HT exposure exhibited LTS-like effects in both tissues, and both LTS and 5-HT effects could be abolished significantly by blocking 5-HT2R. In HepG2 cells dexamethasone or palmitate-induced mTOR activation with triglycerides and VLDL overproduction were accompanied by up-regulations of 5-HT synthesis and 5-HT2R, which were significantly abolished by gene silencing Tph1 or 5-HT2R and were almost fully abolished by co-silencing of both, especially on VLDL overproduction. Chemical inhibition of Tph1 or/and 5-HT2R in both hepatocytes exhibited similar abolishment with genetic inhibition on dexamethason-induced effects. 5-HT-stimulated effects in both hepatocytes were fully abolished by blocking 5-HT2R, while 5-HT itself also up-regulated 5-HT2R. In conclusion, up-regulated hepatic 5-HT synthesis and 5-HT2R induced by both glucocorticoid and FFAs are crucial for LTS-induced hepatic steatosis with VLDL overproduction, while 5-HT by acting on 5-HT2R mediates mTOR activation in liver. PMID:26884719

  10. Quercetin inhibits the 5-hydroxytryptamine type 3 receptor-mediated ion current by interacting with pre-transmembrane domain I.

    PubMed

    Lee, Byung-Hwan; Jeong, Sang-Min; Jung, Sang-Min; Lee, Jun-Ho; Kim, Jong-Hoon; Yoon, In-Soo; Lee, Joon-Hee; Choi, Sun-Hye; Lee, Sang-Mok; Chang, Choon-Gon; Kim, Hyung-Chun; Han, YeSun; Paik, Hyun-Dong; Kim, Yangmee; Nah, Seung-Yeol

    2005-08-31

    The flavonoid, quercetin, is a low molecular weight substance found in apple, tomato and other fruit. Besides its antioxidative effect, quercetin, like other flavonoids, has a wide range of neuropharmacological actions including analgesia, and motility, sleep, anticonvulsant, sedative and anxiolytic effects. In the present study, we investigated its effect on mouse 5-hydroxytryptamine type 3 (5-HT3A) receptor channel activity, which is involved in pain transmission, analgesia, vomiting, and mood disorders. The 5-HT3A receptor was expressed in Xenopus oocytes, and the current was measured with the two-electrode voltage clamp technique. In oocytes injected with 5-HT3A receptor cRNA, quercetin inhibited the 5-HT-induced inward peak current (I(5-HT)) with an IC50 of 64.7 +/- 2.2 microM. Inhibition was competitive and voltage-independent. Point mutations of pre-transmembrane domain 1 (pre-TM1) such as R222T and R222A, but not R222D, R222E and R222K, abolished inhibition, indicating that quercetin interacts with the pre-TM1 of the 5-HT3A receptor. PMID:16258243

  11. Arachidonate metabolism, 5-hydroxytryptamine release and aggregation in human platelets activated by palmitaldehyde acetal phosphatidic acid.

    PubMed Central

    Brammer, J. P.; Maguire, M. H.

    1984-01-01

    Palmitaldehyde acetal phosphatidic acid ( PGAP ) caused dose-dependent aggregation of human platelets resuspended in modified Tyrode medium, with a threshold concentration of 0.5-1 microM and an EC50 of 4 microM. Concentrations of PGAP which elicited biphasic irreversible aggregation concomitantly induced formation of 1.02 +/- 0.029 nmol (mean +/- s.e. mean) of malondialdehyde (MDA) per 10(9) platelets and caused release of 58 +/- 2.8% of platelet [14C]-5-hydroxytryptamine ([14C]-5-HT) from prelabelled platelets; no MDA formation or [14C]-5-HT release occurred at lower doses of PGAP which elicited only monophasic reversible aggregation. Adenosine 5'-pyrophosphate (ADP)-induced platelet activation resulted in formation of 0.344 +/- 0.004 nmol of MDA per 10(9) platelets in association with irreversible aggregation and 49.1 +/- 1% release of [14C]-5-HT. Mepacrine, a phospholipase A2 inhibitor, at 2.5 microM reduced PGAP -induced MDA formation and [14C]-5-HT release by the resuspended platelets without affecting irreversible aggregation; higher concentrations of mepacrine abolished all three responses. Chlorpromazine, a calmodulin antagonist, similarly inhibited PGAP -induced MDA formation and irreversible aggregation, and at 100 microM abolished monophasic aggregation. The cyclo-oxygenase inhibitor indomethacin caused a concentration-dependent reduction of PGAP -induced MDA formation by resuspended human platelets without significantly inhibiting [14C]-5-HT release or irreversible aggregation; concentrations (greater than or equal to 1.75 microM) which inhibited MDA formation by more than 94% abolished [14C]-5-HT release, and converted second phase irreversible aggregation to an extensive reversible response. 2-Methylthioadenosine 5'-phosphate (2 methylthio-AMP), an ADP antagonist, inhibited PGAP -induced MDA formation, [14C]-5-HT release and second phase aggregation in the human platelet suspensions in a parallel, concentration-dependent manner; at 9.4 microM 2

  12. Regulator of G-protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin-mediated activation of the 5-HT(1A) receptor-adenylyl cyclase axis.

    PubMed

    Stewart, Adele; Maity, Biswanath; Wunsch, Amanda M; Meng, Fantao; Wu, Qi; Wemmie, John A; Fisher, Rory A

    2014-04-01

    Targeting serotonin (5-HT) bioavailability with selective 5-HT reuptake inhibitors (SSRIs) remains the most widely used treatment for mood disorders. However, their limited efficacy, delayed onset of action, and side effects restrict their clinical utility. Endogenous regulator of G-protein signaling (RGS) proteins have been implicated as key inhibitors of 5-HT(1A)Rs, whose activation is believed to underlie the beneficial effects of SSRIs, but the identity of the specific RGS proteins involved remains unknown. We identify RGS6 as the critical negative regulator of 5-HT(1A)R-dependent antidepressant actions. RGS6 is enriched in hippocampal and cortical neurons, 5-HT(1A)R-expressing cells implicated in mood disorders. RGS6(-/-) mice exhibit spontaneous anxiolytic and antidepressant behavior rapidly and completely reversibly by 5-HT(1A)R blockade. Effects of the SSRI fluvoxamine and 5-HT(1A)R agonist 8-OH-DPAT were also potentiated in RGS6(+/-) mice. The phenotype of RGS6(-/-) mice was associated with decreased CREB phosphorylation in the hippocampus and cortex, implicating enhanced Gα(i)-dependent adenylyl cyclase inhibition as a possible causative factor in the behavior observed in RGS6(-/-) animals. Our results demonstrate that by inhibiting serotonergic innervation of the cortical-limbic neuronal circuit, RGS6 exerts powerful anxiogenic and prodepressant actions. These findings indicate that RGS6 inhibition may represent a viable means to treat mood disorders or enhance the efficacy of serotonergic agents. PMID:24421401

  13. 5-Hydroxytryptamine release from platelets by different red wines: implications for migraine.

    PubMed

    Pattichis, K; Louca, L L; Jarman, J; Sandler, M; Glover, V

    1995-01-13

    We have confirmed our earlier finding that most red wines are able to bring about 5-hydroxytryptamine (5-HT, serotonin) release from platelets in vitro. Platelets from individual subjects manifested varying degrees of releasing ability but responded to different wines with a similar rank ordering. There was a high correlation (r = 0.87) between the effect of red wine and that of reserpine in different individuals. Some types of red wine caused a consistently higher release of 5-HT than others in all subjects; one red wine in particular resulted in negligible release. When several brands of this 'low-releasing' red wine were further examined, they all showed a lower activity than all the brands of a 'high-releasing' red wine type. This variation in releasing power was not related to intensity of red colour. Partial purification of red wine was achieved by column chromatography and showed releasing activity to be associated with a low molecular weight orange fraction. Preliminary studies, using solid phase extraction methods, showed that the active components lie mainly in a subgroup of the flavonoid fraction. If any of the adverse effects of red wine, such as headache induction, derive from this 5-HT releasing ability, then it may be possible to prepare red wines free from the chemical substances responsible. PMID:7720790

  14. Contributions of 5-HT Neurons to Respiratory Control: Neuromodulatory and Trophic Effects

    PubMed Central

    Hodges, Matthew R.; Richerson, George B.

    2008-01-01

    Serotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter produced by a small number of neurons in the midbrain, pons and medulla. These neurons project widely throughout the neuraxis, where they release 5-HT and co-localized neuropeptides such as substance P (SP) and thyrotropin-releasing hormone (TRH). Each of these chemicals produce effects largely through G protein-coupled receptors, second messenger systems and subsequent neuromodulatory effects on target neurons. Emerging evidence suggests that 5-HT has additional modes of action during development and in adult mammals, including trophic effects (neurogenesis, cell differentiation, proliferation, migration and maturation) and influences on synaptic plasticity. Here, we discuss some of the neuromodulatory and trophic roles of 5-HT in general and in the context of respiratory control, as well as the regulation of release of modulatory neurotransmitters from 5-HT neurons. Future directions of study are also discussed. PMID:18595785

  15. Evidence that 5-HT1D receptors mediate inhibition of sympathetic ganglionic transmission in anaesthetized cats.

    PubMed Central

    Jones, J. F.; Martin, G. R.; Ramage, A. G.

    1995-01-01

    In anaesthetized cats, 5-carboxamidotryptamine (5-CT) or 5-hydroxytryptamine (5-HT) (0.3-300 micrograms kg-1,i.v.) inhibited the postganglionic compound action potential evoked by preganglionic electrical stimulation (0.5 Hz) with a similar potency in the stellate and splanchnic ganglia. In the 5-HT experiments transmission thorough the inferior mesenteric ganglia was also recorded. The maximal inhibitory effect of 5-HT was greater on the stellate and splanchnic ganglia (60 +/- 4 and 52 +/- 5%) than on the inferior mesenteric (15 +/- 2%). The effects of 5-HT were unaffected by pretreatment with antagonists (1 mg kg-1;i.v.) for 5-HT2 (BW501C67), 5-HT1A (WAY-100635) and 5-HT3 receptors (ondansetron). However, responses to both 5-HT and 5-CT were attenuated significantly by GR127935 (1 mg kg-1) except the responses to 5-HT at the inferior mesenteric ganglia. These results are consistent with the involvement of 5-HT1D receptors mediating inhibition of sympathetic ganglionic transmission in vivo. PMID:8528548

  16. Analysis of the agonist activity of fenoldopam (SKF 82526) at the vascular 5-HT2 receptor.

    PubMed Central

    Christie, M. I.; Harper, D.; Smith, G. W.

    1992-01-01

    1. The 5-HT2 receptor agonist activity of fenoldopam (SKF 82526) was characterized in the rabbit isolated aorta preparation. 2. Fenoldopam was an agonist at the vascular 5-HT2 receptor with lower affinity and efficacy than the naturally occurring agonist 5-hydroxytryptamine (5-HT). Fenoldopam had an affinity (pKA) of 5.84 +/- 0.04 and efficacy (tau) of 0.57 +/- 0.04, whereas 5-HT had a pKA of 6.65 +/- 0.12 and tau of 2.66 +/- 0.41. 3. The constrictor effects of fenoldopam and 5-HT were competitively antagonized by the 5-HT2 antagonist, ketanserin, with pKB values of 8.81 +/- 0.11 and 8.83 +/- 0.10 respectively. 4. Prior incubation with fenoldopam produced a concentration-related rightward shift of a subsequent 5-HT concentration-response curve. This inhibition was specific for 5-HT since constrictor responses to angiotensin II were unaffected. 5. This study indicates that the D1 receptor agonist, fenoldopam, acts as an agonist at the vascular 5-HT2 receptor, but with an affinity and efficacy less than that of the naturally occurring agonist, 5-HT. PMID:1361397

  17. Central serotonin-2A (5-HT2A) receptor dysfunction in depression and epilepsy: the missing link?

    PubMed Central

    2015-01-01

    5-Hydroxytryptamine 2A receptors (5-HT2A-Rs) are G-protein coupled receptors. In agreement with their location in the brain, they have been implicated not only in various central physiological functions including memory, sleep, nociception, eating and reward behaviors, but also in many neuropsychiatric disorders. Interestingly, a bidirectional link between depression and epilepsy is suspected since patients with depression and especially suicide attempters have an increased seizure risk, while a significant percentage of epileptic patients suffer from depression. Such epidemiological data led us to hypothesize that both pathologies may share common anatomical and neurobiological alteration of the 5-HT2A signaling. After a brief presentation of the pharmacological properties of the 5-HT2A-Rs, this review illustrates how these receptors may directly or indirectly control neuronal excitability in most networks involved in depression and epilepsy through interactions with the monoaminergic, GABAergic and glutamatergic neurotransmissions. It also synthetizes the preclinical and clinical evidence demonstrating the role of these receptors in antidepressant and antiepileptic responses. PMID:25852551

  18. Evidence of 5-HT components in human sperm: implications for protein tyrosine phosphorylation and the physiology of motility

    PubMed Central

    Jiménez-Trejo, Francisco; Tapia-Rodríguez, Miguel; Cerbón, Marco; Kuhn, Donald M; Manjarrez-Gutiérrez, Gabriel; Mendoza-Rodríguez, C Adriana; Picazo, Ofir

    2016-01-01

    Serotonin (5-hydroxytryptamine; C10H12N2O (5-HT)) is produced in the CNS and in some cells of peripheral tissues. In the mammalian male reproductive system, both 5-HT and tryptophan hydroxylase (TPH) have been described in Leydig cells of the testis and in principal cells of the caput epididymis. In capacitated hamster sperm, it has been shown that 5-HT promotes the acrosomal reaction. The aim of this work was to explore the existence of components of the serotoninergic system and their relevance in human sperm physiology. We used both immunocytochemistry and western blot to detect serotoninergic markers such as 5-HT, TPH1, MAOA, 5-HT1B, 5-HT3, and 5HTT; HPLC for TPH enzymatic activity; Computer Assisted Semen Analysis assays to measure sperm motility parameters and pharmacological approaches to show the effect of 5-HT in sperm motility and tyrosine phosphorylation was assessed by western blot. We found the presence of serotoninergic markers (5-HT, TPH1, MAOA, 5-HT1B, 5-HT2A, 5-HT3, 5-HTT, and TPH enzymatic activity) in human sperm. In addition, we observed a significant increase in tyrosine phosphorylation and changes in sperm motility after 5-HT treatment. In conclusion, our data demonstrate the existence of components of a serotoninergic system in human sperm and support the notion for a functional role of 5-HT in mammalian sperm physiology, which can be modulated pharmacologically. PMID:23028123

  19. Increased hypothalamic 5-HT2A receptor gene expression and effects of pharmacologic 5-HT2A receptor inactivation in obese A{sup y} mice

    SciTech Connect

    Nonogaki, Katsunori . E-mail: knonogaki-tky@umin.ac.jp; Nozue, Kana; Oka, Yoshitomo

    2006-12-29

    Serotonin (5-hydroxytryptamine; 5-HT) 2A receptors contribute to the effects of 5-HT on platelet aggregation and vascular smooth muscle cell proliferation, and are reportedly involved in decreases in plasma levels of adiponectin, an adipokine, in diabetic subjects. Here, we report that systemic administration of sarpogrelate, a 5-HT2A receptor antagonist, suppressed appetite and increased hypothalamic pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript, corticotropin releasing hormone, 5-HT2C, and 5-HT1B receptor gene expression. A{sup y} mice, which have ectopic expression of the agouti protein, significantly increased hypothalamic 5-HT2A receptor gene expression in association with obesity compared with wild-type mice matched for age. Systemic administration of sarpogrelate suppressed overfeeding, body weight gain, and hyperglycemia in obese A{sup y} mice, whereas it did not increase plasma adiponectin levels. These results suggest that obesity increases hypothalamic 5-HT2A receptor gene expression, and pharmacologic inactivation of 5-HT2A receptors inhibits overfeeding and obesity in A{sup y} mice, but did not increase plasma adiponectin levels.

  20. 5-Hydroxytryptamine 1A and 2B serotonin receptors in neurite outgrowth: involvement of early growth response protein 1.

    PubMed

    Anelli, Tonino; Cardarelli, Silvia; Ori, Michela; Nardi, Irma; Biagioni, Stefano; Poiana, Giancarlo

    2013-01-01

    Neurotransmitters play important roles in neurogenesis; in particular, acetylcholine and serotonin may regulate neurite elongation. Acetylcholine may also activate transcription factors such as early growth response protein 1 (EGR-1), which plays a role in neurite extension. N18TG2 neuroblastoma cells (which do not produce neurotransmitters and constitutively express muscarinic acetylcholine receptors) were transfected with constructs containing the cDNA for choline acetyltransferase, 5-hydroxytryptamine 1A (5-HT1A) and 5-HT2B serotonin receptors to study acetylcholine and serotonin interplay in neurite outgrowth. 5-HT1A receptor stimulation causes a decrease in EGR-1 levels and inhibition of neurite outgrowth; 5-HT2B stimulation, however, has no effect. Muscarinic cholinergic stimulation, on the other end, increases EGR-1 levels and fiber outgrowth. Inhibition of EGR-1 binding reduces fiber outgrowth activity. When both cholinergic and 5-HT1A receptors are stimulated, fiber outgrowth is restored; therefore, acetylcholine counterbalances the inhibitory effect of serotonin on neurite outgrowth. These results suggest that EGR-1 plays a role in the interplay of acetylcholine and serotonin in the regulation of neurite extension during development. PMID:24158140

  1. Effects of morphine, physostigmine and raphe nuclei stimulation on 5-hydroxytryptamine release from the cerebral cortex of the cat.

    PubMed Central

    Aiello-Malmberg, P; Bartolini, A; Bartolini, R; Galli, A

    1979-01-01

    1. The release of 5-hydroxytryptamine (5-HT) from the cerebral cortex and caudate nucleus of brainstem-transected cats and from the cerebral cortex of rats anaesthetized with urethane was determined by radioenzymatic and biological assay. 2. The stimulation of nucleus linearis intermedius of raphe doubles the basal 5-HT release in the caudate nucleus and increases it 3 fold in the cerebral cortex. The effects of the electrical stimulation of the raphe are potentiated by chlorimipramine. 3. Brain 5-HT release is greatly increased by morphine hydrochloride (6 mg/kg i.v.) and by physostigmine (100 microgram/kg i.v.), but not by DL-DOPA (50 mg/kg i.v.). 4. It is suggested that the 5-HT releasing action of physostigmine can contribute to some of its pharmacological effects such as the analgesic effect so far attributed exclusively to its indirect cholinomimetic activity. 5. The 5-HT releasing action of physostigmine seems unrelated to its anticholinesterase activity. PMID:435680

  2. The 5-HT3 receptor is essential for exercise-induced hippocampal neurogenesis and antidepressant effects.

    PubMed

    Kondo, M; Nakamura, Y; Ishida, Y; Shimada, S

    2015-11-01

    Exercise has a variety of beneficial effects on brain structure and function, such as hippocampal neurogenesis, mood and memory. Previous studies have shown that exercise enhances hippocampal neurogenesis, induces antidepressant effects and improves learning behavior. Brain serotonin (5-hydroxytryptamine, 5-HT) levels increase following exercise, and the 5-HT system has been suggested to have an important role in these exercise-induced neuronal effects. However, the precise mechanism remains unclear. In this study, analysis of the 5-HT type 3A receptor subunit-deficient (htr3a(-/-)) mice revealed that lack of the 5-HT type 3 (5-HT3) receptor resulted in loss of exercise-induced hippocampal neurogenesis and antidepressant effects, but not of learning enhancement. Furthermore, stimulation of the 5-HT3 receptor promoted neurogenesis. These findings demonstrate that the 5-HT3 receptor is the critical target of 5-HT action in the brain following exercise, and is indispensable for hippocampal neurogenesis and antidepressant effects induced by exercise. This is the first report of a pivotal 5-HT receptor subtype that has a fundamental role in exercise-induced morphological changes and psychological effects. PMID:25403840

  3. 5-HT potentiation of the GABAA response in the rat sacral dorsal commissural neurones

    PubMed Central

    Xu, Tian-Le; Pang, Zhi-Ping; Li, Ji-Shuo; Akaike, Norio

    1998-01-01

    The modulatory effect of 5-hydroxytryptamine (5-HT) on the γ-aminobutyric acidA (GABAA) response was investigated in the neurones freshly dissociated from the rat sacral dorsal commissural nucleus (SDCN) using the nystatin perforated patch recording configuration under the voltage-clamp conditions.5-HT potentiated GABA-induced Cl− current (IGABA) without affecting the reversal potential of IGABA and the apparent affinity of GABA to its receptor.α-Methyl-5-HT mimicked the potentiation effect of 5-HT on IGABA while ketanserine blocked it. 1-Oleoyl-2-acetyl-glycerol (OAG) potentiated IGABA, and the effect of 5-HT on IGABA was occluded by OAG pretreatment. In the presence of chelerythrine, 5-HT failed to potentiate IGABA, suggesting that protein kinase C (PKC) is involved in the pathway through which the activation of the 5-HT2 receptor potentiates the IGABA.The facilitatory effect of 5-HT on IGABA remained in the presence of BAPTA-AM. LiCl also had no effect on 5-HT-induced potentiation of IGABA.H-89, genistein, okadaic acid and pervanadate all had no effects on 5-HT potentiation of IGABA. Pertussis toxin treatment for 6–8 h did not block the facilitatory effect of 5-HT on IGABA.The present results show that GABAA receptor in the rat SDCN could be modulated in situ by 5-HT, one of the major transmitters involved in the supraspinal control of nociception, and that the phosphorylation of GABAA receptor by PKC may be sufficient to support such modulation. The results also strongly support the hypothesis that the cotransmission by 5-HT and GABA has an important role in the spinal cord. PMID:9690871

  4. 5-HT1A Autoreceptors in the Dorsal Raphe Nucleus Convey Vulnerability to Compulsive Cocaine Seeking.

    PubMed

    You, In-Jee; Wright, Sherie R; Garcia-Garcia, Alvaro L; Tapper, Andrew R; Gardner, Paul D; Koob, George F; David Leonardo, E; Bohn, Laura M; Wee, Sunmee

    2016-04-01

    Cocaine addiction and depression are comorbid disorders. Although it is well recognized that 5-hydroxytryptamine (5-HT; serotonin) plays a central role in depression, our understanding of its role in addiction is notably lacking. The 5-HT system in the brain is carefully controlled by a combined process of regulating 5-HT neuron firing through 5-HT autoreceptors, neurotransmitter release, enzymatic degradation, and reuptake by transporters. This study tests the hypothesis that activation of 5-HT1A autoreceptors, which would lessen 5-HT neuron firing, contributes to cocaine-seeking behaviors. Using 5-HT neuron-specific reduction of 5-HT1A autoreceptor gene expression in mice, we demonstrate that 5-HT1A autoreceptors are necessary for cocaine conditioned place preference. In addition, using designer receptors exclusively activated by designer drugs (DREADDs) technology, we found that stimulation of the serotonergic dorsal raphe nucleus (DRN) afferents to the nucleus accumbens (NAc) abolishes cocaine reward and promotes antidepressive-like behaviors. Finally, using a rat model of compulsive-like cocaine self-administration, we found that inhibition of dorsal raphe 5-HT1A autoreceptors attenuates cocaine self-administration in rats with 6 h extended access, but not 1 h access to the drug. Therefore, our findings suggest an important role for 5-HT1A autoreceptors, and thus DRNNAc 5-HT neuronal activity, in the etiology and vulnerability to cocaine reward and addiction. Moreover, our findings support a strategy for antagonizing 5-HT1A autoreceptors for treating cocaine addiction. PMID:26324408

  5. Cholestasis of pregnancy, pruritus and 5-hydroxytryptamine 3 receptor antagonists.

    PubMed

    Schumann, Roman; Hudcova, Jana

    2004-09-01

    Pruritus, an early symptom of intrahepatic cholestasis of pregnancy, may be severe. Conventional treatment includes ursodeoxycholic acid and cholestyramine. Ondansetron, a 5-hydroxytryptamine 3 receptor antagonist antiemetic, has been shown to reduce pruritus of different etiologies including cholestasis. We now report the successful preoperative use of ondansetron in a patient with pruritus from intrahepatic cholestasis of pregnancy. While the mechanism for our patient's response is poorly understood, 5-hydroxytryptamine 3 receptor antagonists should be further evaluated and possibly considered as a treatment option for intrahepatic cholestasis of pregnancy-related pruritus. PMID:15315599

  6. Increase of 5-hydroxytryptamine in the rat brain by raunescine

    PubMed Central

    Paasonen, M. K.; Kärki, N. T.

    1959-01-01

    The Rauwolfia alkaloid raunescine (5 mg./kg., intraperitoneally) increased the concentration of 5-hydroxytryptamine in the brains of rats after iproniazid pre-treatment. This was evident 3 to 4 hr. after raunescine administration. There was no general increase in the noradrenaline content of the brains. In the intestine, raunescine depleted the 5-hydroxytryptamine content by about 50% within 3 to 4 hr. if the animals had been pre-treated with iproniazid. Iproniazid did not increase the content of noradrenaline in the intestine. PMID:13662567

  7. Increased expression of 5-HT(2A) and 5-HT(2B) receptors in detrusor muscle after partial bladder outlet obstruction in rats.

    PubMed

    Michishita, Mai; Yano, Kazuo; Kasahara, Ken-ichi; Tomita, Ken-ichi; Matsuzaki, Osamu

    2015-01-01

    Serotonin (5-hydroxytryptamine; 5-HT)-induced bladder contraction is enhanced after partial bladder outlet obstruction (pBOO) in rats. We investigated time-dependent changes in bladder contraction and expression of 5-HT(2A) and 5-HT(2B) receptor mRNA in bladder tissue to elucidate the mechanism of this enhancement. On day 3 and 7 after pBOO, contractile responses of isolated rat bladder strips to 5-HT were increased compared with that in sham-operated rats; on day 14, the response had decreased to the same level as that in sham rat bladders. In contrast, carbacholinduced contraction was not enhanced by pBOO at any time point. In sham rats, 5-HT(2A) receptor mRNA was expressed in the urothelium, and 5-HT(2B) receptor mRNA was expressed in the detrusor muscle layer. In pBOO rats, both receptor mRNAs were increased in the detrusor muscle and subserosal layers, but not in the urothelium. The increase of 5-HT(2A) receptor mRNA was maintained from day 3 to day 14 after pBOO, and 5-HT(2B) receptor mRNA was increased on day 7 after pBOO. These results suggested that pBOO induced up-regulation of the 5-HT(2A) and 5-HT(2B) receptors in the detrusor muscle and subserosal layers of the bladder, and such up-regulation may be related to the enhanced bladder contractile response to 5-HT. PMID:26106048

  8. 5-Hydroxytryptamine 1A receptors in the dorsomedial hypothalamus connected to dorsal raphe nucleus inputs modulate defensive behaviours and mediate innate fear-induced antinociception.

    PubMed

    Biagioni, Audrey Franceschi; de Oliveira, Rithiele Cristina; de Oliveira, Ricardo; da Silva, Juliana Almeida; dos Anjos-Garcia, Tayllon; Roncon, Camila Marroni; Corrado, Alexandre Pinto; Zangrossi, Hélio; Coimbra, Norberto Cysne

    2016-03-01

    The dorsal raphe nucleus (DRN) is an important brainstem source of 5-hydroxytryptamine (5-HT), and 5-HT plays a key role in the regulation of panic attacks. The aim of the present study was to determine whether 5-HT1A receptor-containing neurons in the medial hypothalamus (MH) receive neural projections from DRN and to then determine the role of this neural substrate in defensive responses. The neurotracer biotinylated dextran amine (BDA) was iontophoretically microinjected into the DRN, and immunohistochemical approaches were then used to identify 5HT1A receptor-labelled neurons in the MH. Moreover, the effects of pre-treatment of the dorsomedial hypothalamus (DMH) with 8-OH-DPAT and WAY-100635, a 5-HT1A receptor agonist and antagonist, respectively, followed by local microinjections of bicuculline, a GABAA receptor antagonist, were investigated. We found that there are many projections from the DRN to the perifornical lateral hypothalamus (PeFLH) but also to DMH and ventromedial (VMH) nuclei, reaching 5HT1A receptor-labelled perikarya. DMH GABAA receptor blockade elicited defensive responses that were followed by antinociception. DMH treatment with 8-OH-DPAT decreased escape responses, which strongly suggests that the 5-HT1A receptor modulates the defensive responses. However, DMH treatment with WAY-100635 failed to alter bicuculline-induced defensive responses, suggesting that 5-HT exerts a phasic influence on 5-HT1A DMH neurons. The activation of the inhibitory 5-HT1A receptor had no effect on antinociception. However, blockade of the 5-HT1A receptor decreased fear-induced antinociception. The present data suggest that the ascending pathways from the DRN to the DMH modulate panic-like defensive behaviours and mediate antinociceptive phenomenon by recruiting 5-HT1A receptor in the MH. PMID:26749090

  9. Preclinical pharmacology and pharmacokinetics of AZD3783, a selective 5-hydroxytryptamine 1B receptor antagonist.

    PubMed

    Zhang, Minli; Zhou, Diansong; Wang, Yi; Maier, Donna L; Widzowski, Daniel V; Sobotka-Briner, Cynthia D; Brockel, Becky J; Potts, William M; Shenvi, Ashok B; Bernstein, Peter R; Pierson, M Edward

    2011-11-01

    The preclinical pharmacology and pharmacokinetic properties of (2R)-6-methoxy-8-(4-methylpiperazin-1-yl)-N-(4-morpholin-4-ylphenyl)chromane-2-carboxamide (AZD3783), a potent 5-hydroxytryptamine 1B (5-HT(1B)) receptor antagonist, were characterized as part of translational pharmacokinetic/pharmacodynamic hypothesis testing in human clinical trials. The affinity of AZD3783 to the 5-HT(1B) receptor was measured in vitro by using membrane preparations containing recombinant human or guinea pig 5-HT(1B) receptors and in native guinea pig brain tissue. In vivo antagonist potency of AZD3783 for the 5HT(1B) receptor was investigated by measuring the blockade of 5-HT(1B) agonist-induced guinea pig hypothermia. The anxiolytic-like potency was assessed using the suppression of separation-induced vocalization in guinea pig pups. The affinity of AZD3783 for human and guinea pig 5-HT(1B) receptor (K(i), 12.5 and 11.1 nM, respectively) was similar to unbound plasma EC(50) values for guinea pig receptor occupancy (11 nM) and reduction of agonist-induced hypothermia (18 nM) in guinea pig. Active doses of AZD3783 in the hypothermia assay were similar to doses that reduced separation-induced vocalization in guinea pig pups. AZD3783 demonstrated favorable pharmacokinetic properties. The predicted pharmacokinetic parameters (total plasma clearance, 6.5 ml/min/kg; steady-state volume of distribution, 6.4 l/kg) were within 2-fold of the values observed in healthy male volunteers after a single 20-mg oral dose. This investigation presents a direct link between AZD3783 in vitro affinity and in vivo receptor occupancy to preclinical disease model efficacy. Together with predicted human pharmacokinetic properties, we have provided a model for the quantitative translational pharmacology of AZD3783 that increases confidence in the optimal human receptor occupancy required for antidepressant and anxiolytic effects in patients. PMID:21825000

  10. Regulation of rat cortical 5-hydroxytryptamine2A-receptor mediated electrophysiological responses by repeated daily treatment with electroconvulsive shock or imipramine

    PubMed Central

    Marek, Gerard J.

    2008-01-01

    Down-regulation of 5-hydroxytryptamine2A (5-HT2A) receptors has been a consistent effect induced by most antidepressant drugs. In contrast, electroconvulsive shock (ECS) up-regulates the number of 5-HT2A receptor binding sites. However, the effects of antidepressants on 5-HT2A receptor-mediated responses on identified cells of the cerebral cortex has not been examined. The purpose of the present study was to compare the effects of the tricyclic antidepressant imipramine and ECS on 5-HT2A receptor-mediated electrophysiological responses involving glutamatergic and GABAergic neurotransmission in the rat medial prefrontal cortex (mPFC) and piriform cortex, respectively. The electrophysiological effects of activating 5-HT2A receptors was consistent with 5-HT2A receptor binding regulation for imipramine and ECS except for the mPFC where chronic ECS decreased the potency of 5-HT at a 5-HT2A receptor-mediated response. These findings are consistent with the general hypothesis that chronic antidepressant treatments shift the balance of serotonergic neurotransmission towards inhibitory effects in the cortex. PMID:18294819

  11. The effect of selective 5-hydroxytryptamine uptake inhibitors on 5-methoxy-N,N-dimethyltryptamine-induced ejaculation in the rat.

    PubMed Central

    Rényi, L.

    1986-01-01

    The ejaculatory response and the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (3 mg kg-1 i.p.) were studied following acute and repeated treatment of rats with the selective uptake inhibitors of 5-HT, fluoxetine, zimeldine, alaproclate, and citalopram. The oral doses used were based on the respective ED50 values for uptake inhibition. Acute doses of fluoxetine and zimeldine significantly reduced the ejaculatory response when given 48 h before 5-MeODMT. This blockade was prevented by treatment of the rats with the postsynaptic 5-HT receptor antagonist methergoline. An acute dose of fluoxetine given 7 and 14 days before 5-MeODMT significantly enhanced the ejaculatory response. On day 24, the response returned to the control level. Repeated treatment every second day (5 times over 9 days and 10 times over 19 days) with fluoxetine caused a longer blockade of the ejaculatory response and the sensitization of the response came later than after an acute dose. Parallel with the ejaculatory response three other components of the 5-HT behavioural syndrome also decreased significantly. Acute doses of alaproclate and citalopram significantly blocked the ejaculatory response at 1 h, but they failed to affect the response at any other time point after either acute or repeated treatment. Neither did these drugs attentuate the 5-HT syndrome. It is concluded that acute and repeated treatment of rats with different selective 5-HT uptake inhibitors does not produce a common alteration in 5-HT2-receptor functions. PMID:2939912

  12. The effect of selective 5-hydroxytryptamine uptake inhibitors on 5-methoxy-N,N-dimethyltryptamine-induced ejaculation in the rat.

    PubMed

    Rényi, L

    1986-04-01

    The ejaculatory response and the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (3 mg kg-1 i.p.) were studied following acute and repeated treatment of rats with the selective uptake inhibitors of 5-HT, fluoxetine, zimeldine, alaproclate, and citalopram. The oral doses used were based on the respective ED50 values for uptake inhibition. Acute doses of fluoxetine and zimeldine significantly reduced the ejaculatory response when given 48 h before 5-MeODMT. This blockade was prevented by treatment of the rats with the postsynaptic 5-HT receptor antagonist methergoline. An acute dose of fluoxetine given 7 and 14 days before 5-MeODMT significantly enhanced the ejaculatory response. On day 24, the response returned to the control level. Repeated treatment every second day (5 times over 9 days and 10 times over 19 days) with fluoxetine caused a longer blockade of the ejaculatory response and the sensitization of the response came later than after an acute dose. Parallel with the ejaculatory response three other components of the 5-HT behavioural syndrome also decreased significantly. Acute doses of alaproclate and citalopram significantly blocked the ejaculatory response at 1 h, but they failed to affect the response at any other time point after either acute or repeated treatment. Neither did these drugs attentuate the 5-HT syndrome. It is concluded that acute and repeated treatment of rats with different selective 5-HT uptake inhibitors does not produce a common alteration in 5-HT2-receptor functions. PMID:2939912

  13. Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine(2B) receptor agonists: implications for drug safety assessment.

    PubMed

    Huang, Xi-Ping; Setola, Vincent; Yadav, Prem N; Allen, John A; Rogan, Sarah C; Hanson, Bonnie J; Revankar, Chetana; Robers, Matt; Doucette, Chris; Roth, Bryan L

    2009-10-01

    Drug-induced valvular heart disease (VHD) is a serious side effect of a few medications, including some that are on the market. Pharmacological studies of VHD-associated medications (e.g., fenfluramine, pergolide, methysergide, and cabergoline) have revealed that they and/or their metabolites are potent 5-hydroxytryptamine(2B) (5-HT(2B)) receptor agonists. We have shown that activation of 5-HT(2B) receptors on human heart valve interstitial cells in vitro induces a proliferative response reminiscent of the fibrosis that typifies VHD. To identify current or future drugs that might induce VHD, we screened approximately 2200 U.S. Food and Drug Administration (FDA)-approved or investigational medications to identify 5-HT(2B) receptor agonists, using calcium-based high-throughput screening. Of these 2200 compounds, 27 were 5-HT(2B) receptor agonists (hits); 14 of these had previously been identified as 5-HT(2B) receptor agonists, including seven bona fide valvulopathogens. Six of the hits (guanfacine, quinidine, xylometazoline, oxymetazoline, fenoldopam, and ropinirole) are approved medications. Twenty-three of the hits were then "functionally profiled" (i.e., assayed in parallel for 5-HT(2B) receptor agonism using multiple readouts to test for functional selectivity). In these assays, the known valvulopathogens were efficacious at concentrations as low as 30 nM, whereas the other compounds were less so. Hierarchical clustering analysis of the pEC(50) data revealed that ropinirole (which is not associated with valvulopathy) was clearly segregated from known valvulopathogens. Taken together, our data demonstrate that patterns of 5-HT(2B) receptor functional selectivity might be useful for identifying compounds likely to induce valvular heart disease. PMID:19570945

  14. Regulation of the amyloid precursor protein ectodomain shedding by the 5-HT4 receptor and Epac.

    PubMed

    Robert, Sylvain; Maillet, Marjorie; Morel, Eric; Launay, Jean-Marie; Fischmeister, Rodolphe; Mercken, Luc; Lezoualc'h, Frank

    2005-02-14

    The serotonin 5-hydroxytryptamine (5-HT4) receptor is of potential interest for the treatment of Alzheimer's disease because it increases memory and learning. In this study, we investigated the effect of zinc metalloprotease inhibitors on the amyloid precursor protein (APP) processing induced by the serotonin 5-HT4 receptor in vitro. We show that secretion of the non-amyloidogenic form of APP, sAPPalpha induced by the 5-HT4(e) receptor isoform was not due to a general boost of the constitutive secretory pathway but rather to its specific effect on alpha-secretase activity. Although the h5-HT4(e) receptor increased IP3 production, inhibition of PKC did not modify its effect on sAPPalpha secretion. In addition, we found that alpha secretase activity is regulated by the cAMP-regulated guanine nucleotide exchange factor, Epac and the small GTPase Rac. PMID:15710402

  15. Critical role of 5-HT1A, 5-HT3, and 5-HT7 receptor subtypes in the initiation, generation, and propagation of the murine colonic migrating motor complex.

    PubMed

    Dickson, Eamonn J; Heredia, Dante J; Smith, Terence K

    2010-07-01

    The colonic migrating motor complex (CMMC) is necessary for fecal pellet propulsion in the murine colon. We have previously shown that 5-hydroxytryptamine (5-HT) released from enterochromaffin cells activates 5-HT(3) receptors on the mucosal processes of myenteric Dogiel type II neurons to initiate the events underlying the CMMC. Our aims were to further investigate the roles of 5-HT(1A), 5-HT(3), and 5-HT(7) receptor subtypes in generating and propagating the CMMC using intracellular microelectrodes or tension recordings from the circular muscle (CM) in preparations with and without the mucosa. Spontaneous CMMCs were recorded from the CM in isolated murine colons but not in preparations without the mucosa. In mucosaless preparations, ondansetron (3 microM; 5-HT(3) antagonist) plus hexamethonium (100 microM) completely blocked spontaneous inhibitory junction potentials, depolarized the CM. Ondansetron blocked the preceding hyperpolarization associated with a CMMC. Spontaneous CMMCs and CMMCs evoked by spritzing 5-HT (10 and 100 microM) or nerve stimulation in preparations without the mucosa were blocked by SB 258719 or SB 269970 (1-5 microM; 5-HT(7) antagonists). Both NAN-190 and (S)-WAY100135 (1-5 microM; 5-HT(1A) antagonists) blocked spontaneous CMMCs and neurally evoked CMMCs in preparations without the mucosa. Both NAN-190 and (S)-WAY100135 caused an atropine-sensitive depolarization of the CM. The precursor of 5-HT, 5-hydroxytryptophan (5-HTP) (10 microM), and 5-carboxamidotryptamine (5-CT) (5 microM; 5-HT(1/5/7) agonist) increased the frequency of spontaneous CMMCs. 5-HTP and 5-CT also induced CMMCs in preparations with and without the mucosa, which were blocked by SB 258719. 5-HT(1A), 5-HT(3), and 5-HT(7) receptors, most likely on Dogiel Type II/AH neurons, are important in initiating, generating, and propagating the CMMC. Tonic inhibition of the CM appears to be driven by ongoing activity in descending serotonergic interneurons; by activating 5-HT(7

  16. Serotonin 5-HT2 Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

    PubMed Central

    Cunningham, Kathryn A.

    2015-01-01

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

  17. Increased contractile responses to 5-hydroxytryptamine and Angiotensin II in high fat diet fed rat thoracic aorta

    PubMed Central

    Ghatta, Srinivas; Ramarao, Poduri

    2004-01-01

    Background Feeding normal rats with high dietary levels of saturated fat leads to pathological conditions, which are quite similar to syndrome X in humans. These conditions such as hypertriglyceridemia, hypercholesterolemia, obesity, and hyperglycemia might induce hypertension through various mechanisms. Metabolic syndrome and the resulting NIDDM represent a major clinical challenge because implementation of treatment strategies is difficult. Vascular abnormalities probably contribute to the etiology of many diabetic complications including nephropathy, neuropathy, retinopathy, and cardiomyopathy. It has been shown that in Streptozotocin induced diabetic animals there is an increase in maximal responses to 5-Hydroxytryptamine and Angiotensin II. The purpose of this study was to evaluate High fat diet fed rats for the development of hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hyperglycemia and to assess their vascular responses to 5-Hydroxytryptamine and Angiotensin II. Methods Male Sprague Dawley rats were used for this study and were divided into two equal groups. One of the groups was fed with normal pellet diet and they served as the control group, whereas the other group was on a high fat diet for 4 weeks. Body weight, plasma triglycerides, plasma cholesterol, and plasma glucose were measured every week. Intraperitoneal glucose tolerance test was performed after 4 weeks of feeding. At the end of fourth week of high fat diet feeding, thoracic aortae were removed, and cut into helical strips for vascular reactivity studies. Dose-response curves of 5-Hydroxytryptamine and Angiotensin II were obtained. Results There was no significant difference in pD2, with 5-Hydroxytryptamine and Angiotensin II in both groups but Emax was increased. Conclusions These results suggest that hypertension in high fat diet rats is associated with increased in vitro vascular reactivity to 5-HT and Ang II. PMID:15287987

  18. Cross-talk between 5-hydroxytryptamine and substance P in the melanogensis and apoptosis of B16F10 melanoma cells.

    PubMed

    Zhou, Jia; Geng, Kun-kun; Ping, Feng-feng; Gao, Yue-ying; Liu, Lei; Feng, Bai-nian

    2016-03-15

    Skin pigmentation is a complex process controlled by many different factors. Substance P (SP) regulates many biological functions, including melanogenesis and stress. Our previous study indicated that regulation of SP on melanocyte function was mediated by neurokinin 1 receptor (NK1 receptor). Substantial evidence has accumulated that psychological stress can be associated with skin pigmentation, so that the impact of 5-hydroxytryptamine (5-HT), one of the important factors participating in stress process, on melanogenesis has also been concerned. It has been reported that 5-HT induces melanin synthesis via 5-HT2A receptor. Furthermore, 5-HT2A receptor and NK1 receptor are G-protein coupled receptors (GPCRs) and both expressed on melanocyte, the present study was designed to investigate whether SP has influence on the adjustment function of 5-HT. Our data demonstrated that, SP inhibited 5-HT2A receptor expression to neutralize the pro-melanogenesis effect of 5-HT on B16F10 cells. The up-regulation of NK1 receptor expression was simultaneous with the down-regulation of 5-HT2A receptor treated by SP. This inhibition of 5-HT2A receptor expression by SP could be reversed by NK1 receptor antagonist Spantide I. Our studies indicated that SP could directly induce B16F10 cells apoptosis in vitro. 5-HT and 5-HT2A receptor agonist could mitigate this apoptotic effect of SP. It is the strong evidence of possible cross-talk between GPCRs and giving enlightenments when screening desirable drugs for target receptors. PMID:26872989

  19. A review of granisetron, 5-hydroxytryptamine3 receptor antagonists, and other antiemetics.

    PubMed

    Hsu, Eric S

    2010-01-01

    Nausea and vomiting are 2 of the most upsetting adverse reactions of chemotherapy. Current guidelines propose 5-hydroxytryptamine3 (5-HT3) receptor antagonists as a pharmacologic intervention for acute and delayed nausea and vomiting [chemotherapy-induced nausea and vomiting (CINV)] associated with moderately and highly emetogenic chemotherapy. Meanwhile, both postoperative nausea and vomiting (PONV) and postdischarge nausea and vomiting are challenging situations after surgeries and procedures. Prophylactic and therapeutic combinations of antiemetics are recommended in patients at high risk of suffering from PONV and postdischarge nausea and vomiting. Granisetron (Kytril) is a selective 5-HT3 receptor antagonist that does not induce or inhibit the hepatic cytochrome P-450 system in vitro. There are also 4 other antagonists of 5-HT3 receptor (dolasetron, ondansetron, palonosetron, and tropisetron) being metabolized via the CYP2D6 and are subject to potential genetic polymorphism. The launch of a new class of antiemetics, the substance P/neurokinin1 receptor antagonists, was attributed to the scientific update on the central generator responsible for emesis and role of substance P. There has been mounting interest in exploring integrative medicine, either acupuncture or acustimulation of P6 (Nei-Kuwan), to complement the western medicine for prevention and management of nausea and vomiting. The potential application of cannabinoids, either alone or in combination with other agents of different mechanism, could contribute further to improve outcome in CINV. Implementation of future treatment guidelines for more effective management of CINV and PONV could certainly improve the efficacy and outcome of cancer and postoperative care. PMID:20844345

  20. Alterations of Ca(v)1.2 and 5-hydroxytryptamine in rat hearts after positional asphyxia.

    PubMed

    Li, X-F; Huang, Q-Y

    2015-01-01

    We investigated alterations of cardiac Ca(v)1.2 and 5-hydroxytryptamine (5-HT) associated with positional asphyxia. Male rats were divided into five groups: a control group with no restraint, group 1 restrained for 1 h, group 2 restrained for 2 h, group 3 restrained for 4 h, and group 4 restrained for 8 h. The rats that were restrained for 8 h ultimately suffered fatal asphyxia. After the restraint periods, the rats were sacrificed and immunohistochemistry was performed to evaluate the expressions of Ca(v)1.2 and 5-HT in the heart. Sections were analyzed by digital image analysis. Cardiac expression of Ca(v)1.2 and 5-HT proteins were significantly decreased by positional asphyxia in the rat, shown by integrated optical density (IOD) compared to controls. Our findings indicate that Ca(v)1.2 and 5-HT alterations could cause abnormal cardiac function, and the proteins investigated here may be useful for investigating the mechanisms underlying positional asphyxia. PMID:26471941

  1. Nocistatin inhibits 5-hydroxytryptamine release in the mouse neocortex via presynaptic Gi/o protein linked pathways

    PubMed Central

    Fantin, M; Fischetti, C; Trapella, C; Morari, M

    2007-01-01

    Background and purpose: Nocistatin (NST) is a neuropeptide generated from cleavage of the nociceptin/orphanin FQ (N/OFQ) precursor. Evidence has been presented that NST acts as a functional antagonist of N/OFQ, although NST receptor and transduction pathways have not yet been identified. We previously showed that N/OFQ inhibited [3H]5-hydroxytryptamine ([3H]5-HT) release from mouse cortical synaptosomes via activation of NOP receptors. We now investigate whether NST regulates [3H]5-HT release in the same preparation. Experimental approach: Mouse and rat cerebrocortical synaptosomes in superfusion, preloaded with [3H]5-HT and stimulated with 1 min pulses of 10 mM KCl, were used. Key results: Bovine NST (b-NST) inhibited the K+-induced [3H]5-HT release, displaying similar efficacy but lower potency than N/OFQ. b-NST action underwent concentration-dependent and time-dependent desensitization, and was not prevented either by the NOP receptor antagonist [Nphe1 Arg14,Lys15]N/OFQ(1-13)-NH2 (UFP-101) or by the non-selective opioid receptor antagonist, naloxone. Contrary to N/OFQ, b-NST reduced [3H]5-HT release from synaptosomes obtained from NOP receptor knockout mice. However, both N/OFQ and NST were ineffective in synaptosomes pre-treated with the Gi/o protein inhibitor, Pertussis toxin. NST-N/OFQ interactions were also investigated. Co-application of maximal concentrations of both peptides did not result in additive effects, whereas pre-application of maximal b-NST concentrations partially attenuated N/OFQ inhibition. Conclusions and implications: We conclude that b-NST inhibits [3H]5-HT release via activation of Gi/o protein linked pathways, not involving classical opioid receptors and the NOP receptor. The present data strengthen the view that b-NST is, per se, a biologically active peptide endowed with agonist activity. PMID:17618307

  2. Treadmill exercise alleviates stress-induced impairment of social interaction through 5-hydroxytryptamine 1A receptor activation in rats

    PubMed Central

    Kim, Tae-Woon; Lim, Baek-Vin; Kim, Kijeong; Seo, Jin-Hee; Kim, Chang-Ju

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) and its receptors tyrosine kinase B (trkB), and cyclic adenosine monophosphate response element binding protein (CREB) have been suggested as the neurobiological risk factors causing depressive disorder. Serotonin (5-hydroxytryptamine, 5-HT) plays an important role in the pathogenesis of depression. We in-vestigated the effect of treadmill exercise on social interaction in relation with BDNF and 5-HT expressions following stress in rats. Stress was induced by applying inescapable 0.2 mA electric foot shock to the rats for 7 days. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 4 weeks. Social interaction test and western blot for BDNF, TrkB, pCREB, and 5-HT1A in the hippocampus were performed. The results indicate that the spend time with unfamiliar partner was decreased by stress, in contrast, treadmill exercise increased the spending time in the stress-induced rats. Expressions of BDNF, TrkB, and pCREB were decreased by stress, in contrast, treadmill exercise enhanced expressions of BDNF, TrkB, and pCREB in the stress-induced rats. In addition, 5-HT1A receptor expression was de-creased by stress, in contrast, treadmill exercise enhanced 5-HT1A expression in the stress-induced rats. In the present study, treadmill exercise alleviated stress-induced social interaction impairment through enhancing hippocampal plasticity and serotonergic function in the hippocampus. These effects of treadmill exercise are achieved through 5-HT1A receptor activation. PMID:26331133

  3. Treadmill exercise alleviates stress-induced impairment of social interaction through 5-hydroxytryptamine 1A receptor activation in rats.

    PubMed

    Kim, Tae-Woon; Lim, Baek-Vin; Kim, Kijeong; Seo, Jin-Hee; Kim, Chang-Ju

    2015-08-01

    Brain-derived neurotrophic factor (BDNF) and its receptors tyrosine kinase B (trkB), and cyclic adenosine monophosphate response element binding protein (CREB) have been suggested as the neurobiological risk factors causing depressive disorder. Serotonin (5-hydroxytryptamine, 5-HT) plays an important role in the pathogenesis of depression. We in-vestigated the effect of treadmill exercise on social interaction in relation with BDNF and 5-HT expressions following stress in rats. Stress was induced by applying inescapable 0.2 mA electric foot shock to the rats for 7 days. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 4 weeks. Social interaction test and western blot for BDNF, TrkB, pCREB, and 5-HT1A in the hippocampus were performed. The results indicate that the spend time with unfamiliar partner was decreased by stress, in contrast, treadmill exercise increased the spending time in the stress-induced rats. Expressions of BDNF, TrkB, and pCREB were decreased by stress, in contrast, treadmill exercise enhanced expressions of BDNF, TrkB, and pCREB in the stress-induced rats. In addition, 5-HT1A receptor expression was de-creased by stress, in contrast, treadmill exercise enhanced 5-HT1A expression in the stress-induced rats. In the present study, treadmill exercise alleviated stress-induced social interaction impairment through enhancing hippocampal plasticity and serotonergic function in the hippocampus. These effects of treadmill exercise are achieved through 5-HT1A receptor activation. PMID:26331133

  4. (1R, 3S)-(−)-Trans-PAT: A novel full-efficacy serotonin 5-HT2C receptor agonist with 5-HT2A and 5-HT2B receptor inverse agonist/antagonist activity

    PubMed Central

    Booth, Raymond G.; Fang, Lijuan; Huang, Yingsu; Wilczynski, Andrzej; Sivendran, Sashikala

    2009-01-01

    The serotonin 5-HT2A, 5-HT2B, and 5-HT2C G protein-coupled receptors signal primarily through Gαq to activate phospholipase C (PLC) and formation of inositol phosphates (IP) and diacylglycerol. The human 5-HT2C receptor, expressed exclusively in the central nervous system, is involved in several physiological and psychological processes. Development of 5-HT2C agonists that do not also activate 5-HT2A or 5-HT2B receptors is challenging because transmembrane domain identity is about 75% among 5-HT2 subtypes. This paper reports 5-HT2 receptor affinity and function of (1R,3S)-(−)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene (PAT), a small molecule that produces anorexia and weight-loss after peripheral administration to mice. (−)-Trans-PAT is a stereoselective full-efficacy agonist at human 5-HT2C receptors, plus, it is a 5-HT2A/5-HT2B inverse agonist and competitive antagonist. The Ki of (−)-trans-PAT at 5-HT2A, 5-HT2B, and 5-HT2C receptors is 410, 1200, and 37 nM, respectively. Functional studies measured activation of PLC/[3H]-IP formation in clonal cells expressing human 5-HT2 receptors. At 5-HT2C receptors, (−)-trans-PAT is an agonist (EC50 = 20 nM) comparable to serotonin in potency and efficacy. At 5-HT2A and 5-HT2B receptors, (−)-trans-PAT is an inverse agonist (IC50 = 490 and 1,000 nM, respectively) and competitive antagonist (KB = 460 and 1400 nM, respectively) of serotonin. Experimental results are interpreted in light of molecular modeling studies indicating the (−)-trans-PAT protonated amine can form an ionic bond with D3.32 of 5-HT2A and 5-HT2C receptors, but, not with 5-HT2B receptors. In addition to probing 5-HT2 receptor structure and function, (−)-trans-PAT is a novel lead regarding 5-HT2C agonist/5-HT2A inverse agonist drug development for obesity and neuropsychiatric disorders. PMID:19397907

  5. Sequential onset of three 5-HT receptors during the 5-hydroxytryptaminergic differentiation of the murine 1C11 cell line.

    PubMed Central

    Kellermann, O.; Loric, S.; Maroteaux, L.; Launay, J. M.

    1996-01-01

    1. The murine 1C11 clone, which derives from a multipotential embryonal carcinoma cell line, has the features of a neuroectodermal precursor. When cultured in the presence of dibutyryl cyclic AMP, the 1C11 cells extend bipolar extensions and express neurone-associated markers. After 4 days, the resulting cells have acquired the ability to synthesize, take up, store and catabolize 5-hydroxytryptamine (5-HT). We have thus investigated the presence of 5-HT receptors during the 5-hydroxytryptaminergic differentiation of this inducible 1C11 cell line. 2. As shown by the binding of [125I]-GTI and the CGS 12066-dependent inhibition of the forskolin-induced cyclic AMP production, functional 5-HT1B/1D receptors become expressed on day 2 of 1C11 cell differentiation. The density of these receptors remained unchanged until day 4. 3. The same holds true for the 5-HT2B receptor, also identified by its pharmacological profile and its positive coupling to the phosphoinositide cascade. 4. On day 4 of 1C11 cell differentiation, a third 5-HT receptor, pharmacologically and functionally similar to 5-HT2A, had become induced. 5. Strikingly, the amounts of each transcript encoding 5-HT1B, 5-HT2A and 5-HT2B receptor did not very significantly during the time course of the 1C11 5-hydroxytryptaminergic differentiation. 6. The clone 1C11 may thus provide a useful in vitro model for studying regulation(s) between multiple G-linked receptors as well as the possible role of 5-HT upon the expression of a complete 5-hydroxytryptamine phenotype. Images Figure 5 PMID:8818339

  6. Serotonin acts as a novel regulator of interleukin-6 secretion in osteocytes through the activation of the 5-HT(2B) receptor and the ERK1/2 signalling pathway.

    PubMed

    Li, Xianxian; Ma, Yuanyuan; Wu, Xiangnan; Hao, Zhichao; Yin, Jian; Shen, Jiefei; Li, Xiaoyu; Zhang, Ping; Wang, Hang

    2013-11-29

    Interleukin-6 (IL-6) is a potent stimulator of osteoclastic bone resorption. Osteocyte secretion of IL-6 plays an important role in bone metabolism. Serotonin (5-HT) has recently been reported to regulate bone metabolism. The aim of this study was to evaluate the effect of serotonin on osteocyte expression of IL-6. The requirement for the 5-HT receptor(s) and the role of the extracellular signal-regulated kinase 1/2 (ERK1/2) in serotonin-induced IL-6 synthesis were examined. In this study, real-time PCR and ELISA were used to analyse IL-6 gene and protein expression in serotonin-stimulated MLO-Y4 cells. ERK1/2 pathway activation was determined by Western blot. We found that serotonin significantly activated the ERK1/2 pathway and induced IL-6 mRNA expression and protein synthesis in cultured MLO-Y4 cells. However, these effects were abolished by pre-treatment of MLO-Y4 cells with a 5-HT2B receptor antagonist, RS127445 or the ERK1/2 inhibitor, PD98059. Our results indicate that serotonin stimulates osteocyte secretion of IL-6 and that this effect is associated with activation of 5-HT2B receptor and the ERK1/2 pathway. These findings provide support for a role of serotonin in bone metabolism by indicating serotonin regulates bone remodelling by mediating an inflammatory cytokine. PMID:24211588

  7. GABA, 5-HT and amino acids in the rotifers Brachionus plicatilis and Brachionus rotundiformis.

    PubMed

    Gallardo, W G; Hagiwara, A; Hara, K; Soyano, K; Snell, T W

    2000-11-01

    gamma-Aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT) have been shown to increase the reproduction of the Brachionus plicatilis (NH3L strain). In the present study, the endogenous presence of GABA and 5-HT in the rotifers B. plicatilis (NH3L and Kamiura strains) and Brachionus rotundiformis (Langkawi strain) were confirmed by dot blot immunoassay and high-performance liquid chromatography (HPLC). HPLC showed that GABA and 5-HT concentrations in the three rotifer strains range from 71 to 188 pmol/mg and from 12 to 64 pmol/mg, respectively. A total of 33 amino acids were also detected in B. plicatilis and B. rotundiformis, with glutamic acid, serine, glycine, taurine, threonine, alanine, arginine, proline, valine and isoleucine in high concentrations relative to other amino acids. PMID:11118940

  8. 3D Pharmacophore, hierarchical methods, and 5-HT4 receptor binding data.

    PubMed

    Varin, Thibault; Saettel, Nicolas; Villain, Jonathan; Lesnard, Aurelien; Dauphin, François; Bureau, Ronan; Rault, Sylvain

    2008-10-01

    5-Hydroxytryptamine subtype-4 (5-HT(4)) receptors have stimulated considerable interest amongst scientists and clinicians owing to their importance in neurophysiology and potential as therapeutic targets. A comparative analysis of hierarchical methods applied to data from one thousand 5-HT(4) receptor-ligand binding interactions was carried out. The chemical structures were described as chemical and pharmacophore fingerprints. The definitions of indices, related to the quality of the hierarchies in being able to distinguish between active and inactive compounds, revealed two interesting hierarchies with the Unity (1 active cluster) and pharmacophore fingerprints (4 active clusters). The results of this study also showed the importance of correct choice of metrics as well as the effectiveness of a new alternative of the Ward clustering algorithm named Energy (Minimum E-Distance method). In parallel, the relationship between these classifications and a previously defined 3D 5-HT(4) antagonist pharmacophore was established. PMID:18821249

  9. Prophylaxis of Radiation-Induced Nausea and Vomiting Using 5-Hydroxytryptamine-3 Serotonin Receptor Antagonists: A Systematic Review of Randomized Trials

    SciTech Connect

    Salvo, Nadia; Doble, Brett; Khan, Luluel; Amirthevasar, Gayathri; Dennis, Kristopher; Pasetka, Mark; DeAngelis, Carlo; Tsao, May; Chow, Edward

    2012-01-01

    Purpose: To systematically review the effectiveness and safety of 5-hydroxytryptamine-3 receptor antagonists (5-HT3 RAs) compared with other antiemetic medication or placebo for prophylaxis of radiation-induced nausea and vomiting. Methods and Materials: We searched the following electronic databases: MEDLINE, Embase, the Cochrane Central Register of Controlled Clinical Trials, and Web of Science. We also hand-searched reference lists of included studies. Randomized, controlled trials that compared a 5-HT3 RA with another antiemetic medication or placebo for preventing radiation-induced nausea and vomiting were included. We excluded studies recruiting patients receiving concomitant chemotherapy. When appropriate, meta-analysis was conducted using Review Manager (v5) software. Relative risks were calculated using inverse variance as the statistical method under a random-effects model. We assessed the quality of evidence by outcome using the Grading of Recommendations Assessment, Development, and Evaluation approach. Results: Eligibility screening of 47 articles resulted in 9 included in the review. The overall methodologic quality was moderate. Meta-analysis of 5-HT3 RAs vs. placebo showed significant benefit for 5-HT3 RAs (relative risk [RR] 0.70; 95% confidence interval [CI] 0.57-0.86 for emesis; RR 0.84, 95% CI 0.73-0.96 for nausea). Meta-analysis comparing 5-HT3 RAs vs. metoclopramide showed a significant benefit of the 5-HT3 RAs for emetic control (RR 0.27, 95% CI 0.15-0.47). Conclusion: 5-Hydroxytryptamine-3 RAs are superior to placebo and other antiemetics for prevention of emesis, but little benefit was identified for nausea prevention. 5-Hydroxytryptamine-3 RAs are suggested for prevention of emesis. Limited evidence was found regarding delayed emesis, adverse events, quality of life, or need for rescue medication. Future randomized, controlled trials should evaluate different 5-HT3 antiemetics and new agents with novel mechanisms of action such at the NK

  10. Cholecystokinin release mediated by 5-HT3 receptors in rat cerebral cortex and nucleus accumbens.

    PubMed Central

    Paudice, P.; Raiteri, M.

    1991-01-01

    1. The effects of 5-hydroxytryptamine (5-HT) on the release of cholexystokinin-like immunoreactivity (CCK-LI) were examined in synaptosomes prepared from rat cerebral cortex and nucleus accumbens and depolarized by superfusion with 15 mM KCl. 2. In both areas 5-HT, tested between 0.1 and 100 nM, increased the calcium-dependent, depolarization-evoked CCK-LI release in a concentration-related manner. The concentration-response curves did not differ significantly between the two brain areas (EC50: 0.4 +/- 0.045 nM and 0.48 +/- 0.053 nM, respectively, in cortical and n. accumbens synaptosomes; maximal effect: about 60% at 10 nM 5-HT). 3. The 5-HT1/5-HT2 receptor antagonist methiothepin (300 nM) did not affect the CCK-LI release elicited by 10 nM 5-HT. However, the effects of 10 nM 5-HT were antagonized in a concentration-dependent manner by the 5-HT3 receptor antagonists (3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester (ICS 205-930; 0.1-100 nM; IC50: 3.56 +/- 0.42 nM in the cortex and 3.90 +/- 0.50 nM in the n. accumbens) and ondasetron (IC50: 8.15 +/- 0.73 nM in the cerebral cortex). 5-HT (10 nM) was also strongly antagonized by 100 nM 1 alpha H, 3 alpha 5 alpha H-tropan-3-yl-3,5-dichlorobenzoate (MDL 72222) another blocker of the 5-HT3 receptor. Moreover, the 5-HT3 receptor agonist 1-phenylbiguanide (tested in the cerebral cortex between 0.1 and 100 nM) enhanced CCK-LI release in a manner almost identical to that of 5-HT (EC50 = 0.64 +/- 0.071 nM). 4. It is concluded that 5-HT can act as a potent releaser of CCK-LI in rat cerebrocortex and nucleus accumbens through the activation of receptors of the 5-HT3 type situated on the CCK-releasing terminals. This interaction may provide a rationale for the clinical development of both 5-HT3 and CCK receptor antagonists as novel anxiolytic drugs. PMID:1933141

  11. 5-HT1A and 5-HT1B receptors control the firing of serotoninergic neurons in the dorsal raphe nucleus of the mouse: studies in 5-HT1B knock-out mice.

    PubMed

    Evrard, A; Laporte, A M; Chastanet, M; Hen, R; Hamon, M; Adrien, J

    1999-11-01

    The characteristics of the spontaneous firing of serotoninergic neurons in the dorsal raphe nucleus and its control by serotonin (5-hydroxytryptamine, 5-HT) receptors were investigated in wild-type and 5-HT1B knock-out (5-HT1B-/-) mice of the 129/Sv strain, anaesthetized with chloral hydrate. In both groups of mice, 5-HT neurons exhibited a regular activity with an identical firing rate of 0.5-4.5 spikes/s. Intravenous administration of the 5-HT reuptake inhibitor citalopram or the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) induced a dose-dependent inhibition of 5-HT neuronal firing which could be reversed by the selective 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xane carboxamide (WAY 100635). Both strains were equally sensitive to 8-OH-DPAT (ED50 approximately 6.3 microgram/kg i.v.), but the mutants were less sensitive than wild-type animals to citalopram (ED50 = 0.49 +/- 0.02 and 0.28 +/- 0.01 mg/kg i.v., respectively, P < 0.05). This difference could be reduced by pre-treatment of wild-type mice with the 5-HT1B/1D antagonist 2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carbox yli c acid [4-methoxy-3-(4-methyl-piperazine-1-yl)-phenyl]amide (GR 127935), and might be accounted for by the lack of 5-HT1B receptors and a higher density of 5-HT reuptake sites (specifically labelled by [3H]citalopram) in 5-HT1B-/- mice. In wild-type but not 5-HT1B-/- mice, the 5-HT1B agonists 3-(1,2,5, 6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94253, 3 mg/kg i.v.) and 5-methoxy-3-(1,2,3, 6-tetrahydropyridin-4-yl)-1H-indole (RU 24969, 0.6 mg/kg i.v.) increased the firing rate of 5-HT neurons (+22.4 +/- 2.8% and +13.7 +/- 6.0%, respectively, P < 0.05), and this effect could be prevented by the 5-HT1B antagonist GR 127935 (1 mg/kg i.v.). Altogether, these data indicate that in the mouse, the firing of 5-HT neurons in the dorsal raphe nucleus is under both an inhibitory control through 5-HT1A

  12. Deletion of GIRK2 Subunit of GIRK Channels Alters the 5-HT1A Receptor-Mediated Signaling and Results in a Depression-Resistant Behavior

    PubMed Central

    Llamosas, Nerea; Bruzos-Cidón, Cristina; Rodríguez, José Julio; Ugedo, Luisa

    2015-01-01

    Background: Targeting dorsal raphe 5-HT1A receptors, which are coupled to G-protein inwardly rectifying potassium (GIRK) channels, has revealed their contribution not only to behavioral and functional aspects of depression but also to the clinical response to its treatment. Although GIRK channels containing GIRK2 subunits play an important role controlling excitability of several brain areas, their impact on the dorsal raphe activity is still unknown. Thus, the goal of the present study was to investigate the involvement of GIRK2 subunit-containing GIRK channels in depression-related behaviors and physiology of serotonergic neurotransmission. Methods: Behavioral, functional, including in vivo extracellular recordings of dorsal raphe neurons, and neurogenesis studies were carried out in wild-type and GIRK2 mutant mice. Results: Deletion of the GIRK2 subunit promoted a depression-resistant phenotype and determined the behavioral response to the antidepressant citalopram without altering hippocampal neurogenesis. In dorsal raphe neurons of GIRK2 knockout mice, and also using GIRK channel blocker tertiapin-Q, the basal firing rate was higher than that obtained in wild-type animals, although no differences were observed in other firing parameters. 5-HT1A receptors were desensitized in GIRK2 knockout mice, as demonstrated by a lower sensitivity of dorsal raphe neurons to the inhibitory effect of the 5-HT1A receptor agonist, 8-OH-DPAT, and the antidepressant citalopram. Conclusions: Our results indicate that GIRK channels formed by GIRK2 subunits determine depression-related behaviors as well as basal and 5-HT1A receptor-mediated dorsal raphe neuronal activity, becoming alternative therapeutic targets for psychiatric diseases underlying dysfunctional serotonin transmission. PMID:25956878

  13. Agonist properties of N,N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors.

    PubMed

    Smith, R L; Canton, H; Barrett, R J; Sanders-Bush, E

    1998-11-01

    Extensive behavioral and biochemical evidence suggests an agonist role at the 5-HT2A receptor, and perhaps the 5-HT2C receptor, in the mechanism of action of hallucinogenic drugs. However the published in vitro pharmacological properties of N,N-dimethyltryptamine (DMT), an hallucinogenic tryptamine analog, are not consistent with this hypothesis. We, therefore, undertook an extensive investigation into the properties of DMT at 5-HT2A and 5-HT2C receptors. In fibroblasts transfected with the 5-HT2A receptor or the 5-HT2C receptor, DMT activated the major intracellular signaling pathway (phosphoinositide hydrolysis) to an extent comparable to that produced by serotonin. Because drug efficacy changes with receptor density and cellular microenvironment, we also examined the properties of DMT in native preparations using a behavioral and biochemical approach. Rats were trained to discriminate an antagonist ketanserin from an agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in a two-lever choice paradigm. Pharmacological studies showed that responding on the DOI and ketanserin lever reflected agonist and antagonist activity at 5-HT2A receptors, and hence, was a suitable model for evaluating the in vivo functional properties of DMT. Like other 5-HT2A receptor agonists, DMT substituted fully for DOI. Intact choroid plexus was used to evaluate the agonist properties at endogenous 5-HT2C receptors; DMT was a partial agonist at 5-HT2C receptors in this native preparation. Thus, we conclude that DMT behaves as an agonist at both 5-HT2A and 5-HT2A receptors. One difference was evident in that the 5-HT2C, but not the 5-HT2A, receptor showed a profound desensitization to DMT over time. This difference is interesting in light of the recent report that the hallucinogenic activity of DMT does not tolerate in humans and suggests the 5-HT2C receptor plays a less prominent role in the action of DMT. PMID:9768567

  14. Gaddum and LSD: the birth and growth of experimental and clinical neuropharmacology research on 5-HT in the UK

    PubMed Central

    Green, A R

    2008-01-01

    The vasoconstrictor substance named serotonin was identified as 5-hydroxytryptamine (5-HT) by Maurice Rapport in 1949. In 1951, Rapport gave Gaddum samples of 5-HT substance allowing him to develop a bioassay to both detect and measure the amine. Gaddum and colleagues rapidly identified 5-HT in brain and showed that lysergic acid diethylamide (LSD) antagonized its action in peripheral tissues. Gaddum accordingly postulated that 5-HT might have a role in mood regulation. This review examines the role of UK scientists in the first 20 years following these major discoveries, discussing their role in developing assays for 5-HT in the CNS, identifying the enzymes involved in the synthesis and metabolism of 5-HT and investigating the effect of drugs on brain 5-HT. It reviews studies on the effects of LSD in humans, including Gaddum's self-administration experiments. It outlines investigations on the role of 5-HT in psychiatric disorders, including studies on the effect of antidepressant drugs on the 5-HT concentration in rodent and human brain, and the attempts to examine 5-HT biochemistry in the brains of patients with depressive illness. It is clear that a rather small group of both preclinical scientists and psychiatrists in the UK made major advances in our understanding of the role of 5-HT in the brain, paving the way for much of the knowledge now taken for granted when discussing ways that 5-HT might be involved in the control of mood and the idea that therapeutic drugs used to alleviate psychiatric illness might alter the function of cerebral 5-HT. PMID:18516072

  15. The Relationship Between Single Nucleotide Polymorphisms in 5-HT2A Signal Transduction-Related Genes and the Response Efficacy to Selective Serotonin Reuptake Inhibitor Treatments in Chinese Patients with Major Depressive Disorder

    PubMed Central

    Li, Heng-Fen; Yu, Xue; He, Cha-Ye; Kou, Shao-Jie; Cao, Su-Xia

    2012-01-01

    Objective: To explore the possible relationship between six single nucleotide polymorphisms (SNPs) (rs6311 and rs6305 of 5-HT2A, rs5443 of Gβ3, rs2230739 of ACDY9, rs1549870 of PDE1A and rs255163 of CREB1, which are all related with 5-HT2A the signal transduction pathway) and the response efficacy to selective serotonin reuptake inhibitor (SSRI) treatments in major depressive disorder (MDD) Chinese. Methods: This study included 194 depressed patients to investigate the influence of 6 polymorphisms in 5-HT2A signal transduction-related genes on the efficacy of SSRIs assessed over 1 year. The efficacies of SSRIs on 194 MDD patients were evaluated in an 8-week open-trial study. Over 1 year, a follow-up study was completed for 174 of them to observe the long-term efficacy of SSRIs. The optimal-scaling regression analysis was used for testing the relationship between the different genotypes of five SNPs and the efficacy in MDD. Results: It showed that the patients with rs5443TT and rs2230739GG have a relatively good efficacy in response to short-term SSRIs. We also found that good efficacy appeared in depressed patients with rs2230739GG in response to long-term SSRIs. Conclusions: It suggested that different genotypes of rs5443 and rs2230739 might influence the signal transduction pathways of second message and affect therapeutic efficacy. PMID:22480177

  16. Therapeutic Potential of 5-HT2C Receptor Agonists for Addictive Disorders.

    PubMed

    Higgins, Guy A; Fletcher, Paul J

    2015-07-15

    The neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) has long been associated with the control of a variety of motivated behaviors, including feeding. Much of the evidence linking 5-HT and feeding behavior was obtained from studies of the effects of the 5-HT releaser (dex)fenfluramine in laboratory animals and humans. Recently, the selective 5-HT2C receptor agonist lorcaserin received FDA approval for the treatment of obesity. This review examines evidence to support the use of selective 5-HT2C receptor agonists as treatments for conditions beyond obesity, including substance abuse (particularly nicotine, psychostimulant, and alcohol dependence), obsessive compulsive, and excessive gambling disorder. Following a brief survey of the early literature supporting a role for 5-HT in modulating food and drug reinforcement, we propose that intrinsic differences between SSRI and serotonin releasers may have underestimated the value of serotonin-based pharmacotherapeutics to treat clinical forms of addictive behavior beyond obesity. We then highlight the critical involvement of the 5-HT2C receptor in mediating the effect of (dex)fenfluramine on feeding and body weight gain and the evidence that 5-HT2C receptor agonists reduce measures of drug reward and impulsivity. A recent report of lorcaserin efficacy in a smoking cessation trial further strengthens the idea that 5-HT2C receptor agonists may have potential as a treatment for addiction. This review was prepared as a contribution to the proceedings of the 11th International Society for Serotonin Research Meeting held in Hermanus, South Africa, July 9-12, 2014. PMID:25870913

  17. Vascular reactivity, 5-HT uptake, and blood pressure in the serotonin transporter knockout rat.

    PubMed

    Linder, A Elizabeth; Diaz, Jessica; Ni, Wei; Szasz, Theo; Burnett, Robert; Watts, Stephanie W

    2008-04-01

    The handling of serotonin [5-hydroxytryptamine (5-HT)] depends on the serotonin transporter (SERT). A SERT knockout (KO) rat is a useful model to test the hypothesis that SERT is the primary mechanism for arterial 5-HT uptake and to investigate the impact of SERT removal on blood pressure. Wild-type (WT) and KO rats were used to measure 5-HT content (plasma, raphe, aorta, carotid, and mesenteric artery), aortic isometric contraction, and blood pressure. HPLC supported the lack of circulating 5-HT in plasma (ng/ml plasma, WT, 310 +/- 96; and KO, 1.0 +/- 0.5; P < 0.05). Immunohistochemistry and Western blot analyses validated the presence of the SERT protein in the WT rats and a lesser expression in the KO rat. The aorta isolated from KO rats had a normal contraction to phenylephrine and norepinephrine and a normal relaxation to the endothelium-dependent agonist acetylcholine compared with the aorta from WT. In contrast, the potency of 5-HT was increased in the aorta from KO rats compared with WT rats [-log EC(50) (M); WT, 5.71 +/- 0.08; and KO, 6.7 +/- 0.18] and maximum contraction was reduced [%phenylephrine (10 muM) contraction, WT, 113 +/- 6%; and KO, 52 +/- 12%]. 5-HT uptake was reduced but not abolished in arteries of the KO compared with the WT rats. Diurnal mean arterial blood pressure, heart rate, and locomotor activity level of the KO rats were similar to the WT rats. These data suggest that there are other mechanisms of 5-HT uptake in the arteries of the rat and that although the absence of circulating 5-HT and/or SERT function sensitizes arteries to 5-HT, SERT dysfunction does not impair normal blood pressure. PMID:18263707

  18. Profiles of 5-HT 1B/1D agonists in acute migraine with special reference to second generation agents.

    PubMed

    Deleu, D; Hanssens, Y

    1999-06-01

    The efficacy of 5-hydroxytryptamine 1B/1D (5-HT 1B/1D) agonists is related to their inhibitory effects on neurogenic inflammation, mediated through serotoninergic control mechanisms. Recently, a series of oral second generation 5-HT 1B/1D agonists (eletriptan, naratriptan, rizatriptan and zolmitriptan) have been developed and are reviewed in this paper. Their in vitro and in vivo pharmacological properties, clinical efficacy, drug interactions, and adverse effects are evaluated and compared to the gold standard in the treatment of acute migraine, sumatriptan. PMID:10427351

  19. A comparison of the effects of chlorpromazine and more selective histamine and 5-hydroxytryptamine antagonists on human IgG synthesis in vitro.

    PubMed

    Martinez, F; Coleman, J W

    1990-01-01

    We have shown previously that chlorpromazine, a drug associated with immunological abnormalities in vivo, significantly potentiates pokeweed mitogen (PWM)-stimulated IgG synthesis by human peripheral blood mononuclear cells (PBMC) in culture. Chlorpromazine is a pharmacological antagonist of histamine and 5-hydroxytryptamine (5-HT) and thus may exert its immune-enhancing effects by competing with these amines for their respective receptors, which are known to be present on lymphocytes. In this report we show that histamine and 5-HT are present at micromolar concentrations in PBMC cultures. To examine the role of histamine and 5-HT in chlorpromazine-induced enhancement of IgG synthesis we incubated PWM-treated cells with a range of selective histamine and 5-HT antagonists, and with the amines added to cultures either alone or in combination with chlorpromazine. The H1 antagonists mepyramine and promethazine and the H2 antagonist cimetidine had no significant effect on IgG synthesis. The combined 5-HT1/5-HT2 antagonists methysergide and methiothepin also failed to modulate synthesis. Neither histamine nor 5-HT at concentrations up to 100 microM modulated IgG synthesis, nor did they abrogate the enhancement of IgG synthesis induced by chlorpromazine. We conclude that the modulation of IgG synthesis in vitro by chlorpromazine cannot be attributed to an interaction of this drug with lymphocyte receptors for histamine and 5-HT. Other possibilities for the mechanism of action of this drug on immune function are discussed. PMID:2329012

  20. The 5-HT4 receptor: molecular cloning and pharmacological characterization of two splice variants.

    PubMed Central

    Gerald, C; Adham, N; Kao, H T; Olsen, M A; Laz, T M; Schechter, L E; Bard, J A; Vaysse, P J; Hartig, P R; Branchek, T A

    1995-01-01

    Molecular cloning efforts have provided primary amino acid sequence and signal transduction data for a large collection of serotonin receptor subtypes. These include five 5-HT1-like receptors, three 5-HT2 receptors, one 5-HT3 receptor, two 5-HT5 receptors, one 5-HT6 receptor and one 5-HT7 receptor. Molecular biological information on the 5-HT4 receptor is notably absent from this list. We now report the cloning of the pharmacologically defined 5-HT4 receptor. Using degenerate oligonucleotide primers, we identified a rat brain PCR fragment which encoded a '5-HT receptor-like' amino acid sequence. The corresponding full length cDNA was isolated from a rat brain cDNA library. Transiently expressed in COS-7 cells, this receptor stimulates adenylyl cyclase activity and is sensitive to the benzamide derivative cisapride. The response is also blocked by ICS-205930. Interestingly, we isolated two splice variants of the receptor, 5-HT4L and 5-HT4S, differing in the length and sequence of their C-termini. In rat brain, the 5-HT4S transcripts are restricted to the striatum, but the 5-HT4L transcripts are expressed throughout the brain, except in the cerebellum where it was barely detectable. In peripheral tissues, differential expression was also observed in the atrium of the heart where only the 5-HT4S isoform was detectable. Images PMID:7796807

  1. Lesions in Guddesn's tegmental nuclei produce behavioral and 5-HT effects similar to those after raphe lesions.

    PubMed

    Lorens, S A; Köhler, C; Guldberg, H C

    1975-01-01

    Lesions largely restricted to the dorsal and ventral tegmental nuclei of Gudden (GTN) produced several effects similar to those seen after midbrain raphe lesions. GTN lesions significantly reduced the 5-hydroxytryptamine (5-HT) concentration of the diencephalon (31 percent), hippocampus (59 percent), and remaining portion of the telencephalon (29 percent). Striatal 5-HT, however, was not affected. GTN lesions enhanced activity in an enclosed field and facilitated two-way avoidance acquisition. Pain sensitivity as measured by the flinch-jump method was not affected. These results suggest that the GTN may be the origin of ascending 5-HT fides and may be involved in the regulation of activity level and the adaptation of an animal to aversive situations. Thus, some of the behavioral and 5-HT effects of lesions in the midbrain raphe nuclei may be due to their involvement of the GTN and associated pathways. PMID:1187729

  2. In vivo labeling of 5-hydroxytryptamine uptake sites in mouse brain with ( sup 3 H)-6-nitroquipazine

    SciTech Connect

    Hashimoto, K.; Goromaru, T. )

    1990-10-01

    6-Nitroquipazine (DU 24565; 6-nitro 2-piperazinylquinoline) is a very potent 5-hydroxytryptamine (5-HT; serotonin) uptake inhibitor. It has been demonstrated very recently that (3H)-6-nitroquipazine is a suitable radioligand for studying 5-HT uptake sites. The present study evaluates (3H)6-nitroquipazine as a radioligand for in vivo labeling of 5-HT uptake sites in mouse brain. Very high uptake of radioactivity in the brain after i.v. administration of (3H)-6-nitroquipazine was shown. Regional distribution of the radioactivity in mouse brain 3 hr after injection of (3H)-6-nitroquipazine was in the order (highest to lowest) hypothalamus greater than midbrain greater than striatum greater than hippocampus greater than cerebral cortex greater than medulla oblongata greater than cerebellum. The regional distribution of in vivo (3H)-6-nitroquipazine binding in mouse brain was highly correlated with that in rat brain obtained from previous in vitro binding studies. Coadministration of carrier 6-nitroquipazine (5 mg/kg) significantly decreased the radioactivity in the hypothalamus, whereas that in the cerebellum and cerebral cortex was increased. Because the cerebellum has very low density of (3H)-6-nitroquipazine binding sites, the radioactivity in the cerebellum could, therefore, reflect the amount on nonspecific binding and free ligand. Kinetic studies showed highest in vivo specific binding 1 hr after injection of (3H)-6-nitroquipazine and slow clearance of specific binding. Specific binding in the hypothalamus was inhibited in a stereoselective manner by the stereoisomers of norzimelidine. Furthermore, specific binding in the hypothalamus was reduced by several 5-HT uptake inhibitors, in a dose-dependent manner.

  3. Nature of 5-HT1-like receptors mediating depressor responses in vagosympathectomized rats; close resemblance to the cloned 5-ht7 receptor.

    PubMed

    De Vries, P; Villalón, C M; Heiligers, J P; Saxena, P R

    1997-07-01

    It has been suggested that the late hypotensive response to serotonin (5-hydroxytryptamine; 5-HT) in vagosympathectomized rats is mediated by '5-HT1-like' receptors since this effect is mimicked by 5-carboxamidotryptamine (5-CT), is not modified by cyproheptadine, ketanserin or MDL 72222, but it is blocked by methysergide. The present study was set out to reanalyze this suggestion in terms of the classification schemes proposed in 1994 and 1996 by the NC-IUPHAR subcommittee on the classification and nomenclature of 5-HT receptors. I.v. bolus injections of 5-CT (0.01-0.3 microg x kg(-1)), 5-HT (1-30 microg x kg(-1)) and 5-methoxytryptamine (5-MeO-T; 1-30 microg x kg(-1)) produced dose-dependent hypotensive responses with a rank order of agonist potency: 5-CT > 5-HT > 5-methoxytryptamine with sumatriptan (30-1000 microg x kg(-1)) inactive. The depressor responses to 5-HT and 5-CT were not attenuated by i.v. GR127935 (300-3000 microg x kg(-1)) or equivalent volumes of saline. In contrast, lisuride, methiothepin, mesulergine, metergoline and clozapine dose-dependently antagonized the responses to 5-HT and 5-CT; the rank order of apparent pA2 values against 5-HT and 5-CT, respectively, was: lisuride (7.7; 7.8) > methiothepin (6.8; 7.0) > or = mesulergine (6.4; 6.6) > clozapine (5.7; 5.8); metergoline displayed variable potencies (5.6; 6.4). Except for lisuride, which also affected isoprenaline-induced hypotension, the antagonism by the other drugs was selective. Based upon the above rank order of agonist potency, the blockade by a series of drugs showing high affinity for the cloned 5-ht7 receptor and the lack of blockade by GR127935, our results indicate that the 5-HT receptor mediating hypotension in vagosympathectomized rats is operationally similar to other putative 5-ht7 receptors mediating vascular and non-vascular responses (e.g. relaxation of the rabbit femoral vein, canine coronary and external carotid arteries and guinea-pig ileum as well as feline tachycardia

  4. Functional expression of 5-HT{sub 2A} receptor in osteoblastic MC3T3-E1 cells

    SciTech Connect

    Hirai, Takao; Kaneshige, Kota; Kurosaki, Teruko; Nishio, Hiroaki

    2010-05-28

    In the previous study, we reported the gene expression for proteins related to the function of 5-hydroxytryptamine (5-HT, serotonin) and elucidated the expression patterns of 5-HT{sub 2} receptor subtypes in mouse osteoblasts. In the present study, we evaluated the possible involvement of 5-HT receptor subtypes and its inactivation system in MC3T3-E1 cells, an osteoblast cell line. DOI, a 5-HT{sub 2A} and 5-HT{sub 2C} receptor selective agonist, as well as 5-HT concentration-dependently increased proliferative activities of MC3T3-E1 cells in their premature period. This effect of 5-HT on cell proliferation were inhibited by ketanserin, a 5-HT{sub 2A} receptor specific antagonist. Moreover, both DOI-induced cell proliferation and phosphorylation of ERK1 and 2 proteins were inhibited by PD98059 and U0126, selective inhibitors of MEK in a concentration-dependent manner. Furthermore, treatment with fluoxetine, a 5-HT specific re-uptake inhibitor which inactivate the function of extracellular 5-HT, significantly increased the proliferative activities of MC3T3-E1 cells in a concentration-dependent manner. Our data indicate that 5-HT fill the role for proliferation of osteoblast cells in their premature period. Notably, 5-HT{sub 2A} receptor may be functionally expressed to regulate mechanisms underlying osteoblast cell proliferation, at least in part, through activation of ERK/MAPK pathways in MC3T3-E1 cells.

  5. Targeting the Serotonin 5-HT7 Receptor in the Search for Treatments for CNS Disorders: Rationale and Progress to Date.

    PubMed

    Nikiforuk, Agnieszka

    2015-04-01

    The 5-HT7 (5-hydroxytryptamine 7, serotonin 7) receptor is one of the most recently identified members of the serotonin receptor family. Pharmacological tools, including selective antagonists and, more recently, agonists, along with 5-HT7 receptor (5-HT7R) knock-out mice have revealed the involvement of this receptor in central nervous system processes. Its well-established role in controlling body temperature and regulating sleep and circadian rhythms has implicated this receptor in mood disorders. Thus, the 5-HT7R has gained much attention as a possible target for the treatment of depression. Although preclinical data support the antidepressant-like actions of 5-HT7R antagonists, their clinical efficacy has not been yet established. Other evidence has implicated the 5-HT7R in learning and memory. Preclinical findings suggest that blockade of this receptor may be beneficial against schizophrenia-like cognitive deficits. Other possible indications include nociception, epilepsy, migraine, autism spectrum disorders, and Rett Syndrome. However, the question is whether the beneficial effects may be achieved by activation or blockade of 5-HT7Rs. Hence, this review briefly summarises the recent findings on the role of 5-HT7Rs and their ligands in CNS disorders. PMID:25721336

  6. Functional evidence for the rapid desensitization of 5-HT(3) receptors on vagal afferents mediating the Bezold-Jarisch reflex

    NASA Technical Reports Server (NTRS)

    Whalen, E. J.; Johnson, A. K.; Lewis, S. J.

    2000-01-01

    The aim of this study was to determine whether 5-hydroxytryptamine (5-HT)(3) receptors on cardiopulmonary afferents mediating the Bezold-Jarisch reflex (BJR) desensitize upon repeated exposure to selective agonists. BJR-mediated falls in heart rate, diastolic arterial blood pressure and cardiac output elicited by the 5-HT(3)-receptor agonists, phenylbiguanide (100 microg/kg, i.v.) or 2-methyl-5-HT (100 microg/kg, i.v.), progressively diminished upon repeated injection in conscious rats. The BJR responses elicited by 5-HT (40 microg/kg, i.v.) were markedly reduced in rats which had received the above injections of phenylbiguanide or 2-methyl-5-HT whereas the BJR responses elicited by L-S-nitrosocysteine (10 micromol/kg, i.v.) were similar before and after the injections of the 5-HT(3) receptor agonists. These findings suggest that tachyphylaxis to 5-HT(3) receptor agonists may be due to the desensitization of 5-HT(3) receptors on cardiopulmonary afferents rather than the impairment of the central or peripheral processing of the BJR.

  7. Activation of 5-HT3 receptors leads to altered responses 6 months after MDMA treatment.

    PubMed

    Gyongyosi, Norbert; Balogh, Brigitta; Katai, Zita; Molnar, Eszter; Laufer, Rudolf; Tekes, Kornelia; Bagdy, Gyorgy

    2010-03-01

    The recreational drug "Ecstasy" [3,4-methylenedioxymethamphetamine (MDMA)] has a well-characterised neurotoxic effect on the 5-hydroxytryptamine (5-HT) neurons in animals. Despite intensive studies, the long-term functional consequencies of the 5-HT neurodegeneration remains elusive. The aim of this study was to investigate whether any alteration of 5-hydroxytryptamine-3 (5-HT(3)) receptor functions on the sleep-wake cycle, motor activity, and quantitative EEG could be detected 6 months after a single dose of 15 mg/kg of MDMA. The selective 5-HT(3) receptor agonist m-chlorophenylbiguanide (mCPBG; 1 mg/kg, i.p.) or vehicle was administered to freely moving rats pre-treated with MDMA (15 mg/kg, i.p.) or vehicle 6 months earlier. Polysomnographic and motor activity recordings were performed. Active wake (AW), passive wake (PW), light slow wave sleep (SWS-1), deep slow wave sleep (SWS-2), and paradoxical sleep were classified. In addition, EEG power spectra were calculated for the second hour after mCPBG treatment for each stage. AW increased and SWS-1 decreased in the second hour after mCPBG treatment in control animals. mCPBG caused significant changes in the EEG power in states with cortical activation (AW, PW, paradoxical sleep). In addition, mCPBG had a biphasic effect on hippocampal theta power in AW with a decrease in 7 Hz and a stage-selective increase in the upper range (8-9 Hz). Effects of mCPBG on the time spent in AW and SWS-1 were eliminated or reduced in MDMA-treated animals. In addition, mCPBG did not increase the upper theta power of AW in rats pre-treated with MDMA. These data suggest long-term changes in 5-HT(3) receptor function after MDMA. PMID:20052506

  8. 5-Hydroxytryptamine(1F) receptors do not participate in vasoconstriction: lack of vasoconstriction to LY344864, a selective serotonin(1F) receptor agonist in rabbit saphenous vein.

    PubMed

    Cohen, M L; Schenck, K

    1999-09-01

    Recently, several novel approaches to the treatment of migraine have been advanced, including selective 5-hydroxytryptamine (or serotonin) 1B/1D (5-HT(1B/1D)) receptor agonists such as sumatriptan and 5-HT(1F) receptor agonists such as LY344864. Many 5-HT(1B/1D) receptor agonists have been identified based on their ability to produce cerebral vascular contraction, whereas LY344864 was identified as an inhibitor of trigeminal nerve-mediated dural extravasation. In our study, several triptan derivatives were compared with LY344864 for their ability to contract the rabbit saphenous vein, a tissue used in the preclinical identification of sumatriptan-related agonists. Sumatriptan, zolmitriptan, rizatriptan, and naratriptan all contracted the rabbit saphenous vein from baseline tone, whereas LY344864 in concentrations up to 10(-4) M did not contract the rabbit saphenous vein. Furthermore, vascular contractions to sumatriptan were markedly augmented in the presence of prostaglandin F(2alpha) (PGF(2alpha)). However, even in the presence of PGF(2alpha) (3 x 10(-7) M), LY344864 did not contract the rabbit saphenous vein in concentrations well in excess of its 5-HT(1F) receptor affinity (pK(i) = 8.2). Only when concentrations exceeded those likely to activate 5-HT(1B) and 5-HT(1D) receptors (>10(-5) M) did modest contractile responses occur in the presence of PGF(2alpha). Use of these serotonergic agonists revealed a significant correlation between the contractile potency in the rabbit saphenous vein and the affinities of these agonists at 5-HT(1B) and 5-HT(1D) receptors, although contractile agonist potencies were not quantitatively similar to 5-HT(1B) or 5-HT(1D) receptor affinities. In contrast, no significant correlation existed between the contractile potencies of these serotonergic agonists in the rabbit saphenous vein and their affinity at 5-HT(1F) receptors. These data support the contention that activation of 5-HT(1F) receptors will not result in vascular

  9. Postnatal maintenance of the 5-Ht1a-Pet1 autoregulatory loop by serotonin in the raphe nuclei of the brainstem

    PubMed Central

    2014-01-01

    Background Despite the importance of 5-HT1A as a major target for the action of several anxiolytics/antidepressant drugs, little is known about its regulation in central serotonin (5-hydroxytryptamine, 5-HT) neurons. Results We report that expression of 5-HT1A and the transcription factor Pet1 was impaired in the rostral raphe nuclei of mice lacking tryptophan hydroxylase 2 (Tph2) after birth. The downregulation of Pet1 was recapitulated in 5-Ht1a -/- mice. Using an explant culture system, we show that reduction of Pet1 and 5-HT1A was rescued in Tph2 -/- brainstem by exogenous 5-HT. In contrast, 5-HT failed to rescue reduced expression of Pet1 in 5-Ht1a -/- brainstem explant culture. Conclusions These results suggest a causal relationship between 5-HT1A and Pet1, and reveal a potential mechanism by which 5-HT1A-Pet1 autoregulatory loop is maintained by 5-HT in a spatiotemporal-specific manner during postnatal development. Our results are relevant to understanding the pathophysiology of certain psychiatric and developmental disorders. PMID:24972638

  10. A protein tyrosine kinase receptor, c-RET signaling pathway contributes to the enteric neurogenesis induced by a 5-HT4 receptor agonist at an anastomosis after transection of the gut in rodents.

    PubMed

    Goto, Kei; Kawahara, Isao; Kuniyasu, Hiroki; Takaki, Miyako

    2015-07-01

    We previously reported that a serotonin 4 (5-HT4) receptor agonist, mosapride citrate (MOS), increased the number of c-RET-positive cells and levels of c-RET mRNA in gel sponge implanted in the necks of rats. The 5-HT4 receptor is a G protein coupled receptor (GPCR) coupled to G protein Gs-cAMP cascades. We investigated the possibility that 5-HT4 receptor activation induced c-RET activation and/or PKA activation by elevating cAMP levels. Rodents were orally administered MOS by adding it to drinking water for 2 weeks after enteric nerve circuit insult via gut transection and anastomosis, together with the RET inhibitors withaferin A (WA) and RPI-1 or the PKA inhibitor H89. We then examined PGP9.5-positive cells in the newly formed granulation tissue at the anastomotic site. MOS significantly increased the number of new neurons, but not when co-administered with WA or RPI-1. Co-administration of H89 failed to alter MOS-induced increases in neurogenesis. In conclusion, the c-RET signaling pathway contributes to enteric neurogenesis facilitated by MOS, though the contribution of PKA activation seems unlikely. PMID:25850922

  11. The 5-HT(7) receptor in learning and memory.

    PubMed

    Roberts, Amanda J; Hedlund, Peter B

    2012-04-01

    The 5-HT(7) receptor is a more recently discovered G-protein-coupled receptor for serotonin. The functions and possible clinical relevance of this receptor are not yet fully understood. The present paper reviews to what extent the use of animal models of learning and memory and other techniques have implicated the 5-HT(7) receptor in such processes. The studies have used a combination of pharmacological and genetic tools targeting the receptor to evaluate effects on behavior and cellular mechanisms. In tests such as the Barnes maze, contextual fear conditioning and novel location recognition that involve spatial learning and memory there is a considerable amount of evidence supporting an involvement of the 5-HT(7) receptor. Supporting evidence has also been obtained in studies of mRNA expression and cellular signaling as well as in electrophysiological experiments. Especially interesting are the subtle but distinct effects observed in hippocampus-dependent models of place learning where impairments have been described in mice lacking the 5-HT(7) receptor or after administration of a selective antagonist. While more work is required, it appears that 5-HT(7) receptors are particularly important in allocentric representation processes. In instrumental learning tasks both procognitive effects and impairments in memory have been observed using pharmacological tools targeting the 5-HT(7) receptor. In conclusion, the use of pharmacological and genetic tools in animal studies of learning and memory suggest a potentially important role for the 5-HT(7) receptor in cognitive processes. PMID:21484935

  12. Memory formation, amnesia, improved memory and reversed amnesia: 5-HT role.

    PubMed

    Perez-Garcia, G; Meneses, A

    2008-12-16

    Traditionally, the search for memory circuits has been focused on examinations of amnesic and AD patients, cerebral lesions and neuroimaging. A complementary alternative has become the use of autoradiography with radioligands, aiming to identify neurobiological markers associated with memory formation, amnesia states and (more recently) recovery from memory deficits. Indeed, ex vivo autoradiographic studies offer the advantage of detecting functionally active receptors altered by pharmacological tools during memory formation, amnesia states and memory recovery. Moreover, serotonin (5-hydroxytryptamine, 5-HT) systems have become a pharmacological and genetic target in the treatment of memory disorders. Herein evidence from studies involving expression of 5-HT(1A), 5-HT(2A), 5-HT(4), and 5-HT(6) receptors in memory formation, amnesia conditions (e.g., pharmacological models or aging) and recovery of memory is reviewed. Thus, specific 5-HT receptors were expressed in trained animals relative to untrained in brain areas such as cortex, hippocampus and amygdala. However, relative to the control group, rats showing amnesia or recovered memory, showed in the hippocampus, region where explicit memory is formed, a complex pattern of 5-HT receptor expression. An intermediate expression occurred in amygdala, septum and some cortical areas in charge of explicit memory storage. Even in brain areas thought to be in charge of procedural memory such as basal ganglia, animals showing recovered memory displayed an intermediate expression, while amnesic groups, depending on the pharmacological amnesia model, showed up- or down-regulation. In conclusion, evidence indicates that autoradiography, by using specific radioligands, offers excellent opportunities to map dynamic changes in brain areas engaged in these cognitive processes. The 5-HT modulatory role strengthens or suppresses memory is critically depend on the timing of the memory formation. PMID:18221797

  13. 5-HT6 Receptor Antagonists: Potential Efficacy for the Treatment of Cognitive Impairment in Schizophrenia.

    PubMed

    de Bruin, Natasja M W J; Kruse, Chris G

    2015-01-01

    5-hydroxytryptamine6 receptor (5-HT6R) antagonists have shown efficacy in animal models for cognitive impairment in multiple cognitive domains relevant for schizophrenia. Improvements were found with 5-HT6R antagonists in preclinical tests for episodic memory, social cognition, executive function, working memory and several other tests for both learning and memory. In contrast, there is little evidence for efficacy on attention. It will be interesting to further investigate 5-HT6R antagonists in neurodevelopmental animal models which are based on prenatal exposure to specific environmental insults, and are characterized by a high level of face, construct and predictive validity for cognitive impairments associated with schizophrenia. It is also important to do more add-on preclinical studies of 5-HT6 antagonists with antipsychotics. Possible mechanisms of action to improve cognition have been described. 5-HT6R antagonists decrease GABA release and GABAergic interneuron excitability, which subsequently disinhibits glutamate and/or acetylcholine release and results in enhancement of synaptic plasticity. Furthermore, cognition could be improved by 5-HT6R antagonists, because these compounds increase the number of NCAM PSA-immunoreactive neurons in the dendate gyrus, inhibit mTOR and Fyn-tyrosine kinase and interact with DARPP-32. Interestingly, there is increasing preclinical evidence that could support additional benefits of 5-HT6R ligandson comorbid conditions in schizophrenia such as drug abuse, depression, anxiety, obesity andantipsychotic-induced EPS. Finally, we briefly give an overview of the 5-HT6R compounds that are currently in clinical development for the treatment of cognitive impairment in both schizophrenia and Alzheimer's disease. PMID:26044973

  14. 5-HT3 receptors as important mediators of nausea and vomiting due to chemotherapy.

    PubMed

    Navari, Rudolph M

    2015-10-01

    Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. The use of a combination of a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, dexamethasone, and a neurokinin-1 (NK-1) receptor antagonist has significantly improved the control of acute and delayed emesis in single-day chemotherapy. The first generation 5-HT3 receptor antagonists have been very effective in the control of chemotherapy induced emesis in the first 24 h postchemotherapy (acute emesis), but have not been as effective against delayed emesis (24-120 h postchemotherapy). Palonosetron, a second generation 5-HT3 receptor antagonist with a different half-life, a different binding capacity, and a different mechanism of action than the first generation 5-HT3 receptor antagonists appears to be the most effective agent in its class. Despite the control of emesis, nausea has not been well controlled by current agents. Olanzapine, a FDA approved antipsychotic that blocks multiple neurotransmitters: dopamine at D1, D2, D3, D4 brain receptors, serotonin at 5-HT2a, 5-HT2c, 5-HT3, 5-HT6 receptors, catecholamines at alpha1 adrenergic receptors, acetylcholine at muscarinic receptors, and histamine at H1 receptors, has emerged in recent trials as an effective preventative agent for chemotherapy-induced emesis and nausea, as well as a very effective agent for the treatment of breakthrough emesis and nausea. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID:25838122

  15. Characterization of putative 5-HT7 receptors mediating tachycardia in the cat

    PubMed Central

    Villalón, Carlos M; Heiligers, Jan P C; Centurión, David; De Vries, Peter; Saxena, Pramod R

    1997-01-01

    It has been suggested that the tachycardic response to 5-hydroxytryptamine (5-HT) in the spinal-transected cat is mediated by ‘5-HT1-like' receptors since this effect, being mimicked by 5-carboxamidotryptamine (5-CT), is not modified by ketanserin or MDL 72222, but it is blocked by methiothepin, methysergide or mesulergine. The present study was set out to reanalyse this suggestion in terms of the IUPHAR 5-HT receptor classification schemes proposed in 1994 and 1996. Intravenous (i.v.) bolus injections of the tryptamine derivatives, 5-CT (0.01, 0.03, 0.1, 0.3, 1, 3, 10 and 30 μg kg−1), 5-HT (3, 10 and 30 μg kg−1) and 5-methoxytryptamine (3, 10 and 30 μg kg−1) as well as the atypical antipsychotic drug, clozapine (1000 and 3000 μg kg−1) resulted in dose-dependent increases in heart rate, with a rank order of agonist potency of 5-CT >> 5-HT > 5-methoxytryptamine >> clozapine. The tachycardic effects of 5-HT and 5-methoxytryptamine were dose-dependently antagonized by i.v. administration of lisuride (30 and 100 μg kg−1), ergotamine (100 and 300 μg kg−1) or mesulergine (100, 300 and 1000 μg kg−1); the highest doses of these antagonists used also blocked the tachycardic effects of 5-CT. Clozapine (1000 and 3000 μg kg−1) did not affect the 5-HT-induced tachycardia, but attenuated, with its highest dose, the responses to 5-methoxytryptamine and 5-CT. However, these doses of clozapine as well as the high doses of ergotamine (300 μg kg−1) and mesulergine (300 and 1000 μg kg−1) also attenuated the tachycardic effects of isoprenaline. In contrast, 5-HT-, 5-methoxytryptamine- and 5-CT-induced tachycardia were not significantly modified after i.v. administration of physiological saline (0.1 and 0.3 ml kg−1), the 5-HT1B/1D receptor antagonist, GR127935 (500 μg kg−1) or the 5-HT3/4 receptor antagonist, tropisetron (3000 μg kg−1). Intravenous injections of the 5-HT1 receptor agonists

  16. 5-HT1B receptor modulation of the serotonin transporter in vivo: studies using KO mice.

    PubMed

    Montañez, Sylvia; Munn, Jaclyn L; Owens, W Anthony; Horton, Rebecca E; Daws, Lynette C

    2014-07-01

    The serotonin transporter (SERT) controls the strength and duration of serotonergic neurotransmission by the high-affinity uptake of serotonin (5-HT) from extracellular fluid. SERT is a key target for many psychotherapeutic and abused drugs, therefore understanding how SERT activity and expression are regulated is of fundamental importance. A growing literature suggests that SERT activity is under regulatory control of the 5-HT1B autoreceptor. The present studies made use of mice with a constitutive reduction (5-HT1B+/-) or knockout of 5-HT1B receptors (5-HT1B-/-), as well as mice with a constitutive knockout of SERT (SERT-/-) to further explore the relationship between SERT activity and 5-HT1B receptor expression. High-speed chronoamperometry was used to measure clearance of 5-HT from CA3 region of hippocampus in vivo. Serotonin clearance rate, over a range of 5-HT concentrations, did not differ among 5-HT1B receptor genotypes, nor did [(3)H]cyanoimipramine binding to SERT in this brain region, suggesting that SERT activity is not affected by constitutive reduction or loss of 5-HT1B receptors; alternatively, it might be that other transport mechanisms for 5-HT compensate for loss of 5-HT1B receptors. Consistent with previous reports, we found that the 5-HT1B receptor antagonist, cyanopindolol, inhibited 5-HT clearance in wild-type mice. However, this effect of cyanopindolol was lost in 5-HT1B-/- mice and diminished in 5-HT1B+/- mice, indicating that the 5-HT1B receptor is necessary for cyanopindolol to inhibit 5-HT clearance. Likewise, cyanopindolol was without effect on 5-HT clearance in SERT-/- mice, demonstrating a requirement for the presence of both SERT and 5-HT1B receptors in order for cyanopindolol to inhibit 5-HT clearance in CA3 region of hippocampus. Our findings are consistent with SERT being under the regulatory control of 5-HT1B autoreceptors. Future studies to identify signaling pathways involved may help elucidate novel therapeutic targets for the

  17. The role of serotonin 5-HT2A receptors in memory and cognition

    PubMed Central

    Zhang, Gongliang; Stackman, Robert W.

    2015-01-01

    Serotonin 5-HT2A receptors (5-HT2ARs) are widely distributed in the central nervous system, especially in brain region essential for learning and cognition. In addition to endogenous 5-HT, several hallucinogens, antipsychotics, and antidepressants function by targeting 5-HT2ARs. Preclinical studies show that 5-HT2AR antagonists have antipsychotic and antidepressant properties, whereas agonist ligands possess cognition-enhancing and hallucinogenic properties. Abnormal 5-HT2AR activity is associated with a number of psychiatric disorders and conditions, including depression, schizophrenia, and drug addiction. In addition to its traditional activity as a G protein-coupled receptor (GPCR), recent studies have defined novel operations of 5-HT2ARs. Here we review progress in the (1) receptor anatomy and biology: distribution, signaling, polymerization and allosteric modulation; and (2) receptor functions: learning and memory, hallucination and spatial cognition, and mental disorders. Based on the recent progress in basic research on the 5-HT2AR, it appears that post-training 5-HT2AR activation enhances non-spatial memory consolidation, while pre-training 5-HT2AR activation facilitates fear extinction. Further, the potential influence that 5-HT2AR-elicited visual hallucinations may have on visual cue (i.e., landmark) guided spatial cognition is discussed. We conclude that the development of selective 5-HT2AR modulators to target distinct signaling pathways and neural circuits represents a new possibility for treating emotional, neuropsychiatric, and neurodegenerative disorders. PMID:26500553

  18. Role of Central Serotonin in Anticipation of Rewarding and Punishing Outcomes: Effects of Selective Amygdala or Orbitofrontal 5-HT Depletion.

    PubMed

    Rygula, Rafal; Clarke, Hannah F; Cardinal, Rudolf N; Cockcroft, Gemma J; Xia, Jing; Dalley, Jeff W; Robbins, Trevor W; Roberts, Angela C

    2015-09-01

    Understanding the role of serotonin (or 5-hydroxytryptamine, 5-HT) in aversive processing has been hampered by the contradictory findings, across studies, of increased sensitivity to punishment in terms of subsequent response choice but decreased sensitivity to punishment-induced response suppression following gross depletion of central 5-HT. To address this apparent discrepancy, the present study determined whether both effects could be found in the same animals by performing localized 5-HT depletions in the amygdala or orbitofrontal cortex (OFC) of a New World monkey, the common marmoset. 5-HT depletion in the amygdala impaired response choice on a probabilistic visual discrimination task by increasing the effectiveness of misleading, or false, punishment and reward, and decreased response suppression in a variable interval test of punishment sensitivity that employed the same reward and punisher. 5-HT depletion in the OFC also disrupted probabilistic discrimination learning and decreased response suppression. Computational modeling of behavior on the discrimination task showed that the lesions reduced reinforcement sensitivity. A novel, unitary account of the findings in terms of the causal role of 5-HT in the anticipation of both negative and positive motivational outcomes is proposed and discussed in relation to current theories of 5-HT function and our understanding of mood and anxiety disorders. PMID:24879752

  19. Effects of white spirits on rat brain 5-HT receptor functions and synaptic remodeling.

    PubMed

    Lam, H R; Plenge, P; Jørgensen, O S

    2001-01-01

    Previously, inhalation exposure to different types of white spirit (i.e. complex mixtures of aliphatic, aromatic, alkyl aromatic, and naphthenic hydrocarbons) has been shown to induce neurochemical effects in rat brains. Especially, the serotonergic system was involved at the global, regional, and subcellular levels. This study investigates the effects of two types of white spirit on 5-hydroxytryptamine (5-HT) transporters (5-HTT), 5-HT(2A) and 5-HT(4) receptor expression in forebrain, and on neural cell adhesion molecule (NCAM) and 25-kDa synaptosomal associated protein (SNAP-25) concentrations when applied as indices for synaptic remodeling in forebrain, hippocampus, and entorhinal cortex. Male Wistar rats were exposed to 0, 400, or 800 ppm of aromatic (20 vol.% aromatic hydrocarbons) or dearomatized white spirit (catalytically hydrogenated white spirit) in the inhaled air for 6 h/day, 7 days/week for 3 weeks. The 5-HTT B(max) and K(d) were not affected. Both types of white spirit at 800 ppm decreased B(max) for the 5-HT(2A) receptor. The aromatic type decreased the K(d) of the 5-HT(2A) and 5-HT(4) receptors at 800 ppm. Aromatic white spirit did not affect NCAM or SNAP-25 concentrations or NCAM/SNAP-25 ratio in forebrain, whereas NCAM increased in hippocampus and the NCAM/SNAP-25 ratio decreased in entorhinal cortex. Dearomatized white spirit did not affect NCAM, SNAP-25, or NCAM/SNAP-25 ratio in any brain region. The affected 5-HT receptor expression and synaptic plasticity marker proteins indicate that inhalation exposure to high concentrations of white spirit may be neurotoxic to rats, especially the aromatic white spirit type. PMID:11792528

  20. Increased extracellular dopamine and 5-hydroxytryptamine levels contribute to enhanced subthalamic nucleus neural activity during exhausting exercise.

    PubMed

    Hu, Y; Liu, X; Qiao, D

    2015-09-01

    The purpose of the study was to explore the mechanism underlying the enhanced subthalamic nucleus (STN) neural activity during exhausting exercise from the perspective of monoamine neurotransmitters and changes of their corresponding receptors. Rats were randomly divided into microdialysis and immunohistochemistry study groups. For microdialysis study, extracellular fluid of the STN was continuously collected with a microdialysis probe before, during and 90 min after one bout of exhausting exercise. Dopamine (DA) and 5-hydroxytryptamine (5-HT) levels were subsequently detected with high-performance liquid chromatography (HPLC). For immunohistochemistry study, the expression of DRD2 and HT2C receptors in the STN, before, immediately after and 90 min after exhaustion was detected through immunohistochemistry technique. Microdialysis study results showed that the extracellular DA and 5-HT neurotransmitters increased significantly throughout the procedure of exhausting exercise and the recovery period (P<0.05 or P<0.01). Immunohistochemistry study results showed that the expression levels of DRD2 and HT2C in the rat STN immediately after exhausting exercise and at the time point of 90 min after exhaustion were both higher than those of the rest condition, but the difference was not significant (P>0.05). Our results suggest that the increased extracellular DA and 5-HT in the STN might be one important factor leading to the enhanced STN neural activity and the development of fatigue during exhausting exercise. This study may essentially offer useful evidence for better understanding of the mechanism of the central type of exercise-induced fatigue. PMID:26424920

  1. Tong Xie Yao Fang relieves irritable bowel syndrome in rats via mechanisms involving regulation of 5-hydroxytryptamine and substance P

    PubMed Central

    Yin, Yue; Zhong, Lei; Wang, Jian-Wei; Zhao, Xue-Ying; Zhao, Wen-Jing; Kuang, Hai-Xue

    2015-01-01

    AIM: To investigate whether the Chinese medicine Tong Xie Yao Fang (TXYF) improves dysfunction in an irritable bowel syndrome (IBS) rat model. METHODS: Thirty baby rats for IBS modeling were separated from mother rats (1 h per day) from days 8 to 21, and the rectum was expanded by angioplasty from days 8 to 12. Ten normal rats were used as normal controls. We examined the effects of TXYF on defection frequency, colonic transit function and smooth muscle contraction, and the expression of 5-hydroxytryptamine (5-HT) and substance P (SP) in colonic and hypothalamus tissues by Western blot and RT-PCT techniques in both normal rats and IBS model rats with characterized visceral hypersensitivity. RESULTS: Defecation frequency was 1.8 ± 1.03 in normal rats and 4.5 ± 1.58 in IBS model rats (P < 0.001). However, the defecation frequency was significantly decreased (3.0 ± 1.25 vs 4.5 ± 1.58, P < 0.05), while the time (in seconds) of colon transit function was significantly increased (256.88 ± 20.32 vs 93.36 ± 17.28, P < 0.001) in IBS + TXYF group rats than in IBS group rats. Increased colonic smooth muscle tension and contract frequency in IBS model rats were significantly decreased by administration of TXYF. Exogenous agonist stimulants increased spontaneous activity and elicited contractions of colon smooth muscle in IBS model rats, and all of these actions were significantly reduced by TXYF involving 5-HT and SP down-regulation. CONCLUSION: TXYF can modulate the activity of the enteric nervous system and alter 5-HT and SP activities, which may contribute to the symptoms of IBS. PMID:25914462

  2. Changes in 5-hydroxytryptamine and cortisol plasma levels in menopausal women after inhalation of clary sage oil.

    PubMed

    Lee, Kyung-Bok; Cho, Eun; Kang, Young-Sook

    2014-11-01

    The purpose of this study was to examine the antidepressant-like effects of clary sage oil on human beings by comparing the neurotransmitter level change in plasma. The voluntary participants were 22 menopausal women in 50's. Subjects were classified into normal and depression tendency groups using each of Korean version of Beck Depression Inventory-I (KBDI-I), KBDI-II, and Korean version of Self-rating Depression Scale. Then, the changes in neurotransmitter concentrations were compared between two groups. After inhalation of clary sage oil, cortisol levels were significantly decreased while 5-hydroxytryptamine (5-HT) concentration was significantly increased. Thyroid stimulating hormone was also reduced in all groups but not statistically significantly. The different change rate of 5-HT concentration between normal and depression tendency groups was variable according to the depression measurement inventory. When using KBDI-I and KBDI-II, 5-HT increased by 341% and 828% for the normal group and 484% and 257% for the depression tendency group, respectively. The change rate of cortisol was greater in depression tendency groups compared with normal groups, and this difference was statistically significant when using KBDI-II (31% vs. 16% reduction) and Self-rating Depression Scale inventory (36% vs. 8.3% reduction). Among three inventories, only KBDI-II differentiated normal and depression tendency groups with significantly different cortisol level. Finally, clary sage oil has antidepressant-like effect, and KBDI-II inventory may be the most sensitive and valid tool in screening for depression status or severity. PMID:24802524

  3. Depressive behavior and alterations in receptors for dopamine and 5-hydroxytryptamine in the brain of the senescence accelerated mouse (SAM)-P10.

    PubMed

    Onodera, T; Watanabe, R; Tha, K K; Hayashi, Y; Murayama, T; Okuma, Y; Ono, C; Oketani, Y; Hosokawa, M; Nomura, Y

    2000-08-01

    The senescence accelerated mouse (SAM) is known as a murine model of aging. SAM consists of senescence accelerated-prone mouse (SAMP) and senescence accelerated-resistant mouse (SAMR). Previous studies reported that SAMP10 exhibits age-related learning impairments and behavioral depression in a tail suspension test after 7 months. We investigated the changes in emotional behavior in a forced swimming test and in receptors for dopamine and 5-hydroxytryptamine (5-HT) in SAMP10. SAMP10 at 8 months showed an increase of immobility in the test compared with SAMR1. Treatment with desipramine (25 mg/kg, i.p., 3 days) in SAMP10 caused a decrease in immobility. In the cortex from SAMP10, [3H]quinpirole binding to D2/D3 dopamine receptors increased significantly compared with control SAMR1. In the hippocampus from SAMP10, [3H]8-hydroxy DPAT binding to 5-HT1A receptor increased. In midbrains from SAMP10, bindings of [3H]quinpirole and [3H]8-hydroxy DPAT increased. [3H]SCH23390 binding to D1/D5 receptors and [3H]ketanserin binding to 5-HT2 receptor in brain regions examined in SAMP10 were similar to those in SAMR1. The present findings represent the first neurochemical evidence of an increase of D2/D3 and 5-HT1A receptors in SAMP10. SAMP10 may be a useful model of aging associated depressive behavior. PMID:11001177

  4. Sensitive determination of norepinephrine, epinephrine, dopamine and 5-hydroxytryptamine by coupling HPLC with [Ag(HIO6 )2 ](5-) -luminol chemiluminescence detection.

    PubMed

    Wu, Dong; Xie, He; Lu, Haifeng; Li, Wei; Zhang, Qunlin

    2016-09-01

    Based on the enhancing effects of norepinephrine (NE), epinephrine (EP), dopamine (DA) and 5-hydroxytryptamine (5-HT) on the chemiluminescence (CL) reaction between [Ag(HIO6 )2 ](5-) and luminol in alkaline solution, a high-performance liquid chromatography (HPLC) method with CL detection was explored for the sensitive determination of monoamine neurotransmitters for the first time. The UV-visible absorption spectra were recorded to study the enhancement mechanism of monoamine neurotransmitters on the CL of [Ag(HIO6 )2 ](5-) and luminol reaction. The HPLC separation of NE, EP, DA and 5-HT was achieved with isocratic elution using a mixture of aqueous 0.2% phosphoric acid and methanol (5:95, v/v) within 11.0 min. Under the optimized conditions, the detection limits of NE, EP, DA, and 5-HT were 4.8, 0.9, 1.9 and 2.3 ng/mL, respectively, corresponding to 17.6-96.0 pg for 20 μL sample injection. The recoveries of monoamine neurotransmitters in rat brain were >95.6% with the precisions expressed by RSD <5.0%. The validated HPLC-CL method was successfully applied for the quantification of NE, EP, DA and 5-HT in rat brain. This method has promising potential for some biological and clinical investigations focusing on the levels of monoamine neurotransmitters. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26876580

  5. A Chemocentric Informatics Approach to Drug Discovery: Identification and Experimental Validation of Selective Estrogen Receptor Modulators as ligands of 5-Hydroxytryptamine-6 Receptors and as Potential Cognition Enhancers

    PubMed Central

    Hajjo, Rima; Setola, Vincent; Roth, Bryan L.; Tropsha, Alexander

    2012-01-01

    We have devised a chemocentric informatics methodology for drug discovery integrating independent approaches to mining biomolecular databases. As a proof of concept, we have searched for novel putative cognition enhancers. First, we generated Quantitative Structure- Activity Relationship (QSAR) models of compounds binding to 5-hydroxytryptamine-6 receptor (5HT6R), a known target for cognition enhancers, and employed these models for virtual screening to identify putative 5-HT6R actives. Second, we queried chemogenomics data from the Connectivity Map (http://www.broad.mit.edu/cmap/) with the gene expression profile signatures of Alzheimer’s disease patients to identify compounds putatively linked to the disease. Thirteen common hits were tested in 5-HT6R radioligand binding assays and ten were confirmed as actives. Four of them were known selective estrogen receptor modulators that were never reported as 5-HT6R ligands. Furthermore, nine of the confirmed actives were reported elsewhere to have memory-enhancing effects. The approaches discussed herein can be used broadly to identify novel drug-target-disease associations. PMID:22537153

  6. Mapping the binding site pocket of the serotonin 5-Hydroxytryptamine2A receptor. Ser3.36(159) provides a second interaction site for the protonated amine of serotonin but not of lysergic acid diethylamide or bufotenin.

    PubMed

    Almaula, N; Ebersole, B J; Zhang, D; Weinstein, H; Sealfon, S C

    1996-06-21

    Like other amine neurotransmitters that activate G-protein-coupled receptors, 5-hydroxytryptamine (5-HT) binds to the 5-HT2A receptor through the interaction of its cationic primary amino group with the conserved Asp3.32(155) in transmembrane helix 3. Computational experiments with a 5-HT2A receptor model suggest that the same functional group of 5-hydroxytryptamine also forms a hydrogen bond with the side chain of Ser3.36(159), which is adjacent in space to Asp3.32(155). However, other 5-HT2A receptor ligands like lysergic acid diethylamide (LSD), in which the amine nitrogen is embedded in a heterocycle, or N,N-dimethyl 5-HT, in which the side chain is a tertiary amine, are found in the computational simulations to interact with the aspartate but not with the serine, due mainly to steric hindrance. The predicted difference in the interaction of various ligands in the same receptor binding pocket was tested with site-directed mutagenesis of Ser3.36(159) --> Ala and Ser3.36(159) --> Cys. The alanine substitution led to an 18-fold reduction in 5-HT affinity and the cysteine substitution to an intermediate 5-fold decrease. LSD affinity, in contrast, was unaffected by either mutation. N,N-Dimethyl 5-HT affinity was unaffected by the cysteine mutation and had a comparatively small 3-fold decrease in affinity for the alanine mutant. These findings identify a mode of ligand-receptor complexation that involves two receptor side chains interacting with the same functional group of specific serotonergic ligands. This interaction serves to orient the ligands in the binding pocket and may influence the degree of receptor activation. PMID:8663249

  7. Pharmacological profiles of presynaptic nociceptin/orphanin FQ receptors modulating 5-hydroxytryptamine and noradrenaline release in the rat neocortex

    PubMed Central

    Marti, Matteo; Stocchi, Sara; Paganini, Francesca; Mela, Flora; Risi, Carmela De; Calo', Girolamo; Guerrini, Remo; Barnes, Timothy A; Lambert, David G; Beani, Lorenzo; Bianchi, Clementina; Morari, Michele

    2003-01-01

    The pharmacological profiles of presynaptic nociceptin/orphanin FQ (N/OFQ) peptide receptors (NOP) modulating 5-hydroxytryptamine (5-HT) and noradrenaline (NE) release in the rat neocortex were characterized in a preparation of superfused synaptosomes challenged with 10 mM KCl. N/OFQ concentration-dependently inhibited K+-evoked [3H]-5-HT and [3H]-NE overflow with similar potency (pEC50 ∼7.9 and ∼7.7, respectively) and efficacy (maximal inhibition ∼40%). N/OFQ (0.1 μM) inhibition of [3H]-5-HT and [3H]-NE overflow was antagonized by selective NOP receptor antagonists of peptide ([Nphe1]N/OFQ(1-13)NH2 and UFP-101; 10 and 1 μM, respectively) and non-peptide (J-113397 and JTC-801; both 0.1 μM) nature. Antagonists were routinely applied 3 min before N/OFQ. However, a 21 min pre-application time was necessary for J-113397 and JTC-801 to prevent N/OFQ inhibition of [3H]-NE overflow. The NOP receptor ligand [Phe1ψ(CH2-NH)Gly2]N/OFQ(1-13)NH2 ([F/G]N/OFQ(1-13)NH2; 3 μM) did not affect K+-evoked [3H]-NE but inhibited K+-evoked [3H]-5-HT overflow in a UFP-101 sensitive manner. [F/G]N/OFQ(1-13)NH2 antagonized N/OFQ actions on both neurotransmitters. The time-dependency of JTC-801 action was studied in CHO cells expressing human NOP receptors. N/OFQ inhibited forskolin-stimulated cAMP accumulation and JTC-801, tested at different concentrations (0.1–10 μM) and pre-incubation times (0, 40 and 90 min), antagonized this effect in a time-dependent manner. The Schild-type analysis excluded a competitive type of antagonism. We conclude that presynaptic NO receptors inhibiting 5-HT and NE release in the rat neocortex have similar pharmacological profiles. Nevertheless, they can be differentiated pharmacologically on the basis of responsiveness to [F/G]N/OFQ(1-13)NH2 and time-dependent sensitivity towards non-peptide antagonists. PMID:12522077

  8. Dogmas and controversies in the handling of nitrogenous wastes: 5-HT2-like receptors are involved in triggering pulsatile urea excretion in the gulf toadfish, Opsanus beta.

    PubMed

    McDonald, M Danielle; Walsh, Patrick J

    2004-05-01

    When injected arterially, serotonin (5-hydroxytryptamine; 5-HT) has been shown to elicit naturally sized urea pulse events in the gulf toadfish, Opsanus beta. The goal of the present study was to determine which 5-HT receptor(s) was involved in mediating this serotonergic stimulation of the pulsatile excretion mechanism. Toadfish were surgically implanted with caudal arterial catheters and intraperitoneal catheters and injected with either 8-OH-DPAT (1 micro mol kg(-1)), a selective 5-HT(1A) receptor agonist, alpha-methyl-5-HT (1 micro mol kg(-1)), a 5-HT(2) receptor agonist, or ketanserin, a 5-HT(2) receptor antagonist (0.01, 0.1, 1 and 10 micro mol kg(-1)) plus alpha-methyl-5-HT. 8-OH-DPAT injection did not mediate an increase in urea excretion, ruling out the involvement of 5-HT(1A) receptors in pulsatile excretion. However, within 5 min, alpha-methyl-5-HT injection caused an increase in the excretion of urea in >95% (N=27) of the fish injected, with an average pulse size of 652+/-102 micro mol N kg(-1) (N=26). With alpha-methyl-5-HT injection there was no corresponding increase in ammonia or [(3)H]PEG 4000 permeability. Urea pulses elicited by alpha-methyl-5-HT were inhibited in a dose-dependent fashion by the 5-HT(2) receptor antagonist ketanserin, which at low doses caused a significant inhibition of pulse size and at higher doses significantly inhibited the occurrence of pulsatile excretion altogether. However, neither 8-OH-DPAT nor alpha-methyl 5-HT injection had an effect on plasma cortisol or plasma urea concentrations. These findings suggest the involvement of a 5-HT(2)-like receptor in the regulation of pulsatile urea excretion. PMID:15143134

  9. Time-course of 5-HT(6) receptor mRNA expression during memory consolidation and amnesia.

    PubMed

    Huerta-Rivas, A; Pérez-García, G; González-Espinosa, C; Meneses, A

    2010-01-01

    Growing evidence indicates that antagonists of the 5-hydroxytryptamine (serotonin) receptor(6) (5-HT(6)) improve memory and reverse amnesia although the mechanisms involved are poorly understood. Hence, in this paper RT-PCR was used to evaluate changes in mRNA expression of 5-HT(6) receptor in trained and untrained rats treated with the 5-HT(6) receptor antagonist SB-399885 and amnesic drugs scopolamine or dizocilpine. Changes in mRNA expression of 5-HT(6) receptor were investigated at different times in prefrontal cortex, hippocampus and striatum. Data indicated that memory in the Pavlovian/instrumental autoshaping task was a progressive process associated to reduced mRNA expression of 5-HT(6) receptor in the three structures examined. SB-399885 improved long-term memory at 48h, while the muscarinic receptor antagonist scopolamine or the non-competitive NMDA receptor antagonist dizocilpine impaired it at 24h. Autoshaping training and treatment with SB-399885 increased 5-HT(6) receptor mRNA expression in (maximum increase) prefrontal cortex and striatum, 24 or 48h. The scopolamine-induced amnesia suppressed 5-HT(6) receptor mRNA expression while the dizocilpine-induced amnesia did not modify 5-HT(6) receptor mRNA expression. SB-399885 and scopolamine or dizocilpine were able to reestablish memory and 5-HT(6) receptor mRNA expression. These data confirmed previous memory evidence and of more interest is the observation that training, SB-399885 and amnesic drugs modulated 5-HT(6) receptor mRNA expression in prefrontal cortex, hippocampus and striatum. Further investigation in different memory tasks, times and amnesia models together with more complex control groups might provide further clues. PMID:19733250

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

    PubMed

    Browne, Caleb J; Fletcher, Paul J

    2016-09-01

    Acute pharmacological elevation of serotonin (5-hydroxytryptamine; 5-HT) activity decreases operant responding for primary reinforcers, suggesting that 5-HT reduces incentive motivation. The mechanism by which 5-HT alters incentive motivation is unknown, but parallel evidence that 5-HT2C receptor agonists also reduce responding for primary reinforcers implicates this receptor as a potential candidate. These experiments examined whether chronic and acute disruptions of serotonin transporter (SERT) activity altered incentive motivation, and whether the 5-HT2C receptor mediated the effects of elevated 5-HT on behavior. To assess incentive motivation, we measured responding for three different reinforcers: a primary reinforcer (saccharin), a conditioned reinforcer (CRf), and an unconditioned sensory reinforcer (USRf). In the chronic condition, responding was compared between SERT knockout (SERT-KO) mice and their wild-type littermates. In the acute condition, responding was examined in wild-type mice following treatment with 10 or 20 mg/kg citalopram, or its vehicle. The ability of the selective 5-HT2C antagonist SB 242084 to prevent the effects of SERT-KO and citalopram on responding was subsequently examined. Both SERT-KO and citalopram reduced responding for saccharin, a CRf, and a USRf. Treatment with SB 242084 enhanced responding for a CRf and a USRf in SERT-KO mice and blocked the effects of citalopram on CRf and USRf responding. However, SB 242084 was unable to prevent the effects of SERT-KO or citalopram on responding for saccharin. These results support a powerful inhibitory function for 5-HT in the control of incentive motivation, and indicate that the 5-HT2C receptor mediates these effects of 5-HT in a reinforcer-dependent manner. PMID:27125304

  11. Involvement of N-methyl-d-aspartate receptors in the antidepressant-like effect of 5-hydroxytryptamine 3 antagonists in mouse forced swimming test and tail suspension test.

    PubMed

    Kordjazy, Nastaran; Haj-Mirzaian, Arya; Amiri, Shayan; Ostadhadi, Sattar; Amini-Khoei, Hossein; Dehpour, Ahmad Reza

    2016-02-01

    Recent evidence indicates that 5-hydroxytryptamine 3 (5-HT3) antagonists such as ondansetron and tropisetron exert positive behavioral effects in animal models of depression. Due to the ionotropic nature of 5-HT3 and N-methyl-d-aspartate (NMDA) receptors, plus their contribution to the pathophysiology of depression, we investigated the possible role of NMDA receptors in the antidepressant-like effect of 5-HT3 receptor antagonists in male mice. In order to evaluate the animals' behavior in response to different treatments, we performed open-field test (OFT), forced swimming test (FST), and tail-suspension test (TST), which are considered as valid tasks for measuring locomotor activity and depressive-like behaviors in mice. Our data revealed that intraperitoneal (i.p.) administration of tropisetron (5, 10, and 30mg/kg) and ondansetron (0.01, and 0.1μg/kg) significantly decreased the immobility time in FST and TST. Also, co-administration of subeffective doses of tropisetron (1mg/kg, i.p.) or ondansetron (0.001μg/kg, i.p.) with subeffective doses of NMDA receptor antagonists, ketamine (1mg/kg, i.p.), MK-801 (0.05mg/kg, i.p.) and magnesium sulfate (10mg/kg, i.p.) resulted in a reduced immobility time both in FST and TST. The subeffective dose of NMDA (NMDA receptor agonist, 75mg/kg, i.p.) abolished the effects of 5-HT3 antagonists in FST and TST, further supporting the presumed interaction between 5-HT3 and NMDA receptors. These treatments did not affect the locomotor behavior of animals in OFT. Finally, the results of our study suggest that the positive effects of 5-HT3 antagonists on the coping behavior of mice in FST and TST are at least partly mediated through NMDA receptors participation. PMID:26604075

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

    PubMed

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

    2015-01-01

    Brain serotonin (5-hydroxytryptamine, 5-HT) dysfunction is considered to promote food intake and eating-related disturbances, especially under stress or negative mood. Vulnerability for 5-HT disturbances is considered to be genetically determined, including a short (S) allele polymorphism in the serotonin transporter gene (5-HTTLPR) that is associated with lower serotonin function. Since 5-HT function may be slightly increased by carbohydrate consumption, S-allele 5-HTTLPR carriers in particular may benefit from a sugar-preload due to their enhanced 5-HT vulnerability. The aim of the current study was to investigate whether a sugar-containing preload may reduce appetite and energy intake after exposure to stress to induce negative mood, depending on genetic 5-HT vulnerability. From a population of 771 healthy young male and female genotyped college students 31 S/S carriers (8 males, 23 females) and 26 long allele (L/L) carriers (9 males, 17 females) (mean ± S.D. 22 ± 1.6 years; body mass index, BMI, 18-33 kg/m(2)) were monitored for changes in appetite and snacking behavior after stress exposure. Results revealed an increased energy intake after mild mental stress (negative mood) mainly for high-fat sweet foods, which was significantly greater in S/S carriers, and only in these genotypes this intake was significantly reduced by a sucrose-containing preload. Although alternative explanations are possible, it is suggested that S/S participants may have enhanced brain (hypothalamic) 5-HT responsiveness to food that makes them more susceptible to the beneficial satiation effects of a sucrose-preload as well as to the negative effects of mild mental stress on weight gain. PMID:25423193

  13. Serotonin (5-HT) 2C Receptor (5-HT2CR) Protein Expression is Enriched in Synaptosomal and Postsynaptic Compartments of Rat Cortex

    PubMed Central

    Anastasio, Noelle C.; Lanfranco, Maria Fe; Bubar, Marcy J.; Seitz, Patricia K.; Stutz, Sonja J.; McGinnis, Andrew G.; Watson, Cheryl S.; Cunningham, Kathryn A.

    2010-01-01

    The action of serotonin (5-HT) at the 5-HT2C receptor (5-HT2CR) in cerebral cortex is emerging as a candidate modulator of neural processes that mediate core phenotypic facets of several psychiatric and neurological disorders. However, our understanding of the neurobiology of the cortical 5-HT2CR protein complex is currently limited. The goal of the present study was to explore the subcellular localization of the 5-HT2CR in synaptosomes and the postsynaptic density, an electron-dense thickening specialized for postsynaptic signaling and neuronal plasticity. Utilizing multiples tissues (brain, peripheral tissues), protein fractions (synaptosomal, postsynaptic density), and controls (peptide neutralization, 5-HT2CR stable-expressing cells), we established the selectivity of two commercially available 5-HT2CR antibodies and employed the antibodies in Western blot and immunoprecipitation studies of PFC and motor cortex, two regions implicated in cognitive, emotional and motor dysfunction. For the first time, we demonstrated the expression of the 5-HT2CR in postsynaptic density-enriched fractions from both PFC and motor cortex. Co-immunoprecipitation studies revealed the presence of PSD-95 within the 5-HT2CR protein complex expressed in PFC and motor cortex. Taken together, these data support the hypothesis that the 5-HT2CR is localized within the postsynaptic thickening of synapses and is therefore positioned to directly modulate synaptic plasticity in cortical neurons. PMID:20345755

  14. Partially Defective Store Operated Calcium Entry and Hem(ITAM) Signaling in Platelets of Serotonin Transporter Deficient Mice

    PubMed Central

    Wolf, Karen; Braun, Attila; Haining, Elizabeth J.; Tseng, Yu-Lun; Kraft, Peter; Schuhmann, Michael K.; Gotru, Sanjeev K.; Chen, Wenchun; Hermanns, Heike M.; Stoll, Guido; Lesch, Klaus-Peter; Nieswandt, Bernhard

    2016-01-01

    Background Serotonin (5-hydroxytryptamin, 5-HT) is an indolamine platelet agonist, biochemically derived from tryptophan. 5-HT is secreted from the enterochromaffin cells into the gastrointestinal tract and blood. Blood 5-HT has been proposed to regulate hemostasis by acting as a vasoconstrictor and by triggering platelet signaling through 5-HT receptor 2A (5HTR2A). Although platelets do not synthetize 5-HT, they take 5-HT up from the blood and store it in their dense granules which are secreted upon platelet activation. Objective To identify the molecular composite of the 5-HT uptake system in platelets and elucidate the role of platelet released 5-HT in thrombosis and ischemic stroke. Methods: 5-HT transporter knockout mice (5Htt-/-) were analyzed in different in vitro and in vivo assays and in a model of ischemic stroke. Results In 5Htt-/- platelets, 5-HT uptake from the blood was completely abolished and agonist-induced Ca2+ influx through store operated Ca2+ entry (SOCE), integrin activation, degranulation and aggregation responses to glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) were reduced. These observed in vitro defects in 5Htt-/- platelets could be normalized by the addition of exogenous 5-HT. Moreover, reduced 5-HT levels in the plasma, an increased bleeding time and the formation of unstable thrombi were observed ex vivo under flow and in vivo in the abdominal aorta and carotid artery of 5Htt-/- mice. Surprisingly, in the transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke 5Htt-/- mice showed nearly normal infarct volume and the neurological outcome was comparable to control mice. Conclusion Although secreted platelet 5-HT does not appear to play a crucial role in the development of reperfusion injury after stroke, it is essential to amplify the second phase of platelet activation through SOCE and plays an important role in thrombus stabilization. PMID:26800051

  15. Differentiation of 5-hydroxytryptamine2 receptor subtypes using sup 125 I-R-(-)2,5-dimethoxy-4-iodo-phenylisopropylamine and sup 3 H-ketanserin

    SciTech Connect

    McKenna, D.J.; Peroutka, S.J. )

    1989-10-01

    The radioligand binding characteristics of 125I-R-(-)4-iodo-2,5-dimethoxyphenylisopropylamine (125I-R-(-)DOI) and 3H-ketanserin were compared in rat and bovine cortical membranes. In rat cortex, 125I-R-(-)DOI labels a relatively low density of binding sites (Bmax = 2.5 +/- 0.2 pmol/gm tissue) with high affinity (KD = 0.63 +/- 0.09 nM). In bovine cortex, specific binding of 125I-R-(-)DOI represents less than 20% of total binding at radioligand concentrations above 0.6 nM, and, therefore, the data cannot be analyzed adequately by Scatchard transformation. By contrast, 3H-ketanserin displays saturable, specific high-affinity binding in both rat cortex (KD = 1.0 +/- 0.1 nM; Bmax = 11 +/- 0.4 pmol/gm tissue) and bovine cortex (KD = 1.2 +/- 0.2 nM; Bmax = 5.3 +/- 0.4 pmol/gm tissue). Ki values for 30 drugs were determined for 125I-R-(-)DOI-labeled sites in rat cortex and 3H-ketanserin-labeled sites in bovine cortex. 5-Hydroxytryptamine (5-HT) displays 250-fold higher selectivity for the 125I-R-(-)DOI-labeled sites (Ki = 3.0 +/- 0.7 nM) than for the 3H-ketanserin-labeled sites (Ki = 750 +/- 50 nM). Structural congeners of R-(-)DOI display 80- to 160-fold higher affinity for the 125I-R-(-)DOI binding site than for the 3H-ketanserin-labeled binding site. d-LSD and putative 5-HT2 antagonists are approximately equipotent at both sites. Significant correlations were found between drug affinities for 125I-R-(-)DOI-labeled sites in rat cortex and putative 5-HT2A sites labeled previously by 77Br-R-(-)DOB (r = 0.93, p less than 0.01), putative 5-HT2B sites labeled by 3H-ketanserin in bovine cortex (r = 0.63, p less than 0.01), and 5-HT1C binding sites that have been characterized by other investigators (r = 0.78, p less than 0.01). No significant correlations were found between drug affinities for 125I-R-(-)DOI-labeled sites in rat cortex and 5-HT1A, 5-HT1B, 5-HT1D, or 5-HT3 sites, as determined by previous investigators.

  16. An enhanced cAMP pathway is responsible for the colonic hyper-secretory response to 5-HT in acute stress rats.

    PubMed

    Li, Y; Li, L S; Zhang, X L; Zhang, Y; Xu, J D; Zhu, J X

    2015-01-01

    5-hydroxytryptamine (5-HT) is involved in the stress-induced alteration of colonic functions, specifically motility and secretion, but its precise mechanisms of regulation remain unclear. In the present study, we have investigated the effects of 5-HT on rat colonic mucosal secretion after acute water immersion restraint stress, as well as the underlying mechanism of this phenomenon, using short circuit current recording (I(SC)), real-time polymerase chain reaction, Western blot analysis, and enzyme-linked immunosorbance assays. After 2 h of water immersion restraint stress, the baseline I(SC) and 5-HT-induced I(SC) responses of the colonic mucosa were significantly increased. Pretreatment with selective 5-HT(4) receptor antagonist, SB204070, inhibited the 5-HT-induced colonic I(SC) response by 96 % in normal rats and 91.2 % in acute-stress rats. However, pretreatment with the selective antagonist of 5-HT(3) receptor, MDL72222 or Y-25130, had no obvious effect on 5-HT-induced I(SC) responses under either set of conditions. Total protein expression of both the mucosal 5-HT(3) receptors and the 5-HT(4) receptors underwent no significant changes following acute stress. Both colonic basal cAMP levels and foskolin-induced I(SC) responses were significantly enhanced in acute stress rats. 5-HT significantly enhanced the intracellular cAMP level via 5-HT(4) receptors in the colonic mucosa from both control and stressed animals, and 5-HT-induced cAMP increase in stressed rats was not more than that in control rats. Taken together, the present results indicate that acute water immersion restraint stress enhances colonic secretory responses to 5-HT in rats, a process in which increased cellular cAMP accumulation is involved. PMID:25536313

  17. Site-dependent effects of an acute intensive exercise on extracellular 5-HT and 5-HIAA levels in rat brain.

    PubMed

    Gomez-Merino, D; Béquet, F; Berthelot, M; Chennaoui, M; Guezennec, C Y

    2001-03-30

    Previous neurochemical studies have reported different pattern of 5-HT release during exercise varying across either exercise conditions or forebrain sites. This in vivo microdialysis study is the first to examine the impact of an acute intensive treadmill running (2 h at 25 m.min(-1), which is close to exhaustion time), on extracellular 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels in two different brain areas in rats, the ventral hippocampus and the frontal cortex. Hippocampal and cortical 5-HT levels increased significantly after 90 min of exercise and were maximal in the first 30 min of recovery. Thereafter, cortical 5-HT levels followed a rapid and significant decrease when hippocampal levels are still maximal. During exercise, changes in extracellular 5-HIAA levels paralleled 5-HT changes, but showed no difference between the two brain areas during recovery. Thus, an intensive exercise induces a delayed increase in brain 5-HT release but recovery seems to display site-dependent patterns. PMID:11248443

  18. Effect of 5-HT2A and 5-HT2C receptors on temporal discrimination by mice.

    PubMed

    Halberstadt, Adam L; Sindhunata, Ivan S; Scheffers, Kees; Flynn, Aaron D; Sharp, Richard F; Geyer, Mark A; Young, Jared W

    2016-08-01

    Timing deficits are observed in patients with schizophrenia. Serotonergic hallucinogens can also alter the subjective experience of time. Characterizing the mechanism through which the serotonergic system regulates timing will increase our understanding of the linkage between serotonin (5-HT) and schizophrenia, and will provide insight into the mechanism of action of hallucinogens. We investigated whether interval timing in mice is altered by hallucinogens and other 5-HT2 receptor ligands. C57BL/6J mice were trained to perform a discrete-trials temporal discrimination task. In the discrete-trials task, mice were presented with two levers after a variable interval. Responding on lever A was reinforced if the interval was <6.5 s, and responding on lever B was reinforced if the interval was >6.5 s. A 2-parameter logistic function was fitted to the proportional choice for lever B (%B responding), yielding estimates of the indifference point (T50) and the Weber fraction (a measure of timing precision). The 5-HT2A antagonist M100907 increased T50, whereas the 5-HT2C antagonist SB-242,084 reduced T50. The results indicate that 5-HT2A and 5-HT2C receptors have countervailing effects on the speed of the internal pacemaker. The hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI; 3 mg/kg IP), a 5-HT2 agonist, flattened the response curve at long stimulus intervals and shifted it to the right, causing both T50 and the Weber fraction to increase. The effect of DOI was antagonized by M100907 (0.03 mg/kg SC) but was unaffected by SB-242,084 (0.1 mg/kg SC). Similar to DOI, the selective 5-HT2A agonist 25CN-NBOH (6 mg/kg SC) reduced %B responding at long stimulus intervals, and increased T50 and the Weber fraction. These results demonstrate that hallucinogens alter temporal perception in mice, effects that are mediated by the 5-HT2A receptor. It appears that 5-HT regulates temporal perception, suggesting that altered serotonergic signaling may contribute to the timing deficits

  19. Mediation of 5-HT-induced external carotid vasodilatation in GR 127935-pretreated vagosympathectomized dogs by the putative 5-HT7 receptor

    PubMed Central

    Villalón, Carlos M; Centurión, David; Luján-Estrada, Miguel; Terrón, José A; Sánchez-López, Araceli

    1997-01-01

    The vasodilator effects of 5-hydroxytryptamine (5-HT) in the external carotid bed of anaesthetized dogs with intact sympathetic tone are mediated by prejunctional sympatho-inhibitory 5-HT1B/1D receptors and postjunctional 5-HT receptors. The prejunctional vasodilator mechanism is abolished after vagosympathectomy which results in the reversal of the vasodilator effect to vasoconstriction. The blockade of this vasoconstrictor effect of 5-HT with the 5-HT1B/1D receptor antagonist, GR 127935, unmasks a dose-dependent vasodilator effect of 5-HT, but not of sumatriptan. Therefore, the present study set out to analyse the pharmacological profile of this postjunctional vasodilator 5-HT receptor in the external carotid bed of vagosympathectomized dogs pretreated with GR 127935 (20 μg kg−1, i.v.).One-minute intracarotid (i.c.) infusions of 5-HT (0.330 μg min−1), 5-carboxamidotryptamine (5-CT; 0.010.3 μg min−1), 5-methoxytryptamine (1100 μg min−1) and lisuride (31000 μg min−1) resulted in dose-dependent increases in external carotid blood flow (without changes in blood pressure or heart rate) with a rank order of agonist potency of 5-CT>>5-HT⩾5-methoxytryptamine>lisuride, whereas cisapride (1001000 μg min−1, i.c.) was practically inactive. Interestingly, lisuride (mean dose of 85±7 μg kg−1, i.c.), but not cisapride (mean dose of 67±7 μg kg−1, i.c.), specifically abolished the responses induced by 5-HT, 5-CT and 5-methoxytryptamine, suggesting that a common site of action may be involved. In contrast, 1 min i.c. infusions of 8-OH-DPAT (33000 μg min−1) produced dose-dependent decreases, not increases, in external carotid blood flow and failed to antagonize (mean dose of 200±33 μg kg−1, i.c.) the agonist-induced vasodilator responses.The external carotid vasodilator responses to 5-HT, 5-CT and 5-methoxytryptamine were not modified by intravenous (i.v.) pretreatment with either saline, (±)-pindolol (4

  20. Design, synthesis and preliminary screening of novel 3-(2-N,N-dimethylaminoethylthio) indole derivatives as potential 5-HT(6) receptor ligands.

    PubMed

    Kambhampati, Ramasastri; Konda, Jagadishbabu; Reballi, Veena; Shinde, Anil K; Dubey, Pramod K; Nirogi, Ramakrishna V S

    2008-06-01

    The synthesis and potential 5-hydroxytryptamine(6) receptor (5-HT6R) antagonist activity of a novel series of N-arylsulfonyl-3-(2-N,N-dimethylaminoethylthio) indoles has been reported. The molecular modeling, synthesis and in-vitro radioligand binding data of this series are discussed. The present article describes 37 derivatives of the title series. It was observed that the increased side-chain length with the insertion of a sulfur atom did not lead to the loss of binding affinity of these compounds, although the affinities were reduced. The compounds exhibited moderate affinity and selectivity to human 5-HT6 receptors. PMID:18569332

  1. 5-HT induces temporomandibular joint nociception in rats through the local release of inflammatory mediators and activation of local β adrenoceptors.

    PubMed

    Oliveira-Fusaro, Maria Cláudia G; Clemente-Napimoga, Juliana Trindade; Teixeira, Juliana Maia; Torres-Chávez, Karla Elena; Parada, Carlos Amílcar; Tambeli, Cláudia Herrera

    2012-09-01

    The 5-hydroxytryptamine (serotonin, 5-HT) is an important inflammatory mediator found in high levels in the synovial fluid of the temporomandibular joint (TMJ) of patients with inflammatory pain. In this study, we used the nociceptive behavior responses, measured as flinching the head and rubbing the orofacial region, as a nociceptive assay. We demonstrated that the local blockade of the 5-HT₃ receptor and β₁ or β₂-adrenoceptors, the depletion of norepinephrine in the sympathetic terminals and the local inhibition of cyclooxygenase significantly reduced 5-HT-induced TMJ nociception. These results demonstrated that 5-HT induces nociception in the TMJ region by the activation of β₁ and β₂ adrenoceptors located in the TMJ region and local release of sympathetic amines and prostaglandins. Therefore, the high levels of 5-HT in the synovial fluid of patients with TMJ inflammatory pain may contribute to TMJ pain by similar mechanisms. PMID:22683622

  2. Drug-induced defaecation in rats: role of central 5-HT1A receptors.

    PubMed Central

    Croci, T.; Landi, M.; Bianchetti, A.; Manara, L.

    1995-01-01

    1. We investigated the acute effects of 5-hydroxytryptamine (5-HT), and of the 5-HT1A receptor agonists, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), buspirone and SR 57746A, on rat faecal pellet output and water content. 2. 5-HT, 8-OH-DPAT, buspirone and SR 57746A, a new selective 5-HT1A receptor agonist, displaced [3H]-8-OH-DPAT from specific binding sites in rat hippocampus membranes (Ki, nM; 1.8, 1.2, 15, 3.1 respectively) and stimulated rat defaecation dose-dependently. SR 57746A and buspirone induced 1 g dry weight of faeces at 1.3 and 6.1 mg kg-1, p.o. (AD1) respectively. 8-OH-DPAT and 5-HT stimulated defaecation after s.c. injection (AD1, 0.07 and 7.5 mg kg-1, respectively). All these agents increased faecal water content. 3. The putative 5-HT1A receptor antagonist, pindolol, injected s.c. or i.c.v., significantly reduced the defaecation induced by systemically administered 8-OH-DPAT, buspirone or SR 57746A, but not 5-HT. 4. Pretreatment with p-chlorophenylalanine (i.p.) or 5,7-dihydroxytryptamine (i.c.v.), according to protocols designed to cause either generalized or CNS-limited 5-HT depletion respectively, also reduced the defaecation induced by buspirone or SR 57746A. 5. No specific 5-HT1A binding sites could be labelled by incubating rat colon membranes with [3H]-8-OH-DPAT, and in vitro preparations of rat colon segments showed no response to 8-OH-DPAT or SR 57746A up to 5 microM. 6. After eight days' repeated daily treatment, complete tolerance developed to the stimulant effects of SR 57746A and buspirone on faecal water content, but not on faecal pellet output.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7647978

  3. Platelet-induced neurogenic coronary contractions due to accumulation of the false neurotransmitter, 5-hydroxytryptamine.

    PubMed Central

    Cohen, R A

    1985-01-01

    The purpose of this study was to determine if 5-hydroxytryptamine released from aggregating platelets could be accumulated and released by canine coronary adrenergic nerves, and if the false neurotransmitter resulted in an abnormal response of the smooth muscle to nerve stimulation. Isometric tension was measured in rings of epicardial coronary suspended in organ chambers filled with physiological salt solution. The response to electrical stimulation or exogenously added norepinephrine was elicited after contraction with prostaglandin F2 alpha. Electrical stimulation and exogenous norepinephrine caused beta-adrenergic relaxation of control rings. However, after rings were exposed for 2 h to aggregating platelets or 5-hydroxytryptamine, electrical stimulation caused frequency-dependent contractions. These contractions were prevented by the serotonergic antagonists, cyproheptadine or ketanserin, or by the neuronal uptake inhibitor, cocaine. The relaxation caused by exogenously added norepinephrine was unchanged after exposure to platelets or 5-hydroxytryptamine, indicating that smooth muscle alpha- and beta-adrenergic responsiveness was unchanged. The electrically stimulated overflow of radiolabeled norepinephrine from superfused strips of coronary artery was not altered by prior exposure to 5-hydroxytryptamine, indicating that the effect of exposure on the response to electrical stimulation is primarily at smooth muscle serotonergic receptors. Canine coronary arteries accumulated and metabolized radiolabeled 5-hydroxytryptamine in vitro. The accumulation of 5-hydroxytryptamine was inhibited by cocaine or by adrenergic denervation with 6-hydroxydopamine but unaffected by removal of endothelium, indicating that the adrenergic nerves were the primary site of accumulation. Electrical stimulation of superfused strips of coronary artery preincubated with radiolabeled 5-hydroxytryptamine caused the release of the intact indoleamine; this was blocked by the neurotoxin

  4. INSIGHTS INTO THE REGULATION OF 5-HT2A RECEPTORS BY SCAFFOLDING PROTEINS AND KINASES

    PubMed Central

    Allen, John A.; Yadav, Prem N.

    2008-01-01

    SUMMARY 5-HT2A serotonin receptors are essential molecular targets for the actions of LSD-like hallucinogens and atypical antipsychotic drugs. 5-HT2A serotonin receptors also mediate a variety of physiological processes in peripheral and central nervous systems including platelet aggregation, smooth muscle contraction, and the modulation of mood and perception. Scaffolding proteins have emerged as important regulators of 5-HT2A receptors and our recent studies suggest multiple scaffolds exist for 5-HT2A receptors including PSD95, arrestin, and caveolin. In addition, a novel interaction has emerged between p90 ribosomal S6 kinase and 5-HT2A receptors which attenuates receptor signaling. This article reviews our recent studies and emphasizes the role of scaffolding proteins and kinases in the regulation of 5-HT2A trafficking, targeting and signaling. PMID:18640136

  5. Synergistic effect of 5-hydroxytryptamine 3 and neurokinin 1 receptor antagonism in rodent models of somatic and visceral pain.

    PubMed

    Greenwood-Van Meerveld, Beverley; Mohammadi, Ehsan; Tyler, Karl; Pietra, Claudio; Bee, Lucy A; Dickenson, Anthony

    2014-10-01

    Synergistic activity has been observed between serotonergic 5-hydroxytryptamine 3 (5-HT3) and tachykinergic neurokinin 1 (NK1) receptor-mediated responses. This study investigated the efficacy of a 5-HT3 antagonist, palonosetron, and a NK1 antagonist, netupitant, alone or in combination in rodent models of somatic and visceral colonic hypersensitivity. In a rat model of experimental neuropathic pain, somatic hypersensitivity was quantified by the number of ipsilateral paw withdrawals to a von Frey filament (6g). Electrophysiologic responses were recorded in the dorsal horn neurons after mechanical or thermal stimuli. Acute colonic hypersensitivity was induced experimentally in rats by infusing dilute acetic acid (0.6%) directly into the colon. Colonic sensitivity was assessed by a visceromotor behavioral response quantified as the number of abdominal contractions in response to graded isobaric pressures (0-60 mm Hg) of colorectal distension. Palonosetron or netupitant was administered alone or in combination via oral gavage. When dosed alone, both significantly reduced somatic sensitivity, decreased the evoked response of spinal dorsal horn neurons to mechanical or thermal stimulation, and caused significant (P < 0.05) inhibition of colonic hypersensitivity in a dose-dependent manner. The combined administration of palonosetron and netupitant at doses that were ineffective alone significantly reduced both somatic and visceral sensitivity and decreased the evoked response of spinal dorsal horn neurons to mechanical or thermal stimulation. In summary, the combination of palonosetron with a NK1 receptor antagonist showed synergistic analgesic activity in rodent models of somatic and visceral hypersensitivity, and may prove to be a useful therapeutic approach to treat pain associated with irritable bowel syndrome. PMID:25077526

  6. Postnatal Treadmill Exercise Alleviates Prenatal Stress-Induced Anxiety in Offspring Rats by Enhancing Cell Proliferation Through 5-Hydroxytryptamine 1A Receptor Activation

    PubMed Central

    2016-01-01

    Purpose: Stress during pregnancy is a risk factor for the development of anxiety-related disorders in offspring later in life. The effects of treadmill exercise on anxiety-like behaviors and hippocampal cell proliferation were investigated using rats exposed to prenatal stress. Methods: Exposure of pregnant rats to a hunting dog in an enclosed room was used to induce stress. Anxiety-like behaviors of offspring were evaluated using the elevated plus maze test. Immunohistochemistry for the detection of 5-bromo-2ʹ- deoxyuridine and doublecortin (DCX) in the hippocampal dentate gyrus and 5-hydroxytryptamine 1A receptors (5-HT1A) in the dorsal raphe was conducted. Brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) levels in the hippocampus were evaluated by western blot analysis. Results: Offspring of maternal rats exposed to stress during pregnancy showed anxiety-like behaviors. Offspring also showed reduced expression of BDNF, TrkB, and DCX in the dentate gyrus, decreased cell proliferation in the hippocampus, and reduced 5-HT1A expression in the dorsal raphe. Postnatal treadmill exercise by offspring, but not maternal exercise during pregnancy, enhanced cell proliferation and expression of these proteins. Conclusions: Postnatal treadmill exercise ameliorated anxiety-like behaviors in offspring of stressed pregnant rats, and the alleviating effect of exercise on these behaviors is hypothesized to result from enhancement of cell proliferation through 5-HT1A activation in offspring rats. PMID:27230461

  7. The 5-HT{sub 2A} serotoninergic receptor is expressed in the MCF-7 human breast cancer cell line and reveals a mitogenic effect of serotonin

    SciTech Connect

    Sonier, Brigitte; Arseneault, Madeleine; Lavigne, Carole; Ouellette, Rodney J.; Vaillancourt, Cathy . E-mail: cathy.vaillancourt@iaf.inrs.ca

    2006-05-19

    Serotonin (5-hydroxytryptamine, 5-HT) has been described as a mitogen in a variety of cell types and carcinomas. It exerts its mitogenic effect by interacting with a wide range of 5-HT receptor types. Certain studies suggest that some selective serotonin re-uptake inhibitors promote breast cancer in animals and humans. This study attempts to clarify the role of serotonin in promoting the growth of neoplastic mammary cells. Expression of the 5-HT{sub 2A} serotoninergic receptor subtype in MCF-7 cells was determined by RT-PCR, Western blotting, and immunofluorescence analysis. The mitogenic effect of 5-HT on MCF-7 cells was determined by means of the MTT proliferation assay. We have demonstrated that the 5-HT{sub 2A} receptor subtype is fully expressed in the MCF-7 human breast cancer cell line, in terms of encoding mRNA and receptor protein. Automated sequencing has confirmed that the 5-HT{sub 2A} receptor present in this cell line is identical to the 5-HT{sub 2A} receptor found in human platelets and in human cerebral cortex. Furthermore, this receptor was found by immunofluorescence to be on the plasma membrane. MTT proliferation assays revealed that 5-HT and DOI, a selective 5-HT{sub 2A} receptor subtype agonist, stimulated MCF-7 cell. These results indicate that 5-HT plays a mitogenic role in neoplastic mammary cells. Our data also indicate that 5-HT exerts this positive growth effect on MCF-7 cells through, in part, the 5-HT{sub 2A} receptor subtype, which is fully expressed in this cell line.

  8. Human Serotonin 5-HT2C G Protein-Coupled Receptor Homology Model from the β2 Adrenoceptor Structure: Ligand Docking and Mutagenesis Studies

    PubMed Central

    RDOVA-SINTJAGO, TANIA CÓ; VILLA, NANCY; CANAL, CLINTON; BOOTH, RAYMOND

    2013-01-01

    Activation of the serotonin (5-hydroxytryptamine, 5-HT) 5HT2C G protein-coupled receptor (GPCR) is proposed as novel pharmacotherapy for obesity and neuropsychiatric disorders. In contrast, activation of the 5-HT2A and 5-HT2B GPCRs is associated with untoward hallucinogenic and cardiopulmonary effects, respectively. There is no crystal structure available to guide design of 5-HT2C receptor-specific ligands. For this reason, a homology model of the 5-HT2C receptor was built based on the crystal structure of the human β2 adrenoceptor GPCR to delineate molecular determinants of ligand–receptor interactions for drug design purposes. Computational and experimental studies were carried out to validate the model. Binding of N(CH3)2-PAT [(1R, 3S)-(−)-trans-1-phenyl-3-N,N-dimethylamino-1,2,3,4-tetrahydronaphthalene], a novel 5-HT2C agonist/5-HT2A/2B inverse agonist, and its secondary [NH(CH3)-PAT] and primary (NH2-PAT) amine analogs were studied at the 5-HT2C wild type (WT) and D3.32A, S3.36A, and Y7.43A 5-HT2C point-mutated receptors. Reference ligands included the tertiary amines lisuride and mesulergine and the primary amine 5-HT. Modeling results indicated that 5-HT2C residues D3.32, S3.36, and Y7.43 play a role in ligand binding. Experimental ligand binding results with WT and point-mutated receptors confirmed the impact of D3.32, S3.36, and Y7.43 on ligand affinity. PMID:24244046

  9. Selective irreversible blockade of 5-hydroxytryptamine1A and 5-hydroxytryptamine1C receptor binding sites in the rat brain by 8-MeO-2'-chloro-PAT: a quantitative autoradiographic study.

    PubMed

    Radja, F; Daval, G; Emerit, M B; Gallissot, M C; Hamon, M; Vergé, D

    1989-01-01

    The possible irreversible blockade of 5-hydroxytryptamine1 receptor subtypes 5-hydroxytryptamine1A, 5-hydroxytryptamine1B/5-hydroxytryptamine1D and 5-hydroxytryptamine1C by the chloramine 8-methoxy-2-(N-2'-chloropropyl,N-propyl)aminotetralin (8-MeO-2'-chloro-PAT) was investigated in rat brain sections by quantitative autoradiography using [3H]8-hydroxy-2-(di-n-propylamino)tetralin [( 3H]8-OH-DPAT), [3H]5-hydroxytryptamine, [125I]BH-8-MeO-N-PAT and [125I]cyanopindolol as radio-ligands. A marked reduction (-50% to -75%) of [3H]8-OH-DPAT and [125I]BH-8-MeO-N-PAT specific binding to 5-hydroxytryptamine1A sites in the hippocampus (CA1 area) and the dorsal raphe nucleus, and of [3H]5-hydroxytryptamine specific binding to 5-hydroxytryptamine1C sites in the choroid plexus was found in sections exposed to 1 microM 8-MeO-2'-chloro-PAT and then washed extensively. In contrast the specific binding of [3H]5-hydroxytryptamine to 5-hydroxytryptamine1B/5-hydroxytryptamine1D sites and of [125I]cyanopindolol to 5-hydroxytryptamine1B sites in the substantia nigra and dorsal subiculum remained unaltered by this treatment. Similarly [125I]cyanopindolol binding to beta-adrenergic receptors was not affected by 8-MeO-2'-chloro-PAT. Prior occupancy of 5-hydroxytryptamine1A sites by 10 microM 5-hydroxytryptamine or 8-OH-DPAT, and of 5-hydroxytryptamine1C sites by 10 microM 5-hydroxytryptamine prevented any subsequent blockade by 8-MeO-2'-chloro-PAT. These data indicate that 8-MeO-2'-chloro-PAT should be a useful alkylating agent for achieving selective irreversible blockade of central 5-hydroxytryptamine1A and 5-hydroxytryptamine1C receptors in vivo in the rat. PMID:2531850

  10. 5-HT6 receptors and Alzheimer's disease

    PubMed Central

    2013-01-01

    During the past 20 years, the 5-HT6 receptor has received increasing attention and become a promising target for improving cognition. Several studies with structurally different compounds have shown that not only antagonists but also 5-HT6 receptor agonists improve learning and memory in animal models. A large number of publications describing the development of ligands for this receptor have come to light, and it is now quite evident that 5-HT6 receptors have great pharmaceutical potential in terms of related patents. However, 5-HT6 receptor functionality is much more complex than initially defined. According to the existing data, different cellular pathways may be activated, depending on the drug being used. This article reviews preclinical and clinical evidence of the effects that 5-HT6 receptor compounds have on cognition. In addition, the biochemical and neurochemical mechanisms of action through which 5-HT6 receptor compounds can influence cognition will be described. Overall, several 5-HT6-targeted compounds can reasonably be regarded as powerful drug candidates for the treatment of Alzheimer's disease. PMID:23607787

  11. Triptan-induced contractile (5-HT1B receptor) responses in human cerebral and coronary arteries: relationship to clinical effect.

    PubMed

    Edvinsson, Lars; Uddman, Erik; Wackenfors, Angelica; Davenport, Anthony; Longmore, Jenny; Malmsjö, Malin

    2005-09-01

    Triptans are agonists at 5-HT1B and 5-HT1D (where 5-HT is 5-hydroxytryptamine; serotonin) receptors and cause vasoconstriction of isolated blood vessels. The aim of the present study was to determine vasoconstrictor potency (EC50) of triptans in human coronary and cerebral arteries and to examine whether there was any relationship with the maximal plasma concentrations (Cmax; nM) of the drugs achieved following oral administration of clinically relevant doses to man using values reported in the literature. We also examined the expression of 5-HT1B receptors in atherosclerotic and normal coronary arteries. The vasocontractile responses to sumatriptan, rizatriptan or eletriptan were characterized by in vitro pharmacology. The ratio of Cmax/EC50 was calculated. 5-HT1B and 5-HT1D receptors were visualized by immunohistochemical techniques in coronary arteries. Sumatriptan, rizatriptan and eletriptan were powerful vasoconstrictors in cerebral artery. The rank order of agonist potency was eletriptan=rizatriptan=sumatriptan. In the coronary artery, the triptans were weaker vasoconstrictors. The rank order of potency was similar. In cerebral artery the ratio of Cmax/EC50 was not significantly different from unity, indicating a relationship between these two parameters. In general for the coronary artery, the ratios were significantly less than unity, indicating no direct relationship. Immunohistochemistry showed expression of 5-HT1B receptors in the medial layer, but did not reveal any obvious difference in 5-HT1B receptor expression between normal and atherosclerotic coronary arteries. The results support the notion that triptans are selective vasoconstrictors of cerebral arteries over coronary arteries and that there is a relationship between vasoconstrictor potency in cerebral arteries and clinically relevant plasma levels. PMID:15853772

  12. 5-HT2A receptors are involved in cognitive but not antidepressant effects of fluoxetine.

    PubMed

    Castañé, Anna; Kargieman, Lucila; Celada, Pau; Bortolozzi, Analía; Artigas, Francesc

    2015-08-01

    The prefrontal cortex (PFC) plays a crucial role in cognitive and affective functions. It contains a rich serotonergic (serotonin, 5-HT) innervation and a high density of 5-HT receptors. Endogenous 5-HT exerts robust actions on the activity of pyramidal neurons in medial PFC (mPFC) via excitatory 5-HT2A and inhibitory 5-HT1A receptors, suggesting the involvement of 5-HT neurotransmission in cortical functions. However, the underlying mechanisms must be elucidated. Here we examine the role of 5-HT2A receptors in the processing of emotional and cognitive signals evoked by increasing the 5-HT tone after acute blockade of the 5-HT transporter. Fluoxetine (5-20mg/kg i.p.) dose-dependently reduced the immobility time in the tail-suspension test in wild-type (WT) and 5-HT2Aknockout (KO2A) mice, with non-significant differences between genotypes. Fluoxetine (10mg/kg i.p.) significantly impaired mice performance in the novel object recognition test 24h post-administration in WT, but not in KO2A mice. The comparable effect of fluoxetine on extracellular 5-HT in the mPFC of both genotypes suggests that presynaptic differences are not accountable. In contrast, single unit recordings of mPFC putative pyramidal neurons showed that fluoxetine (1.8-7.2mg/kg i.v.) significantly increased neuronal discharge in KO2A but not in WT mice. This effect is possibly mediated by an altered excitatory/inhibitory balance in the PFC in KO2A mice. Overall, the present results suggest that 5-HT2A receptors play a detrimental role in long-term memory deficits mediated by an excess 5-HT in PFC. PMID:25914158

  13. Down-regulation of 5-HT1B and 5-HT1D receptors inhibits proliferation, clonogenicity and invasion of human pancreatic cancer cells.

    PubMed

    Gurbuz, Nilgun; Ashour, Ahmed A; Alpay, S Neslihan; Ozpolat, Bulent

    2014-01-01

    Pancreatic ductal adenocarcinoma is characterized by extensive local tumor invasion, metastasis and early systemic dissemination. The vast majority of pancreatic cancer (PaCa) patients already have metastatic complications at the time of diagnosis, and the death rate of this lethal type of cancer has increased over the past decades. Thus, efforts at identifying novel molecularly targeted therapies are priorities. Recent studies have suggested that serotonin (5-HT) contributes to the tumor growth in a variety of cancers including prostate, colon, bladder and liver cancer. However, there is lack of evidence about the impact of 5-HT receptors on promoting pancreatic cancer. Having considered the role of 5-HT-1 receptors, especially 5-HT1B and 5-HT1D subtypes in different types of malignancies, the aim of this study was to investigate the role of 5-HT1B and 5-HT1D receptors in PaCa growth and progression and analyze their potential as cytotoxic targets. We found that knockdown of 5-HT1B and 5-HT1D receptors expression, using specific small interfering RNA (siRNA), induced significant inhibition of proliferation and clonogenicity of PaCa cells. Also, it significantly suppressed PaCa cells invasion and reduced the activity of uPAR/MMP-2 signaling and Integrin/Src/Fak-mediated signaling, as integral tumor cell pathways associated with invasion, migration, adhesion, and proliferation. Moreover, targeting 5-HT1B and 5-HT1D receptors down-regulates zinc finger ZEB1 and Snail proteins, the hallmarks transcription factors regulating epithelial-mesenchymal transition (EMT), concomitantly with up-regulating of claudin-1 and E-Cadherin. In conclusion, our data suggests that 5-HT1B- and 5-HT1D- mediated signaling play an important role in the regulation of the proliferative and invasive phenotype of PaCa. It also highlights the therapeutic potential of targeting of 5-HT1B/1D receptors in the treatment of PaCa, and opens a new avenue for biomarkers identification, and valuable new

  14. Down-regulation of 5-HT1B and 5-HT1D receptors inhibits proliferation, clonogenicity and invasion of human pancreatic cancer cells.

    PubMed

    Gurbuz, Nilgun; Ashour, Ahmed A; Alpay, S Neslihan; Ozpolat, Bulent

    2014-01-01

    Pancreatic ductal adenocarcinoma is characterized by extensive local tumor invasion, metastasis and early systemic dissemination. The vast majority of pancreatic cancer (PaCa) patients already have metastatic complications at the time of diagnosis, and the death rate of this lethal type of cancer has increased over the past decades. Thus, efforts at identifying novel molecularly targeted therapies are priorities. Recent studies have suggested that serotonin (5-HT) contributes to the tumor growth in a variety of cancers including prostate, colon, bladder and liver cancer. However, there is lack of evidence about the impact of 5-HT receptors on promoting pancreatic cancer. Having considered the role of 5-HT-1 receptors, especially 5-HT1B and 5-HT1D subtypes in different types of malignancies, the aim of this study was to investigate the role of 5-HT1B and 5-HT1D receptors in PaCa growth and progression and analyze their potential as cytotoxic targets. We found that knockdown of 5-HT1B and 5-HT1D receptors expression, using specific small interfering RNA (siRNA), induced significant inhibition of proliferation and clonogenicity of PaCa cells. Also, it significantly suppressed PaCa cells invasion and reduced the activity of uPAR/MMP-2 signaling and Integrin/Src/Fak-mediated signaling, as integral tumor cell pathways associated with invasion, migration, adhesion, and proliferation. Moreover, targeting 5-HT1B and 5-HT1D receptors down-regulates zinc finger ZEB1 and Snail proteins, the hallmarks transcription factors regulating epithelial-mesenchymal transition (EMT), concomitantly with up-regulating of claudin-1 and E-Cadherin. In conclusion, our data suggests that 5-HT1B- and 5-HT1D-mediated signaling play an important role in the regulation of the proliferative and invasive phenotype of PaCa. It also highlights the therapeutic potential of targeting of 5-HT1B/1D receptors in the treatment of PaCa, and opens a new avenue for biomarkers identification, and valuable new

  15. Blockade of 5-hydroxytryptamine(3) receptors prevents cisplatin-induced but not motion- or xylazine-induced emesis in the cat

    NASA Technical Reports Server (NTRS)

    Lucot, James B.

    1989-01-01

    The effects of the 5-hydroxytryptamine(3) (5-HT-3) antagonists ICS 205-930 and MDL 72222 on the emesis induced by motion or by emetic doses of xylazine (0.66 mg/kg administered SC) or cisplatin (7.5 mg/kg infused over a period of 4-5 min) were investigated in cats. It was found that neither the low (0.1 mg/kg) or the high (1.0 mg.kg) doses of ICS 205-930 or MDL 72222 prevented emesis elicited by screening motion challenges or xylazine. On the other hand, treatment cats by 1.0 mg/kg of ICS 205-930 was effective against cisplatin-induced motion sickness, in agreement with earlier results obtained on other mammals.

  16. Low-dose prazosin in combination with 5-HT6 antagonist PRX-07034 has antipsychotic effects.

    PubMed

    Abraham, Renny; Nirogi, Ramakrishna; Shinde, Anil; Irupannanavar, Shantaveer

    2015-01-01

    An extensive amount of research has focused on the development of new pharmacological agents to treat schizophrenia. Varying from person to person, schizophrenia is a heterogeneous disease with symptoms of positive, negative, and cognitive deficits. PRX-07034, a 5-hydroxytryptamine6 (5-HT6) receptor antagonist has been evaluated for its potential in treating obesity and cognitive deficits. This study evaluated PRX-07034 (0.1, 0.3, and 1.0 mg/kg body mass, by intraperitoneal (i.p.) injection), in combination with a low dose of prazosin (0.3 mg/kg, i.p.), for its antipsychotic potential. The research utilized a stereotypy assay, an open field test, an object recognition task, and prepulse inhibition. Dizocilpine, a non-competitive N-methyl-d-aspartate (NMDA) antagonist, was also administered in the above-mentioned assays as a psychomimetic. The combination of PRX-07034 and prazosin alleviated stereotypy and hyperlocomotor activity while enhancing memory in an object recognition task, and reversed sensory-gating deficits induced by dizocilpine. Examination of the medial prefrontal cortex revealed that a combination of PRX-07034 and prazosin reduced the dizocilpine-mediated increase of 5-HT. These results suggest that the combination of a 5-HT6 antagonist with low doses of prazosin could have therapeutic potential in the treatment of schizophrenia. PMID:25429515

  17. Neuronal Ablation of p-Akt at Ser473 Leads to Altered 5-HT1A/2A Receptor Function

    PubMed Central

    Saunders, Christine; Siuta, Michael; Robertson, Sabrina D.; Davis, Adeola R.; Sauer, Jennifer; Matthies, Heinrich J.G.; Gresch, Paul J.; Airey, David; Lindsley, Craig W.; Schetz, John A.; Niswender, Kevin D.

    2014-01-01

    The serotonergic system regulates a wide range of behavior, including mood and impulsivity, and its dysregulation has been associated with mood disorders, autism spectrum disorder, and addiction. Diabetes is a risk factor for these conditions. Insulin resistance in the brain is specifically associated with susceptibility to psychostimulant abuse. Here, we examined whether phosphorylation of Akt, a key regulator of the insulin signaling pathway, controls serotonin (5-HT) signaling. To explore how impairment in Akt function regulates 5-HT homeostasis, we used a brain-specific rictor knockout (KO) mouse model of impaired neuronal phosphorylation of Akt at Ser473. Cortical 5-HT1A and 5-HT2A receptor binding was significantly elevated in rictor KO mice. Concomitant with this elevated receptor expression, the 5-HT1A receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) led to an increased hypothermic response in rictor KO mice. The increased cortical 5-HT1A receptor density was associated with higher 5-HT1A receptor levels on the cortical cell surface. In contrast, rictor KO mice displayed significantly reduced head-twitch response (HTR) to the 5-HT2A/C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI), with evidence of impaired 5-HT2A/C receptor signaling. In vitro, pharmacological inhibition of Akt significantly increased 5-HT1A receptor expression and attenuated DOI-induced 5-HT2A receptor signaling, thereby lending credence to the observed in vivo cross-talk between neuronal Akt signaling and 5-HT receptor regulation. These data reveal that defective central Akt function alters 5-HT signaling as well as 5-HT-associated behaviors, demonstrating a novel role for Akt in maintaining neuronal 5-HT receptor function. PMID:24090638

  18. The impact of 5-hydroxytryptamine-receptor antagonists on chemotherapy treatment adherence, treatment delay, and nausea and vomiting

    PubMed Central

    Palli, Swetha Rao; Grabner, Michael; Quimbo, Ralph A; Rugo, Hope S

    2015-01-01

    Purpose To determine the incidence of chemotherapy-induced nausea/vomiting (CINV) and chemotherapy treatment delay and adherence among patients receiving palonosetron versus other 5-hydroxytryptamine receptor antagonist (5-HT3 RA) antiemetics. Materials and methods This retrospective claims analysis included adults with primary malignancies who initiated treatment consisting of single-day intravenous highly emetogenic chemotherapy (HEC) or moderately EC (MEC) regimens. Treatment delay was defined as a gap in treatment at least twice the National Comprehensive Cancer Network-specified cycle length, specific to each chemotherapy regimen. Treatment adherence was determined by the percentage of patients who received the regimen-specific recommended number of chemotherapy cycles within the recommended time frame. Results We identified 1,832 palonosetron and 2,387 other 5-HT3 RA (“other”) patients who initiated HEC therapy, and 1,350 palonosetron users and 1,379 patients on other antiemetics who initiated MEC therapy. Fewer patients receiving palonosetron experienced CINV versus other (HEC, 27.5% versus 32.2%, P=0.0011; MEC, 36.1% versus 41.7%, P=0.0026), and fewer treatment delays occurred among patients receiving palonosetron versus other (HEC, 3.2% versus 6.0%, P<0.0001; MEC, 17.0% versus 26.8%, P<0.0001). Compared with the other cohort, patients receiving palonosetron were significantly more adherent to the index chemotherapy regimen with respect to the recommended time frame (HEC, 74.7% versus 69.7%, P=0.0004; MEC, 43.1% versus 37.3%, P=0.0019) and dosage (HEC, 27.3% versus 25.8%, P=0.0004; MEC, 15.0% versus 12.6%, P=0.0019). Conclusion Palonosetron more effectively reduced occurrence of CINV in patients receiving HEC or MEC compared with other agents in this real-world setting. Additionally, patients receiving palonosetron had better adherence and fewer treatment delays than patients receiving other 5-HT3 RAs. PMID:26124681

  19. Cerebral circulatory and metabolic effects of 5-hydroxytryptamine in anesthetized baboons.

    PubMed Central

    Harper, M A; MacKenzie, E T

    1977-01-01

    1. The cerebral circulatory effects of the intracarotid administration of 5-hydroxytryptamine were examined in anaesthetized baboons. Cerebral blood flow was measured by the intracarotid 133Xe technique, cerebral O2 consumption and glucose uptake were measured as indices of brain metabolism and electrocortical activity was continuously monitored. 2. Despite a marked reduction in the calibre of the internal carotid artery (assessed angiographically), the intracarotid infusion of 5-hydroxytryptamine 0-1 microgram/kg. min did not effect any significant changes in cerebral blood flow, O2 consumption or glucose uptake. 3. Following transient osmotic disruption of the blood-brain barrier with the intracarotid infusion of hypertonic urea, the same dose of 5-hydroxytryptamine effected a marked reduction in cerebral blood flow from 51 +/- 2 to 36 +/- 2 ml./100 g. min (mean +/- S.E.; P less than 0-01). Both indices of cerebral metabolism were reduced significantly and the e.e.g. showed a more pronounced suppression-burst pattern. 4. We postulate that the cerebral circulatory responses to 5-hydroxytryptamine are dependent upon the integrity of the blood-brain barrier and the predominant effect of the intravascular administration of 5-hydroxytryptamine is on cortical activity or metabolism, rather than on cerebrovascular smooth muscle. Images Plate 1 PMID:411921

  20. Aromatic interactions impact ligand binding and function at serotonin 5-HT2C G protein-coupled receptors: receptor homology modelling, ligand docking, and molecular dynamics results validated by experimental studies

    NASA Astrophysics Data System (ADS)

    Córdova-Sintjago, Tania; Villa, Nancy; Fang, Lijuan; Booth, Raymond G.

    2014-02-01

    The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2 G protein-coupled receptor (GPCR) family consists of types 2A, 2B, and 2C that share ∼75% transmembrane (TM) sequence identity. Agonists for 5-HT2C receptors are under development for psychoses; whereas, at 5-HT2A receptors, antipsychotic effects are associated with antagonists - in fact, 5-HT2A agonists can cause hallucinations and 5-HT2B agonists cause cardiotoxicity. It is known that 5-HT2A TM6 residues W6.48, F6.51, and F6.52 impact ligand binding and function; however, ligand interactions with these residues at the 5-HT2C receptor have not been reported. To predict and validate molecular determinants for 5-HT2C-specific activation, results from receptor homology modelling, ligand docking, and molecular dynamics simulation studies were compared with experimental results for ligand binding and function at wild type and W6.48A, F6.51A, and F6.52A point-mutated 5-HT2C receptors.

  1. Distinct Circuits Underlie the Effects of 5-HT1B Receptors on Aggression and Impulsivity.

    PubMed

    Nautiyal, Katherine M; Tanaka, Kenji F; Barr, Mary M; Tritschler, Laurent; Le Dantec, Yannick; David, Denis J; Gardier, Alain M; Blanco, Carlos; Hen, René; Ahmari, Susanne E

    2015-05-01

    Impulsive and aggressive behaviors are both modulated by serotonergic signaling, specifically through the serotonin 1B receptor (5-HT1BR). 5-HT1BR knockout mice show increased aggression and impulsivity, and 5-HT1BR polymorphisms are associated with aggression and drug addiction in humans. To dissect the mechanisms by which the 5-HT1BR affects these phenotypes, we developed a mouse model to spatially and temporally regulate 5-HT1BR expression. Our results demonstrate that forebrain 5-HT1B heteroreceptors expressed during an early postnatal period contribute to the development of the neural systems underlying adult aggression. However, distinct heteroreceptors acting during adulthood are involved in mediating impulsivity. Correlating with the impulsivity, dopamine in the nucleus accumbens is elevated in the absence of 5-HT1BRs and normalized following adult rescue of the receptor. Overall, these data show that while adolescent expression of 5-HT1BRs influences aggressive behavior, a distinct set of 5-HT1B receptors modulates impulsive behavior during adulthood. PMID:25892302

  2. Distinct circuits underlie the effects of 5-HT1B receptors on aggression and impulsivity

    PubMed Central

    Nautiyal, Katherine M.; Tanaka, Kenji F.; Barr, Mary M.; Tritschler, Laurent; Le Dantec, Yannick; David, Denis J.; Gardier, Alain M.; Blanco, Carlos; Hen, René; Ahmari, Susanne E.

    2015-01-01

    Summary Impulsive and aggressive behaviors are both modulated by serotonergic signaling, specifically through the serotonin 1B receptor (5-HT1BR). 5-HT1BR knockout mice show increased aggression and impulsivity, and 5-HT1BR polymorphisms are associated with aggression and drug addiction in humans. To dissect the mechanisms by which the 5-HT1BR affects these phenotypes, we developed a mouse model to spatially and temporally regulate 5-HT1BR expression. Our results demonstrate that forebrain 5-HT1B heteroreceptors expressed during an early postnatal period contribute to the development of the neural systems underlying adult aggression. However, distinct heteroreceptors acting during adulthood are involved in mediating impulsivity. Correlating with the impulsivity, dopamine in the nucleus accumbens is elevated in the absence of 5-HT1BRs, and normalized following adult rescue of the receptor. Overall, these data show that while adolescent expression of 5-HT1BRs influences aggressive behavior, a distinct set of 5-HT1B receptors modulate impulsive behavior during adulthood. PMID:25892302

  3. The Type 7 Serotonin Receptor, 5-HT7, Is Essential in the Mammary Gland for Regulation of Mammary Epithelial Structure and Function

    PubMed Central

    Pai, Vaibhav P.; Hernandez, Laura L.; Stull, Malinda A.; Horseman, Nelson D.

    2015-01-01

    Autocrine-paracrine activity of serotonin (5-hydroxytryptamine, 5-HT) is a crucial homeostatic parameter in mammary gland development during lactation and involution. Published studies suggested that the 5-HT7 receptor type was important for mediating several effects of 5-HT in the mammary epithelium. Here, using 5-HT7 receptor-null (HT7KO) mice we attempt to understand the role of this receptor in mediating 5-HT actions within the mammary gland. We demonstrate for the first time that HT7KO dams are inefficient at sustaining their pups. Histologically, the HT7KO mammary epithelium shows a significant deviation from the normal secretory epithelium in morphological architecture, reduced secretory vesicles, and numerous multinucleated epithelial cells with atypically displaced nuclei, during lactation. Mammary epithelial cells in HT7KO dams also display an inability to transition from lactation to involution as normally seen by transition from a columnar to a squamous cell configuration, along with alveolar cell apoptosis and cell shedding. Our results show that 5-HT7 is required for multiple actions of 5-HT in the mammary glands including core functions that contribute to changes in cell shape and cell turnover, as well as specialized secretory functions. Understanding these actions may provide new interventions to improve lactation performance and treat diseases such as mastitis and breast cancer. PMID:25664318

  4. Sex-specific and region-specific changes in BDNF-TrkB signalling in the hippocampus of 5-HT1A receptor and BDNF single and double mutant mice.

    PubMed

    Wu, YeeWen Candace; Hill, Rachel A; Klug, Maren; van den Buuse, Maarten

    2012-05-01

    Brain-derived neurotrophic factor (BDNF) and serotonin 5-HT1A receptors are implicated in the pathophysiology of depression and the mechanism of action of antidepressant drugs. Here, we explore possible reciprocal interactions of 5-HT1A receptor knockout and the expression of BDNF, its receptor TrkB and downstream mitogen-activated protein kinase (MAPK) in the ventral (VHP) and dorsal hippocampus (DHP). We compared female and male double mutant mice (5-HT1A(-/-)/BDNF(+/-)) with single mutant mice (5-HT1A(-/-), BDNF(+/-)) and wildtype (WT) controls. Protein expression of BDNF, TrkB, phosphorylation of TrkB (pTrkB) and MAPKs (ERK1, ERK2) was examined using Western blot analysis (n=5-7). As expected, the BDNF(+/-) mice showed ~50% BDNF reduction. Loss of 5-HT1A receptors induced a significant decrease in BDNF levels in the VHP in female mice. The pTrkB/TrkB ratio was also significantly decreased in female 5-HT1A(-/-) mice and 5-HT1A(-/-)/BDNF(+/-) mice but not in males. Despite markedly reduced BDNF levels in BDNF(+/-) mice and double mutants, ERK1 activation was unchanged in the female mice. In contrast, ERK2 activation was significantly elevated in the VHP of female BDNF(+/-) mice and double mutants. Given the greater vulnerability of women to develop depression and the role of the VHP in stress responses and anxiety-related behaviours, our results may shed more light on sex differences in depression and other psychiatric disorders with BDNF and 5-HT1A receptor dysfunction. PMID:22464183

  5. Different efficacy of specific agonists at 5-HT3 receptor splice variants: the role of the extra six amino acid segment

    PubMed Central

    Niemeyer, M-I; Lummis, S C R

    1998-01-01

    Whole cell voltage clamp electrophysiology and radioligand binding were used to examine the agonist characteristics of the two splice variants of the 5-HT3 receptor which have been cloned from neuronal cell lines. Homo-oligomeric 5-HT3 receptors were examined in HEK 293 cells stably transfected with either long (5-HT3-L) or short (5-HT3-S) receptor subunit DNAs. Functional homo-oligomeric receptors were formed from both subunits, and responses to 5-HT3 receptor agonists (5-hydroxytryptamine (5-HT), 2-methyl 5-HT and m-chlorophenylbiguanide) were qualitatively similar. Maximum currents (Rmax) elicited by the 5-HT3 receptor agonists m-chlorophenylbiguanide (mCPBG) and 2-methyl-5-HT (2-Me-5-HT), as compared to 5-HT, differed in the two splice variants: Rmax mCPBG/Rmax 5-HT values were 0.68±0.04 and 0.91±0.01 in 5-HT3-L and 5-HT3-S receptors, respectively. Comparable values for 2-Me-5-HT were 0.30±0.02 and 0.23±0.02. Radioligand binding data showed no difference in affinity of agonist or antagonist binding sites; thus the six amino acid deletion appears to cause differences in agonist efficacy. The role of the 6 amino acid insertion was further investigated by use of site-directed mutagenesis to create two mutant receptors, one where serine 286 was replaced with alanine, and the second where all 6 amino acids were replaced with alanines. Examination of the mutant receptors when stably expressed in HEK 293 cells revealed agonist properties resembling long and not short 5-HT3 receptors. Thus specific amino acids in this region are not responsible for the observed differences. The data show intracellular structure can have significant effects on ligand-gated ion channel function, and suggest that minor changes in structure may be responsible for differences in function observed when ligand-gated ion channel proteins are modulated intracellularly. PMID:9517385

  6. Bystander effects of ionizing radiation can be modulated by signaling amines

    SciTech Connect

    Poon, R.C.C.; Agnihotri, N.; Seymour, C.; Mothersill, C.

    2007-10-15

    Actual risk and risk management of exposure to ionizing radiation are among the most controversial areas in environmental health protection. Recent developments in radiobiology especially characterization of bystander effects have called into question established dogmas and are thought to cast doubt on the scientific basis of the risk assessment framework, leading to uncertainty for regulators and concern among affected populations. In this paper we test the hypothesis that small signaling molecules widely used throughout the animal kingdom for signaling stress or environmental change, such as 5-Hydroxytryptamine (5-HT, serotonin), L-DOPA, glycine or nicotine are involved in bystander signaling processes following ionizing radiation exposure. We report data which suggest that nano to micromolar concentrations of these agents can modulate bystander-induced cell death. Depletion of 5-HT present in tissue culture medium, occurred following irradiation of cells. This suggested that 5-HT might be bound by membrane receptors after irradiation. Expression of 5-HT type 3 receptors which are Ca{sup 2+} ion channels was confirmed in the cells using immunocytochemistry and receptor expression could be increased using radiation or 5-HT exposure. Zofran and Kitryl, inhibitors of 5-HT type 3 receptors, and reserpine a generic serotonin antagonist block the bystander effect induced by radiation or by serotonin. The results may be important for the mechanistic understanding of how low doses of radiation interact with cells to produce biological effects.

  7. The major role of peripheral release of histamine and 5-hydroxytryptamine in formalin-induced nociception.

    PubMed

    Parada, C A; Tambeli, C H; Cunha, F Q; Ferreira, S H

    2001-01-01

    Formalin injected subcutaneously into the paw is a widely used model of pain. This procedure evokes a short-lasting period of flinching (phase 1) and a long-lasting period of intense flinching (phase 2) following a very short period of quiescence. Phase 2 has been extensively used to support the involvement of central (spinal cord) sensitization in inflammatory hyperalgesia. The present study evaluated the contribution of stimulation of peripheral nociceptors by the release of endogenous mediators at the site of lesion. The participation of histamine and 5-hydroxytryptamine was demonstrated by the treatment of the rat hindpaws with selective histamine H1 (pyrilamine and meclizine) and histamine H2 (cimetidine) receptor antagonists or selective 5-hydroxytryptamine(1A) (WAY100,135) and 5-hydroxytryptamine(4/3) (tropisetron) receptor antagonists. The co-administration of pyrilamine or meclizine with formalin (1%) significantly reduced phases 1 and 2, while cimetidine had no effect. Pyrilamine administration during the period of quiescence (10min after formalin administration) caused strong dose-related inhibition of phase 2. The co-administration of tropisetron with formalin caused a blockade of both phases, while with WAY100,135 caused only inhibition of the phase 2. In contrast, tropisetron administrated during the period of quiescence did not cause antinociception. Histamine and 5-hydroxytryptamine receptors could be strongly activated in naïve animals by administration of a mixture of both agonists or compound 48/80 (2microg/paw) which is known to release both mediators from mast cells. Pretreatment of the paws with a mast cell stabilizer, sodium cromoglycate, significantly reduced the second phase of the formalin injection model. From these results we suggest that phases 1 and 2 of the formalin test are dependent upon the ongoing afferent input. Furthermore, while histamine H1 participates in both phases, 5-hydroxytryptamine(4/3) participates in phase 1 and 5

  8. Serotonin receptor diversity in the human colon: Expression of serotonin type 3 receptor subunits 5-HT3C, 5-HT3D, and 5-HT3E

    PubMed Central

    Kapeller, Johannes; Möller, Dorothee; Lasitschka, Felix; Autschbach, Frank; Hovius, Ruud; Rappold, Gudrun; Brüss, Michael; Gershon, Michael D.

    2011-01-01

    Since the first description of 5-HT3 receptors more than 50 years ago, there has been speculation about the molecular basis of their receptor heterogeneity. We have cloned the genes encoding novel 5-HT3 subunits 5-HT3C, 5-HT3D, and 5-HT3E and have shown that these subunits are able to form functional heteromeric receptors when coexpressed with the 5-HT3A subunit. However, whether these subunits are actually expressed in human tissue remained to be confirmed. In the current study, we performed immunocytochemistry to locate the 5-HT3A as well as the 5-HT3C, 5-HT3D, and 5-HT3E subunits within the human colon. Western blot analysis was used to confirm subunit expression, and RT-PCR was employed to detect transcripts encoding 5-HT3 receptor subunits in microdissected tissue samples. This investigation revealed, for the first time, that 5-HT3C, 5-HT3D, and 5-HT3E subunits are coexpressed with 5-HT3A in cell bodies of myenteric neurons. Furthermore, 5-HT3A and 5-HT3D were found to be expressed in submucosal plexus of the human large intestine. These data provide a strong basis for future studies of the roles that specific 5-HT3 receptor subtypes play in the function of the enteric and central nervous systems and the contribution that specific 5-HT3 receptors make to the pathophysiology of gastrointestinal disorders such as irritable bowel syndrome and dyspepsia. PMID:21192076

  9. Characterization of a ( sub 3 H)-5-hydroxtyryptamine binding site in rabbit caudate nucleus that differs from the 5-HT sub 1A , 5-HT sub 1B , 5-HT sub 1C and 5-HT sub 1D subtypes

    SciTech Connect

    Xiong, Wencheng; Nelson, D.L. )

    1989-01-01

    ({sup 3}H)5-HT binding sites were analyzed in membranes prepared from the rabbit caudate nucleus (CN). ({sup 3}H)5-HT labeled both 5-HT{sub 1A} and 5-HT{sub 1C} recognition sites, defined by nanomolar affinity for 8-OH-DPAT and mesulergine respectively; however, these represented only a fraction of total specific ({sup 3}H)5-HT binding. Saturation experiments of ({sup 3}H)5-HT binding in the presence of 100 nM 8-OH-DPAT and 100 nM mesulergine to block 5-HT{sub 1A} and 5-HT{sub 1C} sites revealed that non-5-HT{sub 1A}/non-5-HT{sub 1C} sites represented about 60% of the total 5-HT{sub 1} sites and that they exhibited saturable, high affinity, and homogeneous binding. The pharmacological profile of the non-5-HT{sub 1A}/non-5-HT{sub 1C} sites (designated 5-HT{sub 1R}) also differed from that of 5-HT{sub 1B} and 5-HT{sub 2} sites, but was similar to that of the 5-HT{sub 1D} site. However, significant differences existed between the 5-HT{sub 1D} and 5-HT{sub 1B} sites for their K{sub i} values for spiperone, spirilene, metergoline, and methiothepin. The study of modulatory agents also showed differences between the 5-HT{sub 1R} and 5-HT{sub 1D} sites. In addition, calcium enhanced the effects of GTP on the 5-HT{sub 1R} sites, whereas calcium inhibited the GTP effect on the 5-HT{sub 1D} sites.

  10. 5-Amino-6-chloro-N-[(1-isobutylpiperidin-4-yl)methyl]-2-methylimidazo[1,2-alpha]pyridine-8-carboxamide (CJ-033,466), a novel and selective 5-hydroxytryptamine4 receptor partial agonist: pharmacological profile in vitro and gastroprokinetic effect in conscious dogs.

    PubMed

    Mikami, Tadayoshi; Ochi, Yasuo; Suzuki, Keiko; Saito, Toshiyuki; Sugie, Yutaka; Sakakibara, Minoru

    2008-04-01

    5-Hydroxytryptamine (5-HT) receptors and dopamine(2) (D(2)) receptor modulate gastrointestinal motility. Gastroprokinetic agents that act on several 5-HT receptor subtypes and/or D(2) receptors are used clinically. Although the 5-HT(4) receptor is known to mediate the gastroprokinetic effects of these agents, the absence of highly selective 5-HT(4) receptor agonists has made it difficult to confirm the physiological consequences of selective 5-HT(4) receptor stimulation. In this study, we report the in vitro pharmacological profiles and the in vivo gastroprokinetic effects of 5-amino-6-chloro-N-[(1-isobutylpiperidin-4-yl)methyl]-2-methylimidazo[1,2-alpha]pyridine-8-carboxamide (CJ-033,466), a novel, potent, and selective 5-HT(4) partial agonist. Compared with preceding 5-HT(4) agonists such as cisapride, mosapride, and tegaserod, CJ-033,466 had a superior in vitro profile, with nanomolar agonistic activities for the 5-HT(4) receptor and 1000-fold greater selectivity for the 5-HT(4) receptor over other 5-HT and D(2) receptors. In vivo studies in conscious dogs showed that CJ-033,466 dose-dependently stimulated gastric antral motility in both the fasted and postprandial states at the same dose range and that it was 30 times more potent than cisapride. Furthermore, CJ-033,466 accelerated the gastric emptying rate in a gastroparesis dog model at the minimally effective dose established in the gastric motility study. In conclusion, CJ-033,466 is a potent and highly selective 5-HT(4) agonist that stimulates physiologically coordinated gastric motility, and it has no activity on other 5-HT receptor subtypes and D(2) receptors. Therefore, CJ-033,466 could be used to treat gastroparesis, providing better gastroprokinetics and reduced side effects mediated by the other receptors. PMID:18198343

  11. The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK.

    PubMed

    Lippiello, Pellegrino; Hoxha, Eriola; Speranza, Luisa; Volpicelli, Floriana; Ferraro, Angela; Leopoldo, Marcello; Lacivita, Enza; Perrone-Capano, Carla; Tempia, Filippo; Miniaci, Maria Concetta

    2016-02-01

    The 5-HT7 receptor (5-HT7R) mediates important physiological effects of serotonin, such as memory and emotion, and is emerging as a therapeutic target for the treatment of cognitive disorders and depression. Although previous studies have revealed an expression of 5-HT7R in cerebellum, particularly at Purkinje cells, its functional role and signaling mechanisms have never been described. Using patch-clamp recordings in cerebellar slices of adult mice, we investigated the effects of a selective 5-HT7R agonist, LP-211, on the main plastic site of the cerebellar cortex, the parallel fiber-Purkinje cell synapse. Here we show that 5-HT7R activation induces long-term depression of parallel fiber-Purkinje cell synapse via a postsynaptic mechanism that involves the PKC-MAPK signaling pathway. Moreover, a 5-HT7R antagonist abolished the expression of PF-LTD, produced by pairing parallel fiber stimulation with Purkinje cell depolarization; whereas, application of a 5-HT7R agonist impaired LTP induced by 1 Hz parallel fiber stimulation. Our results indicate for the first time that 5-HT7R exerts a fine regulation of cerebellar bidirectional synaptic plasticity that might be involved in cognitive processes and neuropsychiatric disorders involving the cerebellum. PMID:26482421

  12. Design and synthesis of dual 5-HT1A and 5-HT7 receptor ligands.

    PubMed

    Ofori, Edward; Zhu, Xue Y; Etukala, Jagan R; Peprah, Kwakye; Jordan, Kamanski R; Adkins, Adia A; Bricker, Barbara A; Kang, Hye J; Huang, Xi-Ping; Roth, Bryan L; Ablordeppey, Seth Y

    2016-08-15

    5-HT1A and 5-HT7 receptors have been at the center of discussions recently due in part to their major role in the etiology of major central nervous system diseases such as depression, sleep disorders, and schizophrenia. As part of our search to identify dual targeting ligands for these receptors, we have carried out a systematic modification of a selective 5HT7 receptor ligand culminating in the identification of several dual 5-HT1A and 5-HT7 receptor ligands. Compound 16, a butyrophenone derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low nanomolar binding affinities to both receptors. Interestingly, compound 16 also displayed moderate affinity to other clinically relevant dopamine receptors. Thus, it is anticipated that compound 16 may serve as a lead for further exploitation in our quest to identify new ligands with the potential to treat diseases of CNS origin. PMID:27312422

  13. Pharmacological analysis of G-protein activation mediated by guinea-pig recombinant 5-HT1B receptors in C6-glial cells: similarities with the human 5-HT1B receptor.

    PubMed

    Pauwels, P J; Wurch, T; Palmier, C; Colpaert, F C

    1998-01-01

    1. The guinea-pig recombinant 5-hydroxytryptamine1B (gp 5-HT1B) receptor stably transfected in rat C6-glial cells was characterized by monitoring G-protein activation in a membrane preparation with agonist-stimulated [35S]-GTPgammaS binding. The intrinsic activity of 5-HT receptor ligands was compared with that determined previously at the human recombinant 5-HT1B (h 5-HT1B) receptor under similar experimental conditions. 2. Membrane preparations of C6-glial/gp 5-HT1B cells exhibited [3H]-5-carboxamidotryptamine (5-CT) and [3H]-N-[4-methoxy-3,4-methylpiperazin-1-yl) phenyl]-3-methyl-4-(4-pyridinyl)benzamide (GR 125743) binding sites with a pKd of 9.62 to 9.85 and a Bmax between 2.1 to 6.4 fmol mg(-1) protein. The binding affinities of a series of 5-HT receptor ligands determined with [3H]-5-CT and [3H]-GR 125743 were similar. Ligand affinities were comparable to and correlated (r2: 0.74, P<0.001) with those determined at the recombinant h 5-HT1B receptor. 3. [35S]-GTPgammaS binding to membrane preparations of C6-glial/gp 5-HT1B cells was stimulated by the 5-HT receptor agonists that were being investigated. The maximal responses of naratriptan, zolmitriptan, sumatriptan, N-methyl-3-[pyrrolidin-2(R)-ylmethyl]-1H-indol-5-ylmethyl sulphonamide (CP 122638), rizatriptan and dihydroergotamine were between 0.76 and 0.85 compared to 5-HT. The potency of these agonists showed a positive correlation (r2: 0.72, P=0.015) with their potency at the recombinant h 5-HT1B receptor. 1-naphthylpiperazine, (+/-)-cyanopindolol and (2'-methyl-4'-(5-methyl[1,2,4] oxadiazole-3-yl)biphenyl-4-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide (GR 127935) elicited an even smaller response (Emax: 0.32 to 0.63). 4. The ligands 1'-methyl-5-(2'-methyl-4'-(5-methyl-1,2,4-oxadiazole-3-yl) biphenyl-4-carbonyl)-2,3,6,7tetrahydrospiro [furo[2,3-f]indole-3-spiro-4'-piperidine] (SB224289), methiothepin and ritanserin displayed inhibition of basal [35S]-GTPgammaS binding at concentrations

  14. Effect of Y-25130, a selective 5-hydroxytryptamine3 receptor antagonist, on gastric emptying in mice.

    PubMed

    Haga, K; Asano, K; Inaba, K; Morimoto, Y; Setoguchi, M

    1994-01-01

    The effect of Y-25130 on gastric emptying of nutrient test meals (solid chow) was examined in mice. In a dose range of 0.01-1 mg/kg, p.o., Y-25130 significantly accelerated gastric emptying of solid meals in a dose-dependent manner, at an ED30 of 0.021 mg/kg. Other 5-hydroxytryptamine3 receptor antagonists and prokinetic agents having 5-hydroxytryptamine3 receptor antagonistic properties accelerated the emptying of solid meals in the following rank order of potency: Y-25130 = granisetron > or = tropisetron > ondansetron > cisapride > metoclopramide. The acceleration of the gastric emptying showed a good correlation with the antagonistic potencies of these compounds on 5-hydroxytryptamine3 receptors, determined by the inhibition test of the von Bezold-Jarisch reflex in anesthetized rats (r2 = 0.99). Domperidone (1 and 10 mg/kg, p.o.) and trimebutine (10 and 100 mg/kg, p.o.) failed to increase the rate of emptying from the stomach. Cisplatin (30 mg/kg, i.p.), a chemotherapeutic agent, significantly delayed the gastric emptying of solid meals, and Y-25130 (0.1-1 mg/kg, p.o.) prevented such a delay in emptying in a dose-dependent manner. These results suggest that Y-25130 accelerates the gastric emptying in mice by antagonism of the 5-hydroxytryptamine3 receptor. PMID:7625886

  15. Impact of 5-HT3 receptor antagonists on chemotherapy-induced nausea and vomiting: a retrospective cohort study

    PubMed Central

    2012-01-01

    Background 1st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV) associated with moderately (MEC) and highly emetogenic CT agents (HEC). This study explores the impact of step therapy policies requiring use of an older 5-HT3 RA before palonosetron on risk of CINV associated with hospital or emergency department (ED) admissions. Methods Patients who received cyclophosphamide post breast cancer (BC) surgery or who were diagnosed with lung cancer on carboplatin (LC-carboplatin) or cisplatin (LC-cisplatin) were selected from PharMetrics’ (IMS LifeLink) claims dataset (2005-2008). Patients were followed for 6 months from initial CT administration for CINV events identified through ICD-9-CM codes. Patients were grouped into those initiated with older, generic 5-HT3 RAs (ondansetron, granisetron, and dolasetron) and those initiated and maintained on palonosetron throughout study follow-up. CINV events and CINV days were analyzed using multivariate regressions controlling for demographic and clinical variables. Results Eligible patients numbered 3,606 in BC, 4,497 in LC-carboplatin and 1,154 in LC-cisplatin cohorts, with 52%, 40%, and 34% in the palonosetron group, respectively. There was no significant difference between the two 5-HT3 RA groups in age or Charlson Comorbidity Index among the two MEC cohorts (BC and LC-carboplatin). Among the LC-cisplatin cohort, palonosetron users were older with more males than the older 5-HT3 RA group (age: 60.1 vs. 61.3; males, 66.9% vs. 56.9%). Compared to the older 5-HT3 RAs, the palonosetron groups incurred 22%-51% fewer 5-HT3 RA pharmacy claims, had fewer patients with CINV events (3.5% vs. 5.5% in BC, 9.5% vs. 12.8% in LC-carboplatin, 16.4% vs. 21.7% in LC-cisplatin), and had lower risk for CINV events (odds ratios 0.62, 0.71, or 0.71, respectively; p < 0.05). The BC and LC

  16. Molecular cloning and expression of the porcine trigeminal ganglion cDNA encoding a 5-ht(1F) receptor.

    PubMed

    Bhalla, Pankaj; Sharma, Hari S; Wurch, Thierry; Pauwels, Petrus J; Saxena, Pramod R

    2002-02-01

    Using a combination of reverse transcription polymerase chain reaction (RT-PCR) and inverse-PCR techniques, we amplified, cloned and sequenced a full-length porcine 5-hydroxytryptamine 1F (5-ht(1F)) receptor complementary DNA (cDNA) derived from porcine trigeminal ganglion. Sequence analysis revealed 1101 base pairs (bp) encoding an open reading frame of 366 amino acids showing a high similarity (>90%) with the 5-ht(1F) receptor sequences from other species, including human. The recombinant porcine 5-ht(1F) receptor was expressed in African green monkey kidney cell lines (COS-7 cells) and its ligand binding profile was determined using [3H]5-HT. The affinities of several agonists (LY334370 (5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole fumarate)>CP122638 (N-methyl-3 [pyrrolidin 2(R)-yl methyl]-1H-indol-5-ylmethyl sulphonamide)=naratriptan =5HT>eletriptan>sumatriptan>frovatriptan =avitriptan>dihydroergotamine>zolmitriptan>5-carboxamidotryptamine>rizatriptan>alniditan=donitriptan>L694247 (2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indole-3-yl] ethylamine) and putative antagonists (methiothepin>GR127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl 4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1-biphenyl]-4-carboxamide hydrochloride)>ritanserin>SB224289 (2,3,6,7-tetrahydro-1'-methyl-5-[2'-methyl-4'(5-methyl-1,2,4-oxadiazol-3-yl) biphenyl-4-carbonyl] furo [2,3-f] indole-3-spiro-4'-piperidine hydrochloride)>BRL155572 ([1-(3-chlorophenyl)-4-[3,3-diphenyl (2-(S,R) hydroxypropanyl)piperazine] hydrochloride)>ketanserin=pindolol) correlated highly with those described for the recombinant human 5-ht(1F) receptor (Spearman correlation coefficient; r(s)=0.942). Nevertheless, as compared to the human homologue, some triptans (i.e. sumatriptan, zolmitriptan and rizatriptan) displayed a 10- to 15-fold lower affinity for the porcine 5-ht(1F) receptor. Using RT-PCR technique, the expression of porcine 5-ht(1F) receptor mRNA was observed in

  17. Evidence that mCPP may have behavioural effects mediated by central 5-HT1C receptors.

    PubMed Central

    Kennett, G. A.; Curzon, G.

    1988-01-01

    1. The effects of 1-(3-chlorophenyl)piperazine (mCPP) and 1-[3-(trifluoromethyl)phenyl] piperazine (TFMPP) on activity of rats in a novel cage, and on the rotorod and elevated bar co-ordination tests was examined. 2. Peripherally administered mCPP and TFMPP dose-dependently reduced locomotion, rearing, and feeding scores but not grooming of freely fed rats placed in a novel observation cage. Yawning behaviour was increased. Similar effects were also observed after injection of mCPP into the 3rd ventricle. 3. Co-ordination on a rotating drum of both untrained and trained rats was impaired following mCPP but co-ordination on an elevated bar was not. 4. The hypoactivity induced by mCPP was opposed by three antagonists with high affinity for the 5-hydroxytryptamine (5-HT1C) site; metergoline, mianserin, cyproheptadine and possibly also by a fourth antagonist mesulergine. Metergoline, mianserin and cyproheptadine also opposed the reduction in feeding scores. However, neither effect of mCPP was antagonized by the 5-HT2-receptor antagonists ketanserin or ritanserin, the 5-HT3-receptor antagonist ICS 205-930, the 5-HT1A and 5-HT1B-receptor antagonists (-)-pindolol, (-)-propranolol and (+/-)-cyanopindolol or the 5-HT1A-, 5-HT2- and dopamine receptor antagonist spiperone. The specific alpha 2-adrenoceptor antagonist idazoxan was also without effect. 5. Hypoactivity induced by TFMPP was similarly antagonized by mianserin but unaffected by (+/-)-cyanopindolol. 6. These results suggest that the hypoactivity is mediated by central 5-HT1C-receptors and that mCPP and possibly TFMPP may be 5-HT1C-receptor agonists. 7. As mianserin, cyproheptadine and mesulergine in the absence of mCPP did not increase locomotion but increased the number of feeding scores, the activation of 5-HT1C-receptors may be of physiological importance in the control of appetite. The possible relevance of these results to the therapeutic and side-effects of clinically used antidepressants (particularly

  18. The chemical coding of 5-hydroxytryptamine containing enteroendocrine cells in the mouse gastrointestinal tract.

    PubMed

    Reynaud, Yohan; Fakhry, Josiane; Fothergill, Linda; Callaghan, Brid; Ringuet, Mitchell; Hunne, Billie; Bravo, David M; Furness, John B

    2016-06-01

    The majority of 5-HT (serotonin) in the body is contained in enteroendocrine cells of the gastrointestinal mucosa. From the time of their discovery over 80 years ago, the 5-HT-containing cells have been regarded as a class of cell that is distinct from enteroendocrine cells that contain peptide hormones. However, recent studies have cast doubt on the concept of there being distinct classes of enteroendocrine cells, each containing a single hormone or occasionally more than one hormone. Instead, data are rapidly accumulating that there are complex patterns of colocalisation of hormones that identify multiple subclasses of enteroendocrine cells. In the present work, multiple labelling immunohistochemistry is used to investigate patterns of colocalisation of 5-HT with enteric peptide hormones. Over 95 % of 5-HT cells in the duodenum also contained cholecystokinin and about 40 % of them also contained secretin. In the jejunum, about 75 % of 5-HT cells contained cholecystokinin but not secretin and 25 % contained 5-HT plus both cholecystokinin and secretin. Small proportions of 5-HT cells contained gastrin or somatostatin in the stomach, PYY or GLP-1 in the small intestine and GLP-1 or somatostatin in the large intestine. Rare or very rare 5-HT cells contained ghrelin (stomach), neurotensin (small and large intestines), somatostatin (small intestine) and PYY (in the large intestine). It is concluded that 5-HT-containing enteroendocrine cells are heterogeneous in their chemical coding and by implication in their functions. PMID:26803512

  19. Evidence that brain glucose availability influences exercise-enhanced extracellular 5-HT level in hippocampus: a microdialysis study in exercising rats.

    PubMed

    Béquet, F; Gomez-Merino, D; Berthelot, M; Guezennec, C Y

    2002-09-01

    The relationship between brain glucose and serotonin is still unclear and no direct evidence of an action of brain glucose on serotonergic metabolism in central fatigue phenomena has been shown yet. In order to determine whether or not brain glucose could influence the brain 5-hydroxytryptamine (5-HT) system, we have monitored in microdialysis the effects of a direct injection of glucose in rat brain hippocampus on serotonergic metabolism [i.e. 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and tryptophan (TRP)], during high intensive treadmill running. The injection was performed just before and after exercise. We have shown that glucose induced a decrease of brain 5-HT levels to a minimum of 73.0 +/- 3.5% of baseline after the first injection (P < 0.01) and to 68.5 +/- 5.5% of baseline after the second injection (P < 0.01) and consequently prevented the exercise-induced 5-HT enhanced levels. We have observed the same phenomenon concerning the 5-HIAA, but brain TRP levels were not decreased by the injections. In conclusion, this study demonstrates that brain glucose can act on serotonergic metabolism and thus can prevent exercise-induced increase of 5-HT levels. The results also suggest that extracellular brain glucose does not act on the synthesis way of 5-HT, but probably on the release/reuptake system. PMID:12193220

  20. Emetic responses to T-2 toxin, HT-2 toxin and emetine correspond to plasma elevations of peptide YY3-36 and 5-hydroxytryptamine.

    PubMed

    Wu, Wenda; Zhou, Hui-Ren; Bursian, Steven J; Link, Jane E; Pestka, James J

    2016-04-01

    Trichothecene mycotoxins are a family of potent translational inhibitors that are associated with foodborne outbreaks of human and animal gastroenteritis in which vomiting is a clinical hallmark. Deoxynivalenol (DON, vomitoxin) and other Type B trichothecenes have been previously demonstrated to cause emesis in the mink (Neovison vison), and this response has been directly linked to secretion of both the satiety hormone peptide YY3-36 (PYY3-36) and neurotransmitter 5-hydroxytryptamine (5-HT). Here, we characterized the emetic responses in the mink to T-2 toxin (T-2) and HT-2 toxin (HT-2), two highly toxic Type A trichothecenes that contaminate cereals, and further compared these effects to those of emetine, a natural alkaloid that is used medicinally and also well known to block translation and cause vomiting. Following intraperitoneal (IP) and oral exposure, all three agents caused vomiting with evident dose-dependent increases in both duration and number of emetic events as well as decreases in latency to emesis. T-2 and HT-2 doses causing emesis in 50 % of treated animals (ED50s) were 0.05 and 0.02 mg/kg BW following IP and oral administration, respectively, whereas the ED50s for emetine were 2.0 and 1.0 mg/kg BW for IP and oral exposure, respectively. Importantly, oral administration of all three toxins elicited marked elevations in plasma concentrations of PYY3-36 and 5-HT that corresponded to emesis. Taken together, the results suggest that T-2 and HT-2 were much more potent than emetine and that emesis induction by all three translational inhibitors co-occurred with increases in circulating levels of PYY3-36 and 5-HT. PMID:25855062

  1. Endothelium-derived relaxing factor released by 5-HT: distinct from nitric oxide in basilar arteries of normotensive and hypertensive rats.

    PubMed Central

    Yokota, Y; Imaizumi, Y; Asano, M; Matsuda, T; Watanabe, M

    1994-01-01

    1. The role of the endothelium in cerebrovascular responses to 5-hydroxytryptamine (5-HT) was investigated in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) in vitro. 2. Cumulative addition of 5-HT caused concentration-dependent contractions in ring preparations of SHR basilar arteries; the contractile response was smaller in WKY basilar arteries. 3. Removal of the endothelium enhanced markedly the contractile responses to 5-HT in WKY arteries but had only a slight effect in SHR arteries. The responsiveness to 5-HT in WKY arteries after removal of endothelium was comparable to that in SHR arteries. 4. The endothelium-dependent relaxation induced by acetylcholine in WKY basilar arteries was almost abolished by treatment with 10 microM methylene blue or 10 microM NG-nitro-L-arginine (L-NOARG). However, the response to 5-HT was not affected by treatment with methylene blue, L-NOARG or indomethacin. 5. Application of 10-20 mM K+ or 3.2 mM tetraethylammonium (TEA) did not change significantly, or only increased slightly, the resting tension, but markedly enhanced the contractile response to 5-HT in WKY arteries with endothelium. In contrast, the submaximal response to 5-HT in SHR arteries with endothelium was significantly enhanced by 0.3 mM TEA. 6. In the presence of 1 mM TEA, the application of 10 microM L-NOARG further enhanced the responses of 5-HT in WKY arteries with endothelium. In SHR arteries with endothelium, 10 microM L-NOARG per se enhanced slightly but significantly the responses to 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7812628

  2. How efficacious are 5-HT1B/D receptor ligands: an answer from GTP gamma S binding studies with stably transfected C6-glial cell lines.

    PubMed

    Pauwels, P J; Tardif, S; Palmier, C; Wurch, T; Colpaert, F C

    1997-01-01

    The intrinsic activity of a series of 5-hydroxytryptamine (serotonin, 5-HT) receptor ligands was analysed at recombinant h5-HT1B and h5-HT1D receptor sites using a [35S]GTP gamma S binding assay and membrane preparations of stably transfected C6-glial cell lines. Compounds either stimulated or inhibited [35S]GTP gamma S binding to a membrane preparation containing either h5-HT1B or h5-HT1D receptors. The potencies observed for most of the compounds at the h5-HT1B receptor subtype correlated with their potencies measured by inhibition of stimulated cAMP formation on intact cells. Apparent agonist potencies in the [35S]GTP gamma S binding assay to C6-glial/h5-HT1D membranes were, with the exception of 2-[5-[3-(4-methylsulphonylamino)benzyl-1 2,4-oxadiazol-5-yl]-1H-indol-3-yl] ethanamine (L694247), 5- to 13-times lower than in the cAMP assay on intact cells. This suggests that receptor coupling in the h5-HT1D membrane preparation is less efficient than that in the intact cell. It further appeared that 6-times more h5-HT1D than h5-HT1B binding sites were required to attain a similar, maximal (73%), 5-HT-stimulated [35S]GTP gamma S binding response: Hence, the h5-HT1B receptor in C6-glial cell membranes could be more efficiently coupled, even though some compounds more readily displayed intrinsic activity at h5-HT1D receptor sites [e.g. dihydroergotamine and (2'-methyl-4'-(5-methyl[1,2,4]oxadiazol-3-yl)biphenyl-4-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide (GR127935)]. Efficacy differences were apparent for most of the compounds (sumatriptan, zolmitriptan, rizatriptan, N-methyl-3-[pyrrolidin-2(R)-ylmethyl]-1H-indol-5-ylmethyl sulfonamide (CP122638), dihydroergotamine, naratriptan and GR127935) that stimulated [35S]GTP gamma S binding compared to the native agonist 5-HT. The observed maximal responses were different for the h5-HT1B and h5-HT1D receptor subtypes. Few compounds behaved as full agonists: L694247, zolmitriptan and sumatriptan did so at

  3. Importance of inositol (1,4,5)-trisphosphate, intracellular Ca2+ release and myofilament Ca2+ sensitization in 5-hydroxytryptamine-evoked contraction of rabbit mesenteric artery.

    PubMed Central

    Seager, J. M.; Murphy, T. V.; Garland, C. J.

    1994-01-01

    1. Small strips from third-order branches of rabbit mesenteric artery (approximately 150-200 microM wide) contracted in response to noradrenaline (10 microM) or 5-hydroxytryptamine (5-HT; 10 microM) in oxygenated Krebs solution containing 2.5 mM Ca2+. In a Ca(2+)-free mock intracellular solution (0 Ca2+ plus 0.2 mM EGTA), noradrenaline (10 microM) and caffeine (10 mM) induced only a single, transient contraction in artery strips, while 5-HT (10 microM) failed to induce any response. 2. In strips of mesenteric artery which had been permeabilized with Staphylococcus alpha-toxin and bathed in Ca(2+)-free mock intracellular solution, noradrenaline (10 microM), caffeine (10 mM) and D-myo-inositol (1,4,5)-trisphosphate (IP3, 100 microM), but not 5-HT (10 or 100 microM) induced a transient contraction. In contrast to the non-permeabilized strips, contractions to noradrenaline, caffeine and IP3 were restored by prior incubation (10 min) in solution containing 0.08 microM Ca2+. The contractions to noradrenaline and IP3 in permeabilized muscle strips required the presence of 100 microM guanosine 5'-triphosphate (GTP), although in the absence of Ca2+. GTP alone did not induce contraction. 3. Exposure of permeabilized mesenteric artery strips to IP3 significantly reduced the subsequent contractile responses to caffeine. Contractile responses to caffeine and IP3 were abolished by the Ca(2+)-ATPase inhibitor, thapsigargin (1 microM). 4. Ca2+ (0.1-10 microM) induced concentration-dependent contraction in permeabilized artery strips. In strips which were submaximally contracted with 0.5 microM Ca2+/100 microM GTP, the subsequent addition of 5-HT (10 microM) stimulated further contraction. The protein kinase C inhibitor, H-7 (1 microM) abolished the 5-HT/GTP-induced contraction, but did not alter the contraction to Ca2+.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8004397

  4. The serotonin 5-HT7 receptors: two decades of research.

    PubMed

    Gellynck, Evelien; Heyninck, Karen; Andressen, Kjetil W; Haegeman, Guy; Levy, Finn Olav; Vanhoenacker, Peter; Van Craenenbroeck, Kathleen

    2013-10-01

    Like most neurotransmitters, serotonin possesses a simple structure. However, the pharmacological consequences are more complex and diverse. Serotonin is involved in numerous functions in the human body including the control of appetite, sleep, memory and learning, temperature regulation, mood, behavior, cardiovascular function, muscle contraction, endocrine regulation, and depression. Low levels of serotonin may be associated with several disorders, namely increase in aggressive and angry behaviors, clinical depression, Parkinson's disease, obsessive-compulsive disorder, eating disorders, migraine, irritable bowel syndrome, tinnitus, and bipolar disease. These effects are mediated via different serotonin (5-HT) receptors. In this review, we will focus on the last discovered member of this serotonin receptor family, the 5-HT7 receptor. This receptor belongs to the G protein-coupled receptor superfamily and was cloned two decades ago. Later, different splice variants were described but no major functional differences have been described so far. All 5-HT7 receptor variants are coupled to Gαs proteins and stimulate cAMP formation. Recently, several interacting proteins have been reported, which can influence receptor signaling and trafficking. PMID:24042216

  5. Regulation of amyloid precursor protein processing by serotonin signaling.

    PubMed

    Pimenova, Anna A; Thathiah, Amantha; De Strooper, Bart; Tesseur, Ina

    2014-01-01

    Proteolytic processing of the amyloid precursor protein (APP) by the β- and γ-secretases releases the amyloid-β peptide (Aβ), which deposits in senile plaques and contributes to the etiology of Alzheimer's disease (AD). The α-secretase cleaves APP in the Aβ peptide sequence to generate soluble APPα (sAPPα). Upregulation of α-secretase activity through the 5-hydroxytryptamine 4 (5-HT4) receptor has been shown to reduce Aβ production, amyloid plaque load and to improve cognitive impairment in transgenic mouse models of AD. Consequently, activation of 5-HT4 receptors following agonist stimulation is considered to be a therapeutic strategy for AD treatment; however, the signaling cascade involved in 5-HT4 receptor-stimulated proteolysis of APP remains to be determined. Here we used chemical and siRNA inhibition to identify the proteins which mediate 5-HT4d receptor-stimulated α-secretase activity in the SH-SY5Y human neuronal cell line. We show that G protein and Src dependent activation of phospholipase C are required for α-secretase activity, while, unexpectedly, adenylyl cyclase and cAMP are not involved. Further elucidation of the signaling pathway indicates that inositol triphosphate phosphorylation and casein kinase 2 activation is also a prerequisite for α-secretase activity. Our findings provide a novel route to explore the treatment of AD through 5-HT4 receptor-induced α-secretase activation. PMID:24466315

  6. Systemic inflammation alters central 5-HT function as determined by pharmacological MRI.

    PubMed

    Couch, Yvonne; Martin, Chris J; Howarth, Clare; Raley, Josie; Khrapitchev, Alexandre A; Stratford, Michael; Sharp, Trevor; Sibson, Nicola R; Anthony, Daniel C

    2013-07-15

    Considerable evidence indicates a link between systemic inflammation and central 5-HT function. This study used pharmacological magnetic resonance imaging (phMRI) to study the effects of systemic inflammatory events on central 5-HT function. Changes in blood oxygenation level dependent (BOLD) contrast were detected in selected brain regions of anaesthetised rats in response to intravenous administration of the 5-HT-releasing agent, fenfluramine (10 mg/kg). Further groups of rats were pre-treated with the bacterial lipopolysaccharide (LPS; 0.5 mg/kg), to induce systemic inflammation, or the selective 5-HT2A receptor antagonist MDL100907 prior to fenfluramine. The resultant phMRI data were investigated further through measurements of cortical 5-HT release (microdialysis), and vascular responsivity, as well as a more thorough investigation of the role of the 5-HT2A receptor in sickness behaviour. Fenfluramine evoked a positive BOLD response in the motor cortex (+15.9±2%) and a negative BOLD response in the dorsal raphe nucleus (-9.9±4.2%) and nucleus accumbens (-7.7±5.3%). In all regions, BOLD responses to fenfluramine were significantly attenuated by pre-treatment with LPS (p<0.0001), but neurovascular coupling remained intact, and fenfluramine-evoked 5-HT release was not affected. However, increased expression of the 5-HT2A receptor mRNA and decreased 5-HT2A-dependent behaviour (wet-dog shakes) was a feature of the LPS treatment and may underpin the altered phMRI signal. MDL100907 (0.5 mg/kg), 5-HT2A antagonist, significantly reduced the BOLD responses to fenfluramine in all three regions (p<0.0001) in a similar manner to LPS. Together these results suggest that systemic inflammation decreases brain 5-HT activity as assessed by phMRI. However, these effects do not appear to be mediated by changes in 5-HT release, but are associated with changes in 5-HT2A-receptor-mediated downstream signalling pathways. PMID:23473937

  7. Systemic inflammation alters central 5-HT function as determined by pharmacological MRI

    PubMed Central

    Couch, Yvonne; Martin, Chris J.; Howarth, Clare; Raley, Josie; Khrapitchev, Alexandre A.; Stratford, Michael; Sharp, Trevor; Sibson, Nicola R.; Anthony, Daniel C.

    2013-01-01

    Considerable evidence indicates a link between systemic inflammation and central 5-HT function. This study used pharmacological magnetic resonance imaging (phMRI) to study the effects of systemic inflammatory events on central 5-HT function. Changes in blood oxygenation level dependent (BOLD) contrast were detected in selected brain regions of anaesthetised rats in response to intravenous administration of the 5-HT-releasing agent, fenfluramine (10 mg/kg). Further groups of rats were pre-treated with the bacterial lipopolysaccharide (LPS; 0.5 mg/kg), to induce systemic inflammation, or the selective 5-HT2A receptor antagonist MDL100907 prior to fenfluramine. The resultant phMRI data were investigated further through measurements of cortical 5-HT release (microdialysis), and vascular responsivity, as well as a more thorough investigation of the role of the 5-HT2A receptor in sickness behaviour. Fenfluramine evoked a positive BOLD response in the motor cortex (+ 15.9 ± 2%) and a negative BOLD response in the dorsal raphe nucleus (− 9.9 ± 4.2%) and nucleus accumbens (− 7.7 ± 5.3%). In all regions, BOLD responses to fenfluramine were significantly attenuated by pre-treatment with LPS (p < 0.0001), but neurovascular coupling remained intact, and fenfluramine-evoked 5-HT release was not affected. However, increased expression of the 5-HT2A receptor mRNA and decreased 5-HT2A-dependent behaviour (wet-dog shakes) was a feature of the LPS treatment and may underpin the altered phMRI signal. MDL100907 (0.5 mg/kg), 5-HT2A antagonist, significantly reduced the BOLD responses to fenfluramine in all three regions (p < 0.0001) in a similar manner to LPS. Together these results suggest that systemic inflammation decreases brain 5-HT activity as assessed by phMRI. However, these effects do not appear to be mediated by changes in 5-HT release, but are associated with changes in 5-HT2A-receptor-mediated downstream signalling pathways. PMID:23473937

  8. Amygdala-Hippocampal Phospholipase D (PLD) Signaling As Novel Mechanism of Cocaine-Environment Maladaptive Conditioned Responses

    PubMed Central

    2016-01-01

    Background: Drug-environment associative memory mechanisms and the resulting conditioned behaviors are key contributors in relapse to cocaine dependence. Recently, we reported rat amygdala phospholipase D as a key convergent downstream signaling partner in the expression of cocaine-conditioned behaviors mediated by glutamatergic and dopaminergic pathways. In the present study, 1 of the 2 known upstream serotonergic targets of phospholipase D, the serotonin (5-hydroxytryptamine) 2C receptor, was investigated for its role in recruiting phospholipase D signaling in cocaine-conditioned behaviors altered in the rat amygdala and dorsal hippocampus. Methods: Using Western-blot analysis, amygdala phospholipase D phosphorylation and total expression of phospholipase D/5-hydroxytryptamine 2C receptor were observed in early (Day-1) and late (Day-14) withdrawal (cocaine-free) states among male Sprague-Dawley rats subjected to 7-day cocaine-conditioned hyperactivity training. Functional studies were conducted using Chinese Hamster Ovary cells with stably transfected human unedited isoform of 5-hydroxytryptamine 2C receptor. Results: Phosphorylation of phospholipase D isoforms was altered in the Day-1 group of cocaine-conditioned animals, while increased amygdala and decreased dorsal hippocampus phospholipase D/5-hydroxytryptamine 2C receptor protein expression were observed in the Day-14 cocaine-conditioned rats. Functional cellular studies established that increased p phospholipase D is a mechanistic response to 5-HT2CR activation and provided the first evidence of a biased agonism by specific 5-hydroxytryptamine 2C receptor agonist, WAY163909 in phospholipase D phosphorylation 2, but not phospholipase D phosphorylation 1 activation. Conclusions: Phospholipase D signaling, activated by dopaminergic, glutamatergic, and serotonergic signaling, can be a common downstream element recruited in associative memory mechanisms altered by cocaine, where increased expression in amygdala

  9. Effects on amine oxidase of substances which antagonize 5-hydroxytryptamine more than tryptamine on the rat fundus strip

    PubMed Central

    Barlow, R. B.

    1961-01-01

    Certain substances, 2-bromolysergic acid diethylamide, dimethyltryptamine (3-(2-dimethylaminoethyl)indole), 2-methyldimethyltryptamine (3-(2-dimethylaminoethyl)-2-methylindole), and 5-benzyloxydimethyltryptamine (5-benzyloxy-3-(2-dimethylaminoethyl)indole), antagonize the effects of 5-hydroxytryptamine on the rat fundus strip more than those of tryptamine. These substances have been tested for their ability to inhibit the oxidation of tryptamine and 5-hydroxytryptamine by suspensions of guinea-pig liver and rat fundus. 2-Bromolysergic acid diethylamide has virtually no inhibitory activity and it is doubtful if the others produce any significant inhibition of amine oxidase in the concentrations which antagonize the effects of 5-hydroxytryptamine more than those of tryptamine. It seems that the differential character of the blocking action of these compounds should be ascribed either to interference with the transport of tryptamine (but not 5-hydroxytryptamine) through the cell wall, coupled with the block of a receptor common to both tryptamine and 5-hydroxytryptamine, or to the existence of separate tryptamine and 5-hydroxytryptamine receptors. The amine oxidases of the guinea-pig liver and rat fundus appear to be a mixture of at least two types of enzyme, one of which has a higher affinity for 5-hydroxytryptamine than the other and is more susceptible to inhibition by 2-methyldimethyltryptamine. PMID:13687054

  10. The 5-HT7 receptor in learning and memory. Importance of the hippocampus

    PubMed Central

    Roberts, Amanda J.; Hedlund, Peter B.

    2011-01-01

    The 5-HT7 receptor is a more recently discovered G-protein-coupled receptor for serotonin. The functions and possible clinical relevance of this receptor are not yet fully understood. The present paper reviews to what extent the use of animal models of learning and memory and other techniques have implicated the 5-HT7 receptor in such processes. The studies have used a combination of pharmacological and genetic tools targeting the receptor to evaluate effects on behavior and cellular mechanisms. In tests such as the Barnes maze, contextual fear conditioning and novel location recognition that involve spatial learning and memory there is a considerable amount of evidence supporting an involvement of the 5-HT7 receptor. Supporting evidence has also been obtained in studies of mRNA expression and cellular signaling as well as in electrophysiological experiments. Especially interesting are the subtle but distinct effects observed in hippocampus-dependent models of place learning where impairments have been described in mice lacking the 5-HT7 receptor or after administration of a selective antagonist. While more work is required, it appears that 5-HT7 receptors are particularly important in allocentric representation processes. In instrumental learning tasks both procognitive effects and impairments in memory have been observed using pharmacological tools targeting the 5-HT7 receptor. In conclusion, the use of pharmacological and genetic tools in animal studies of learning and memory suggest a potentially important role for the 5-HT7 receptor in cognitive processes. PMID:21484935

  11. The effect of atropine on the activation of 5-hydroxytryptamine3 channels in rat nodose ganglion neurons.

    PubMed

    Fan, P; Weight, F F

    1994-10-01

    It has been suggested that changes in brain 5-hydroxytryptamine3 receptor function may contribute to some behavior disorders, such as anxiety, schizophrenia and drug abuse. We are using the whole-cell version of the patch-clamp technique to study the function of 5-hydroxytryptamine3 channels in neurons freshly dissociated from rat nodose ganglion. In these cells, 5-hydroxytryptamine elicits an inward current over the concentration range of 0.25-100 microM (EC50 = 2.62 microM) by activating 5-hydroxytryptamine3 receptors. The muscarinic cholinergic antagonist atropine reduced the amplitude of 5-hydroxytryptamine activated inward current in a concentration-dependent manner. Other muscarinic antagonists, scopolamine, dexetimide, the M1 muscarinic receptor antagonist pirenzepine, the M2 receptor antagonist methoctramine and the M3 receptor antagonist 4-DAMP methiodide also inhibited 5-hydroxytryptamine-induced inward current. Atropine did not appear to change the reversal potential of this current. In the presence of 5 microM atropine, the concentration-response curve for 5-hydroxytryptamine current was shifted to the right in a parallel fashion. The EC50 value for 5-hydroxytryptamine was increased from 2.62 to 8.76 microM. Schild plots of increasing atropine and 5-hydroxytryptamine concentrations revealed a pA2 value of 5.74 for atropine (apparent KD = 1.8 microM). These observations suggest that atropine competitively antagonizes the activation of a receptor for the neurotransmitter serotonin, a novel action of muscarinic antagonists in the nervous system. This effect of atropine may contribute to the clinical symptoms seen in severe atropine intoxication. PMID:7531305

  12. Diurnal variation in 5-HT1B autoreceptor function in the anterior hypothalamus in vivo: effect of chronic antidepressant drug treatment

    PubMed Central

    Sayer, Tamsin J O; Hannon, Serina D; Redfern, Peter H; Martin, Keith F

    1999-01-01

    Intracerebral microdialysis was used to examine the function of the terminal 5-hydroxytryptamine (5-HT) autoreceptor in the anterior hypothalamus of anaesthetized rats at two points in the light phase of the light–dark cycle.Infusion of the 5-HT1A/1B agonist 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (RU24969) 0.1, 1.0 and 10 μM through the microdialysis probe led to a concentration-dependent decrease (49, 56 and 65% respectively) in 5-HT output. The effect of RU24969 (1 and 5 μM) was prevented by concurrent infusion of methiothepin (1 and 10 μM) into the anterior hypothalamus via the microdialysis probe. Infusion of methiothepin alone (1.0 and 10 μM) increased (15 and 142% respectively) 5-HT output.Infusion of RU24969 (5 μM) through the probe at mid-light and end-light resulted in a quantitatively greater decrease in 5-HT output at end-light compared with mid-light.Following treatment with either paroxetine hydrochloride (10 mg kg−1 i.p.) or desipramine hydrochloride (10 mg kg−1 i.p.) for 21 days the function of the terminal 5-HT1B autoreceptor was more markedly attenuated at end-light.The data show that, as defined by the response to RU24969, the function of the 5-HT1B receptors that control 5-HT output in the anterior hypothalamus is attenuated following chronic desipramine or paroxetine treatment in a time-of-day-dependent manner. PMID:10372820

  13. The effects of a selective 5-HT2 receptor antagonist (ICI 170,809) on platelet aggregation and pupillary responses in healthy volunteers.

    PubMed Central

    Millson, D S; Jessup, C L; Swaisland, A; Haworth, S; Rushton, A; Harry, J D

    1992-01-01

    1. ICI 170,809 (2-(2-dimethylamino-2-methylpropylthio)-3-phenylquinoline hydrochloride) is a potent 5-hydroxytryptamine (5-HT) type 2 postsynaptic receptor antagonist. 2. Effects of ICI 170,809 as single oral doses (3, 7, 15 and 30 mg) or placebo were studied on the duration of antagonism for the ex vivo platelet aggregatory response to 5-HT and to the pupillary light constrictor response in eight healthy male volunteers. 3. Pupillary dark adapted responses to a 0.5 s light stimulus were measured using a portable infrared pupillometer, for up to 24 h after dosing. 4. The in vitro platelet 5-HT aggregation response was reduced by ICI 170,809, with depression of the dose-response curve to 5-HT at all concentrations of 5-HT and with no evidence for a parallel shift. 5. The ex vivo platelet 5-HT response demonstrated a dose related significant (P less than 0.02) decrease in aggregation reaching a maximum at 2 h after dosing with the effect persisting for at least 8 h after dosing with the 7 and 15 mg doses. 6. Resting pupil diameter (RPD), and light induced pupillary responses in the dark adapted pupil, showed a significant (P less than 0.01) dose related reduction with significant (P less than 0.05) effects still present with the 15 and 30 mg doses at 8 h after dosing. 7. We conclude that, changes in both ex vivo platelet aggregation to 5-HT and dark adapted pupil size, are significantly correlated (P less than 0.0001) with log plasma concentrations (ng ml-1) of ICI 170,809, enabling the assessment of 5-HT2-receptor antagonism in man. PMID:1576048

  14. Association of 5-HT3B Receptor Gene Polymorphisms with the Efficacy of Ondansetron for Postoperative Nausea and Vomiting

    PubMed Central

    Kim, Min-Soo; Lee, Jeong-Rim; Choi, Eun-Mi; Kim, Eun Ho

    2015-01-01

    Purpose Postoperative nausea and vomiting (PONV) is a common problem after general anesthesia. Although 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists have significantly reduced PONV, over 35% of patients treated with ondansetron can experience PONV. In this study, we investigated whether the Y129S and -100_-102AAG deletion polymorphisms of the 5-HT3B receptor gene affect the efficacy of ondansetron in preventing PONV. Materials and Methods Two hundred and forty-five adult patients who underwent laparoscopic cholecystectomy were enrolled. Ondansetron 0.1 mg/kg was intravenously administered 30 minutes before the end of surgery. Genomic DNA was prepared from blood samples using a nucleic acid isolation device. Both the Y129S variant and the -100_-102AAG deletion variant were screened for using a single base primer extension assay and a DNA direct sequencing method, respectively. The relationship between genetic polymorphisms and clinical outcomes of ondansetron treatment was investigated. Results Among the 5-HT3B AAG deletion genotypes, the incidence of PONV was higher in patients with the homomutant than with other genotypes during the first 2 hours after surgery (p=0.02). There were no significant differences in the incidence of PONV among genotypes at 2-24 hours after surgery. In the Y129S variants of the 5-HT3B receptor gene, there were no significant differences in the incidence of PONV among genotypes during the first 2 hours and at 2-24 hours after surgery. Conclusion The response to ondansetron for PONV was significantly influenced by the -100_-102AAG deletion polymorphisms of the 5-HT3B gene. Thus, the -100_-102AAG deletion variants may be a pharmacogenetic predictor for responsiveness to ondansetron for PONV. PMID:26256989

  15. Prostacyclin biosynthesis and reduced 5-HT uptake after complement-induced endothelial injury in the dog isolated lung.

    PubMed Central

    Bult, H.; Heiremans, J. J.; Herman, A. G.; Malcorps, C. M.; Peeters, F. A.

    1988-01-01

    1. Pulmonary prostacyclin (PGI2) biosynthesis was evaluated in relation to endothelial integrity before and after complement activation in isolated plasma-perfused lung lobes of the dog. 2. The plasma was activated with zymosan (ZAP, n = 4), yeast cells (YAP, n = 4) or yeast with 3 microM indomethacin (Indo + YAP, n = 3). Immunoreactive 6-oxo-prostaglandin F1 alpha (i-6-oxo-PGF1 alpha) and thromboxane B2 (iTXB2) were measured to monitor PGI2 and TXA2 biosynthesis. 3. The kinetic parameters Km and Vmax of 5-hydroxytryptamine (5-HT) uptake were calculated on the basis of multiple indicator diffusion data to evaluate endothelial integrity. 4. YAP and ZAP induced a biphasic increase of the arterial perfusion pressure. The immediate pressure peak was partly mediated by TXA2 and the TXB2 was subsequently cleared by the lung. 5. The apparent Vmax of 5-HT uptake remained constant throughout the experiment. Thus, complement activation did not affect the number of endothelial 5-HT carrier sites available to the perfusate. 6. The apparent Km of 5-HT uptake was enhanced in 9 lungs exposed to activated plasma complement for 20 min. This decreased affinity for 5-HT probably reflects endothelial injury. It was transient as the apparent Km had returned to the baseline value after 60 min. 7. PGI2 clearance and biosynthesis were virtually absent in the control period. PGI2 formation increased drastically after infusion of ZAP or YAP and was proportional to the endothelial injury expressed as elevated Km or pulmonary oedema. Thus, PGI2 biosynthesis might be a marker of severe endothelial distress. PMID:3291998

  16. The 5-hydroxytryptamine4 receptor enables differentiation of informational content and encoding in the hippocampus.

    PubMed

    Twarkowski, Hannah; Hagena, Hardy; Manahan-Vaughan, Denise

    2016-07-01

    Long-term synaptic plasticity, represented by long-term depression (LTD) and long-term potentiation (LTP) comprise cellular processes that enable memory. Neuromodulators such as serotonin regulate hippocampal function, and the 5-HT4 -receptor contributes to processes underlying cognition. It was previously shown that in the CA1-region, 5-HT4 -receptors regulate the frequency-response relationship of synaptic plasticity: patterned afferent stimulation that has no effect on synaptic strength (i.e., a θm-frequency), will result in LTP or LTD, when given in the presence of a 5-HT4 -agonist, or antagonist, respectively. Here, we show that in the dentate gyrus (DG) and CA3 regions of freely behaving rats, pharmacological manipulations of 5-HT4 -receptors do not influence responses generated at θm-frequencies, but activation of 5-HT4 -receptors prevents persistent LTD in mossy fiber (mf)-CA3, or perforant path-DG synapses. Furthermore, the regulation by 5-HT4 -receptors of LTP is subfield-specific: 5-HT4 -receptor-activation prevents mf-CA3-LTP, but does not strongly affect DG-potentiation. These data suggest that 5-HT4 -receptor activation prioritises information encoding by means of LTP in the DG and CA1 regions, and suppresses persistent information storage in mf-CA3 synapses. Thus, 5-HT4 -receptors serve to shape information storage across the hippocampal circuitry and specify the nature of experience-dependent encoding. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc. PMID:26800645

  17. Small molecule drug screening in Drosophila identifies the 5HT2A receptor as a feeding modulation target

    PubMed Central

    Gasque, Gabriel; Conway, Stephen; Huang, Juan; Rao, Yi; Vosshall, Leslie B.

    2013-01-01

    Dysregulation of eating behavior can lead to obesity, which affects 10% of the adult population worldwide and accounts for nearly 3 million deaths every year. Despite this burden on society, we currently lack effective pharmacological treatment options to regulate appetite. We used Drosophila melanogaster larvae to develop a high-throughput whole organism screen for drugs that modulate food intake. In a screen of 3630 small molecules, we identified the serotonin (5-hydroxytryptamine or 5-HT) receptor antagonist metitepine as a potent anorectic drug. Using cell-based assays we show that metitepine is an antagonist of all five Drosophila 5-HT receptors. We screened fly mutants for each of these receptors and found that serotonin receptor 5-HT2A is the sole molecular target for feeding inhibition by metitepine. These results highlight the conservation of molecular mechanisms controlling appetite and provide a method for unbiased whole-organism drug screens to identify novel drugs and molecular pathways modulating food intake. PMID:23817146

  18. High trait aggression in men is associated with low 5-HT levels, as indexed by 5-HT4 receptor binding.

    PubMed

    da Cunha-Bang, Sofi; Mc Mahon, Brenda; Fisher, Patrick MacDonald; Jensen, Peter Steen; Svarer, Claus; Knudsen, Gitte Moos

    2016-04-01

    Impulsive aggression has commonly been associated with a dysfunction of the serotonin (5-HT) system: many, but not all, studies point to an inverse relationship between 5-HT and aggression. As cerebral 5-HT4 receptor (5-HT4R) binding has recently been recognized as a proxy for stable brain levels of 5-HT, we here test the hypothesis in healthy men and women that brain 5-HT levels, as indexed by cerebral 5-HT4R, are inversely correlated with trait aggression and impulsivity. Sixty-one individuals (47 men) underwent positron emission tomography scanning with the radioligand [(11)C]SB207145 for quantification of brain 5-HT4R binding. The Buss-Perry Aggression Questionnaire (BPAQ) and the Barratt Impulsiveness Scale were used for assessment of trait aggression and trait impulsivity. Among male subjects, there was a positive correlation between global 5-HT4R and BPAQ total score (P = 0.037) as well as BPAQ physical aggression (P = 0.025). No main effect of global 5-HT4R on trait aggression or impulsivity was found in the mixed gender sample, but there was evidence for sex interaction effects in the relationship between global 5-HT4R and BPAQ physical aggression. In conclusion we found that low cerebral 5-HT levels, as indexed by 5-HT4R binding were associated with high trait aggression in males, but not in females. PMID:26772668

  19. Serotonin (5-HT) and 5-HT2A receptor agonists suppress lipolysis in primary rat adipose cells.

    PubMed

    Hansson, Björn; Medina, Anya; Fryklund, Claes; Fex, Malin; Stenkula, Karin G

    2016-05-27

    Serotonin (5-HT) is a biogenic monoamine that functions both as a neurotransmitter and a circulating hormone. Recently, the metabolic effects of 5-HT have gained interest and peripheral 5-HT has been proposed to influence lipid metabolism in various ways. Here, we investigated the metabolic effects of 5-HT in isolated, primary rat adipose cells. Incubation with 5-HT suppressed β-adrenergically stimulated glycerol release and decreased phosphorylation of protein kinase A (PKA)-dependent substrates, hormone sensitive lipase (Ser563) and perilipin (Ser522). The inhibitory effect of 5-HT on lipolysis enhanced the anti-lipolytic effect of insulin, but sustained in the presence of phosphodiesterase inhibitors, OPC3911 and isobuthylmethylxanthine (IBMX). The relative expression of 5-HT1A, -2B and -4 receptor class family were significantly higher in adipose tissue compared to adipose cells, whereas 5-HT1D, -2A and -7 were highly expressed in isolated adipose cells. Similar to 5-HT, 5-HT2 receptor agonists reduced lipolysis while 5-HT1 receptor agonists rather decreased non-stimulated and insulin-stimulated glucose uptake. Together, these data provide evidence of a direct effect of 5-HT on adipose cells, where 5-HT suppresses lipolysis and glucose uptake, which could contribute to altered systemic lipid- and glucose metabolism. PMID:27109474

  20. Antiallodynic effect of tianeptine via modulation of the 5-HT7 receptor of GABAergic interneurons in the spinal cord of neuropathic rats.

    PubMed

    Lin, Hai; Heo, Bong Ha; Kim, Woong Mo; Kim, Yong Chul; Yoon, Myung Ha

    2015-06-26

    Although tianeptine, an atypical antidepressant has been reported to have antinociceptive effects, the mode of action is different from that of tricyclic antidepressants despite structural similarities. We examined the antiallodynic effect of intrathecal tianeptine in neuropathic pain rats and determined the involvement of 5-hydroxytryptamine type 7 (5-HT7) receptor of the GABAergic interneurons in the spinal cord. Neuropathic pain was induced by spinal nerve ligation (SNL). After observation of the effect from intrathecal tianeptine, a 5-HT7 receptor antagonist (SB-269970) was administered intrathecally 10 min before delivery of tianeptine, to determine the contribution of spinal 5-HT7 receptor on the activity of tianeptine. GAD expression and GABA concentrations were assessed. Intrathecal tianeptine dose-dependently attenuated mechanical allodynia in SNL rats. Pre-treatment with intrathecal SB-269970 reversed the antiallodynic effect of tianeptine. Both GAD65 expression and the GABA concentration in the spinal cord were decreased in neuropathic rats but were increased by tianeptine. Additionally, 5-HT7 receptor and GAD65 were co-localized in the spinal cord. Intrathecal tianeptine reduces neuropathic pain. 5-HT7 receptor of the GABAergic interneurons together with GAD65 plays a role in the activity of tianeptine at the spinal cord level. PMID:25982324

  1. Aryl biphenyl-3-ylmethylpiperazines as 5-HT7 receptor antagonists.

    PubMed

    Kim, Jeeyeon; Kim, Youngjae; Tae, Jinsung; Yeom, Miyoung; Moon, Bongjin; Huang, Xi-Ping; Roth, Bryan L; Lee, Kangho; Rhim, Hyewhon; Choo, Il Han; Chong, Youhoon; Keum, Gyochang; Nam, Ghilsoo; Choo, Hyunah

    2013-11-01

    The 5-HT7 receptor (5-HT7 R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5-HT7 R antagonist SB-269970 exhibited antidepressant-like activity, whereas systemic administration of the 5-HT7 R agonist AS-19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5-HT7 R antagonists or agonists, aryl biphenyl-3-ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5-HT7 R. Among the synthesized compounds, 1-([2'-methoxy-(1,1'-biphenyl)-3-yl]methyl)-4-(2-methoxyphenyl)piperazine (28) was the best binder to the 5-HT7 R (pKi =7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5-HT7 R over other serotonin receptor subtypes, such as 5-HT1 R, 5-HT2 R, 5-HT3 R, and 5-HT6 R. In a molecular modeling study, the 2-methoxyphenyl moiety attached to the piperazine ring of compound 28 was proposed to be essential for the antagonistic function. PMID:24039134

  2. Relative activities on and uptake by human blood platelets of 5-hydroxytryptamine and several analogues

    PubMed Central

    Born, G. V. R.; Juengjaroen, Kanchana; Michal, F.

    1972-01-01

    1. The specificity of platelet receptor sites for 5-HT uptake and for the rapid morphological change and aggregation was investigated with 5-hydroxy-tryptamine (5-HT) and seventeen analogues as well as with some antagonists of 5-HT. 2. The analogues, with the exception of 5-hydroxy-N'N'-dibutyltryptamine, caused the rapid morphological change in platelets. In concentrations below those needed to produce the agonistic action (viz. 0.05-2.0 μM), these analogues themselves inhibited competitively the shape change caused by 5-HT. 3. The velocity of change in shape caused by 5-HT was reduced in low Na media. 4. Ten analogues produced platelet aggregation; three of these, viz. 5-methoxy-α-methyltryptamine, 5-hydroxy-α-methyltryptamine and 5-hydroxy-N'N'-diisopropyltryptamine), were approximately equipotent with 5-HT. Six analogues did not induce platelet aggregation. 5. All the analogues which prevented the initial change in shape of platelets caused by 5-HT also inhibited its aggregating effect, apparently competitively with low Ki values (0.02-1.6 μM). 6. As with the inhibition of shape change, the inhibition of aggregation shows relatively low structural specificity of the receptor site. 7. Methysergide was a potent inhibitor of shape change and aggregation (Ki∼0.03 μM); imipramine was much less inhibitory (Ki∼5-10 μM). 8. Only one analogue (5-hydroxy-α-methyltryptamine) was taken up like 5-HT by platelets. All the other analogues inhibited the uptake of 5-HT by platelets (Ki=0.2-2.7 μM). 9. Methysergide was a weak inhibitor of 5-HT uptake (Ki∼125 μM) whereas imipramine was very effective (Ki∼0.3 μM). 10. Our results show that the initial change in shape of platelets is required for and precedes aggregation. The structural specificity of the platelet receptor concerned with shape change and aggregation caused by 5-HT appears low whereas the uptake mechanism is a highly specific one. The uptake probably proceeds through more than one step, the

  3. Relative activities on and uptake by human blood platelets of 5-hydroxytryptamine and several analogues.

    PubMed

    Born, G V; Juengjaroen, K; Michal, F

    1972-01-01

    1. The specificity of platelet receptor sites for 5-HT uptake and for the rapid morphological change and aggregation was investigated with 5-hydroxy-tryptamine (5-HT) and seventeen analogues as well as with some antagonists of 5-HT.2. The analogues, with the exception of 5-hydroxy-N'N'-dibutyltryptamine, caused the rapid morphological change in platelets. In concentrations below those needed to produce the agonistic action (viz. 0.05-2.0 muM), these analogues themselves inhibited competitively the shape change caused by 5-HT.3. The velocity of change in shape caused by 5-HT was reduced in low Na media.4. Ten analogues produced platelet aggregation; three of these, viz. 5-methoxy-alpha-methyltryptamine, 5-hydroxy-alpha-methyltryptamine and 5-hydroxy-N'N'-diisopropyltryptamine), were approximately equipotent with 5-HT. Six analogues did not induce platelet aggregation.5. All the analogues which prevented the initial change in shape of platelets caused by 5-HT also inhibited its aggregating effect, apparently competitively with low K(i) values (0.02-1.6 muM).6. As with the inhibition of shape change, the inhibition of aggregation shows relatively low structural specificity of the receptor site.7. Methysergide was a potent inhibitor of shape change and aggregation (K(i) approximately 0.03 muM); imipramine was much less inhibitory (K(i) approximately 5-10 muM).8. Only one analogue (5-hydroxy-alpha-methyltryptamine) was taken up like 5-HT by platelets. All the other analogues inhibited the uptake of 5-HT by platelets (K(i)=0.2-2.7 muM).9. Methysergide was a weak inhibitor of 5-HT uptake (K(i) approximately 125 muM) whereas imipramine was very effective (K(i) approximately 0.3 muM).10. Our results show that the initial change in shape of platelets is required for and precedes aggregation. The structural specificity of the platelet receptor concerned with shape change and aggregation caused by 5-HT appears low whereas the uptake mechanism is a highly specific one. The

  4. 5-HT2C Receptor Desensitization Moderates Anxiety in 5-HTT Deficient Mice: From Behavioral to Cellular Evidence

    PubMed Central

    Martin, Cédric BP; Martin, Vincent S.; Trigo, José M.; Chevarin, Caroline; Maldonado, Rafael; Fink, Latham H.; Cunningham, Kathryn A.; Hamon, Michel; Lanfumey, Laurence

    2015-01-01

    Background: Desensitization and blockade of 5-HT2C receptors (5-HT2CR) have long been thought to be central in the therapeutic action of antidepressant drugs. However, besides behavioral pharmacology studies, there is little in vivo data documenting antidepressant-induced 5-HT2CR desensitization in specific brain areas. Methods: Mice lacking the 5-HT reuptake carrier (5-HTT-/-) were used to model the consequences of chronic 5-HT reuptake inhibition with antidepressant drugs. The effect of this mutation on 5-HT2CR was evaluated at the behavioral (social interaction, novelty-suppressed feeding, and 5-HT2CR–induced hypolocomotion tests), the neurochemical, and the cellular (RT-qPCR, mRNA editing, and c-fos–induced expression) levels. Results: Although 5-HTT-/- mice had an anxiogenic profile in the novelty-suppressed feeding test, they displayed less 5-HT2CR–mediated anxiety in response to the agonist m-chlorophenylpiperazine in the social interaction test. In addition, 5-HT2CR–mediated inhibition of a stress-induced increase in 5-HT turnover, measured in various brain areas, was markedly reduced in 5-HTT-/- mutants. These indices of tolerance to 5-HT2CR stimulation were associated neither with altered levels of 5-HT2CR protein and mRNA nor with changes in pre-mRNA editing in the frontal cortex. However, basal c-fos mRNA production in cells expressing 5-HT2CR was higher in 5-HTT-/- mutants, suggesting an altered basal activity of these cells following sustained 5-HT reuptake carrier inactivation. Furthermore, the increased c-fos mRNA expression in 5-HT2CR–like immune-positive cortical cells observed in wild-type mice treated acutely with the 5-HT2CR agonist RO-60,0175 was absent in 5-HTT-/- mutants. Conclusions: Such blunted responsiveness of the 5-HT2CR system, observed at the cell signaling level, probably contributes to the moderation of the anxiety phenotype in 5-HTT-/- mice. PMID:25522398

  5. The 5-HT3B subunit affects high-potency inhibition of 5-HT3 receptors by morphine

    PubMed Central

    Baptista-Hon, Daniel T; Deeb, Tarek Z; Othman, Nidaa A; Sharp, Douglas; Hales, Tim G

    2012-01-01

    BACKGROUND AND PURPOSE Morphine is an antagonist at 5-HT3A receptors. 5-HT3 and opioid receptors are expressed in many of the same neuronal pathways where they modulate gut motility, pain and reinforcement. There is increasing interest in the 5-HT3B subunit, which confers altered pharmacology to 5-HT3 receptors. We investigated the mechanisms of inhibition by morphine of 5-HT3 receptors and the influence of the 5-HT3B subunit. EXPERIMENTAL APPROACH 5-HT-evoked currents were recorded from voltage-clamped HEK293 cells expressing human 5-HT3A subunits alone or in combination with 5-HT3B subunits. The affinity of morphine for the orthosteric site of 5-HT3A or 5-HT3AB receptors was assessed using radioligand binding with the antagonist [3H]GR65630. KEY RESULTS When pre-applied, morphine potently inhibited 5-HT-evoked currents mediated by 5-HT3A receptors. The 5-HT3B subunit reduced the potency of morphine fourfold and increased the rates of inhibition and recovery. Inhibition by pre-applied morphine was insurmountable by 5-HT, was voltage-independent and occurred through a site outside the second membrane-spanning domain. When applied simultaneously with 5-HT, morphine caused a lower potency, surmountable inhibition of 5-HT3A and 5-HT3AB receptors. Morphine also fully displaced [3H]GR65630 from 5-HT3A and 5-HT3AB receptors with similar potency. CONCLUSIONS AND IMPLICATIONS These findings suggest that morphine has two sites of action, a low-affinity, competitive site and a high-affinity, non-competitive site that is not available when the channel is activated. The affinity of morphine for the latter is reduced by the 5-HT3B subunit. Our results reveal that morphine causes a high-affinity, insurmountable and subunit-dependent inhibition of human 5-HT3 receptors. PMID:21740409

  6. The 5-HT2A serotonin receptor in executive function: Implications for neuropsychiatric and neurodegenerative diseases.

    PubMed

    Aznar, Susana; Hervig, Mona El-Sayed

    2016-05-01

    Executive function entails the interplay of a group of cognitive processes enabling the individual to anticipate consequences, attain self-control, and undertake appropriate goal-directed behaviour. Serotonin signalling at serotonin 2A receptors (5-HT2AR) has important effects on these behavioural and cognitive pathways, with the prefrontal cortex (PFC) as the central actor. Indeed, the 5-HT2ARs are highly expressed in PFC, where they modulate cortical activity and local network oscillations (brain waves). Numerous psychiatric and neurodegenerative diseases result in disrupted executive function. Animal and human studies have linked these disorders with alterations in the 5-HT2AR system, making this an important pharmacological target for the treatment of disorders with impaired cognitive function. This review aims to describe the current state of knowledge on the role of 5-HT2AR signalling in components of executive function, and how 5-HT2AR systems may relate to executive dysfunctions occurring in psychiatric and neurodegenerative diseases. We hope thereby to provide insight into how pharmacotherapy targeting the 5-HT2AR may ameliorate (or exacerbate) aspects of these disorders. PMID:26891819

  7. Impaired Social Behavior in 5-HT3A Receptor Knockout Mice

    PubMed Central

    Smit-Rigter, Laura A.; Wadman, Wytse J.; van Hooft, Johannes A.

    2010-01-01

    The 5-HT3 receptor is a ligand-gated ion channel expressed on interneurons throughout the brain. So far, analysis of the 5-HT3A knockout mouse revealed changes in nociceptive processing and a reduction in anxiety related behavior. Recently, it was shown that the 5-HT3 receptor is also expressed on Cajal-Retzius cells which play a key role in cortical development and that knockout mice lacking this receptor showed aberrant growth of the dendritic tree of cortical layer II/III pyramidal neurons. Other mouse models in which serotonergic signaling was disrupted during development showed similar morphological changes in the cortex, and in addition, also deficits in social behavior. Here, we subjected male and female 5-HT3A knockout mice and their non-transgenic littermates to several tests of social behavior. We found that 5-HT3A knockout mice display impaired social communication in the social transmission of food preference task. Interestingly, we showed that in the social interaction test only female 5-HT3A knockout mice spent less time in reciprocal social interaction starting after 5 min of testing. Moreover, we observed differences in preference for social novelty for male and female 5-HT3A knockout mice during the social approach test. However, no changes in olfaction, exploratory activity and anxiety were detected. These results indicate that the 5-HT3A knockout mouse displays impaired social behavior with specific changes in males and females, reminiscent to other mouse models in which serotonergic signaling is disturbed in the developing brain. PMID:21103015

  8. Chronic activation of 5-HT4 receptors or blockade of 5-HT6 receptors improve memory performances.

    PubMed

    Quiedeville, Anne; Boulouard, Michel; Hamidouche, Katia; Da Silva Costa-Aze, Virginie; Nee, Gerald; Rochais, Christophe; Dallemagne, Patrick; Fabis, Frédéric; Freret, Thomas; Bouet, Valentine

    2015-10-15

    5-HT4 and 5-HT6 serotonergic receptors are located in brain structures involved in memory processes. Neurochemical and behavioural studies have demonstrated that acute activation of 5-HT4 receptors (5-HT4R) or blockade of 5-HT6 receptors (5-HT6R) improves memory. To evaluate the potential of these two receptors as targets in the treatment of memory disorders encountered in several situations (ageing, Alzheimer's disease, schizophrenia, etc.), it is necessary to assess whether their beneficial effects occur after chronic administration, and if such treatment induces adverse effects. The goal of this study was to assess the effects of chronic 5-HT4R or 5-HT6R modulation on recognition memory, and to observe the possible manifestation of side effects (modification of weight gain, locomotor activity or exploratory behaviour, etc.). Mice were treated for 14 days with a 5-HT4R partial agonist (RS-67333) or a 5-HT6R antagonist (SB-271046) at increasing doses. Memory performances, locomotor activity, and exploration were assessed. Both chronic 5-HT4R activation and 5-HT6R blockade extended memory traces in an object recognition test, and were not associated with any adverse effects in the parameters assessed. Chronic modulation of one or both of these receptors thus seems promising as a potential strategy for the treatment memory deficits. PMID:26187692

  9. Circadian variation in the activity of the 5-HT1B autoreceptor in the region of the suprachiasmatic nucleus, measured by microdialysis in the conscious freely-moving rat

    PubMed Central

    Garabette, M L; Martin, K F; Redfern, P H

    2000-01-01

    Intracerebral microdialysis was used to examine the function of the terminal 5-hydroxytryptamine1B (5-HT1B) autoreceptor in the region of the suprachiasmatic nuclei (SCN) of freely moving conscious rats at six time points or zeitgeber times (ZTs) across the light:dark cycle. Infusion of the 5-HT1A/1B agonist 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (RU24969) (1 μM) via the microdialysis probe produced a decrease in 5-HT output when applied at ZTs 3, 6, 15 and 21 (69.8±11.9, 59±11.7, 43.9±17.2 and 45.7±17.0% respectively). At ZTs 9 and 18 RU24969 (1 μm) failed to affect the 5-HT output significantly (28.0±11 and 32.8±24.6% decrease respectively). The profile of inhibition of 5-HT output following infusion of RU24969 (1 μM) at ZT 6 was unaffected by concurrent infusion of the specific 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100635) (1 μM) (52.48±17.5% decrease). The data demonstrate a circadian rhythm in the activity of the 5-HT1B autoreceptor in the region of the SCN. PMID:11139433

  10. In Vivo Quantification of 5-HT2A Brain Receptors in Mdr1a KO Rats with 123I-R91150 Single-Photon Emission Computed Tomography.

    PubMed

    Dumas, Noé; Moulin-Sallanon, Marcelle; Fender, Pascal; Tournier, Benjamin B; Ginovart, Nathalie; Charnay, Yves; Millet, Philippe

    2015-01-01

    Our goal was to identify suitable image quantification methods to image 5-hydroxytryptamine2A (5-HT2A) receptors in vivo in Mdr1a knockout (KO) rats (i.e., P-glycoprotein KO) using 123I-R91150 single-photon emission computed tomography (SPECT). The 123I-R91150 binding parameters estimated with different reference tissue models (simplified reference tissue model [SRTM], Logan reference tissue model, and tissue ratio [TR] method) were compared to the estimates obtained with a comprehensive three-tissue/seven-parameter (3T/7k)-based model. The SRTM and Logan reference tissue model estimates of 5-HT2A receptor (5-HT2AR) nondisplaceable binding potential (BPND) correlated well with the absolute receptor density measured with the 3T/7k gold standard (r > .89). Quantification of 5-HT2AR using the Logan reference tissue model required at least 90 minutes of scanning, whereas the SRTM required at least 110 minutes. The TR method estimates were also highly correlated to the 5-HT2AR density (r > .91) and only required a single 20-minute scan between 100 and 120 minutes postinjection. However, a systematic overestimation of the BPND values was observed. The Logan reference tissue method is more convenient than the SRTM for the quantification of 5-HT2AR in Mdr1a KO rats using 123I-R91150 SPECT. The TR method is an interesting and simple alternative, despite its bias, as it still provides a valid index of 5-HT2AR density. PMID:26105563

  11. Maternal lipopolysaccharide treatment differentially affects 5-HT(2A) and mGlu2/3 receptor function in the adult male and female rat offspring.

    PubMed

    Wischhof, Lena; Irrsack, Ellen; Dietz, Frank; Koch, Michael

    2015-10-01

    Maternal infection during pregnancy increases the risk for the offspring to develop schizophrenia. However, it is still not fully understood which biochemical mechanisms are responsible for the emergence of neuropsychiatric symptoms following prenatal immune activation. The serotonin (5-hydroxytryptamine, 5-HT) and glutamate system have prominently been associated with the schizophrenia pathophysiology but also with the mechanism of antipsychotic drug actions. Here, we investigated the behavioral and cellular response to 5-HT2A and metabotropic glutamate (mGlu)2/3 receptor stimulation in male and female offspring born to lipopolysaccharide (LPS)-treated mothers. Additionally, we assessed protein expression levels of prefrontal 5-HT2A and mGlu2 receptors. Prenatally LPS-exposed male and female offspring showed locomotor hyperactivity and increased head-twitch behavior in response to the 5-HT2A receptor agonist DOI. In LPS-exposed male offspring, the mGlu2/3 receptor agonist LY379268 failed to reduce DOI-induced prepulse inhibition deficits. In LPS-males, the behavioral changes were further accompanied by enhanced DOI-induced c-Fos protein expression and an up-regulation of prefrontal 5-HT2A receptors. No changes in either 5-HT2A or mGlu2 receptor protein levels were found in female offspring. Our data support the hypothesis of an involvement of maternal infection during pregnancy contributing, at least partially, to the pathology of schizophrenia. Identifying biochemical alterations that parallel the behavioral deficits may help to improve therapeutic strategies in the treatment of this mental illness. Since most studies in rodents almost exclusively include male subjects, our data further contribute to elucidating possible gender differences in the effects of prenatal infection on 5-HT2A and mGlu2/3 receptor function. PMID:26051401

  12. Potentiating effect of spinosin, a C-glycoside flavonoid of Semen Ziziphi spinosae, on pentobarbital-induced sleep may be related to postsynaptic 5-HT(1A) receptors.

    PubMed

    Wang, L-E; Cui, X-Y; Cui, S-Y; Cao, J-X; Zhang, J; Zhang, Y-H; Zhang, Q-Y; Bai, Y-J; Zhao, Y-Y

    2010-05-01

    Previous results have suggested that spinosin, a C-glycoside flavonoid of Semen Ziziphi spinosae, potentiates pentobarbital-induced sleep via the serotonergic system. The present study investigated whether spinosin potentiates pentobarbital-induced sleep via serotonin-1A (5-hydroxytryptamine, 5-HT(1A)) receptors. The results demonstrated that spinosin significantly augmented pentobarbital (35 mg/kg, i.p.)-induced sleep in rats, reflected by reduced sleep latency and increased total sleep time, non-rapid eye movement (NREM) sleep time, and REM sleep time. With regard to NREM sleep duration, spinosin mainly increased slow-wave sleep (SWS). Additionally, spinosin (15mg/kg, i.g.) significantly antagonized 5-HT(1A) agonist 8-OH-DPAT (0.1mg/kg, i.p.)-induced reductions in total sleep time, NREM sleep, REM sleep, and SWS in pentobarbital-treated rats. These results suggest that spinosin may be an antagonist at postsynaptic 5-HT(1A) receptors because these effects of 8-OH-DPAT were considered to be mediated via postsynaptic 5-HT(1A) receptors. Moreover, co-administration of spinosin and the 5-HT(1A) antagonist 4-iodo-N-{2-[4-(methoxyphenyl)-1-piperazinyl]ethyl}-N-2-pyridinylbenzamide (p-MPPI), at doses that are ineffective when administered alone (spinosin 5mg/kg, p-MPPI 1mg/kg), had significant augmentative effects on pentobarbital-induced sleep, reflected by reduced sleep latency and increased total sleep time, NREM sleep, and REM sleep. In contrast to the attenuating effects of p-MPPI on REM sleep via presynaptic 5-HT(1A) autoreceptors, 15mg/kg spinosin significantly increased REM sleep. These results suggest that the effect of spinosin on REM sleep in pentobarbital-treated rats may be related to postsynaptic 5-HT(1A) receptors. PMID:20171860

  13. 5-HT6 receptor agonism facilitates emotional learning

    PubMed Central

    Pereira, Marcela; Martynhak, Bruno J.; Andreatini, Roberto; Svenningsson, Per

    2015-01-01

    Serotonin (5-HT) and its receptors play crucial roles in various aspects of mood and cognitive functions. However, the role of specific 5-HT receptors in these processes remains to be better understood. Here, we examined the effects of the selective and potent 5-HT6 agonist (WAY208466) on mood, anxiety and emotional learning in mice. Male C57Bl/6J mice were therefore tested in the forced swim test (FST), elevated plus-maze (EPM), and passive avoidance tests (PA), respectively. In a dose-response experiment, mice were treated intraperitoneally with WAY208466 at 3, 9, or 27 mg/kg and examined in an open field arena open field test (OFT) followed by the FST. 9 mg/kg of WAY208466 reduced immobility in the FST, without impairing the locomotion. Thus, the dose of 9 mg/kg was subsequently used for tests of anxiety and emotional learning. There was no significant effect of WAY208466 in the EPM. In the PA, mice were trained 30 min before the treatment with saline or WAY208466. Two separate sets of animals were used for short term memory (tested 1 h post-training) or long term memory (tested 24 h post-training). WAY208466 improved both short and long term memories, evaluated by the latency to enter the dark compartment, in the PA. The WAY208466-treated animals also showed more grooming and rearing in the light compartment. To better understand the molecular mechanisms and brain regions involved in the facilitation of emotional learning by WAY208466, we studied its effects on signal transduction and immediate early gene expression. WAY208466 increased the levels of phospho-Ser845-GluA1 and phospho-Ser217/221-MEK in the caudate-putamen. Levels of phospho-Thr202/204-Erk1/2 and the ratio mature BDNF/proBDNF were increased in the hippocampus. Moreover, WAY208466 increased c-fos in the hippocampus and Arc expression in both hippocampus and prefrontal cortex (PFC). The results indicate antidepressant efficacy and facilitation of emotional learning by 5-HT6 receptor agonism via

  14. Investigation of the mechanisms underlying the hypophagic effects of the 5-HT and noradrenaline reuptake inhibitor, sibutramine, in the rat

    PubMed Central

    Jackson, Helen C; Bearham, M Clair; Hutchins, Lisa J; Mazurkiewicz, Sarah E; Needham, Andrew M; Heal, David J

    1997-01-01

    Sibutramine is a novel 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotonin- noradrenaline reuptake inhibitor, SNRI) which is currently being developed as a treatment for obesity. Sibutramine has been shown to decrease food intake in the rat. In this study we have used a variety of monoamine receptor antagonists to examine the pharmacological mechanisms underlying sibutramine-induced hypophagia. Individually-housed male Sprague-Dawley rats were maintained on reversed phase lighting with free access to food and water. Drugs were administered at 09 h 00 min and food intake was monitored over the following 8 h dark period. Sibutramine (10 mg kg−1, p.o.) produced a significant decrease in food intake during the 8 h following drug administration. This hypophagic response was fully antagonized by the α1-adrenoceptor antagonist, prazosin (0.3 and 1 mg kg−1, i.p.), and partially antagonized by the β1-adrenoceptor antagonist, metoprolol (3 and 10 mg kg−1, i.p.) and the 5-HT receptor antagonists, metergoline (non-selective; 0.3 mg kg−1, i.p.); ritanserin (5-HT2A/2C; 0.1 and 0.5 mg kg−1, i.p.) and SB200646 (5-HT2B/2C; 20 and 40 mg kg−1, p.o.). By contrast, the α2-adrenoceptor antagonist, RX821002 (0.3 and 1 mg kg−1, i.p.) and the β2-adrenoceptor antagonist, ICI 118,551 (3 and 10 mg kg−1, i.p.) did not reduce the decrease in food intake induced by sibutramine. These results demonstrate that β1-adrenoceptors, 5-HT2A/2C-receptors and particularly α1-adrenoceptors, are involved in the effects of sibutramine on food intake and are consistent with the hypothesis that sibutramine-induced hypophagia is related to its ability to inhibit the reuptake of both noradrenaline and 5-HT, with the subsequent activation of a variety of noradrenaline and 5-HT receptor systems. PMID:9283694

  15. Evidence that the branched-chain amino acid L-valine prevents exercise-induced release of 5-HT in rat hippocampus.

    PubMed

    Gomez-Merino, D; Béquet, F; Berthelot, M; Riverain, S; Chennaoui, M; Guezennec, C Y

    2001-07-01

    The branched-chain amino acid L-valine competes with tryptophan for transport into the brain and has previously been shown to decrease brain 5-HT synthesis. The purpose of this study was to assess, using a combined venous catheterization and in vivo microdialysis method, the effect of pre-exercise L-valine administration on 5-hydroxytryptamine (5-HT) metabolism in the ventral hippocampus of rats submitted to an acute intensive treadmill running (120 min at 25 m x min(-1) followed by 150 min of recovery). The presented results include measurement of extracellular tryptophan (TRP), the 5-HT precursor, and extracellular 5-hydroxyindoleacetic acid (5-HIAA), the 5-HT metabolite. The data clearly demonstrate that exercise induces 5-HT release in the rat hippocampus: in control group, hippocampal 5-HT levels increase from 123.7 +/- 6.4% at the end of exercise to 133.9 +/- 6.4% after 60 min of recovery. Moreover, two hours of intensive running induced significant increases both in extracellular TRP levels (from 120 min of exercise to 30 min of recovery) and 5-HIAA levels (from 90 min of exercise to 90 min of recovery). Pre-exercise administration of L-valine prevents significantly the exercise-induced 5-HT release: 5-HT levels are maintained to baseline during exercise and recovery. With regard to the competitive effect of L-valine with TRP, we could observe a treatment-induced decrease in brain TRP levels (from 120 min of exercise to the end of recovery). Besides, L-valine does not prevent exercise-induced increase in 5-HIAA levels. The present study evidences that an acute intensive exercise stimulates 5-HT metabolism in the rat hippocampus, and that a pre-exercise administration of L-valine prevents, via a limiting effect on 5-HT synthesis, exercise-induced 5-HT release. This study provides some anwers to previous human and animal investigations, showing physiological and psychological benefits of branched-chain amino acids supplementation on performance. PMID:11510866

  16. Optimising PET approaches to measuring 5-HT release in human brain.

    PubMed

    Tyacke, Robin J; Nutt, David J

    2015-10-01

    A major goal in neuroscience is the measurement of neurotransmitters in living human brain. To date this has only been done reliably with dopamine using certain PET and SPECT radiotracers. The use of this technique has greatly advanced our understanding of dopamine and the dopaminergic system in normal and abnormal brain function. Transferring this technology to other neurotransmitter systems has proved less fruitful. The serotonergic system (5-HT) is one such system. 5-HT has been implicated in a wide range of brain functions and their disorders. The ability to measure 5-HT using this technique would be invaluable. In this article, we explore the key pharmacological features of current radiotracers for 5-HT receptors that might be sensitive to endogenous 5-HT. We also estimate the likely brain concentrations of the current available tranche of agents that might be used to enhance synaptic 5-HT concentration, so taking into account the potential for these to interact with the receptors directly and produce a spurious displacement signal. PMID:26089243

  17. Stability of tramadol with three 5-HT3 receptor antagonists in polyolefin bags for patient-controlled delivery systems

    PubMed Central

    Chen, Fu-chao; Zhu, Jun; Li, Bin; Yuan, Fang-jun; Wang, Lin-hai

    2016-01-01

    Background Mixing 5-hydroxytryptamine-3 (5-HT3) receptor antagonists with patient-controlled analgesia (PCA) solutions of tramadol has been shown to decrease the incidence of nausea and vomiting associated with the use of tramadol PCA for postoperative pain. However, such mixtures are not commercially available, and the stability of the drug combinations has not been duly studied. The study aimed to evaluate the stability of tramadol with three 5-HT3 receptor antagonists in 0.9% sodium chloride injection for PCA administration. Materials and methods Test samples were prepared by adding 1,000 mg tramadol hydrochloride, 8 mg ondansetron hydrochloride, and 6 mg granisetron hydrochloride or 5 mg tropisetron hydrochloride to 100 mL of 0.9% sodium chloride injection in polyolefin bags. The samples were prepared in triplicates, stored at either 25°C or 4°C for 14 days, and assessed using the following compatibility parameters: precipitation, cloudiness, discoloration, and pH. Chemical stability was also determined using a validated high-pressure liquid chromatography method. Results All of the mixtures were clear and colorless throughout the initial observation period. No change in the concentration of tramadol hydrochloride occurred with any of the 5-HT3 receptor antagonists during the 14 days. Similarly, little or no loss of the 5-HT3 receptor antagonists occurred over the 14-day period. Conclusion Our results suggest that mixtures of tramadol hydrochloride, ondansetron hydrochloride, granisetron hydrochloride, or tropisetron hydrochloride in 0.9% sodium chloride injection were physically and chemically stable for 14 days when stored in polyolefin bags at both 4°C and 25°C. PMID:27350741

  18. Effects of mesulergine treatment on diet selection, brain serotonin (5-HT) and dopamine (DA) turnover in free feeding rats.

    PubMed

    Giannakopoulos, G; Galanopoulou, P; Daifotis, Z; Couvaris, C

    1998-07-01

    1. The effects of mesulergine, a 5-hydroxytryptamine (5-HT) receptor antagonist with dopamine (DA) agonistic properties, on rats diet selection over a seven day period and on 5-HT and DA turnover was studied. 2. Three groups of male Wistar rats were individually caged and ad libitum fed with a standard (SD) and 50% sweet carbohydrate enriched diet (CED). Food intake was measured daily 4 hrs and 24 hrs after i.p. injections of mesulergine (1 and 3 mg/kg) or vehicle. 5-HT and 5-HIAA in hypothalamus (Hy), Striatum (St) and hippocampus (Hi) as well as DA and DOPAC in (Hy) and (St) were assayed at the 8th day of the experiment. 3. There was a dose dependent increase of SD consumption 4 hrs after mesulergine treatment while the CED remained unchanged with total food intake dose dependently increased as a consequence. At 24 hrs measurements SD consumption was increased only for the dose of 1 mg/kg of mesulergine, while a dose dependent decrease of CED intake was observed. Total food intake was unchanged for the dose of 1 mg/kg and decreased with the dose of 3 mg/kg consequently. A dose dependent decrease of rats body weight was observed too. 4. A significant increase of 5-HIAA/5-HT ratio in (Hy) and (St) for the dose of 1 mg/kg and in (Hi) for the dose of 3 mg/kg with no changes of DA turnover were found. 5. The above data suggest a dual mode of action of mesulergine presented as a short term hyperphagia due to simultaneous antiserotonergic and dopaminergic activity and long-term hypophagia due to long-term agonistic effects of dopaminergic neurons. PMID:9723121

  19. Serotonin Regulates Calcium Homeostasis in Lactation by Epigenetic Activation of Hedgehog Signaling

    PubMed Central

    Laporta, Jimena; Keil, Kimberly P.; Weaver, Samantha R.; Cronick, Callyssa M.; Prichard, Austin P.; Crenshaw, Thomas D.; Heyne, Galen W.; Vezina, Chad M.; Lipinski, Robert J.

    2014-01-01

    Calcium homeostasis during lactation is critical for maternal and neonatal health. We previously showed that nonneuronal/peripheral serotonin [5-hydroxytryptamine (5-HT)] causes the lactating mammary gland to synthesize and secrete PTHrP in an acute fashion. Here, using a mouse model, we found that genetic inactivation of tryptophan hydroxylase 1 (Tph1), which catalyzes the rate-limiting step in peripheral 5-HT synthesis, reduced circulating and mammary PTHrP expression, osteoclast activity, and maternal circulating calcium concentrations during the transition from pregnancy to lactation. Tph1 inactivation also reduced sonic hedgehog signaling in the mammary gland during lactation. Each of these deficiencies was rescued by daily injections of 5-hydroxy-L-tryptophan (an immediate precursor of 5-HT) to Tph1-deficient dams. We used immortalized mouse embryonic fibroblasts to demonstrate that 5-HT induces PTHrP through a sonic hedgehog-dependent signal transduction mechanism. We also found that 5-HT altered DNA methylation of the Shh gene locus, leading to transcriptional initiation at an alternate start site and formation of a variant transcript in mouse embryonic fibroblasts in vitro and in mammary tissue in vivo. These results support a new paradigm of 5-HT-mediated Shh regulation involving DNA methylation remodeling and promoter switching. In addition to having immediate implications for lactation biology, identification and characterization of a novel functional regulatory relationship between nonneuronal 5-HT, hedgehog signaling, and PTHrP offers new avenues for the study of these important factors in development and disease. PMID:25192038

  20. 5-HT modulation by acute tryptophan depletion of human instrumental contingency judgements

    PubMed Central

    Crockett, Molly J.; Msetfi, Rachel M.; Murphy, Robin A.; Clark, Luke; Sahakian, Barbara J.; Robbins, Trevor W.

    2010-01-01

    Introduction The concept of ‘depressive realism’, that depression leads to more accurate perception of causal control, has been influential in the field of depression research, but remains controversial. Recent work testing contingency learning has suggested that contextual processing might determine realism-like effects. Serotonin (5-hydroxytryptamine, (5-HT)), which is implicated in the pathophysiology of depression, might also influence contextual processing. Using acute tryptophan depletion (ATD), we tested the hypothesis that dysfunctional serotoninergic neurotransmission influences contingency judgements in dysphoric subjects via an effect on contextual processing. Materials and methods We employed a novel contingency learning task to obtain separate measures (ratings) of the causal effect of partcipants’ responses and efficacy of the background context over an outcome. Participants, without a history of depression, completed this task on and off ATD in a double-blind, placebo-controlled, within-subjects design. Results As with other work on contingency learning, the effects of ATD were related to baseline mood levels. Although no overall effects of ATD were observed, the subgroup of participants with low Beck depression inventory (BDI) scores showed reduced ratings of contextual control and improved accuracy of contingency judgements under positive contingencies following ATD, compared to placebo. High BDI participants demonstrated low accuracy in contingency judgements, regardless of serotoninergic status. Conclusions No effect of ATD on contingency judgements was observed in the group as a whole, but effects were observed in a subgroup of participants with low BDI scores. We discuss these data in light of the context processing hypothesis, and prior research on 5-HT and depressive realism. Electronic supplementary material The online version of this article (doi:10.1007/s00213-010-1934-4) contains supplementary material, which is available to

  1. Synthesis and SAR of Imidazo[1,5-a]pyridine derivatives as 5-HT4 receptor partial agonists for the treatment of cognitive disorders associated with Alzheimer's disease.

    PubMed

    Nirogi, Ramakrishna; Mohammed, Abdul Rasheed; Shinde, Anil K; Bogaraju, Narsimha; Gagginapalli, Shankar Reddy; Ravella, Srinivasa Rao; Kota, Laxman; Bhyrapuneni, Gopinadh; Muddana, Nageswara Rao; Benade, Vijay; Palacharla, Raghava Chowdary; Jayarajan, Pradeep; Subramanian, Ramkumar; Goyal, Vinod Kumar

    2015-10-20

    Alzheimer's disease (AD) is a neurodegenerative disease which has a higher prevalence and incidence in older people. The need for improved AD therapies is unmet. The 5-hydroxytryptamine4 receptor (5-HT4R) partial agonists may be of benefit for both the symptomatic and disease-modifying treatment of cognitive disorders associated with AD. Herein, we report the design, synthesis and SAR of imidazo[1,5-a] pyridine derivatives as 5-HT4R partial agonists. The focused SAR, optimization of ADME properties resulted the discovery of compound 5a as potent, selective, brain penetrant 5-HT4 partial agonist as a lead compound with good ADME properties and efficacy in both symptomatic and disease modifying animal models of cognition. PMID:26363507

  2. The release of nucleotides, 5-hydroxytryptamine and enzymes from human blood platelets during aggregation

    PubMed Central

    Mills, D. C. B.; Robb, I. A.; Roberts, G. C. K.

    1968-01-01

    1. Adenosine diphosphate (ADP) and adrenaline caused the aggregation of human platelets suspended in plasma containing citrate anticoagulant and stirred at 37° C. The aggregation occurred in two phases and the second phase was associated with the appearance in the plasma of up to 30% of the ATP and 55% of the ADP present in the platelets. The concentration of ADP appearing in the plasma was up to 7 times the concentration added. 2. Radioactivity was released by ADP and by adrenaline from platelets labelled with radioactive 5-hydroxytryptamine; this release was closely correlated with the second phase of aggregation and with the release of nucleotides. 3. Acid phosphatase, β-glucuronidase and adenylate kinase were released to a small extent during second phase aggregation by ADP or adrenaline; thrombin and collagen particles caused significantly greater release of β-glucuronidase than of either acid phosphatase or of adenylate kinase. 4. Morphological changes indicating degranulation of the platelets were observed during the second phase of aggregation produced by adrenaline and by ADP. 5. The second phase of aggregation, degranulation of platelets, and the release of nucleotides, of labelled 5-hydroxytryptamine and of enzymes, were all inhibited by concentrations of amitriptyline which did not inhibit aggregation. ImagesPlate 1Plate 2 PMID:5649642

  3. Involvement of 5HT3 Receptors in Anti-Inflammatory Effects of Tropisetron on Experimental TNBS-Induced Colitis in Rat

    PubMed Central

    Motavallian, Azadeh; Minaiyan, Mohsen; Rabbani, Mohammad; Andalib, Sasan; Mahzouni, Parvin

    2013-01-01

    Introduction: There is a pressing need for research leading to the development of new effective drugs with lower side effects and more efficacy for treating inflammatory bowel disease (IBD). The analgesic and anti-inflammatory properties of 5-Hydroxytryptamine (5-HT)-3 receptor antagonists have been shown in in vivo and in vitro studies. The present study was designed to investigate the effects of tropisetron, a 5-HT3 receptor antagonist, on an immune-based animal model of IBD. Methods: In the present study, the trinitrobenzenesulfonic acid (TNBS) model of colitis in the rat was used. Two hours after induction of colitis in rats, tropisetron (2 mg/kg), dexamethasone (1 mg/kg), meta-chlorophenylbiguanide (mCPBG, 5 mg/kg), a 5-HT3 receptor agonist, or tropisetron + mCPBG were intraperitoneally (i.p.) administrated for 6 days. Animals were then sacrificed; macroscopic, histological, biochemical (myeloperoxidase [MPO]) assessments and ELISA test (tumor necrosis factor-alpha, interleukin-6 and interleukin-1 beta) were performed on distal colon samples. Results: Tropisetron or dexamethasone treatment significantly reduced macroscopic and microscopic colonic damages. In addition, a significant reduction in MPO activity and colonic levels of inflammatory cytokines was seen. The beneficial effects of tropisetron were antagonized by concurrent administration of mCPBG. Conclusion: The present study indicates that the protective effects of tropisetron on TNBS-induced colitis can be mediated by 5-HT3 receptors. PMID:24455480

  4. RU 24969-induced emesis in the cat - 5-HT1 sites other than 5-HT1A, 5-HT1B or 5-HT1C implicated

    NASA Technical Reports Server (NTRS)

    Lucot, James B.

    1990-01-01

    RU 24969 was administered s.c. to cats and found to elicit emesis with a maximally effective dose of 1.0 mg/kg 5-Methoxytryptamine was found to have lower efficacy and to produce a higher incidence of nonspecific effects while trifluoromethylphenylpiperizine (TFMPP) was devoid of emetic effects. The emesis elicited by 1.0 mg/kg of RU 24969 was not altered by pretreatment with phentolamine, haloperidol, yohimbine or (-)-propranolol, indicating that catecholamines played no role in this response. The emesis was prevented by metergoline and methysergide but not by ketanserin, cyproheptadine, mesulergine, ICS 205 930, methiothepin, trimethobenzamide or BMY 7378. An indirect argument is presented that implicates a role for 5-HT1D sites. This conclusion must remain tentative until drugs selective for this site are synthesized and tested. The emesis was also prevented by 8-hydroxy-2-(di-n-propylamine)tetralin (8-OH-DPAT), confirming that this drug has a general antiemetic effect in cats.

  5. Incubation of cocaine cue reactivity associates with neuroadaptations in the cortical serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system.

    PubMed

    Swinford-Jackson, S E; Anastasio, N C; Fox, R G; Stutz, S J; Cunningham, K A

    2016-06-01

    Intensification of craving elicited by drug-associated cues during abstinence occurs over time in human cocaine users while elevation of cue reactivity ("incubation") is observed in rats exposed to extended forced abstinence from cocaine self-administration. Incubation in rodents has been linked to time-dependent neuronal plasticity in the medial prefrontal cortex (mPFC). We tested the hypothesis that incubation of cue reactivity during abstinence from cocaine self-administration is accompanied by lower potency and/or efficacy of the selective serotonin (5-HT) 5-HT2C​ receptor (5-HT2CR) agonist WAY163909 to suppress cue reactivity and a shift in the subcellular localization profile of the mPFC 5-HT2CR protein. We observed incubation of cue reactivity (measured as lever presses reinforced by the discrete cue complex) between Day 1 and Day 30 of forced abstinence from cocaine relative to sucrose self-administration. Pharmacological and biochemical analyses revealed that the potency of the selective 5-HT2CR agonist WAY163909 to suppress cue reactivity, the expression of synaptosomal 5-HT2CR protein in the mPFC, and the membrane to cytoplasmic expression of the 5-HT2CR in mPFC were lower on Day 30 vs. Day 1 of forced abstinence from cocaine self-administration. Incubation of cue reactivity assessed during forced abstinence from sucrose self-administration did not associate with 5-HT2CR protein expression in the mPFC. Collectively, these outcomes are the first indication that neuroadaptations in the 5-HT2CR system may contribute to incubation of cocaine cue reactivity. PMID:26926963

  6. Potentiating action of MKC-242, a selective 5-HT1A receptor agonist, on the photic entrainment of the circadian activity rhythm in hamsters

    PubMed Central

    Moriya, T; Yoshinobu, Y; Ikeda, M; Yokota, S; Akiyama, M; Shibata, S

    1998-01-01

    Serotonergic projections from the midbrain raphe nuclei to the suprachiasmatic nuclei (SCN) are known to regulate the photic entrainment of circadian clocks. However, it is not known which 5-hydroxytryptamine (5-HT) receptor subtypes are involved in the circadian regulation. In order to verify the role of 5-HT1A receptors, we examined the effects of 5-{3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy}-1,3-benzodioxole HCl (MKC-242), a selective 5-HT1A receptor agonist, on photic entrainment of wheel-running circadian rhythms of hamsters.MKC-242 (3 mg kg−1, i.p.) significantly accelerated the re-entrainment of wheel-running rhythms to a new 8 h delayed or advanced light-dark cycle.MKC-242 (3 mg kg−1, i.p.) also potentiated the phase advance of the wheel-running rhythm produced by low (5 lux) or high (60 lux) intensity light pulses. In contrast, 8-hydroxy-dipropylaminotetralin (8-OH-DPAT)(5 mg kg−1, i.p.), a well known 5-HT1A/5-HT7 receptor agonist, only suppressed low intensity (5 lux) light-induced phase advances.The potentiating actions of MKC-242 on light pulse-induced phase advances were observed even when injected 20 or 60 min after the light exposure.The potentiating action of MKC-242 was antagonized by WAY100635, a selective 5-HT1A receptor blocker, but not by ritanserin, a 5-HT2/5-HT7 receptor blocker, indicating that MKC-242 is activating 5-HT1A receptors.Light pulse-induced c-fos expression in the SCN and the intergeniculate leaflet (IGL) were unaffected by MKC-242 (3 mg kg−1, i.p.).HPLC analysis demonstrated that MKC-242 (3 mg kg−1, i.p.) decreased the 5-HIAA content in the SCN.The present results suggest that presynaptic 5-HT1A receptor activation may be involved in the potentiation of photic entrainment by MKC-242 in hamsters. PMID:9863658

  7. Potentiating action of MKC-242, a selective 5-HT1A receptor agonist, on the photic entrainment of the circadian activity rhythm in hamsters.

    PubMed

    Moriya, T; Yoshinobu, Y; Ikeda, M; Yokota, S; Akiyama, M; Shibata, S

    1998-11-01

    Serotonergic projections from the midbrain raphe nuclei to the suprachiasmatic nuclei (SCN) are known to regulate the photic entrainment of circadian clocks. However, it is not known which 5-hydroxytryptamine (5-HT) receptor subtypes are involved in the circadian regulation. In order to verify the role of 5-HT1A receptors, we examined the effects of 5-¿3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]-propoxy¿-1,3-b enzodioxole HCl (MKC-242), a selective 5-HT1A receptor agonist, on photic entrainment of wheel-running circadian rhythms of hamsters. MKC-242 (3 mg kg(-1), i.p.) significantly accelerated the re-entrainment of wheel-running rhythms to a new 8 h delayed or advanced light-dark cycle. MKC-242 (3 mg kg(-1), i.p.) also potentiated the phase advance of the wheel-running rhythm produced by low (5 lux) or high (60 lux) intensity light pulses. In contrast, 8-hydroxydipropylaminotetralin (8-OH-DPAT)(5 mg kg(-1), i.p.), a well known 5-HT1A/5-HT7 receptor agonist, only suppressed low intensity (5 lux) light-induced phase advances. The potentiating actions of MKC-242 on light pulse-induced phase advances were observed even when injected 20 or 60 min after the light exposure. The potentiating action of MKC-242 was antagonized by WAY100635, a selective 5-HT1A receptor blocker, but not by ritanserin, a 5-HT2/5-HT7 receptor blocker, indicating that MKC-242 is activating 5-HT1A receptors. Light pulse-induced c-fos expression in the SCN and the intergeniculate leaflet (IGL) were unaffected by MKC-242 (3 mg kg(-1), i.p.). HPLC analysis demonstrated that MKC-242 (3 mg kg(-1), i.p.) decreased the 5-HIAA content in the SCN. The present results suggest that presynaptic 5-HT1A receptor activation may be involved in the potentiation of photic entrainment by MKC-242 in hamsters. PMID:9863658

  8. Serotonin signalling is crucial in the induction of PUVA-induced systemic suppression of delayed-type hypersensitivity but not local apoptosis or inflammation of the skin.

    PubMed

    Wolf, Peter; Byrne, Scott N; Limon-Flores, Alberto Y; Hoefler, Gerald; Ullrich, Stephen E

    2016-07-01

    Psoralen and UVA (PUVA) has immunosuppressive and proapoptotic effects, which are thought to be responsible alone or in combination for its therapeutic efficacy. However, the molecular mechanism by which PUVA mediates its effects is not well understood. Activation of the serotonin (5-hydroxytryptamine, 5-HT) pathway has been suggested to be involved in the modulation of T-cell responses and found to mediate UVB-induced immune suppression. In particular, the activation of the 5-HT2A receptor has been proposed as one mechanism responsible for UV-induced immune suppression. We therefore hypothesized that 5-HT may play a role in PUVA-induced effects. The model of systemic suppression of delayed-type hypersensitivity (DTH) to Candida albicans was used to study immune function after exposure of C3H and KIT(W) (-Sh/W-Sh) mice to a minimal inflammatory dose of topical PUVA. The intra-peritoneal injection of the 5-HT2 receptor antagonist ketanserin or cyproheptadine or an anti-5-HT antibody immediately before PUVA exposure entirely abrogated suppression of DTH but had no significant effect on inflammation, as measured by swelling and cellular infiltration of the skin, and apoptosis as determined by the number of sunburn cells in C3H mice. Importantly, the systemic injection of 5-HT recapitulated PUVA immune suppression of DTH but did not induce inflammation or apoptosis in the skin. KIT(W) (-Sh/W-Sh) mice (exhibiting myelopoietic abnormalities, including lack of 5-HT-containing mast cells) were resistant to PUVA-induced suppression of DTH but not local skin swelling. Thus, this points towards a crucial role of 5-HT signalling in PUVA-induced immune suppression but not inflammation or apoptosis in situ in the skin. PMID:26914366

  9. Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors

    PubMed Central

    Watson, J; Brough, S; Coldwell, M C; Gager, T; Ho, M; Hunter, A J; Jerman, J; Middlemiss, D N; Riley, G J; Brown, A M

    1998-01-01

    Xanomeline [3(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine] has been reported to act as a functionally selective muscarinic partial agonist with potential use in the treatment of Alzheimer's disease. This study examined the functional activity of xanomeline at 5-HT1 and 5-HT2 receptors in native tissue and/or human cloned receptors.Xanomeline had affinity for muscarinic receptors in rat cortical membranes where the ratio of the displacement affinity of [3H]-Quinuclidinyl benzilate vs that of [3H]-Oxotremorine-M was 16, indicative of partial agonist activity. Radioligand binding studies on human cloned receptors confirmed that xanomeline had substantial affinity for M1, M2, M3, M4, M5 receptors and also for 5-HT1 and 5-HT2 receptor subtypes.Carbachol and xanomeline stimulated basal [35S]-GTPγS binding in rat cortical membranes with micromolar affinity. The response to carbachol was attenuated by himbacine and pirenzepine with pA2 of 8.2, 6.9 respectively consistent with the response being mediated, predominantly, via M2 and M4 receptors. Xanomeline-induced stimulation of [35S]-GTPγS binding was inhibited by himbacine with an apparent pKb of 6.3, was not attenuated by pirenzepine up to 3 μM and was inhibited by the selective 5-HT1A antagonist WAY100635 with an apparent pKb of 9.4. These data suggest the agonist effect of xanomeline in this tissue is, in part, via 5-HT1A receptors. Similar studies on human cloned receptors confirmed that xanomeline is an agonist at human cloned 5-HT1A and 5-HT1B receptors.In studies using the fluorescent cytoplasmic Ca2+ indicator FLUO-3AM, xanomeline induced an increase in cytoplasmic Ca2+ concentration in SH-SY5Y cells expressing recombinant human 5-HT2C receptors. Atropine antagonized this response, consistent with mediation via endogenously-expressed muscarinic receptors. In the presence of atropine, xanomeline antagonized 5-HT-induced cytoplasmic changes in Ca2+ concentration in cells expressing h5

  10. GABA and 5-HT systems are implicated in the anxiolytic-like effect of spinosin in mice.

    PubMed

    Liu, Jie; Zhai, Wei-Min; Yang, Yuan-Xiao; Shi, Jin-Li; Liu, Qian-Tong; Liu, Guo-Lin; Fang, Nan; Li, Jian; Guo, Jian-You

    2015-01-01

    The present study investigated the anxiolytic-like effects of spinosin, one of the major flavonoids in Ziziphi Spinosae Semen (ZSS), in experimental models of anxiety compared with a known anxiolytic, diazepam. Repeated treatment with spinosin (2.5 and 5mg/kg/day, p.o.) significantly increased the percentage of entries into and time spent on the open arms of the elevated plus maze compared with the control group. In the light/dark box test, spinosin exerted an anxiolytic-like effect at 5mg/kg. In the open-field test, 5mg/kg spinosin increased the number of central entries. Spinosin did not affect spontaneous activity. The anxiolytic-like effects of spinosin in the elevated plus maze, light/dark box test, and open field test were blocked by the γ-aminobutyric acid-A (GABAA) receptor antagonist flumazenil (3mg/kg, i.p.) and 5-hydroxytryptamine-1A (5-HT1A) receptor antagonist WAY-100635 (1mg/kg, i.p.). These results suggest that spinosin exerts anxiolytic-like effects, and its mechanism of action appears to be modulated by GABAA and 5-HT1A receptors. PMID:25449359

  11. Serotonin homeostasis and serotonin receptors as actors of cortical construction: special attention to the 5-HT3A and 5-HT6 receptor subtypes

    PubMed Central

    Vitalis, Tania; Ansorge, Mark S.; Dayer, Alexandre G.

    2013-01-01

    Cortical circuits control higher-order cognitive processes and their function is highly dependent on their structure that emerges during development. The construction of cortical circuits involves the coordinated interplay between different types of cellular processes such as proliferation, migration, and differentiation of neural and glial cell subtypes. Among the multiple factors that regulate the assembly of cortical circuits, 5-HT is an important developmental signal that impacts on a broad diversity of cellular processes. 5-HT is detected at the onset of embryonic telencephalic formation and a variety of serotonergic receptors are dynamically expressed in the embryonic developing cortex in a region and cell-type specific manner. Among these receptors, the ionotropic 5-HT3A receptor and the metabotropic 5-HT6 receptor have recently been identified as novel serotonergic targets regulating different aspects of cortical construction including neuronal migration and dendritic differentiation. In this review, we focus on the developmental impact of serotonergic systems on the construction of cortical circuits and discuss their potential role in programming risk for human psychiatric disorders. PMID:23801939

  12. Prostaglandin potentiates 5-HT responses in stomach and ileum innervating visceral afferent sensory neurons.

    PubMed

    Kim, Sojin; Jin, Zhenhua; Lee, Goeun; Park, Yong Seek; Park, Cheung-Seog; Jin, Young-Ho

    2015-01-01

    Gastrointestinal disorder is a common symptom induced by diverse pathophysiological conditions that include food tolerance, chemotherapy, and irradiation for therapy. Prostaglandin E2 (PGE2) level increase was often reported during gastrointestinal disorder and prostaglandin synthetase inhibitors has been used for ameliorate the symptoms. Exogenous administration of PGE2 induces gastrointestinal disorder, however, the mechanism of action is not known. Therefore, we tested PGE2 effect on visceral afferent sensory neurons of the rat. Interestingly, PGE2 itself did not evoked any response but enhanced serotonin (5-HT)-evoked currents up to 167% of the control level. The augmented 5-HT responses were completely inhibited by a 5-HT type 3 receptor antagonist, ondansetron. The PGE2-induced potentiation were blocked by a selective E-prostanoid type 4 (EP4) receptors antagonist, L-161,982, but type 1 and 2 receptor antagonist AH6809 has no effect. A membrane permeable protein kinase A (PKA) inhibitor, KT5720 also inhibited PGE2 effects. PGE2 induced 5-HT current augmentation was observed on 15% and 21% of the stomach and ileum projecting neurons, respectively. Current results suggest a synergistic signaling in visceral afferent neurons underlying gastrointestinal disorder involving PGE2 potentiation of 5-HT currents. Our findings may open a possibility for screen a new type drugs with lower side effects than currently using steroidal prostaglandin synthetase inhibitors by selectively targeting EP4 receptor/PKA pathway without interrupt prostaglandin synthesis. PMID:25446121

  13. Differential expression of 5-HT-related genes in symptomatic pulmonary embolism patients

    PubMed Central

    Jin, Yun; Wang, Lemin; Duan, Qianglin; Gong, Zhu; Yang, Fan; Song, Yanli

    2015-01-01

    Objective: Whole human genome oligo microarrays were employed to systematically investigate the mRNA expression profile of 5-HT synthetase, transporter, receptor, and factors in 5-HT signaling pathway in peripheral blood karyocytes from pulmonary embolism (PE) patients. Methods: A total of 20 PE patients and 20 healthy subjects matched in gender and age were recruited. The human genome microarrays were performed to detect the mRNA expression profile of 5-HT synthetase, transporter, receptor, and factors in 5-HT signal pathway of two groups. The random variance model corrected t-test was used for analysis. Results: Our results showed (1) tryptophan hydroxylase (TPH1)-related gene expression was markedly down-regulated in PE patients (P < 0.01); (2) monoamine oxidases (MAO)-related gene (MAOB) expression was significantly up-regulated in PE patients (P < 0.01); (3) the expression of 17 genes of 7 5-HT receptors showed a down-regulated tendency in PE patients, and significant difference was observed in the expression of HTR1E, HTR3B, HTR4 and HTR5A between them (P < 0.05); (4) the expression of DalDAG-GEF I, Tubby, PKA and EPAC in 5-HT signal pathways was dramatically up-regulated in PE patients (P < 0.05); the expression of SPA1, RIAM, RAPL, Talin, PKC, PLC and Pyk2 was remarkably up-regulated in PE patients (P < 0.05); (5) the expression of integrin genes ITGA2B, ITGB1 and ITGB3 was significantly up-regulated in PE patients (P < 0.05). Conclusion: In PE patients, the expression of TPH1 and HTR4 was down-regulated as a negative feedback; the MAOB expression was up-regulated. Consistent with the expression of 5-HTR1E and 5-HTR4 and the abnormally activated Tubby, the expression of integrins in platelets was activated. PMID:25785024

  14. The involvement of intracellular Ca2+ in 5-HT1B/1D receptor-mediated contraction of the rabbit isolated renal artery

    PubMed Central

    Hill, P B; Dora, K A; Hughes, A D; Garland, C J

    2000-01-01

    5-Hydroxytryptamine1B/1D (5-HT1B/1D) receptor coupling to contraction was investigated in endothelium-denuded rabbit isolated renal arteries, by simultaneously measuring tension and intracellular [Ca2+], and tension in permeabilized smooth muscle cells.In intact arterial segments, 1 nM–10 μM 5-HT failed to induce contraction or increase the fura-2 fluorescence ratio (in the presence of 1 μM ketanserin and prazosin to block 5-HT2 and α1-adrenergic receptors, respectively). However, in vessels pre-exposed to either 20 mM K+ or 30 nM U46619, 5-HT stimulated concentration-dependent increases in both tension and intracellular [Ca2+].1 nM–10 μM U46619 induced concentration-dependent contractions. In the presence of nifedipine (0.3 and 1 μM) the maximal contraction to U46619 (10 μM) was reduced by around 70%. The residual contraction was abolished by the putative receptor operated channel inhibitor, SKF 96365 (2 μM).With 0.3 μM nifedipine present, 100 nM U46619 evoked similar contraction to 30 nM U46619 in the absence of nifedipine, but contraction to 5-HT (1 nM–10 μM) was abolished.In permeabilized arterial segments, 10 mM caffeine, 1 μM IP3 or 100 μM phenylephrine, each evoked transient contractions by releasing Ca2+ from intracellular stores, whereas 5-HT had no effect. In intact arterial segments pre-stimulated with 20 mM K+, 5-HT-evoked contractions were unaffected by 1 μM thapsigargin, which inhibits sarco- and endoplasmic reticulum calcium-ATPases.In vessels permeabilized with α-toxin and then pre-contracted with Ca2+ and GTP, 5-HT evoked further contraction, reflecting increased myofilament Ca2+-sensitivity.Contraction linked to 5-HT1B/1D receptor stimulation in the rabbit renal artery can be explained by an influx of external Ca2+ through voltage-dependent Ca2+ channels and sensitization of the contractile myofilaments to existing levels of Ca2+, with no release of Ca2+ from intracellular stores. PMID

  15. Carrier-dependent and Ca2+-dependent 5-HT and dopamine release induced by (+)-amphetamine, 3,4-methylendioxy-methamphetamine, p-chloroamphetamine and (+)-fenfluramine

    PubMed Central

    Crespi, Daniela; Mennini, Tiziana; Gobbi, Marco

    1997-01-01

    The mechanism underlying 5-hydroxytryptamine (5-HT) and/or dopamine release induced by (+)-amphetamine ((+)-Amph), 3,4-methylendioxymethamphetamine (MDMA), p-chloroamphetamine (pCA) and (+)-fenfluramine ((+)-Fen) was investigated in rat brain superfused synaptosomes preloaded with the 3H neurotransmitters. Their rank order of potency for [3H]-5-HT-releasing activity was the same as for inhibition of 5-HT uptake (pCA⩾MDMA⩾(+)-Fen>>(+)-Amph). Similarly, their rank order as [3H]-dopamine releasers and dopamine uptake inhibitors was the same ((+)-Amph>>pCA=MDMA>>(+)-Fen). We also confirmed that the release induced by these compounds was prevented by selective transporter inhibitors (indalpine or nomifensine). [3H]-5-HT and/or [3H]-dopamine release induced by all these compounds was partially (31–80%), but significantly Ca2+-dependent. Lack of extracellular Ca2+ did not alter uptake mechanisms nor did it modify the carrier-dependent dopamine-induced [3H]-dopamine release. (+)-Amph-induced [3H]-dopamine release and pCA- and MDMA-induced [3H]-5-HT release were significantly inhibited by ω-agatoxin-IVA, a specific blocker of P-type voltage-operated Ca2+-channels, similar to the previous results on (+)-Fen-induced [3H]-5-HT release. Methiothepin inhibited the Ca2+-dependent component of (+)-Amph-induced [3H]-dopamine release with high potency (70 nM), as previously found with (+)-Fen-induced [3H]-5-HT release. The inhibitory effect of methiothepin was not due to its effects as a transporter inhibitor or Ca2+-channel blocker and is unlikely to be due to its antagonist properties on 5-HT1/2, dopamine or any other extracellular receptor. These results indicate that the release induced by these compounds is both ‘carrier-mediated' and Ca2+-dependent (possibly exocytotic-like), with the specific carrier allowing the amphetamines to enter the synaptosome. The Ca2+-dependent release is mediated by Ca2+-influx (mainly through P-type Ca2+-channels), possibly triggered by

  16. A-to-I editing of the 5HT2C receptor and behaviour.

    PubMed

    Gardiner, Katheleen; Du, Yunzhi

    2006-03-01

    Site-specific deamination of five adenosine residues in the pre-mRNA of the serotonin 2C receptor, 5HT2CR, alters the amino acid sequence of the encoded protein. Such RNA editing can produce 32 mRNA variants, encoding 24 protein isoforms that vary in biochemical and pharmacological properties. Because serotonin functions in the regulation of mood and behaviour, modulation of serotonin signalling by RNA editing may be relevant to such psychiatric disorders as anxiety and depression. Several recent human studies have reported changes in 5HT2CR editing in schizophrenia, major depression or suicide, but results are variable and not conclusive. Rodent studies have begun to examine effects of drug treatments and stress. Understanding the importance of 5HT2CR editing in mood and behaviour will be assisted by experiments designed to analyse multiple strains of mice, in different behavioural tests, with optimal evaluation of the time course of molecular changes. PMID:16769676

  17. Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors.

    PubMed

    Linge, Raquel; Jiménez-Sánchez, Laura; Campa, Leticia; Pilar-Cuéllar, Fuencisla; Vidal, Rebeca; Pazos, Angel; Adell, Albert; Díaz, Álvaro

    2016-04-01

    Cannabidiol (CBD), the main non-psychotomimetic component of marihuana, exhibits anxiolytic-like properties in many behavioural tests, although its potential for treating major depression has been poorly explored. Moreover, the mechanism of action of CBD remains unclear. Herein, we have evaluated the effects of CBD following acute and chronic administration in the olfactory bulbectomy mouse model of depression (OBX), and investigated the underlying mechanism. For this purpose, we conducted behavioural (open field and sucrose preference tests) and neurochemical (microdialysis and autoradiography of 5-HT1A receptor functionality) studies following treatment with CBD. We also assayed the pharmacological antagonism of the effects of CBD to dissect out the mechanism of action. Our results demonstrate that CBD exerts fast and maintained antidepressant-like effects as evidenced by the reversal of the OBX-induced hyperactivity and anhedonia. In vivo microdialysis revealed that the administration of CBD significantly enhanced serotonin and glutamate levels in vmPFCx in a different manner depending on the emotional state and the duration of the treatment. The potentiating effect upon neurotransmitters levels occurring immediately after the first injection of CBD might underlie the fast antidepressant-like actions in OBX mice. Both antidepressant-like effect and enhanced cortical 5-HT/glutamate neurotransmission induced by CBD were prevented by 5-HT1A receptor blockade. Moreover, adaptive changes in pre- and post-synaptic 5-HT1A receptor functionality were also found after chronic CBD. In conclusion, our findings indicate that CBD could represent a novel fast antidepressant drug, via enhancing both serotonergic and glutamate cortical signalling through a 5-HT1A receptor-dependent mechanism. PMID:26711860

  18. Effect of 5-HT7 receptor agonist, LP-211, on micturition following spinal cord injury in male rats

    PubMed Central

    Norouzi-Javidan, Abbas; Javanbakht, Javad; Barati, Fardin; Fakhraei, Nahid; Mohammadi, Fatemeh; Dehpour, Ahmad Reza

    2016-01-01

    Background and Purpose: Central and peripheral 5-hydroxytryptamine (5-HT) receptors play a critical role in regulation of micturition reflex. The aim of this study was to evaluate effect of a 5-HT7 receptor agonist, LP-211 (N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide) on micturition reflex in acute spinal cord-injured (SCI) rats during infusion of vehicle into the bladder. Methods: SCI was induced by compressing T10 segment using an aneurysm clip, extradurally in male rats. Following two weeks, LP-211 doses (0.003-0.3 mg/kg) were administered cumulatively (intraperitoneally, i.p.) with 20 min interval. The 5-HT7 antagonist, SB-269970 ((R)-3-[2-[2-(4-Methylpiperidin-1-yl) ethyl] pyrrolidine-1-sulfonyl] phenol hydrochloride), was administered after achievement of LP-211 dose-response. A cystometric study was performed 2 weeks after spinal crushing in all the animals. Cystometric variables consisting of micturition volume (voided volume), residual volume (volume remaining in the bladder after voiding), and bladder capacity (micturition volume plus residual volume). Voiding efficiency was calculated as the percent of micturition volume to bladder capacity. Findings: Intact and sham-operated rats showed few significant changes in micturition reflex. SCI rats responded to LP-211 (0.003-0.3, mg/kg, i.v.) with dose-dependent increases in bladder capacity, and residual volume. In this treatment group, LP-211 induced significant dose-dependent increases in micturition volume, resulting in significant increases in voiding efficiency (P<0.001) compared to intact and sham-operated rats, SB-269970 (0.1 mg/kg, i.v.) completely reversed the LP-211-induced changes on micturition volume and voiding efficiency was decreased significantly. Conclusion: The 5-HT7 receptors activation by LP-211 facilitated the micturition reflex. Furthermore, 5-HT7 receptors do seem to play an important role in physiological regulation of micturition, and as a result, may represent a

  19. Attenuation of phencyclidine-induced object recognition deficits by the combination of atypical antipsychotic drugs and pimavanserin (ACP 103), a 5-hydroxytryptamine(2A) receptor inverse agonist.

    PubMed

    Snigdha, S; Horiguchi, M; Huang, M; Li, Z; Shahid, M; Neill, J C; Meltzer, H Y

    2010-02-01

    Subchronic administration of the N-methyl-d-aspartate receptor antagonist, phencyclidine (PCP), in rodents has been shown to produce impairment in novel object recognition (NOR), a model of visual learning and memory. We tested the hypothesis that the selective 5-HT(2A) inverse agonists, pimavanserin and (R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl]-4-piperidinemethanol (M100907), would potentiate subeffective doses of atypical antipsychotic drugs (APDs) to reverse the NOR deficits. Female rats received vehicle or PCP (2 mg/kg b.i.d.) for 7 days, followed by a 7-day washout. Pimavanserin (3 mg/kg) or M100907 (1 mg/kg) alone, or four atypicial APDs, risperidone (0.05-0.1 mg/kg), melperone (1-3 mg/kg), olanzapine (1-2 mg/kg), or N-desmethylclozapine (1-2 mg/kg), and the typical APD, haloperidol (0.05-0.1 mg/kg), were administered alone, or in combination with pimavanserin or M100907, before NOR testing. The exploration times of objects during 3-min acquisition and retention trials, separated by a 1-min interval, were compared by analysis of variance. Vehicle-, but not PCP-treated, animals, explored the novel object significantly more than the familiar in the retention trial (p < 0.05-0.01). Pretreatment with the higher doses of the atypical APDs, but not pimavanserin, M100907, or haloperidol alone, reversed the effects of PCP. The effect of risperidone was blocked by haloperidol pretreatment. Coadministration of pimavanserin or M100907, with ineffective doses of the atypical APDs, but not haloperidol, also reversed the PCP-induced deficit in NOR. These results support the importance of 5-hydroxytryptamine(2A) receptor blockade relative to D(2) receptor blockade in the ability of atypicals to ameliorate the effect of subchronic PCP, a putative measure of cognitive dysfunction in schizophrenia. PMID:19864614

  20. A Meta-Analysis of the Effects of the 5-Hydroxytryptamine Transporter Gene-Linked Promoter Region Polymorphism on Susceptibility to Lifelong Premature Ejaculation

    PubMed Central

    Wu, Sheng; Shao, Hongbao; Dai, Feng; Peng, Tao; Qin, Feng; Feng, Ninghan

    2013-01-01

    Objective Premature ejaculation (PE) has been reported as the most common male sexual dysfunction with global prevalence rates estimated at approximately 30%. The neurobiogenesis of ejaculation is very complex and involves the serotoninergic (5-hydroxytryptamine, 5-HT) system. Recently, genetic polymorphisms located on SLC6A4 gene codifying for 5-HT transporter (5-HTT), the major regulator of serotonic neurotransmission, have been linked with the pathogenesis and risk of PE. Apparently studies of this type of polymorphism in PE have show conflicting results. Methods A meta-analysis was performed that are available in relation with 5-HTT gene-linked promoter region (5-HTTLPR) polymorphism and the risk of lifelong PE (LPE) in men to clarify this relationship. We searched Pubmed and Embase (last search updated on Aug 2012) using ‘premature ejaculation’, ‘polymorphism or variant’, ‘genotype’, ‘ejaculatory function’, and ‘rapid ejaculation’ as keywords and reference lists of studies corresponded to the inclusion criteria for meta-analysis. These studies involved the total number of 481 LPE men and 466 health control men subjects. Odds ratio (OR) and 95% confidence intervals (CIs) were used to evaluate this relationship. Results In the overall analysis, significant associations between LPE risk and 5-HTTLPR polymorphism were found (L-allele vs. S-allele OR = 0.86, 95% CI = 0.79–0.95, P = 0.002; LL vs. SS: OR = 0.80, 95% CI = 0.68–0.95, P = 0.009; LS vs. SS: OR = 0.85, 95% CI = 0.76–0.97, P = 0.012 and LL+LS vs. SS: OR = 0.88, 95% CI = 0.81–0.95, P = 0.002). Moreover, in subgroup analysis based on ethnicity, similar significant associations were detected. The Egger’s test did not reveal presence of a publication bias. Conclusions Our investigations demonstrate that 5-HTTLPR (L>S) polymorphism might protect men against LPE risk. Further studies based on larger sample size and gene

  1. Prostaglandin potentiates 5-HT responses in stomach and ileum innervating visceral afferent sensory neurons

    SciTech Connect

    Kim, Sojin; Jin, Zhenhua; Lee, Goeun; Park, Yong Seek; Park, Cheung-Seog; Jin, Young-Ho

    2015-01-02

    Highlights: • Prostaglandin E2 (PGE{sub 2}) effect was tested on visceral afferent neurons. • PGE{sub 2} did not evoke response but potentiated serotonin (5-HT) currents up to 167%. • PGE{sub 2}-induced potentiation was blocked by E-prostanoid type 4 receptors antagonist. • PGE{sub 2} effect on 5-HT response was also blocked by protein kinase A inhibitor KT5720. • Thus, PGE{sub 2} modulate visceral afferent neurons via synergistic signaling with 5-HT. - Abstract: Gastrointestinal disorder is a common symptom induced by diverse pathophysiological conditions that include food tolerance, chemotherapy, and irradiation for therapy. Prostaglandin E{sub 2} (PGE{sub 2}) level increase was often reported during gastrointestinal disorder and prostaglandin synthetase inhibitors has been used for ameliorate the symptoms. Exogenous administration of PGE{sub 2} induces gastrointestinal disorder, however, the mechanism of action is not known. Therefore, we tested PGE{sub 2} effect on visceral afferent sensory neurons of the rat. Interestingly, PGE{sub 2} itself did not evoked any response but enhanced serotonin (5-HT)-evoked currents up to 167% of the control level. The augmented 5-HT responses were completely inhibited by a 5-HT type 3 receptor antagonist, ondansetron. The PGE{sub 2}-induced potentiation were blocked by a selective E-prostanoid type4 (EP{sub 4}) receptors antagonist, L-161,982, but type1 and 2 receptor antagonist AH6809 has no effect. A membrane permeable protein kinase A (PKA) inhibitor, KT5720 also inhibited PGE{sub 2} effects. PGE{sub 2} induced 5-HT current augmentation was observed on 15% and 21% of the stomach and ileum projecting neurons, respectively. Current results suggest a synergistic signaling in visceral afferent neurons underlying gastrointestinal disorder involving PGE{sub 2} potentiation of 5-HT currents. Our findings may open a possibility for screen a new type drugs with lower side effects than currently using steroidal prostaglandin

  2. Antidepressants and antipsychotic drugs colocalize with 5-HT3 receptors in raft-like domains.

    PubMed

    Eisensamer, Brigitte; Uhr, Manfred; Meyr, Sabrina; Gimpl, Gerald; Deiml, Tobias; Rammes, Gerhard; Lambert, Jeremy J; Zieglgänsberger, Walter; Holsboer, Florian; Rupprecht, Rainer

    2005-11-01

    Despite different chemical structure and pharmacodynamic signaling pathways, a variety of antidepressants and antipsychotics inhibit ion fluxes through 5-HT3 receptors in a noncompetitive manner with the exception of the known competitive antagonists mirtazapine and clozapine. To further investigate the mechanisms underlying the noncompetitive inhibition of the serotonin-evoked cation current, we quantified the concentrations of different types of antidepressants and antipsychotics in fractions of sucrose flotation gradients isolated from HEK293 (human embryonic kidney 293) cells stably transfected with the 5-HT3A receptor and of N1E-115 neuroblastoma cells in relation to the localization of the 5-HT3 receptor protein within the cell membrane. Western blots revealed a localization of the 5-HT3 receptor protein exclusively in the low buoyant density (LBD) fractions compatible with a localization within raft-like domains. Also, the antidepressants desipramine, fluoxetine, and reboxetine and the antipsychotics fluphenazine, haloperidol, and clozapine were markedly enriched in LBD fractions, whereas no accumulation occurs for mirtazapine, carbamazepine, moclobemide, and risperidone. The concentrations of psychopharmacological drugs within LBD fractions was strongly associated with their inhibitory potency against serotonin-induced cation currents. The noncompetitive antagonism of antidepressants at the 5-HT3 receptor was not conferred by an enhancement of receptor internalization as shown by immunofluorescence studies, assessment of receptor density in clathrin-coated vesicles, and electrophysiological recordings after coexpression of a dominant-negative mutant of dynamin I, which inhibits receptor internalization. In conclusion, enrichment of antidepressants and antipsychotics in raft-like domains within the cell membrane appears to be crucial for their antagonistic effects at ligand-gated ion channels such as 5-HT3 receptors. PMID:16267227

  3. 5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation

    PubMed Central

    Samarajeewa, Anshula; Goldemann, Lolita; Vasefi, Maryam S.; Ahmed, Nawaz; Gondora, Nyasha; Khanderia, Chandni; Mielke, John G.; Beazely, Michael A.

    2014-01-01

    The serotonin (5-HT) type 7 receptor is expressed throughout the CNS including the cortex and hippocampus. We have previously demonstrated that the application of 5-HT7 receptor agonists to primary hippocampal neurons and SH-SY5Y cells increases platelet-derived growth factor (PDGF) receptor expression and promotes neuroprotection against N-methyl-D-aspartate-(NMDA)-induced toxicity. The tropomyosin-related kinase B (TrkB) receptor is one of the receptors for brain-derived neurotrophic factor (BDNF) and is associated with neurodevelopmental and neuroprotective effects. Application of LP 12 to primary cerebral cortical cultures, SH-SY5Y cells, as well as the retinal ganglion cell line, RGC-5, increased both the expression of full length TrkB as well as its basal phosphorylation state at tyrosine 816. The increase in TrkB expression and phosphorylation was observed as early as 30 min after 5-HT7 receptor activation. In addition to full-length TrkB, kinase domain-deficient forms may be expressed and act as dominant-negative proteins toward the full length receptor. We have identified distinct patterns of TrkB isoform expression across our cell lines and cortical cultures. Although TrkB receptor expression is regulated by cyclic AMP and Gαs-coupled GPCRs in several systems, we demonstrate that, depending on the model system, pathways downstream of both Gαs and Gα12 are involved in the regulation of TrkB expression by 5-HT7 receptors. Given the number of psychiatric and degenerative diseases associated with TrkB/BDNF deficiency and the current interest in developing 5-HT7 receptor ligands as pharmaceuticals, identifying signaling relationships between these two receptors will aid in our understanding of the potential therapeutic effects of 5-HT7 receptor ligands. PMID:25426041

  4. Prebiotic administration normalizes lipopolysaccharide (LPS)-induced anxiety and cortical 5-HT2A receptor and IL1-β levels in male mice.

    PubMed

    Savignac, Helene M; Couch, Yvonne; Stratford, Michael; Bannerman, David M; Tzortzis, George; Anthony, Daniel C; Burnet, Philip W J

    2016-02-01

    The manipulation of the enteric microbiota with specific prebiotics and probiotics, has been shown to reduce the host's inflammatory response, alter brain chemistry, and modulate anxiety behaviour in both rodents and humans. However, the neuro-immune and behavioural effects of prebiotics on sickness behaviour have not been explored. Here, adult male CD1 mice were fed with a specific mix of non-digestible galacto-oligosaccharides (Bimuno®, BGOS) for 3 weeks, before receiving a single injection of lipopolysaccharide (LPS), which induces sickness behaviour and anxiety. Locomotor and marble burying activities were assessed 4h after LPS injection, and after 24h, anxiety in the light-dark box was assessed. Cytokine expression, and key components of the serotonergic (5-Hydroxytryptamine, 5-HT) and glutamatergic system were evaluated in the frontal cortex to determine the impact of BGOS administration at a molecular level. BGOS-fed mice were less anxious in the light-dark box compared to controls 24h after the LPS injection. Elevated cortical IL-1β concentrations in control mice 28 h after LPS were not observed in BGOS-fed animals. This significant BGOS×LPS interaction was also observed for 5HT2A receptors, but not for 5HT1A receptors, 5HT, 5HIAA, NMDA receptor subunits, or other cytokines. The intake of BGOS did not influence LPS-mediated reductions in marble burying behaviour, and its effect on locomotor activity was equivocal. Together, our data show that the prebiotic BGOS has an anxiolytic effect, which may be related to the modulation of cortical IL-1β and 5-HT2A receptor expression. Our data suggest a potential role for prebiotics in the treatment of neuropsychiatric disorders where anxiety and neuroinflammation are prominent clinical features. PMID:26476141

  5. 5-HT loss in rat brain following 3,4-methylenedioxymethamphetamine (MDMA), p-chloroamphetamine and fenfluramine administration and effects of chlormethiazole and dizocilpine.

    PubMed Central

    Colado, M. I.; Murray, T. K.; Green, A. R.

    1993-01-01

    1. The present study has investigated whether the neurotoxic effects of the relatively selective 5-hydroxytryptamine (5-HT) neurotoxins, 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy'), p-chloroamphetamine (PCA) and fenfluramine on hippocampal and cortical 5-HT terminals in rat brain could be prevented by administration of either chlormethiazole or dizocilpine. 2. Administration of MDMA (20 mg kg-1, i.p.) resulted in an approximate 30% loss of cortical and hippocampal 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) content 4 days later. Injection of chlormethiazole (50 mg kg-1) 5 min before and 55 min after the MDMA provided complete protection in both regions, while dizocilpine (1 mg kg-1, i.p.) protected only the hippocampus. 3. Administration of a single dose of chlormethiazole (100 mg kg-1) 20 min after the MDMA also provided complete protection to the hippocampus but not the cortex. This regime also attenuated the sustained hyperthermia (approx +2.5 degrees C) induced by the MDMA injection. 4. Injection of PCA (5 mg kg-1, i.p.) resulted in a 70% loss of 5-HT and 5-HIAA content in hippocampus and cortex 4 days later. Injection of chlormethiazole (100 mg kg-1, i.p.) or dizocilpine (1 mg kg-1, i.p.) 5 min before and 55 min after the PCA failed to protect against the neurotoxicity, nor was protection afforded by chlormethiazole when a lower dose of PCA (2.5 mg kg-1, i.p.) was given which produced only a 30% loss of 5-HT content.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7682129

  6. 5-HT2B antagonism arrests non-canonical TGF-β1-induced valvular myofibroblast differentiation

    PubMed Central

    Hutcheson, Joshua D.; Ryzhova, Larisa M.; Setola, Vincent; Merryman, W. David

    2012-01-01

    Transforming growth factor-β1 (TGF-β1) induces myofibroblast activation of quiescent aortic valve interstitial cells (AVICs), a differentiation process implicated in calcific aortic valve disease (CAVD). The ubiquity of TGF-β1 signaling makes it difficult to target in a tissue specific manner; however, the serotonin 2B receptor (5-HT2B) is highly localized to cardiopulmonary tissues and agonism of this receptor displays pro-fibrotic effects in a TGF-β1-dependent manner. Therefore, we hypothesized that antagonism of 5-HT2B opposes TGF-β1-induced pathologic differentiation of AVICs and may offer a druggable target to prevent CAVD. To test this hypothesis, we assessed the interaction of 5-HT2B antagonism with canonical and non-canonical TGF-β1 pathways to inhibit TGF-β1-induced activation of isolated porcine AVICs in vitro. Here we show that AVIC activation and subsequent calcific nodule formation is completely mitigated by 5-HT2B antagonism. Interestingly, 5-HT2B antagonism does not inhibit canonical TGF-β1 signaling as identified by Smad3 phosphorylation and activation of a partial plasminogen activator inhibitor-1 promoter (PAI-1, a transcriptional target of Smad3), but prevents non-canonical p38 MAPK phosphorylation. It was initially suspected that 5-HT2B antagonism prevents Src tyrosine kinase phosphorylation; however, we found that this is not the case and time-lapse microscopy indicates that 5-HT2B antagonism prevents non-canonical TGF-β1 signaling by physically arresting Src tyrosine kinase. This study demonstrates the necessity of non-canonical TGF-β1 signaling in leading to pathologic AVIC differentiation. Moreover, we believe that the results of this study suggest 5-HT2B antagonism as a novel therapeutic approach for CAVD that merits further investigation. PMID:22940605

  7. Gi-protein-coupled 5-HT1B/D receptor agonist sumatriptan induces type I hyperalgesic priming.

    PubMed

    Araldi, Dioneia; Ferrari, Luiz F; Levine, Jon D

    2016-08-01

    We have recently described a novel form of hyperalgesic priming (type II) induced by agonists at two clinically important Gi-protein-coupled receptors (Gi-GPCRs), mu-opioid and A1-adenosine. Like mu-opioids, the antimigraine triptans, which act at 5-HT1B/D Gi-GPCRs, have been implicated in pain chronification. We determined whether sumatriptan, a prototypical 5-HT1B/D agonist, produces type II priming. Characteristic of hyperalgesic priming, intradermal injection of sumatriptan (10 ng) induced a change in nociceptor function such that a subsequent injection of prostaglandin-E2 (PGE2) induces prolonged mechanical hyperalgesia. However, onset to priming was delayed 3 days, characteristic of type I priming. Also characteristic of type I priming, a protein kinase Cε, but not a protein kinase A inhibitor attenuated the prolongation phase of PGE2 hyperalgesia. The prolongation of PGE2 hyperalgesia was also permanently reversed by intradermal injection of cordycepin, a protein translation inhibitor. Also, hyperalgesic priming did not occur in animals pretreated with pertussis toxin or isolectin B4-positive nociceptor toxin, IB4-saporin. Finally, as observed for other agonists that induce type I priming, sumatriptan did not induce priming in female rats. The prolongation of PGE2 hyperalgesia induced by sumatriptan was partially prevented by coinjection of antagonists for the 5-HT1B and 5-HT1D, but not 5-HT7, serotonin receptors and completely prevented by coadministration of a combination of the 5-HT1B and 5-HT1D antagonists. Moreover, the injection of selective agonists, for 5-HT1B and 5-HT1D receptors, also induced hyperalgesic priming. Our results suggest that sumatriptan, which signals through Gi-GPCRs, induces type I hyperalgesic priming, unlike agonists at other Gi-GPCRs, which induce type II priming. PMID:27075428

  8. Ion permeation and conduction in a human recombinant 5-HT3 receptor subunit (h5-HT3A)

    PubMed Central

    Brown, A M; Hope, A G; Lambert, J J; Peters, J A

    1998-01-01

    A human recombinant homo-oligomeric 5-HT3 receptor (h5-HT3A) expressed in a human embryonic kidney cell line (HEK 293) was characterized using the whole-cell recording configuration of the patch clamp technique. 5-HT evoked transient inward currents (EC50 = 3.4 μm; Hill coefficient = 1.8) that were blocked by the 5-HT3 receptor antagonist ondansetron (IC50 = 103 pm) and by the non-selective agents metoclopramide (IC50 = 69 nm), cocaine (IC50 = 459 nm) and (+)-tubocurarine (IC50 = 2.8 μm). 5-HT-induced currents rectified inwardly and reversed in sign (E5-HT) at a potential of −2.2 mV. N-Methyl-d-glucamine was finitely permeant. Permeability ratios PNa/PCs and PNMDG/PCs were 0.90 and 0.083, respectively. Permeability towards divalent cations was assessed from measurements of E5-HT in media where Ca2+ and Mg2+ replaced Na+. PCa/PCs and PMg/PCs were calculated to be 1.00 and 0.61, respectively. Single channel chord conductance (γ) estimated from fluctuation analysis of macroscopic currents increased with membrane hyperpolarization from 243 fS at −40 mV to 742 fS at −100 mV. Reducing [Ca2+]o from 2 to 0.1 mm caused an increase in the whole-cell current evoked by 5-HT. A concomitant reduction in [Mg2+]o produced further potentiation. Fluctuation analysis indicates that a voltage-independent augmentation of γ contributes to this phenomenon. The data indicate that homo-oligomeric receptors composed of h5-HT3A subunits form inwardly rectifying cation-selective ion channels of low conductance that are permeable to Ca2+ and Mg2+. PMID:9508827

  9. Selective 5-HT2C agonists as potential antidepressants.

    PubMed

    Leysen, D C

    1999-02-01

    The antidepressants currently used need improvement, especially in terms of efficacy, relapse rate and onset of action. In this review the clinical and experimental data which support the rationale for 5-HT2C agonists in the treatment of depression are listed. Next, the results obtained with the non-selective 5-HT2C agonists on the market and in clinical development are described. Finally, the preclinical data on the more selective 5-HT2C agonists are summarized. These recent preclinical results reveal a greater potency and effect size compared to fluoxetine, good tolerability and no evidence of tolerance development. Selective 5-HT2C agonists might become innovative drugs for the treatment of depression, panic, obsessive-compulsive disorder (OCD), some forms of aggression and eating disorders. PMID:16160946

  10. Direct interaction and functional coupling between human 5-HT6 receptor and the light chain 1 subunit of the microtubule-associated protein 1B (MAP1B-LC1).

    PubMed

    Kim, Soon-Hee; Kim, Dong Hyuk; Lee, Kang Ho; Im, Sun-Kyoung; Hur, Eun-Mi; Chung, Kwang Chul; Rhim, Hyewhon

    2014-01-01

    Serotonin (5-HT) receptors of type 6 (5-HT6R) play important roles in mood, psychosis, and eating disorders. Recently, a growing number of studies support the use of 5-HT6R-targeting compounds as promising drug candidates for treating cognitive dysfunction associated with Alzheimer's disease. However, the mechanistic linkage between 5-HT6R and such functions remains poorly understood. By using yeast two-hybrid, GST pull-down, and co-immunoprecipitation assays, here we show that human 5-HT6R interacts with the light chain 1 (LC1) subunit of MAP1B protein (MAP1B-LC1), a classical microtubule-associated protein highly expressed in the brain. Functionally, we have found that expression of MAP1B-LC1 regulates serotonin signaling in a receptor subtype-specific manner, specifically controlling the activities of 5-HT6R, but not those of 5-HT4R and 5-HT7R. In addition, we have demonstrated that MAP1B-LC1 increases the surface expression of 5-HT6R and decreases its endocytosis, suggesting that MAP1B-LC1 is involved in the desensitization and trafficking of 5-HT6R via a direct interaction. Together, we suggest that signal transduction pathways downstream of 5-HT6R are regulated by MAP1B, which might play a role in 5-HT6R-mediated signaling in the brain. PMID:24614691

  11. Direct Interaction and Functional Coupling between Human 5-HT6 Receptor and the Light Chain 1 Subunit of the Microtubule-Associated Protein 1B (MAP1B-LC1)

    PubMed Central

    Kim, Soon-Hee; Kim, Dong Hyuk; Lee, Kang Ho; Im, Sun-Kyoung; Hur, Eun-Mi; Chung, Kwang Chul; Rhim, Hyewhon

    2014-01-01

    Serotonin (5-HT) receptors of type 6 (5-HT6R) play important roles in mood, psychosis, and eating disorders. Recently, a growing number of studies support the use of 5-HT6R-targeting compounds as promising drug candidates for treating cognitive dysfunction associated with Alzheimer’s disease. However, the mechanistic linkage between 5-HT6R and such functions remains poorly understood. By using yeast two-hybrid, GST pull-down, and co-immunoprecipitation assays, here we show that human 5-HT6R interacts with the light chain 1 (LC1) subunit of MAP1B protein (MAP1B-LC1), a classical microtubule-associated protein highly expressed in the brain. Functionally, we have found that expression of MAP1B-LC1 regulates serotonin signaling in a receptor subtype-specific manner, specifically controlling the activities of 5-HT6R, but not those of 5-HT4R and 5-HT7R. In addition, we have demonstrated that MAP1B-LC1 increases the surface expression of 5-HT6R and decreases its endocytosis, suggesting that MAP1B-LC1 is involved in the desensitization and trafficking of 5-HT6R via a direct interaction. Together, we suggest that signal transduction pathways downstream of 5-HT6R are regulated by MAP1B, which might play a role in 5-HT6R-mediated signaling in the brain. PMID:24614691

  12. Radioimmunoassay of serotonin (5-hydroxytryptamine) in cerebrospinal fluid, plasma, and serum

    SciTech Connect

    Engbaek, F.; Voldby, B

    1982-04-01

    A direct radioimmunoassay is described for serotonin (5-hydroxytryptamine) in cerebrospinal fluid, platelet-poor plasma, and serum. Antisera in rabbits was raised against serotonin diazotized to a conjugate of bovine albumin and D,L-p-aminophenylalanine. Polyethylene glycol, alone or in combination with anti-rabbit immunoglobulins, is used to separate bound and unbound tritiated serotonin. The minimum concentration of serotonin detectable is 2 nmol/L in a 200-..mu..L sample. Within-day precision (CV) is 4.3% between-day precision 7.7%. Analytical recoveries of serotonin are 109% and 101% for cerebrospinal fluid and plasma, respectively. Tryptophan, 5-hydroxytryptophan, 5-hydroxyindoleacetic acid, and 5-hydroxytryptophol do not interfere with the assay. However, 5-methoxytryptamine and tryptamine cross react. Of samples of cerebrospinal fluid from patients with disc herniations (n=21) or low-pressure hydrocephalus (n=10), one-third had concentrations of 2-4 nmol/L and two-thirds were below the minimum detectable concentration. The observed range for the concentration of serotonin in plasma of 14 normal subjects was 5-14 nmol/L (mean +/- SD, 9 +/- 3 nmol/L). The observed ranges for serotonin in serum were: for 10 women 520-900 (mean +/- SD: 695 +/- 110) nmol/L and for 10 men 380-680 (520 +/- 94) nmol/L.

  13. 5-HT(1A) receptors transactivate the platelet-derived growth factor receptor type beta in neuronal cells.

    PubMed

    Kruk, Jeff S; Vasefi, Maryam S; Liu, Hui; Heikkila, John J; Beazely, Michael A

    2013-01-01

    In the absence of ligand, certain growth factor receptors can be activated via G-protein coupled receptor (GPCR) activation in a process termed transactivation. Serotonin (5-HT) receptors can transactivate platelet-derived growth factor (PDGF) β receptors in smooth muscle cells, but it is not known if similar pathways occur in neuronal cells. Here we show that 5-HT can transiently increase the phosphorylation of PDGFβ receptors through 5-HT(1A) receptors in a time- and dose-dependent manner in SH-SY5Y neuroblastoma cells. 5-HT also transactivates PDGFβ receptors in primary cortical neurons. This transactivation pathway is pertussis-toxin sensitive and Src tyrosine kinase-dependent. This pathway is also dependent on phospholipase C activity and intracellular calcium signaling. Several studies involving PDGFβ receptor transactivation by GPCRs have also demonstrated a PDGFβ receptor-dependent increase in the phosphorylation of ERK1/2. Yet in SH-SY5Y cells, 5-HT treatment causes a PDGFβ receptor-independent increase in ERK1/2 phosphorylation. This crosstalk between 5-HT and PDGFβ receptors identifies a potentially important signaling link between the serotonergic system and growth factor signaling in neurons. PMID:23006663

  14. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates, the selective 5-hydroxytryptamine 1a agonist (R)-(+)-8-OHDPAT inhibits levodopa-induced dyskinesia but only with\\ increased motor disability.

    PubMed

    Iravani, Mahmoud M; Tayarani-Binazir, Kayhan; Chu, Wing B; Jackson, Michael J; Jenner, Peter

    2006-12-01

    5-Hydroxytryptamine 1a (5-HT(1a)) receptor agonists, such as sarizotan and tandospirone, are reported to reduce levodopa-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques and in Parkinson's disease without worsening motor disability. However, these compounds are not specific for 5-HT(1a) receptors and also possess dopamine antagonist actions. We now report on the effects of (2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin [(R)-(+)-8-OHDPAT], a selective 5-HT(1a) agonist lacking dopaminergic activity, on motor disability and dyskinesia (chorea and dystonia) in levodopa-primed MPTP-treated common marmosets. Administration of (R)-(+)-8-OHDPAT (0.2, 0.6, and 2.0 mg/kg s.c), in conjunction with levodopa/carbidopa (12.5 mg/kg each p.o.) to levodopa-primed animals, dose-dependently reduced levodopa-induced chorea but did not affect dystonic movements. However, (R)-(+)-8-OHDPAT treatment also reduced locomotor activity and the reversal of motor disability. Administration of (R)-(+)-8-OHDPAT alone had no effects of motor behaviors. The effects of (R)-(+)-8-OHDPAT on levodopa-induced motor behaviors were antagonized by the 5-HT(1a) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate (WAY-100635) (1.0 mg/kg s.c.). Administration of (R)-(+)-8-OHDPAT (0.6 mg/kg s.c.) also reduced chorea produced by the administration of the D(2)/D(3) dopamine receptor agonist pramipexole (0.06 mg/kg p.o.) to levodopa-primed MPTP-treated animals. However, again the increase in locomotor activity and reversal of motor disability produced by pramipexole were also inhibited. These data suggest that selective 5-HT(1a) agonists do not provide an effective means of suppressing levodopa-induced dyskinesia, except with worsening of parkinsonism. PMID:16959959

  15. Modulation of dopamine transmission by 5HT2C and 5HT3 receptors: a role in the antidepressant response.

    PubMed

    Dremencov, Eliyahu; Weizmann, Yifat; Kinor, Noa; Gispan-Herman, Iris; Yadid, Gal

    2006-02-01

    Dopaminergic mesolimbic and mesocortical systems are fundamental in hedonia and motivation. Therefore their regulation should be central in understanding depression treatment. This review highlights the dopaminergic activity in relation to depressive behavior and suggests two putative receptors as potential targets for research and development of future antidepressants. In this article we review data that describe the role of serotonin in regulating dopamine release, via 5HT2C and 5HT3 receptors. This action of serotonin appears to be linked to depressive-like behavior and to onset of behavioral effects of antidepressants in an animal model of depression. We suggest that drugs or strategies that decrease 5HT2C and increase 5HT3 receptor-mediated dopamine release in the limbic areas of the brain may provide a fast onset of therapeutic effect. Clinical and basic research data supporting this hypothesis are discussed. PMID:16475958

  16. Effects of dominance status on conditioned defeat and expression of 5-HT1A and 5-HT2A receptors

    PubMed Central

    Morrison, Kathleen E.; Swallows, Cody L.; Cooper, Matthew A.

    2011-01-01

    Past experience can alter how individuals respond to stressful events. The brain serotonin system is a key factor modulating stress-related behavior and may contribute to individual variation in coping styles. In this study we investigated whether dominant and subordinate hamsters respond differently to social defeat and whether their behavioral responses are associated with changes in 5-HT1A and 5-HT2A receptor immunoreactivity in several limbic brain regions. We paired weight-matched hamsters in daily aggressive encounters for two weeks so that they formed a stable dominance relationship. We also included controls that were exposed to an empty cage each day for two weeks. Twenty-four hours after the final pairing or empty cage exposure, subjects were socially defeated in 3, 5-min encounters with a more aggressive hamster. Twenty-four hours after social defeat, animals were tested for conditioned defeat in a 5-min social interaction test with a non-aggressive intruder. We collected brains following conditioned defeat testing and performed immunohistochemistry for 5-HT1A and 5-HT2A receptors. We found that dominants showed less submissive and defensive behavior at conditioned defeat testing compared to both subordinates and controls. Additionally, both dominants and subordinates had an increased number of 5-HT1A immunopositive cells in the basolateral amygdala compared to controls. Subordinates also had more 5-HT1A immunopositive cells in the dorsal medial amygdala than did controls. Finally, dominants had fewer 5-HT1A immunopositive cells in the paraventricular nucleus of the hypothalamus compared to controls. Our results indicate that dominant social status results in a blunted conditioned defeat response and a distinct pattern of 5-HT1A receptor expression, which may contribute to resistance to conditioned defeat. PMID:21362435

  17. Preclinical profile of the mixed 5-HT1A/5-HT2A receptor antagonist S 21,357.

    PubMed

    Griebel, G; Blanchard, D C; Rettori, M C; Guardiola-Lemaître, B; Blanchard, R J

    1996-06-01

    This study evaluated the pharmacological and behavioral effects of S 21,357, a drug with high affinity for both 5-HT1A and 5-HT2A receptors. The drug behaved as antagonist at both 5-HT1A autoreceptors and postsynaptic 5-HT1A receptors, as it prevented the inhibitory effect of lesopitron on the electrical discharge of the dorsal raphé nucleus (DRN) 5-HT neurons and the activity of forskolin-stimulated adenylate cyclase in hippocampal homogenates. In addition, S 21,357 (4 and 128 mg/kg, PO) inhibited 5-HTP-induced head-twitch responses in mice, indicating that it possesses 5-HT2A antagonistic properties. In a test battery designed to assess defensive behaviors of Swiss-Webster mice to the presence of, or situations associated with, a natural threat stimulus (i.e., rat), S 21,357 (0.12-2 mg/kg, IP) reduced contextual defense reactions after the rat was removed, risk assessment activities when the subject was chased, and finally, defensive attack behavior. These behavioral changes are consistent with fear/anxiety reduction. Furthermore, the drug strongly reduced flight reactions in response to the approaching rat. This last finding, taken together with recent results with panic-modulating drugs, suggest that S 21,357 may have potential efficacy against panic attack. Finally, our results suggest that compounds sharing high affinities for both 5-HT1A and 5-HT2A receptors may directly or synergistically increase the range of defensive behaviors affected. PMID:8743616

  18. Testosterone and its metabolites modulate 5HT1A and 5HT1B agonist effects on intermale aggression.

    PubMed

    Simon, N G; Cologer-Clifford, A; Lu, S F; McKenna, S E; Hu, S

    1998-01-01

    Our understanding of the neurochemical and neuroendocrine systems' regulating the display of offensive intermale aggression has progressed substantially over the past twenty years. Pharmacological studies have shown that serotonin, via its action at 5HT1A and/or 5HT1B receptor sites, modulates the display of intermale aggressive behavior and that its effects serve to decrease behavioral expression. Neuroendocrine investigations, in turn, have demonstrated that male-typical aggression is testosterone-dependent and studies of genetic effects, metabolic function and steroid receptor binding have shown that facilitation of behavioral displays can occur via independent androgen-sensitive or estrogen-sensitive pathways. Remarkably, there have been virtually no studies that examined the interrelationship between these facilitative and inhibitory systems. As an initial step toward characterizing the interaction between the systems, studies were conducted that assessed hormonal modulation of serotonin function at 5HT1A and 5HT1B receptor sites. They demonstrated: (1) that the androgenic and estrogenic metabolites of testosterone differentially modulate the ability of systemically administered 8-OH-DPAT (a 5HT1A agonist) and CGS12066B (a 5HT1B agonist) to decrease offensive aggression; and (2) when microinjected into the lateral septum (LS) or medial preoptic area (MPO), the aggression-attenuating effects of 1A and 1B agonists differ regionally and vary with the steroidal milieu. In general, the results suggest that estrogens establish a restrictive environment for attenuation of T-dependent aggression by 8-OH-DPAT and CGS 12066B, while androgens either do not inhibit, or perhaps even facilitate, the ability of 5HT1A and 5HT1B agonists to reduce aggression. Potential mechanisms involved in the production of these steroidal effects are discussed and emerging issues that may impact on efforts to develop an integrative neurobiological model of offensive, intermale aggression

  19. 5-hydroxytryptamine and Lyme disease. Opportunity for a novel therapy to reduce the cerebellar tremor?

    PubMed

    Maximov, G K; Maximov, K G; Chokoeva, A A; Lotti, T; Wollina, U; Patterson, J W; Guarneri, C; Tana, C; Fioranelli, M; Roccia, M G; Kanazawa, N; Tchernev, G

    2016-01-01

    Lyme boreliosis is caused by the spirochete Borrelia burdorferi, which is transmitted by ticks. A 59 year-old woman developed pyrexia, strong headaches, ataxia, dysarthria and tremor of the limbs after a tick bite. She was unable to work and eat on her own. She was hospitalized three times and diagnosed with cerebellar intention tremor, cerebellar ataxia, dysarthria, bilateral horizontal gaze paralysis and a central lesion of the left facial nerve. There were no pyramidal, sensory or psychiatric disturbances. The brain MRI showed multifocal leucoencephalopathy with many hyperintense areas in both hemispheres, as well as in the left superior pedunculus cerebellaris. Diagnosis was confirmed by serologic examination. Treatment with cephtriaxone, doxycycline, methylprednisolone, cephixime and ciprofloxacine was administered without effect on the tremor, ataxia and horizontal gaze paralysis. Treatment was then administered with 5-hydroxytriptamine (5-HT) in increased doses. The result of the three-month treatment with 5-HT was a gradual diminution of the tremor and the ataxia and an increase in the ability to eat, walk and work independently. PMID:27373127

  20. The effects of nabumetone, a cyclooxygenase-2 inhibitor, on cisplatin-induced 5-hydroxytryptamine release from the isolated rat ileum.

    PubMed

    Kudo, C; Minami, M; Hirafuji, M; Endo, T; Hamaue, N; Akita, K; Murakami, T; Kawaguchi, H

    2001-01-01

    In order to elucidate 5-HT release influenced by PGE2 in the background of the anticancer drug-induced emesis, the effect of nabumetone, a COX-2 inhibitor, on the release of 5-HT from the isolated rat ileum was investigated. PGE2 produced a concentration-dependent increase (10(-9) to 10 M) and decrease (10(-8) to 10(-6) M) in 5-HT release. Arachidonic acid also demonstrated a similar bell-shaped 5-HT release. The arachidonic acid-induced 5-HT release at 3 x 10(-6) M (313.04 +/- 25.90%) was significantly inhibited by the concomitant perfusion with BRL10720 (10(-6) M) (161.98 +/- 19.4%, p<0.01), an active metabolite of nabumetone, or indomethacin (3 x 10(-7) M)(190.01 +/- 16.19%, p<0.05). BRL10720 (10(-6) M)(428.57 +/- 51.72%, p<0.05) significantly inhibited the increase in 5-HT release induced by cisplatin (10(-6) M)(748.56 +/- 136.31%), suggesting that PGE2would be involved in cisplatin-induced 5-HT release. The increase in 5-HT release from the isolated ileum 72 hrs after cisplatin administration, in a delayed-emesis animal model, was significantly inhibited by the in vivo 3-day administration of nabumetone or BRL10720, but was not affected by the 3-day administration of dexamethasone. After 72 hours, however, the in vivo 3-days administration of nabumetone, BRL10720 or dexamethasone had no effect on the increase in ileal 5-HT levels induced by cisplatin. The use of COX-2 inhibitors to ameliorate delayed emesis induced by cisplatin-based anticancer chemotherapy has been proposed. On the other hand, there is a possibility that dexamethasone works through a mechanism other than 5-HT release in delayed emesis. PMID:12090350

  1. Combined serotonin (5-HT)1A agonism, 5-HT(2A) and dopamine D₂ receptor antagonism reproduces atypical antipsychotic drug effects on phencyclidine-impaired novel object recognition in rats.

    PubMed

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

    2015-05-15

    Subchronic administration of an N-methyl-D-aspartate receptor (NMDAR) antagonist, e.g. phencyclidine (PCP), produces prolonged impairment of novel object recognition (NOR), suggesting they constitute a hypoglutamate-based model of cognitive impairment in schizophrenia (CIS). Acute administration of atypical, e.g. lurasidone, but not typical antipsychotic drugs (APDs), e.g. haloperidol, are able to restore NOR following PCP (acute reversal model). Furthermore, atypical APDs, when co-administered with PCP, have been shown to prevent development of NOR deficits (prevention model). Most atypical, but not typical APDs, are more potent 5-HT(2A) receptor inverse agonists than dopamine (DA) D2 antagonists, and have been shown to enhance cortical and hippocampal efflux and to be direct or indirect 5-HT(1A) agonists in vivo. To further clarify the importance of these actions to the restoration of NOR by atypical APDs, sub-effective or non-effective doses of combinations of the 5-HT(1A) partial agonist (tandospirone), the 5-HT(2A) inverse agonist (pimavanserin), or the D2 antagonist (haloperidol), as well as the combination of all three agents, were studied in the acute reversal and prevention PCP models of CIS. Only the combination of all three agents restored NOR and prevented the development of PCP-induced deficit. Thus, this triple combination of 5-HT(1A) agonism, 5-HT(2A) antagonism/inverse agonism, and D2 antagonism is able to mimic the ability of atypical APDs to prevent or ameliorate the PCP-induced NOR deficit, possibly by stimulating signaling cascades from D1 and 5-HT(1A) receptor stimulation, modulated by D2 and 5-HT(2A) receptor antagonism. PMID:25448429

  2. Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats: evidence for direct 5-HT receptor modulation.

    PubMed

    Jensen, Jesper Bornø; du Jardin, Kristian Gaarn; Song, Dekun; Budac, David; Smagin, Gennady; Sanchez, Connie; Pehrson, Alan Lars

    2014-01-01

    Depressed patients suffer from cognitive dysfunction, including memory deficits. Acute serotonin (5-HT) depletion impairs memory and mood in vulnerable patients. The investigational multimodal acting antidepressant vortioxetine is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transporter (SERT) inhibitor that enhances memory in normal rats in novel object recognition (NOR) and conditioned fear (Mørk et al., 2013). We hypothesized that vortioxetine's 5-HT receptor mechanisms are involved in its memory effects, and therefore investigated these effects in 5-HT depleted rats. Four injections of the irreversible tryptophan hydroxylase inhibitor 4-chloro-dl-phenylalanine methyl ester hydrochloride (PCPA, 86mg/kg, s.c.) induced 5-HT depletion, as measured in hippocampal homogenate and microdialysate. The effects of acute challenge with vortioxetine or the 5-HT releaser fenfluramine on extracellular 5-HT were measured in PCPA-treated and control rats. PCPA's effects on NOR and spontaneous alternation (SA) performance were assessed along with the effects of acute treatment with 5-hydroxy-l-tryptophan (5-HTP), vortioxetine, the selective 5-HT reuptake inhibitor escitalopram, or the 5-HT norepinephrine reuptake inhibitor duloxetine. SERT occupancies were estimated by ex vivo autoradiography. PCPA depleted central 5-HT by >90% in tissue and microdialysate, and impaired NOR and SA performance. Restoring central 5-HT with 5-HTP reversed these deficits. At similar SERT occupancies (>90%) vortioxetine, but not escitalopram or duloxetine, restored memory performance. Acute fenfluramine significantly increased extracellular 5-HT in control and PCPA-treated rats, while vortioxetine did so only in control rats. Thus, vortioxetine restores 5-HT depletion impaired memory performance in rats through one or more of its receptor activities. PMID:24284262

  3. Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: a potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism.

    PubMed

    du Jardin, Kristian Gaarn; Jensen, Jesper Bornø; Sanchez, Connie; Pehrson, Alan L

    2014-01-01

    We previously reported that the investigational multimodal antidepressant, vortioxetine, reversed 5-HT depletion-induced memory deficits while escitalopram and duloxetine did not. The present report studied the effects of vortioxetine and the potential impact of its 5-HT1A receptor agonist and 5-HT3 receptor antagonist properties on 5-HT depletion-induced memory deficits. Recognition and spatial working memory were assessed in the object recognition (OR) and Y-maze spontaneous alternation (SA) tests, respectively. 5-HT depletion was induced in female Long-Evans rats using 4-cholro-DL-phenylalanine methyl ester HCl (PCPA) and receptor occupancies were determined by ex vivo autoradiography. Rats were acutely dosed with vortioxetine, ondansetron (5-HT3 receptor antagonist) or flesinoxan (5-HT1A receptor agonist). The effects of chronic vortioxetine administration on 5-HT depletion-induced memory deficits were also assessed. 5-HT depletion reliably impaired memory performance in both the tests. Vortioxetine reversed PCPA-induced memory deficits dose-dependently with a minimal effective dose (MED) ≤0.1mg/kg (∼80% 5-HT3 receptor occupancy; OR) and ≤3.0mg/kg (5-HT1A, 5-HT1B, 5-HT3 receptor occupancy: ∼15%, 60%, 95%) in SA. Ondansetron exhibited a MED ≤3.0μg/kg (∼25% 5-HT3 receptor occupancy; OR), but was inactive in the SA test. Flesinoxan had a MED ≤1.0mg/kg (∼25% 5-HT1A receptor occupancy; SA); only 1.0mg/kg ameliorated deficits in the NOR. Chronic p.o. vortioxetine administration significantly improved memory performance in OR and occupied 95%, 66%, and 9.5% of 5-HT3, 5-HT1B, and 5-HT1A receptors, respectively. Vortioxetine's effects on SA performance may involve 5-HT1A receptor agonism, but not 5-HT3 receptor antagonism, whereas the effects on OR performance may involve 5-HT3 receptor antagonism and 5-HT1A receptor agonism. PMID:23916504

  4. [Regulation of potential-dependant calcium channels by 5-HT1B serotonin receptors in various populations of hippocampal cells].

    PubMed

    Kononov, A V; Ivanov, S V; Zinchenko, V P

    2013-01-01

    Metabotropic serotonin receptors of 5HT1-type in brain neurons participate in regulation of such human emotional states as aggression, fear and dependence on alcohol. Activated presynaptic 5-HT1B receptors suppress the Ca2+ influx through the potential-dependent calcium channels in certain neurons. The Ca2+ influx into the cells has been measured by increase of calcium ions concentration in cytoplasm in reply to the depolarization caused by 35mM KC1. Using system of image analysis in hippocampal cells culture we found out that Ca2+-signals to depolarization oin various populations of neurons differed in form, speed and amplitude. 5HT1B receptor agonists in 86 +/- 3 % of neurons slightly suppressed the activity of potential-dependent calcium channels. Two minor cell populations (5-8 % of cells each) were found out, that strongly differed in Ca2+ signal desensitization. Calcium signal caused by depolarization in one cells population differed in characteristic delay and high rate of decay. 5HT1B receptor agonists strongly inhibited the amplitude of the Ca2+ response on KCl only in this population of neurons. The calcium signal in second cell population differed by absence desensitization and smaller amplitude which constantly increased during depolarization. 5HT 1 B receptor agonists increased the calcium response amplitude to depolarization in this population of neurons. Thus we show various sensitivity of potential-dependent calcium channels of separate neurons to 5HTB1 receptor agonist. PMID:23659057

  5. Identification of domains influencing assembly and ion channel properties in α7 nicotinic receptor and 5-HT3 receptor subunit chimaeras

    PubMed Central

    Gee, V J; Kracun, S; Cooper, S T; Gibb, A J; Millar, N S

    2007-01-01

    Background and purpose: Nicotinic acetylcholine receptors (nAChRs) and 5-hydroxytryptamine type 3 receptors (5-HT3Rs) are members of the superfamily of neurotransmitter-gated ion channels. Both contain five subunits which assemble to form either homomeric or heteromeric subunit complexes. With the aim of identifying the influence of subunit domains upon receptor assembly and function, a series of chimaeras have been constructed containing regions of the neuronal nAChR α7 subunit and the 5-HT3 receptor 3A subunit. Experimental approach: A series of subunit chimaeras containing α7 and 5-HT3A subunit domains have been constructed and expressed in cultured mammalian cells. Properties of the expressed receptors have been examined by means of radioligand binding, agonist-induced changes in intracellular calcium and patch-clamp electrophysiology. Key results: Subunit domains which influence properties such as rectification, desensitization and conductance have been identified. In addition, the influence of subunit domains upon subunit folding, receptor assembly and cell-surface expression has been identified. Co-expression studies with the nAChR-associated protein RIC-3 revealed that, in contrast to the potentiating effect of RIC-3 on α7 nAChRs, RIC-3 caused reduced levels of cell-surface expression of some α7/5-HT3A chimaeras. Conclusions and implications: Evidence has been obtained which demonstrates that subunit transmembrane domains are critical for efficient subunit folding and assembly. In addition, functional characterization of subunit chimaeras revealed that both extracellular and cytoplasmic domains exert a dramatic and significant influence upon single-channel conductance. These data support a role for regions other than hydrophobic transmembrane domains in determining ion channel properties. PMID:17721553

  6. Synergistic effect between prelimbic 5-HT3 and CB1 receptors on memory consolidation deficit in adult male Sprague-Dawley rats: An isobologram analysis.

    PubMed

    Ahmadi-Mahmoodabadi, N; Nasehi, M; Emam Ghoreishi, M; Zarrindast, M-R

    2016-03-11

    The serotonergic system has often been defined as a neuromodulator system, and is specifically involved in learning and memory via its various receptors. Serotonin is involved in many of the same processes affected by cannabinoids. The present study investigated the influence of bilateral post-training intra-prelimbic (PL) administrations of serotonergic 5-hydroxytryptamine type-3 (5-HT3) receptor agents on arachidonylcyclopropylamide (ACPA) (cannabinoid CB1 receptor agonist)-induced amnesia, using the step-through inhibitory avoidance (IA) task to assess memory in adult male Sprague-Dawley rats. The results indicated that sole intra-PL microinjection of ACPA (0.1 and 0.5μg/rat) and 5-HT3 serotonin receptor agonist (m-Chlorophenylbiguanide hydrochloride, m-CPBG; 0.001, 0.01 and 0.1μg/rat) impaired, whereas Y-25130 (a selective 5-HT3 serotonin receptor antagonist; 0.001 and 0.01 and 0.1μg/rat) did not alter IA memory consolidation, by itself. Moreover, intra-PL administration of subthreshold dose of m-CPBG (0.0005μg/rat) potentiated, while Y-25130 (0. 1μg/rat) restored ACPA-induced memory consolidation deficit. The isobologram analysis showed that there is a synergistic effect between ACPA and m-CPBG on memory consolidation deficit. These findings suggest that 5-HT3 receptor mechanism(s), at least partly, play(s) a role in modulating the effect of ACPA on memory consolidation in the PL area. PMID:26701293

  7. Evidence for 5-HT7 receptors mediating relaxation of human colonic circular smooth muscle

    PubMed Central

    Prins, Nicolaas H; Briejer, Michel R; Van Bergen, Patrick J E; Akkermans, Louis M A; Schuurkes, Jan A J

    1999-01-01

    5-HT4 receptors mediate relaxation of human colon circular muscle. However, after 5-HT4 receptor blockade (SB 204070 10 nM), 5-HT still induced a relaxation (pEC50 6.3). 5-HT4 receptors were sufficiently blocked, as the curves to 5-HT obtained in the presence of 10 and 100 nM SB 204070 were indistinguishable. This 5-HT-induced relaxation was tetrodotoxin-insensitive, indicative of a smooth muscle relaxant 5-HT receptor. This, and the rank order of potency (5-CT=5-MeOT=5-HT) suggested involvement of 5-HT1 or 5-HT7 receptors. Mesulergine, a 5-HT7 receptor antagonist at nanomolar concentrations, and a 5-HT1 receptor antagonist at micromolar concentrations, competitively antagonized the 5-HT-induced relaxation (pKB 8.3) and antagonized the relaxation to 5-CT. Methysergide antagonized the 5-HT-induced relaxation (pA2 7.6). It is concluded that the profile of the smooth muscle inhibitory 5-HT receptor resembles that of the 5-HT7 receptor. These data provide the first evidence for functional human 5-HT7 receptors. PMID:10556917

  8. Variation within the serotonin (5-HT) 5-HT2C receptor system aligns with vulnerability to cocaine cue reactivity

    PubMed Central

    Anastasio, N C; Liu, S; Maili, L; Swinford, S E; Lane, S D; Fox, R G; Hamon, S C; Nielsen, D A; Cunningham, K A; Moeller, F G

    2014-01-01

    Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity. Environmental contexts and stimuli become reliably associated with its use leading to durable conditioned responses (‘cue reactivity') that can predict relapse as well as treatment success. Individual variation in the magnitude and influence of cue reactivity over behavior in humans and animals suggest that cue-reactive individuals may be at greater risk for the progression to addiction and/or relapse. In the present translational study, we investigated the contribution of variation in the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system in individual differences in cocaine cue reactivity in humans and rodents. We found that cocaine-dependent subjects carrying a single nucleotide polymorphism (SNP) in the HTR2C gene that encodes for the conversion of cysteine to serine at codon 23 (Ser23 variant) exhibited significantly higher attentional bias to cocaine cues in the cocaine-word Stroop task than those carrying the Cys23 variant. In a model of individual differences in cocaine cue reactivity in rats, we identified that high cocaine cue reactivity measured as appetitive approach behavior (lever presses reinforced by the discrete cue complex) correlated with lower 5-HT2CR protein expression in the medial prefrontal cortex and blunted sensitivity to the suppressive effects of the selective 5-HT2CR agonist WAY163909. Our translational findings suggest that the functional status of the 5-HT2CR system is a mechanistic factor in the generation of vulnerability to cocaine-associated cues, an observation that opens new avenues for future development of biomarker and therapeutic approaches to suppress relapse in cocaine dependence. PMID:24618688

  9. Native serotonin 5-HT2C receptors are expressed as homodimers on the apical surface of choroid plexus epithelial cells.

    PubMed

    Herrick-Davis, Katharine; Grinde, Ellinor; Lindsley, Tara; Teitler, Milt; Mancia, Filippo; Cowan, Ann; Mazurkiewicz, Joseph E

    2015-04-01

    G protein-coupled receptors (GPCRs) are a prominent class of plasma membrane proteins that regulate physiologic responses to a wide variety of stimuli and therapeutic agents. Although GPCR oligomerization has been studied extensively in recombinant cells, it remains uncertain whether native receptors expressed in their natural cellular environment are monomers, dimers, or oligomers. The goal of this study was to determine the monomer/oligomer status of a native GPCR endogenously expressed in its natural cellular environment. Native 5-HT2C receptors in choroid plexus epithelial cells were evaluated using fluorescence correlation spectroscopy (FCS) with photon counting histogram (PCH). An anti-5-HT2C fragment antigen binding protein was used to label native 5-HT2C receptors. A known monomeric receptor (CD-86) served as a control for decoding the oligomer status of native 5-HT2C receptors by molecular brightness analysis. FCS with PCH revealed molecular brightness values for native 5-HT2C receptors equivalent to the molecular brightness of a homodimer. 5-HT2C receptors displayed a diffusion coefficient of 5 × 10(-9) cm(2)/s and were expressed at 32 receptors/μm(2) on the apical surface of choroid plexus epithelial cells. The functional significance and signaling capabilities of the homodimer were investigated in human embryonic kidney 293 cells using agonists that bind in a wash-resistant manner to one or both protomers of the homodimer. Whereas agonist binding to one protomer resulted in G protein activation, maximal stimulation required occupancy of both protomers. This study is the first to demonstrate the homodimeric structure of 5-HT2C receptors endogenously expressed in their native cellular environment, and identifies the homodimer as a functional signaling unit. PMID:25609374

  10. Native Serotonin 5-HT2C Receptors Are Expressed as Homodimers on the Apical Surface of Choroid Plexus Epithelial Cells

    PubMed Central

    Grinde, Ellinor; Lindsley, Tara; Teitler, Milt; Mancia, Filippo; Cowan, Ann; Mazurkiewicz, Joseph E.

    2015-01-01

    G protein–coupled receptors (GPCRs) are a prominent class of plasma membrane proteins that regulate physiologic responses to a wide variety of stimuli and therapeutic agents. Although GPCR oligomerization has been studied extensively in recombinant cells, it remains uncertain whether native receptors expressed in their natural cellular environment are monomers, dimers, or oligomers. The goal of this study was to determine the monomer/oligomer status of a native GPCR endogenously expressed in its natural cellular environment. Native 5-HT2C receptors in choroid plexus epithelial cells were evaluated using fluorescence correlation spectroscopy (FCS) with photon counting histogram (PCH). An anti–5-HT2C fragment antigen binding protein was used to label native 5-HT2C receptors. A known monomeric receptor (CD-86) served as a control for decoding the oligomer status of native 5-HT2C receptors by molecular brightness analysis. FCS with PCH revealed molecular brightness values for native 5-HT2C receptors equivalent to the molecular brightness of a homodimer. 5-HT2C receptors displayed a diffusion coefficient of 5 × 10−9 cm2/s and were expressed at 32 receptors/μm2 on the apical surface of choroid plexus epithelial cells. The functional significance and signaling capabilities of the homodimer were investigated in human embryonic kidney 293 cells using agonists that bind in a wash-resistant manner to one or both protomers of the homodimer. Whereas agonist binding to one protomer resulted in G protein activation, maximal stimulation required occupancy of both protomers. This study is the first to demonstrate the homodimeric structure of 5-HT2C receptors endogenously expressed in their native cellular environment, and identifies the homodimer as a functional signaling unit. PMID:25609374

  11. Cardiovascular afferents cause the release of 5-HT in the nucleus tractus solitarii; this release is regulated by the low- (PMAT) not the high-affinity transporter (SERT).

    PubMed

    Hosford, Patrick S; Millar, Julian; Ramage, Andrew G

    2015-04-01

    The nucleus tractus solitarii (NTS) integrates inputs from cardiovascular afferents and thus is crucial for cardiovascular homeostasis. These afferents primarily release glutamate, although 5-HT has also been shown to play a role in their actions. Using fast-cyclic voltammetry, an increase in 5-HT concentrations (range 12-50 nm) could be detected in the NTS in anaesthetized rats in response to electrical stimulation of the vagus and activation of cardiopulmonary, chemo- and baroreceptor reflexes. This 5-HT signal was not potentiated by the serotonin transporter (SERT) or the noradrenaline transporter (NET) inhibitors citalopram and desipramine (1 mg kg(-1) ). However, decynium-22 (600 μg kg(-1) ), an organic cation 3 transporter (OCT3)/plasma membrane monoamine transporter (PMAT) inhibitor, increased the 5-HT signal by 111 ± 21% from 29 ± 10 nm. The effectiveness of these inhibitors was tested against the removal time of 5-HT and noradrenaline applied by microinjection to the NTS. Citalopram and decynium-22 attenuated the removal of 5-HT but not noradrenaline, whereas desipramine had the reverse action. The OCT3 inhibitor corticosterone (10 mg kg(-1) ) had no effect. Blockade of glutamate receptors with topical kynurenate (10-50 nm) reduced the vagally evoked 5-HT signal by 50%, indicating that this release was from at least two sources. It is concluded that vagally evoked 5-HT release is under the regulation of the high-capacity, low-affinity transporter PMAT, not the low-capacity, high-affinity transporter SERT. This is the first demonstration that PMAT may be playing a physiological role in the regulation of 5-HT transmission and this could indicate that 5-HT is acting, in part, as a volume transmitter within the NTS. PMID:25694117

  12. 5-HT3 Receptor Brain-Type B-Subunits are Differentially Expressed in Heterologous Systems

    PubMed Central

    2015-01-01

    Genes for five different 5-HT3 receptor subunits have been identified. Most of the subunits have multiple isoforms, but two isoforms of the B subunits, brain-type 1 (Br1) and brain-type 2 (Br2) are of particular interest as they appear to be abundantly expressed in human brain, where 5-HT3B subunit RNA consists of approximately 75% 5-HT3Br2, 24% 5-HT3Br1, and <1% 5-HT3B. Here we use two-electrode voltage-clamp, radioligand binding, fluorescence, whole cell, and single channel patch-clamp studies to characterize the roles of 5-HT3Br1 and 5-HT3Br2 subunits on function and pharmacology in heterologously expressed 5-HT3 receptors. The data show that the 5-HT3Br1 transcriptional variant, when coexpressed with 5-HT3A subunits, alters the EC50, nH, and single channel conductance of the 5-HT3 receptor, but has no effect on the potency of competitive antagonists; thus, 5-HT3ABr1 receptors have the same characteristics as 5-HT3AB receptors. There were some differences in the shapes of 5-HT3AB and 5-HT3ABr1 receptor responses, which were likely due to a greater proportion of homomeric 5-HT3A versus heteromeric 5-HT3ABr1 receptors in the latter, as expression of the 5-HT3Br1 compared to the 5-HT3B subunit is less efficient. Conversely, the 5-HT3Br2 subunit does not appear to form functional channels with the 5-HT3A subunit in either oocytes or HEK293 cells, and the role of this subunit is yet to be determined. PMID:25951416

  13. The 5-HT[subscript 3A] Receptor Is Essential for Fear Extinction

    ERIC Educational Resources Information Center

    Kondo, Makoto; Nakamura, Yukiko; Ishida, Yusuke; Yamada, Takahiro; Shimada, Shoichi

    2014-01-01

    The 5-HT [subscript 3] receptor, the only ionotropic 5-HT receptor, is expressed in limbic regions, including the hippocampus, amygdala, and cortex. However, it is not known whether it has a role in fear memory processes. Analysis of 5-HT [subscript 3A] receptor knockout mice in fear conditioning paradigms revealed that the 5-HT [subscript 3A]…

  14. 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate insulin sensitivity in liver

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mice lacking 5-HT 2C receptors displayed hepatic insulin resistance, a phenotype normalized by re-expression of 5-HT2CRs only in pro-opiomelanocortin (POMC) neurons. 5-HT2CR deficiency also abolished the anti-diabetic effects of meta-chlorophenylpiperazine (a 5-HT2CR agonist); these effects were re...

  15. 5-HT2 receptors mediate functional modulation of GABAa receptors and inhibitory synaptic transmissions in human iPS-derived neurons

    PubMed Central

    Wang, Haitao; Hu, Lingli; Liu, Chunhua; Su, Zhenghui; Wang, Lihui; Pan, Guangjin; Guo, Yiping; He, Jufang

    2016-01-01

    Neural progenitors differentiated from induced pluripotent stem cells (iPS) hold potentials for treating neurological diseases. Serotonin has potent effects on neuronal functions through multiple receptors, underlying a variety of neural disorders. Glutamate and GABA receptors have been proven functional in neurons differentiated from iPS, however, little is known about 5-HT receptor-mediated modulation in such neuronal networks. In the present study, human iPS were differentiated into cells possessing featured physiological properties of cortical neurons. Whole-cell patch-clamp recording was used to examine the involvement of 5-HT2 receptors in functional modulation of GABAergic synaptic transmission. We found that serotonin and DOI (a selective agonist of 5-HT2A/C receptor) reversibly reduced GABA-activated currents, and this 5-HT2A/C receptor mediated inhibition required G protein, PLC, PKC, and Ca2+ signaling. Serotonin increased the frequency of miniature inhibitory postsynaptic currents (mIPSCs), which could be mimicked by α-methylserotonin, a 5-HT2 receptor agonist. In contrast, DOI reduced both frequency and amplitude of mIPSCs. These findings suggested that in iPS-derived human neurons serotonin postsynaptically reduced GABAa receptor function through 5-HT2A/C receptors, but presynaptically other 5-HT2 receptors counteracted the action of 5-HT2A/C receptors. Functional expression of serotonin receptors in human iPS-derived neurons provides a pre-requisite for their normal behaviors after grafting. PMID:26837719

  16. Distribution of 125I-galanin binding sites, immunoreactive galanin, and its coexistence with 5-hydroxytryptamine in the cat spinal cord: Biochemical, histochemical, and experimental studies at the light and electron microscopic level

    SciTech Connect

    Arvidsson, U.; Ulfhake, B.; Cullheim, S.; Bergstrand, A.; Theodorson, E.; Hoekfelt, T. )

    1991-06-01

    The distribution of galanin-like immunoreactivity (GAL-LI) in the spinal cord of the cat was studied by use of indirect histochemistry and the peroxidase-antiperoxidase (PAP) technique. In the ventral horn GAL-immunoreactive (IR) axonal fibers and terminals were most frequent in the ventral part of the motor nucleus. The GAL-IR axons also contained 5-hydroxytryptamine (5-HT)-LI, and they disappeared after spinal cord transection. It was concluded that these GAL-IR fibers belong to the serotoninergic bublospinal pathway. In the medulla oblongata from normal cats, scattered GAL-IR cell bodies were encountered within the nucleus raphe obscurus and nucleus raphe pallidus. Electron microscopic observations revealed that the fine structure of the GAL-IR axonal boutons in the motor nucleus was similar to that of 5-HT-IR boutons with a varying number of immunoreactive large dense core vesicles. The postsynaptic element in all cases studied was a dendrite. A dense GAL-IR axonal plexus was found in the superficial laminae I-II of the dorsal horn. Coexistence was found between the GAL- and substance P-LI in fibers within the dorsal horn plexus. Spinal cord transection did not alter the pattern of GAL-LI in the dorsal horn, while the vast majority of GAL-IR axonal swellings disappeared following dorsal root sectioning. Electron microscopic observations in lamina II (substantia gelatinosa) revealed that the GAL-IR axonal terminals could be divided into two main groups. One with small to medium-sized axonal boutons formed synaptic contacts with both dendritic and axonal profiles. The other formed the central axon terminals of glomeruli, suggesting that GAL-LI may be present in C-type primary afferents. Numerous small GAL-IR cell bodies were encountered in laminae II and III. GAL-IR cell bodies were also observed in lamina X.

  17. Potentially hallucinogenic 5-hydroxytryptamine receptor ligands bufotenine and dimethyltryptamine in blood and tissues.

    PubMed

    Kärkkäinen, J; Forsström, T; Tornaeus, J; Wähälä, K; Kiuru, P; Honkanen, A; Stenman, U H; Turpeinen, U; Hesso, A

    2005-01-01

    Bufotenine and N,N-dimethyltryptamine (DMT) are hallucinogenic dimethylated indolethylamines (DMIAs) formed from serotonin and tryptamine by the enzyme indolethylamine N-methyltransferase (INMT) ubiquitously present in non-neural tissues. In mammals, endogenous bufotenine and DMT have been identified only in human urine. The DMIAs bind effectively to 5HT receptors and their administration causes a variety of autonomic effects, which may reflect their actual physiological function. Endogenous levels of bufotenine and DMT in blood and a number of animal and human tissues were determined using highly sensitive and specific quantitative mass spectrometric techniques. A new finding was the detection of large amounts of bufotenine in stools, which may be an indication of its role in intestinal function. It is suggested that fecal and urinary bufotenine originate from epithelial cells of the intestine and the kidney, respectively, although the possibility of their synthesis by intestinal bacteria cannot be excluded. Only small amounts of the DMIAs were found in somatic or neural tissues and none in blood. This can be explained by rapid catabolism of the DMIAs by mitochondrial monoamino-oxidase or by the fact that the dimethylated products of serotonin and tryptamine are not formed in significant amounts in most mammalian tissues despite the widespread presence of INMT in tissues. PMID:16095048

  18. Serotonin (5-HT) Affects Expression of Liver Metabolic Enzymes and Mammary Gland Glucose Transporters during the Transition from Pregnancy to Lactation

    PubMed Central

    Laporta, Jimena; Peters, Tonia L.; Merriman, Kathryn E.; Vezina, Chad M.; Hernandez, Laura L.

    2013-01-01

    The aim of this experiment was to demonstrate the ability of feeding serotonin (5-HT; 5-hydroxytryptamine) precursors to increase 5-HT production during the transition from pregnancy to lactation and the effects this has on maternal energy metabolism in the liver and mammary gland. Pregnant rats (n = 45) were fed one of three diets: I) control (CON), II) CON supplemented with 0.2% 5-hydroxytryptophan (5-HTP) or III) CON supplemented with 1.35% L-tryptophan (L-TRP), beginning on d13 of pregnancy through d9 of lactation (d9). Serum (pre and post-partum), milk (daily), liver and mammary gland tissue (d9) were collected. Serum 5-HT was increased in the 5-HTP fed dams beginning on d20 of gestation and remained elevated through d9, while it was only increased on d9 in the L-TRP fed dams. 5-HT levels were increased in mammary gland and liver of both groups. Additionally, 5-HTP fed dams had serum and milk glucose levels similar to the CON, while L-TRP had decreased serum (d9) and milk glucose (all dates evaluated). Feeding 5-HTP resulted in increased mRNA expression of key gluconeogenic and glycolytic enzymes in liver and glucose transporters 1 and 8 (GLUT-1, -8) in the mammary gland. We demonstrated the location of GLUT-8 in the mammary gland both in the epithelial and vascular endothelial cells. Finally, phosphorylated 5′ AMP-activated protein kinase (pAMPK), a known regulator of intracellular energy status, was elevated in mammary glands of 5-HTP fed dams. Our results suggest that increasing 5-HT production during the transition from pregnancy to lactation increases mRNA expression of enzymes involved in energy metabolism in the liver, and mRNA abundance and distribution of glucose transporters within the mammary gland. This suggests the possibility that 5-HT may be involved in regulating energy metabolism during the transition from pregnancy to lactation. PMID:23469086

  19. Nucleus accumbens shell excitability is decreased by methamphetamine self-administration and increased by 5-HT2C receptor inverse agonism and agonism

    PubMed Central

    Graves, Steven M.; Clark, Mary J.; Traynor, John R.; Hu, Xiu-Ti; Napier, T. Celeste

    2014-01-01

    Methamphetamine profoundly increases brain monoamines and is a widely abused psychostimulant. The effects of methamphetamine self-administration on neuron function are not known for the nucleus accumbens, a brain region involved in addictive behaviors, including drug-seeking. One therapeutic target showing preclinical promise at attenuating psychostimulant-seeking is 5-HT2C receptors; however, the effects of 5-HT2C receptor ligands on neuronal physiology are unclear. 5-HT2C receptor agonism decreases psychostimulant-mediated behaviors, and the putative 5-HT2C receptor inverse agonist, SB 206553, attenuates methamphetamine-seeking in rats. To ascertain the effects of methamphetamine, and 5-HT2C receptor inverse agonism and agonism, on neuronal function in the nucleus accumbens, we evaluated methamphetamine, SB 206553, and the 5-HT2C receptor agonist and Ro 60-0175, on neuronal excitability within the accumbens shell subregion using whole-cell current-clamp recordings in forebrain slices ex vivo. We reveal that methamphetamine self-administration decreased generation of evoked action potentials. In contrast, SB 206553 and Ro 60-0175 increased evoked spiking, effects that were prevented by the 5-HT2C receptor antagonist, SB 242084. We also assessed signaling mechanisms engaged by 5-HT2C receptors, and determined that accumbal 5-HT2C receptors stimulated Gq, but not Gi/o. These findings demonstrate that methamphetamine-induced decreases in excitability of neurons within the nucleus accumbens shell were abrogated by both 5-HT2C inverse agonism and agonism, and this effect likely involved activation of Gq–mediated signaling pathways. PMID:25229719

  20. Functional characterization of 5-HT1D autoreceptors on the modulation of 5-HT release in guinea-pig mesencephalic raphe, hippocampus and frontal cortex.

    PubMed Central

    el Mansari, M.; Blier, P.

    1996-01-01

    1. The aims of the present study were (i) to characterize further the pharmacology of 5-HT1D autoreceptors modulating 5-HT release in guinea-pig mesencephalic raphe, hippocampus and frontal cortex; (ii) to determine whether 5-HT1D receptors in the mesencephalic raphe are located on 5-HT neurones; (iii) to determine whether 5-HT1D autoreceptors are coupled to G proteins; and (iv) to assess their sensitivity following long-term 5-HT reuptake blockade and inhibition of type-A monoamine oxidase. 2. In mesencephalic raphe, hippocampus and frontal cortex slices, the 5-HT1D/1B receptor agonist, sumatriptan and the 5-HT1 receptor agonist, 5-methoxytryptamine (5-MeOT) but not the 5-HT1B receptor agonist, CP93129, inhibited electrically the evoked release of [3H]-5-HT in a concentration-dependent manner. This effect was antagonized by the 5-HT1D/1B receptor antagonist GR127935 in the three structures, but not by the 5-HT1A receptor antagonist, (+)-WAY100635 in mesencephalic raphe slices. These results confirm the presence of functional 5-HT1D autoreceptors controlling 5-HT release within the mesencephalic raphe as well as in terminal regions. 3. The inhibitory effect of sumatriptan on K(+)-evoked release of [3H]-5-HT was not reduced by the addition of the Na+ channel blocker, tetrodotoxin to the superfusion medium, suggesting that these 5-HT1D receptors in the mesencephalic raphe are located on 5-HT neurones and may be considered autoreceptors. 4. The in vitro treatment with the alkylating agent N-ethylmaleimide (NEM) was used to determine whether these 5-HT1D autoreceptors are coupled to G proteins. The inhibitory effect of sumatriptan on electrically evoked release of [3H]-5-HT was attenuated in NEM-pretreated slices from mesencephalic raphe, hippocampus and frontal cortex, indicating that the 5-HT1D autoreceptors activated by sumatriptan are coupled to G proteins in these three structures. Taken together with our previous results, this suggests that, in addition to the 5

  1. 5-Hydroxytryptamine1A receptor-activation hyperpolarizes pyramidal cells and suppresses hippocampal gamma oscillations via Kir3 channel activation

    PubMed Central

    Johnston, April; McBain, Chris J; Fisahn, André

    2014-01-01

    Rhythmic cortical neuronal oscillations in the gamma frequency band (30–80 Hz, gamma oscillations) have been associated with cognitive processes such as sensory perception and integration, attention, learning, and memory. Gamma oscillations are disrupted in disorders for which cognitive deficits are hallmark symptoms such as schizophrenia and Alzheimer's disease. In vitro, various neurotransmitters have been found to modulate gamma oscillations. Serotonin (5-HT) has long been known to be important for both behavioural and cognitive functions such as learning and memory. Multiple 5-HT receptor subtypes are expressed in the CA3 region of the hippocampus and high doses of 5-HT reduce the power of induced gamma oscillations. Hypothesizing that 5-HT may have cell- and receptor subtype-specific modulatory effects, we investigated the receptor subtypes, cell types and cellular mechanisms engaged by 5-HT in the modulation of gamma oscillations in mice and rats. We found that 5-HT decreases the power of kainate-induced hippocampal gamma oscillations in both species via the 5-HT1A receptor subtype. Whole-cell patch clamp recordings demonstrated that this decrease was caused by a hyperpolarization of CA3 pyramidal cells and a reduction of their firing frequency, but not by alteration of inhibitory neurotransmission. Finally, our results show that the effect on pyramidal cells is mediated via the G protein-coupled receptor inwardly rectifying potassium channel Kir3. Our findings suggest this novel cellular mechanism as a potential target for therapies that are aimed at alleviating cognitive decline by helping the brain to maintain or re-establish normal gamma oscillation levels in neuropsychiatric and neurodegenerative disorders. PMID:25107925

  2. Adding 5-hydroxytryptamine receptor type 3 antagonists may reduce drug-induced nausea in poor insight obsessive-compulsive patients taking off-label doses of selective serotonin reuptake inhibitors: a 52-week follow-up case report

    PubMed Central

    2010-01-01

    Poor-insight obsessive-compulsive disorder (PI-OCD) is a severe form of OCD where the 'typically obsessive' features of intrusive, 'egodystonic' feelings and thoughts are absent. PI-OCD is difficult to treat, often requiring very high doses of serotonergic drugs as well as antipsychotic augmentation. When this occurs, unpleasant side effects as nausea are common, eventually further reducing compliance to medication and increasing the need for pharmacological alternatives. We present the case of a PI-OCD patient who developed severe nausea after response to off-label doses of the selective serotonin reuptake inhibitor (SSRI), fluoxetine. Drug choices are discussed, providing pharmacodynamic rationales and hypotheses along with reports of rating scale scores, administered within a follow-up period of 52 weeks. A slight reduction of fluoxetine dose, augmentation with mirtazapine and a switch from amisulpride to olanzapine led to resolution of nausea while preserving the anti-OCD therapeutic effect. Mirtazapine and olanzapine have already been suggested for OCD treatment, although a lack of evidence exists about their role in the course of PI-OCD. Both mirtazapine and olanzapine also act as 5-hydroxytryptamine receptor type 3 (5-HT3) blockers, making them preferred choices especially in cases of drug-induced nausea. PMID:21143969

  3. Altered serotonin and dopamine metabolism in the CNS of serotonin 5-HT(1A) or 5-HT(1B) receptor knockout mice.

    PubMed

    Ase, A R; Reader, T A; Hen, R; Riad, M; Descarries, L

    2000-12-01

    Measurements of serotonin (5-HT), dopamine (DA), and noradrenaline, and of 5-HT and DA metabolites, were obtained by HPLC from 16 brain regions and the spinal cord of 5-HT(1A) or 5-HT(1B) knockout and wild-type mice of the 129/Sv strain. In 5-HT(1A) knockouts, 5-HT concentrations were unchanged throughout, but levels of 5-HT metabolites were higher than those of the wild type in dorsal/medial raphe nuclei, olfactory bulb, substantia nigra, and locus coeruleus. This was taken as an indication of increased 5-HT turnover, reflecting an augmented basal activity of midbrain raphe neurons and consequent increase in their somatodendritic and axon terminal release of 5-HT. It provided a likely explanation for the increased anxious-like behavior observed in 5-HT(1A) knockout mice. Concomitant increases in DA content and/or DA turnover were interpreted as the result of a disinhibition of DA, whereas increases in noradrenaline concentration in some territories of projection of the locus coeruleus could reflect a diminished activity of its neurons. In 5-HT(1B) knockouts, 5-HT concentrations were lower than those of the wild type in nucleus accumbens, locus coeruleus, spinal cord, and probably also several other territories of 5-HT innervation. A decrease in DA, associated with increased DA turnover, was measured in nucleus accumbens. These changes in 5-HT and DA metabolism were consistent with the increased aggressiveness and the supersensitivity to cocaine reported in 5-HT(1B) knockout mice. Thus, markedly different alterations in CNS monoamine metabolism may contribute to the opposite behavioral phenotypes of these two knockouts. PMID:11080193

  4. Centrally acting hypotensive agents with affinity for 5-HT1A binding sites inhibit forskolin-stimulated adenylate cyclase activity in calf hippocampus.

    PubMed Central

    Schoeffter, P.; Hoyer, D.

    1988-01-01

    1. A number of centrally acting hypotensive agents and other ligands with high affinity for 5-hydroxytryptamine1A (5-HT1A) recognition sites have been tested on forskolin-stimulated adenylate cyclase activity in calf hippocampus, a functional model for 5-HT1A-receptors. 2. Concentration-dependent inhibition of forskolin-stimulated adenylate cyclase activity was elicited by the reference 5-HT1-receptor agonists (mean EC50 value, nM): 5-HT (22), 5-carboxamidotryptamine (5-CT, 3.2), 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, 8.6), N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT, 2.3), 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine (PAPP or LY 165163, 20), 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole (RU 24969, 20), buspirone (65) and ipsapirone (56). Emax amounted to 18-20% inhibition for all but the latter two agonists (14%). 3. The following hypotensive agents with high affinity for 5-HT1A sites were potent agonists in this system (mean EC50 value, nM): flesinoxan (24), indorenate (99), erythro-1-(1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-piperidyl )- 2-benzimidazolinone (R 28935, 2.5), urapidil (390) and 5-methyl-urapidil (3.5). The first two agents were full agonists, whereas the latter three acted as partial agonists with 60-80% efficacy. 4. Metergoline and methysergide behaved as full agonists and cyanopindolol as a partial agonist with low efficacy. Spiroxatrine and 2-(2,6-dimethoxyphenoxyethyl)aminomethyl- 1,4-benzodioxane (WB 4101) which bind to 5-HT1A sites with nanomolar affinity, were agonists and inhibited potently forskolin-stimulated adenylate cyclase in calf hippocampus, showing mean EC50 values of 23 and 15 nM, respectively. Spiroxatrine and WB 4101 yielded 90% and 50% efficacy, respectively. 5. Spiperone and methiothepin (each 1 microM) caused rightward shifts of the concentration-effect curve to 8-OH-DPAT, without loss of the maximal effect, as did the partial agonist cyanopindolol (0.1 microM) and the

  5. The 5-HT1A receptor in Major Depressive Disorder.

    PubMed

    Kaufman, Joshua; DeLorenzo, Christine; Choudhury, Sunia; Parsey, Ramin V

    2016-03-01

    Major Depressive Disorder (MDD) is a highly prevalent psychiatric diagnosis that is associated with a high degree of morbidity and mortality. This debilitating disorder is currently one of the leading causes of disability nationwide and is predicted to be the leading cause of disease burden by the year 2030. A large body of previous research has theorized that serotonergic dysfunction, specifically of the serotonin (5-HT) 1A receptor, plays a key role in the development of MDD. The purpose of this review is to describe the evolution of our current understanding of the serotonin 1A (5-HT1A) receptor and its role in the pathophysiology MDD through the discussion of animal, post-mortem, positron emission tomography (PET), pharmacologic and genetic studies. PMID:26851834

  6. Localized Release of Serotonin (5-Hydroxytryptamine) by a Fecal Pellet Regulates Migrating Motor Complexes in Murine Colon

    PubMed Central

    HEREDIA, DANTE J.; DICKSON, EAMONN J.; BAYGUINOV, PETER O.; HENNIG, GRANT W.; SMITH, TERENCE K.

    2009-01-01

    Background & Aims The colonic migrating motor complex (CMMC) is a motor pattern that regulates the movement of fecal matter, through a rhythmic sequence of electrical activity and/or contractions, along the large bowel. CMMCs have largely been studied in empty preparations; we investigated whether local reflexes generated by a fecal pellet modify the CMMC to initiate propulsive activity. Methods Recordings of CMMCs were made from the isolated murine large bowel, with or without a fecal pellet. Transducers were placed along the colon to record muscle tension and propulsive force on the pellet and microelectrodes were used to record electrical activity from circular muscle cells anal and oral of a pellet and in colons without the mucosa. Results Spontaneous CMMCs propagated in both an oral or anal direction. When a pellet was inserted, CMMCs increased in frequency and propagated anally, exerting propulsive force on the pellet. The amplitude of slow waves increased during the CMMC. Localized mucosal stimulation/circumferential stretch evoked a CMMC, regardless of stimulus strength. The serotonin (5-hydroxytryptamine-3) antagonist ondansetron reduced the amplitude of the CMMC, the propulsive force on the pellet, and the response to mucosal stroking, but increased the apparent conduction velocity of the CMMC. Removing the mucosa abolished spontaneous CMMCs, which still could be evoked by electrical stimulation. Conclusions The fecal pellet activates local mucosal reflexes, which release serotonin (5-hydroxytryptamine) from enterochromaffin cells, and stretch reflexes that determine the site of origin and propagation of the CMMC, facilitating propulsion. PMID:19138686

  7. Expression of the spinal 5-HT7 receptor and p-ERK pathway in the carrageenan inflammatory pain of rats

    PubMed Central

    Cho, Soo Young; Ki, Hyoung Gon; Kim, Joung Min; Oh, Jin Myung; Yang, Ji Hoon; Kim, Woong Mo; Lee, Hyung Gon; Yoon, Myung Ha

    2015-01-01

    Background Although the inhibitory role of the 5-hydroxytrypatmine receptor 7(5-HT7R) on nociceptive processing is generally recognized, an excitatory effect associated with a reduced 5-HT7R expression has also been observed in the nerve injury model. In the carrageenan model, no significant effect is produced by the 5-HT7R activation, but the change in 5-HT7R expression has not been examined. Lesioning of the spinal serotonergic pathway enhances allodynia in the carrageenan model, but it also relieves several other pain states, including in the formalin model. While lesioning suppresses the activation of the extracellular signal-regulated kinase (ERK) of the spinal cord in the formalin model, its role in the carrageenan model has not been reported. Methods Following intraplantar injections of carrageenan, the spinal 5-HT7R expression was examined using Western blotting in male Sprague-Dawley rats. The effect of serotonergic pathway lesioning with intrathecal 5,7-dihydroxytryptamine (5,7-DHT) on the expression of the phospho-ERK was measured. Results The expression of the 5-HT7R in the carrageenan model was not significantly different from that of naive animals. The expression of the spinal p-ERK in the carrageenan model was significantly increased, but returned to the level of a naive rat 1 hour after the carrageenan injection. However, it remained significantly higher 1 hour after the injection in the animals treated with 5,7-DHT than in the naive and control rats. Conclusions The expression of the spinal 5-HT7R is not altered by peripheral inflammation with carrageenan, suggesting that the lack of antinociceptive effect of the 5-HT7R activation is partly attributable to the absence of changes in the expression of the 5-HT7R in the spinal cord. The extended increase of the spinal p-ERK might be related to the enhanced pain behavior in the animals with lesions of the spinal serotonergic pathway in the carrageenan model. PMID:25844136

  8. Conversion of the ion selectivity of the 5-HT(3a) receptor from cationic to anionic reveals a conserved feature of the ligand-gated ion channel superfamily.

    PubMed

    Gunthorpe, M J; Lummis, S C

    2001-06-15

    The 5-hydroxytryptamine(3) (5-HT(3)) receptor is a member of a superfamily of ligand-gated ion channels, which includes nicotinic acetylcholine, gamma-aminobutyric acid, and glycine receptors. The receptors are either cation or anion selective, leading to their distinctive involvement in either excitatory or inhibitory neurotransmission. Using a combination of site-directed mutagenesis and electrophysiological characterization of homomeric 5-HT(3A) receptors expressed in HEK293 cells, we have identified a set of mutations that convert the ion selectivity of the 5-HT(3A) receptor from cationic to anionic; these were substitution of V13'T in M2 together with neutralization of glutamate residues (E-1'A) and the adjacent insertion of a proline residue (P-1') in the M1-M2 loop. Mutant receptors showed significant chloride permeability (P(Cl)/P(Na) = 12.3, P(Na)/P(Cl) = 0.08), whereas WT receptors are predominantly permeable to sodium (P(Na)/P(Cl) > 20, P(Cl)/P(Na) < 0.05). Since the equivalent mutations have previously been shown to convert alpha7 nicotinic acetylcholine receptors from cationic to anionic (Galzi J.-L., Devillers-Thiery, A, Hussy, N., Bertrand, S. Changeux, J. P., and Bertrand, D. (1992) Nature 359, 500-505) and, recently, the converse mutations have allowed the construction of a cation selective glycine receptor (Keramidas, A., Moorhouse, A. J., French, C. R., Schofield, P. R., and Barry, P. H. (2000) Biophys. J. 78, 247-259), it appears that the determinants of ion selectivity represent a conserved feature of the ligand-gated ion channel superfamily. PMID:11439930

  9. Modulation of nicotinic ACh-, GABAA- and 5-HT3-receptor functions by external H-7, a protein kinase inhibitor, in rat sensory neurones

    PubMed Central

    Hu, Hong-Zhen; Li, Zhi-Wang

    1997-01-01

    The effects of external H-7, a potent protein kinase inhibitor, on the responses mediated by γ-aminobutyric acid A type (GABAA)-, nicotinic acetylcholine (nicotinic ACh)-, ionotropic 5-hydroxytryptamine (5-HT3)-, adenosine 5′-triphosphate (ATP)-, N-methyl-D-aspartate (NMDA)- and kainate (KA)-receptors were studied in freshly dissociated rat dorsal root ganglion neurone by use of whole cell patch-clamp technique. External H-7 (1–1000 μM) produced a reversible, dose-dependent inhibition of whole cell currents activated by GABA, ACh and 5-HT. Whole-cell currents evoked by ATP, 2-methylthio-ATP, NMDA and KA were insensitive to external H-7. External H-7 shifted the dose-response curve of GABA-activated currents downward without changing the EC50 significantly (from 15.0±4.0 μM to 18.0±5.0 μM). The maximum response to GABA was depressed by 34.0±5.3%. This inhibitory action of H-7 was voltage-independent. Intracellular application of H-7 (20 μM), cyclic AMP (1 mM) and BAPTA (10 mM) could not reverse the H-7 inhibition of GABA-activated currents. The results suggest that external H-7 selectively and allosterically modulates the functions of GABAA-, nicotine ACh- and 5-HT3 receptors via a common conserved site in the external domain of these receptors. PMID:9401786

  10. Conversion of the ion selectivity of the 5-HT(3a) receptor from cationic to anionic reveals a conserved feature of the ligand-gated ion channel superfamily.

    PubMed

    Gunthorpe, M J; Lummis, S C

    2001-04-01

    The 5-hydroxytryptamine(3) (5-HT(3)) receptor is a member of a superfamily of ligand-gated ion channels, which includes nicotinic acetylcholine, gamma-aminobutyric acid, and glycine receptors. The receptors are either cation or anion selective, leading to their distinctive involvement in either excitatory or inhibitory neurotransmission. Using a combination of site-directed mutagenesis and electrophysiological characterization of homomeric 5-HT(3A) receptors expressed in HEK293 cells, we have identified a set of mutations that convert the ion selectivity of the 5-HT(3A) receptor from cationic to anionic; these were substitution of V13'T in M2 together with neutralization of glutamate residues (E-1'A) and the adjacent insertion of a proline residue (P-1') in the M1-M2 loop. Mutant receptors showed significant chloride permeability (P(Cl)/P(Na) = 12.3, P(Na)/P(Cl) = 0.08), whereas WT receptors are predominantly permeable to sodium (P(Na)/P(Cl) > 20, P(Cl)/P(Na) < 0.05). Since the equivalent mutations have previously been shown to convert alpha7 nicotinic acetylcholine receptors from cationic to anionic (Galzi J.-L., Devillers-Thiery, A, Hussy, N., Bertrand, S. Changeux, J. P., and Bertrand, D. (1992) Nature 359, 500-505) and, recently, the converse mutations have allowed the construction of a cation selective glycine receptor (Keramidas, A., Moorhouse, A. J., French, C. R., Schofield, P. R., and Barry, P. H. (2000) Biophys. J. 78, 247-259), it appears that the determinants of ion selectivity represent a conserved feature of the ligand-gated ion channel superfamily. PMID:11139582

  11. Differences in regional cerebral blood flow response to a 5HT3 antagonist in early- and late-onset cocaine-dependent subjects.

    PubMed

    Adinoff, Bryon; Devous, Michael D; Williams, Mark J; Harris, Thomas S; Best, Susan E; Dong, Hongyun; Zielinski, Tanya

    2014-03-01

    5-hydroxytryptamine 3 (5HT3) receptors are important modulators of mesostriatal dopaminergic transmission and have been implicated in the pathophysiology of cocaine reward, withdrawal and self-administration. In addition, the 5HT3 antagonist ondansetron is effective in treating early-onset, but not late-onset, alcohol-dependent subjects. To explore the role of 5HT3 receptor systems in cocaine addiction using functioning imaging, we administered ondansetron to 23 abstinent, treatment-seeking cocaine-addicted and 22 sex-, age- and race-matched healthy control participants. Differences between early- (first use before 20 years, n = 10) and late-onset (first use after 20 years, n = 10) cocaine-addicted subjects were also assessed. On two separate days, subjects were administered ondansetron (0.15 mg/kg intravenously over 15 minutes) or saline. Regional cerebral blood flow (rCBF) was measured following each infusion with single photon emission computed tomography. No significant rCBF differences between the cocaine-addicted and control participants were observed following ondansetron relative to saline. Early-onset subjects, however, showed increased (P < 0.001) right posterior parahippocampal rCBF following ondansetron. In contrast, late-onset su