Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the rat, intravenous (i.v.) serotonin (5-HT) is a noxious stimulus which produces distinct vagal afferent-mediated pseudoaffective responses, a passive avoidance behavior, a vagal afferent-mediated inhibition of the nociceptive tail-flick (TF) reflex and a complex triad of cardiovascular responses. In the present study, we have used a variety of 5-HT receptor antagonists to characterize the receptor subtype(s) in the rat that mediate (1) inhibition of the TF reflex and (2) the cardiovascular responses produced by i.v. 5-HT. 5-HT produced a dose-dependent (3-72 micrograms/kg, i.v.) inhibition of the TF reflex (ED50 = 15.3 +/- 0.7 micrograms/kg). Following administration of the 5-HT2 receptor-selective antagonists ketanserin (50-250 micrograms/kg, i.v.) or xylamidine (10-100 micrograms/kg, i.v.), or the 5-HT3 receptor-selective antagonists ICS 205-930 (50-250 micrograms/kg, i.v.) or MDL 72222 (25-250 micrograms/kg, i.v.), there appeared to be a parallel shift of the 5-HT dose-response curve to the right. Following co-administration of xylamidine (50 micrograms/kg, i.v.) with ICS 205-930 (100 micrograms/kg, i.v.), the 5-HT-induced inhibition of the TF reflex was completely abolished at all doses of 5-HT tested (3-288 micrograms/kg, i.v.). In contrast, administration of the centrally acting 5-HT2 receptor-selective antagonist LY 53857 (10-100 micrograms/kg, i.v.) or the non-specific receptor antagonist methysergide (25-500 micrograms/kg, i.v.) resulted in a dose-dependent, but not parallel shift of the 5-HT dose-response curve to the right. The maximal doses of LY 53857 and methysergide tested (250 micrograms/kg and 500 micrograms/kg, respectively) completely abolished the effects of 5-HT (3-288 micrograms/kg, i.v.). Administration of the alpha 1-adrenoceptor antagonist prazosin (25-100 micrograms/kg, i.v.) failed to alter the 5-HT dose-response curve, indicating that the effects of ketanserin were due to blockage of 5-HT2 receptors rather than alpha 1 receptors. Administration of each of the antagonists also produced marked, but selective effects on components of the complex cardiovascular response to i.v. 5-HT. Each of the 5-HT3 receptor selective antagonists (ICS 205-930 or MDL 72222) produced a dose-dependent attenuation of the Bezold-Jarisch reflex-mediated hypotension and bradycardia, and each of the 5-HT2 receptor selective antagonists (xylamidine, ketanserin or LY 53857) produced a dose-dependent attenuation of the pressor response. The non-specific 5-HT receptor antagonist methysergide produced a dose-dependent attenuation of the 5-HT-induced pressor response.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Vagal afferent-mediated inhibition of a nociceptive reflex by i.v. serotonin in the rat. II. Role of 5-HT receptor subtypes. 151 36

Inhibition of deprivation-induced intake by naloxone was significantly enhanced by the 5-hydroxytryptamine3 (5-HT3) antagonist ICS-205,930. Interactions between naloxone and either the general 5-HT antagonist methysergide or the 5-HT2 antagonist ritanserin or ketanserin produced smaller effects. The present study evaluated whether 2-deoxy-D-glucose (2DG, 400 mg/kg) hyperphagia was affected by methysergide (0.5-5 mg/kg), ritanserin (0.25-2.5 mg/kg), or ICS-205,930 (0.5-5 mg/kg) alone or in combination with naltrexone (0.25 and 2.5 mg/kg). Only ICS-205,930 stimulated spontaneous intake for up to 4 h in the light cycle. Only ritanserin (1.25 mg/kg) transiently reduced 2DG hyperphagia. The dose-dependent decreases in 2DG hyperphagia by naltrexone were significantly enhanced by the dose range of ICS-205,930. The inhibition of 2DG hyperphagia by the low naltrexone dose was enhanced by methysergide (5 mg/kg) and ritanserin (1.25 mg/kg). These data suggest that the 5-HT3 receptor primarily interacts with opioid systems to modulate 2DG hyperphagia and that one possible locus of interaction is in the caudal brainstem.
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PMID:Naltrexone, serotonin receptor subtype antagonists, and glucoprivic intake: 1. 2-Deoxy-D-glucose. 151 47

Opiate antagonist inhibition of deprivation-induced intake and 2-deoxy-D-glucose (2DG) hyperphagia is significantly enhanced by the 5-hydroxytryptamine3 (5-HT3) antagonist, ICS-205,930. Interactions between opiate antagonists and either 5-HT or 5-HT2 antagonists produced smaller effects. The present study evaluated whether insulin (5 U/kg) hyperphagia was affected by methysergide (0.5-5 mg/kg), ritanserin (0.25-2.5 mg/kg), and ICS-205,930 (0.5-5 mg/kg) alone or in combination with naltrexone (2.5-10 mg/kg). Whereas ICS-205,930 stimulated insulin hyperphagia across the 6-h time course, ritanserin and, to a lesser degree, methysergide reduced insulin hyperphagia. Naltrexone marginally (19-33%) reduced insulin hyperphagia. Pairing naltrexone with either ICS-205,930 or ritanserin significantly suppressed insulin hyperphagia after 2 h. Pairing naltrexone with each of the serotonin antagonists significantly enhanced insulin hyperphagia after 4 and 6 h. These data suggest that 5-HT2 and 5-HT3 receptor subtypes interact with opioid systems to modulate insulin hyperphagia. Given that central insulin reduces food intake and body weight, the interaction between serotonergic and opioid systems may occur peripherally.
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PMID:Naltrexone, serotonin receptor subtype antagonists, and glucoprivic intake: 2. Insulin. 151 48

Administration of 1-(3-chlorophenyl)-biguanide (mCPB), a 5-HT3 receptor agonist (1 and 10 mg/kg IP), was found to be significantly anxiogenic in vehicle treated rats tested in the plus-maze, while having no significant effect in rats withdrawn for 24 h from 21 days diazepam treatment (2 mg/kg/day), suggesting a decreased agonist action at 5-HT3 receptors following withdrawal from chronic diazepam treatment. In the social interaction test, diazepam withdrawn rats showed a significant decrease in social interaction when compared to the chronic vehicle treated group. This anxiogenic response was reversed by low doses of zacopride (0.0001-0.01 mg/kg IP); in the vehicle treated animals 0.1 mg/kg was significantly anxiogenic. The overall pattern of results with zacopride is explained by suggesting that the anxiogenic effects of high doses of zacopride are detectable at low levels of 5-HT function and are due to an agonist action of the S-isomer in the rat at 5-HT3 receptors. The anxiolytic action of low doses is attributed to the R-isomer acting at the R-zacopride binding site and is enhanced in conditions of high 5-HT function, e.g. in the diazepam withdrawn rats. If this hypothesis is correct, then we would predict the R-isomer alone would be more effective in reversing the anxiogenic effects of diazepam withdrawal than the racemate, used here.
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PMID:Are there changes in sensitivity to 5-HT3 receptor ligands following chronic diazepam treatment? 152 83

5-HT3 receptor antagonists, ondansetron, granisetron and tropisetron are highly specific for the 5-HT3 receptor and have a selectivity ratio of approximately 1000:1 compared with affinities for other receptors. Other 5-HT3 receptor antagonists, largely those having a benzamide structure, are non-selective. These include metoclopramide, renzapride and zacopride which stimulate gastric motility via activation of 5-HT4 receptors; metoclopramide is also a potent dopamine receptor antagonist. Selective 5-HT3 receptor antagonists are a major advance in the treatment of chemotherapy- and radiotherapy-induced emesis in cancer patients. These agents inhibit emesis by blocking 5-HT3 receptors on vagal afferent nerve terminals in the gastrointestinal mucosa and on terminals on the same vagal nerves in the vomiting system. Inhibition of acute emesis appears to be produced by blocking the initiation of the emetic reflex induced via 5-HT3 receptors and by 5-HT released from enterochromaffin cells in the small intestine, as well as by blocking 5-HT3 receptors in the hindbrain vomiting system.
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PMID:Selectivity of 5-HT3 receptor antagonists and anti-emetic mechanisms of action. 152 96

The cardiovascular effects of DAU 6215, a novel 5-HT3 receptor antagonist were studied. DAU 6215 (20 micrograms/kg) inhibited the serotonin-induced Bezold-Jarisch reflex in anaesthetized rats, but did not affect the mean blood pressure and heart rate in anaesthetized rats, in anaesthetized animals after bilateral vagotomy and in pithed rats. This substance also did not affect the serotonin-induced rise in blood pressure in pithed rats and did not influence the response of the isolated rat tail artery to 5-HT. Moreover, DAU 6215 did not change the cardiovascular effects of noradrenaline- and angiotensin-II-stimulated constriction of rat tail artery. Our data suggest that DAU 6215 is rather a selective antagonist, without an affinity to 5-HT2, alpha-adrenoceptors, beta-adrenoceptors and angiotensin II receptors.
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PMID:Influence of DAU 6215, a novel 5-HT3 receptor antagonist, on the cardiovascular system in anaesthetized and pithed rats. 152 6

In light of evidence suggesting the proinflammatory and nociceptive action of peripheral serotonin (5-HT), the present study examined dose-dependent parameters of edema and algesia produced by intraplantar injections of 5-HT and the role of heterogeneous 5-HT receptors in these 5-HT-induced responses. Intraplantar 5-HT (0.05, 0.25, 0.5, or 1.0 mumols) produced paw edema at each 5-HT concentration and produced concentration-dependent increases in the nociceptive response as indexed by lifts of, and licks to the affected paw. Intraplantar pretreatment with the 5-HT1 receptor antagonist methysergide at concentrations greater than or equal to 3 nmol attenuated the 5-HT-induced (25 mumols) inflammatory and nociceptive responses. At concentrations greater than or equal to 300 nmol, both 5-HT2 receptor antagonist ketanserin and 5-HT3 receptor antagonist odansetron pretreatment blocked 5-HT-induced inflammatory and nociceptive responses. These results more completely define peripheral 5-HT-receptor-dependent systems of 5-HT-induced inflammation and nociception in rats.
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PMID:Receptor mediation of 5-HT-induced inflammation and nociception in rats. 153 5

5-Hydroxytryptamine (5-HT) mechanisms may play a role in opioid-mediated antinociception. Since opioid mechanisms have been implicated in nitrous oxide antinociception, this study was conducted to determine the possible role of 5-HT receptors in nitrous oxide antinociception. Male Swiss Webster mice were pretreated with one of two 5-HT receptor blockers and then tested in the acetic acid abdominal constriction test for their antinociceptive response to nitrous oxide, the kappa-opioid agonist U-50,488H, or the mu-opioid agonist sufentanil. Results indicate that the 5-HT3 receptor blocker ICS-205,930 antagonized both nitrous oxide and U-50,488H effects but not that of sufentanil. Mianserin, a 5-HT1c/5-HT2 receptor blocker, effects but not that of sufentanil. Mianserin, a 5-HT1c/5-HT2 receptor blocker, potentiated effects of both nitrous oxide and U-50,488H but not that of sufentanil. These findings show similarities in nitrous oxide and U-50,488H antinociception and further support our hypothesis that nitrous oxide works through central kappa-opioid mechanisms in mice. The results also suggest different roles for 5-HT receptor subtypes in mediating or modulating the antinociceptive effect of nitrous oxide.
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PMID:Contrasting influences of 5-hydroxytryptamine receptors in nitrous oxide antinociception in mice. 153 64

In the present study, we investigated the effects of various serotonin (5-HT) antagonists on 5-HT's action on medial prefrontal cortical cells (mPFc) using the techniques of single cell recording and microiontophoresis. The microiontophoretic application of 5-HT (10-80 nA) produced a current-dependent suppression of mPFc cell firing and this effect was blocked by the selective 5-HT3 receptor antagonists (+/-)-zacopride, ICS 205930 and granisetron at currents of 5-20 nA. Furthermore, the intravenous (i.v.) administration of (+/-)-zacopride (5-50 micrograms/kg) markedly attenuates the suppressive action of 5-HT on mPFc cell firing. In contrast, the microiontophoresis of 5-HT1 and 5-HT2 receptor antagonists such as (+/-)-pindolol, spiperone, metergoline, and ritanserin (10-20 nA) failed to block 5-HT's effect. In fact, in some cells, spiperone and ritanserin potentiated 5-HT's action and prolonged neuronal recovery. In addition, the intravenous administration of either ritanserin (5-2,000 micrograms/kg) or metergoline (4-2,400 micrograms/kg) failed to alter 5-HT's action. The electrical stimulation of the caudal linear raphe nucleus (CLi) suppressed the spontaneous activity of 83% of the mPFc cells tested by 45 +/- 2%. This suppression was significantly attenuated by the iontophoresis of granisetron (2.5-5 nA) but not by the 5-HT2 and 5-HT1C receptor antagonist ritanserin or the relatively selective 5-HT2 receptor antagonist (+)-MDL 11,939 (10-40 nA). However, the i.v. administration of ritanserin (0.5-1.5 mg/kg) or S-zacopride (0.1 mg/kg) significantly blocked the suppression of mPFc cell firing produced by CLi stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Action of serotonin in the medial prefrontal cortex: mediation by serotonin3-like receptors. 153 32

Two new classes of potent 5-HT3 agents have been developed and examined as inhibitors of cytotoxic drug induced emesis in the ferret and dog. The absolute configuration of the most active molecules 10 and 18 have been determined by X-ray crystallography. These two compounds are more potent than known 5-HT3 receptor antagonists both in vivo and in vitro in blocking 5-HT3 receptor activation and preventing chemotherapeutic induced emesis. Compared with 5-HT3 antagonists, such as GR 38032F, zacopride, BRL 43694, and ICS 205-930, compound 10 was more potent in (1) inhibiting binding to 5-HT3 receptor binding sites in rat cortex (Ki = 0.17 nM), (2) blocking the von Bezold-Jarisch effect in the rat (lowest effective dose, 1 microgram/kg iv), and (3) inhibiting 5-HT-induced contraction of guinea pig ileum (lowest effective concentration, 10(-9) M). This novel agent was as effective given po as when given iv in reducing cisplatin-induced emetic episodes in the ferret (ED50 = 4 micrograms/kg iv or po). A 1 mg/kg po dose of 10 virtually abolished cisplatin-induced emesis for 10 h in the ferret. However, it was inactive against apomorphine or copper sulfate-induced vomiting. These data, coupled with receptor binding studies of ligands for D2-dopamine, a1, a2, 5-HT1, 5-HT2, and muscarinic receptors demonstrate that 10 is a highly selective 5-HT3 receptor antagonist with remarkable potency in vivo.
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PMID:Development of high-affinity 5-HT3 receptor antagonists. 2. Two novel tricyclic benzamides. 154 79


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