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

The ability of 5-HT3 receptor agonists to modulate the resting efflux or K(+)-evoked release of [3H]5-HT from superfused synaptosomes from the spinal cord of the rat was investigated. Phenylbiguanide did not alter the resting efflux of [3H]5-HIAA or [3H]5-HT or modify the K(+)-evoked release of [3H]5-HT. 2-Methyl-5-HT (10 microM) caused an increase in resting efflux of [3H]5-HIAA, an effect that was blocked by the inhibitor of the uptake of 5-HT fluoxetine. No effect on K(+)-evoked release of tritium was observed. Bufotenine (100-1000 nM) increased the resting efflux of [3H]5-HT and [3H]5-HIAA. These effects were not antagonized by the 5-HT3 antagonist ICS 205-930 but were antagonized by fluoxetine. The drug ICS 205-930 (1 microM) did not alter resting efflux or block the ability of serotonin (30 and 100 nM) to decrease K(+)-evoked release of tritium. Quipazine, a potent antagonist of peripheral 5-HT3 receptors (subnanomolar concentrations), was also unable to alter resting or K(+)-evoked release of [3H]5-HT. It did, however, attenuate the inhibitory effect 5-HT on K(+)-evoked release. The concentrations required were in the micromolar range, consistent with the ability of the drug to antagonize the 5-HT1B autoreceptor. These results support the idea that 5-HT3 receptors do not act as nerve terminal autoreceptors in the spinal cord of the rat.
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PMID:5-HT3 receptors are not involved in the modulation of the K(+)-evoked release of [3H]5-HT from spinal cord synaptosomes of rat. 138 44

In the present study, the emetic effect of the anticancer drug cisplatin, and protective effects of 5-HT3 receptor antagonists against cisplatin emesis were investigated in the pigeon. The experimental setting involved the i.v. administration of drugs and subsequent observation of the percentage of vomiting animals and number of emetic episodes per vomiting animal over a period of 5 h. In some experiments, the 5-HT and 5-HIAA content in tissues was estimated by the HPLC technique. It was observed that cisplatin (2.5-10 mg/kg) is able to induce dose-dependent emesis in the pigeon. 5-HT3 receptor antagonists (500 micrograms/kg) afford partial protection against cisplatin emesis, although some of them, i.e. indolic derivatives and zacopride, display intrinsic emetic activity at doses of 50-500 micrograms/kg. A serotonergic mechanism appears to be involved in both cisplatin- and 5-HT3 receptor antagonist-induced emesis, since pretreatment with an inhibitor of 5-HT synthesis, para-chlorophenylalanine (300 mg/kg x 3 days), is able to hamper vomiting induced by either cisplatin or 5-HT3 receptor antagonists. It is concluded that the intrinsic emetic effects of 5-HT3 receptor antagonists in the pigeon provide pharmacological evidence of species differences in the properties of 5 HT3 receptors.
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PMID:A dual effect of some 5-HT3 receptor antagonists on cisplatin-induced emesis in the pigeon. 147 Dec 30

The effects of conditioned fear stress (CFS) on 5-HT release in the medial prefrontal cortex were studied by in vivo microdialysis. CFS (exposure to an environment in which foot-shock had been delivered previously) induced a marked suppression of motility-that is, freezing behavior. The extracellular concentration of 5-HT in the medial prefrontal cortex increased during this freezing behavior, but no significant changes were observed in the concentration of its metabolite, 5-HIAA. The increased 5-HT concentration returned to pretreatment levels when the animals were returned to their home cages. Diazepam (0.5 mg/kg, intraperitoneally) reduced the CFS-induced freezing behavior and prevented the increases in extracellular 5-HT levels. A 5-HT3 receptor antagonist, tropisetron (10 and 100 micrograms/kg), also inhibited both the CFS-induced increase in 5-HT release and the freezing behavior. These findings suggest that there is a relationship between anxiety and 5-HT release in the prefrontal cortex and that the 5-HT3 receptor antagonist tropisetron might have anxiolytic properties.
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PMID:Effects of conditioned fear stress on 5-HT release in the rat prefrontal cortex. 766 78

Carboplatin has proven efficacy in the treatment of ovarian cancer and has been proven to be less toxic compared to the parent compound cisplatin. Nevertheless, emesis is still a major problem associated with carboplatin-containing chemotherapy. Several investigators have focussed on the understanding of the pathophysiology and pattern of cisplatin-induced emesis. Data describing both the pathomechanisms and pattern of carboplatin-induced emesis are still lacking. This paper combines data from the literature with our own experience with the pattern and control of carboplatin-induced emesis, and presents data contributing to the understanding of the underlying pathomechanisms. Carboplatin induces a significant increase in urinary 5-HIAA excretion, the main metabolite of serotonin. 5-HIAA excretion levels remain elevated over 3 days following chemotherapy. Carboplatin-induced emesis is observed in about 40% of patients despite anti-emetic prophylaxis with 5-HT3 antagonists. Vomiting after carboplatin extends over days 1-3 with an equal distribution regarding the severity on each day. Analysis of the pattern of emesis revealed that delayed emesis (> 24 h after chemotherapy) is a major problem associated with carboplatin therapy. Description of the pattern of emesis as 'prolonged emesis' seems to be appropriate. 5-HT3 receptor antagonists such as ondansetron seem to be efficacious both in the control of acute and prolonged emesis following carboplatin chemotherapy, but randomly controlled data comparing ondansetron with other anti-emetic regimens have not yet been published. Univariate analysis reveals gender and combination therapy containing carboplatin and cyclophosphamide and/or anthracyclines as risk factors for emesis.
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PMID:Pathophysiology, severity, pattern, and risk factors for carboplatin-induced emesis. 869 51

The involvement of abdominal afferent vagal activity and serotonergic mechanisms were examined following intravenous administration of talipexole, a dopamine D2 receptor agonist used for treatment of Parkinson's disease, in anesthetized rats. Intravenous administration of dopamine receptor agonists including D1/D2 components increased the spontaneous firing of afferent vagal neurons as did 2-methyl-5-hydroxytryptamine. Both talipexole (0.25-1.0 mg/kg) and bromocriptine (1.0-10.0 mg/kg) increased vagal nerve activity in a dose-dependent manner, and the effect of 10 mg/kg of bromocriptine was significantly greater than that noted with 1.0 mg/kg of talipexole. Increasing vagal firing induced by talipexole was prevented by pretreatment with granisetron, but not with metoclopramide or by spinal section, indicating that afferent vagal firing was mediated via stimulation of the 5-HT3 receptors on the neurons and secondarily caused by stimulation of dopamine receptors. On the other hand, bromocriptine at 5 mg/kg increased 5-HIAA concentration in the ileum, and serotonin turnover (5-HIAA/5-HT) was increased approximately 4-fold when compared to the vehicle group. Bromocriptine also increased the activities of tryptophan hydroxylase and monoamine oxidase. Talipexole at 0.5 mg/kg did not affect ileal 5-HT metabolism and the enzymatic activities. These findings suggest that dopamine receptor agonists may induce changes in abdominal afferent vagal activity and ileal 5-HT metabolism similar to those observed with emetic compounds, and that talipexole has a much smaller influence on serotonin-mediated responses than does bromocriptine with equipotent antiparkinsonian doses. One of the possible reason why talipexole showed fewer emetic side effects in patients with Parkinson's disease may be that the emetic responses triggered by D2 receptor stimulation may secondarily cause an increase of abdominal afferent vagal activity, which may be weakened by the 5-HT3 receptor antagonistic property of talipexole.
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PMID:Effects of talipexole on emesis-related changes in abdominal afferent vagal activity and ileal serotonin metabolism in rats. 905 50

Irritable bowel syndrome (IBS) is a debilitating disease, which is characterised by recurrent abdominal cramping and pain, and is associated with either constipation and/or diarrhoea. It is approximately twice as prevalent in women as it is in men and is among the most common gastrointestinal (GI) disorders encountered in primary care. The aetiology of the disease is poorly understood but may include motility dysregulation, visceral sensitivity, inflammation, bacterial infection, dietary antigens, psychological stress, GI surgery or a gut-brain phenomenon. At present, there is no acceptable treatment for IBS, although recent advances indicate that some relief may be achieved by the administration of compounds that act on 5-HT (serotonin) receptors. This suggestion is the result of numerous studies which have shown that 5-HT may exert a number of diverse effects on human GI tissues. In addition, it has emerged that the levels of the 5-HT metabolite (5-HIAA) are raised in the plasma of IBS patients and that administration of 5-HT-like compounds may mimic the symptoms of IBS. It has therefore been proposed that therapy with compounds that act at 5-HT receptors will return the intestine to normal activity and alleviate the pain experienced by these patients. One compound (alosetron, a 5-HT3 receptor antagonist) has already been released onto the market but showed benefit in female patients only and only in those whose primary symptom was diarrhoea. In addition, the compound was recently withdrawn following concerns over its safety. The reasons why alosetron only appears to show efficacy in females, why these treatments are only effective in a subset of the population of IBS patients and why alosetron elicits its particular side effect profile have not been elucidated. One further serotonergic compound, tegaserod (Zelmac, a 5-HT4 receptor agonist), has shown promise for the treatment of patients with constipation-predominant IBS and is currently in pre-registration for this indication. It is clear, however, that further research will have to take place before the utility of serotonergic modulation in the treatment of IBS can be fully validated.
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PMID:Serotonergic modulation and irritable bowel syndrome. 1598 96