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)

1. Distension of the duodenum in anaesthetized rats, by rapid application of intraluminal pressures (10-75 cmH2O), evoked falls in diastolic blood pressure and intragastric pressure. 2. The distension-induced responses were blocked by pretreatment with morphine (20 mg kg-1, s.c.), an action reversible by injection of naloxone (5 mg kg-1, i.v.). 3. Bilateral cervical vagotomy reduced the distension-evoked fall in intragastric pressure but had no effect on the corresponding fall in blood pressure. 4. Granisetron or ICS 205-930 (1-1000 micrograms kg-1, i.v.) had no effects on duodenal intraluminal pressure, but reduced the responses to distension with a bell-shaped dose-response relationship. Ondansetron (1-1000 micrograms kg-1, i.v.) did not reduce the reflex responses. 5. These results show that the 5-HT3 receptor antagonists used exerted different effects on the reflex responses to duodenal distension.
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PMID:The effects of granisetron, ICS 205-930 and ondansetron on the visceral pain reflex induced by duodenal distension. 216 34

Cancer therapy with cytotoxic drugs such as cisplatin or cyclophosphamide is usually associated with violent crisis of vomiting. Recently, it was shown that 5-HT3 receptor antagonists block cisplatin-induced vomiting but the mechanisms and their sites of action remain unknown. We tested the hypothesis that these agents act on structures within the central nervous system by evaluating the effectiveness of vagal stimulation in eliciting fictive vomiting in decerebrate, paralyzed and ventilated cats before and after administration of such agents. Fictive vomiting was defined as a series of large bursts of synchronous activity in the phrenic and abdominal (expiratory) nerves (retching) followed by a burst in which the abdominal activity was prolonged (expulsion). The latency and number of these co-activations were measured before and after intravenous administration of three 5-HT3 receptor antagonists (GR 38032F (Ondansetron). Zacopride, and BRL 43694A (Granisetron]. All compounds, administered at doses of 1 and 2 mg/kg failed to block vomiting behaviour in 100% and 68% of trials, respectively. Nor did their administration affect the latency and number of co-activations. We conclude that intravenous administration of 5-HT3 receptor antagonists do not act centrally on either the brainstem neuronal network known as the "vomiting center" or related neuronal structures. Our results suggest that the anti-emetic effect of 5-HT3 receptor antagonists in cisplatin-induced vomiting is mediated peripherally rather than centrally.
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PMID:Vagal-induced vomiting in decerebrate cat is not suppressed by specific 5-HT3 receptor antagonists. 229 1

Three main types of 5-HT (serotonin) receptor have been recognised. The 5-HT3 receptor is located on neuronal tissues in the peripheral and central nervous systems. Ondansetron is a highly selective and potent antagonist for this receptor type. The severe nausea and vomiting caused by cytotoxic agents and radiotherapy can be reduced by metoclopramide treatment, but extrapyramidal side effects are common due to antagonism of dopamine receptors. Ondansetron has been found to significantly delay the onset of emesis, and reduce the number of retches and vomits in ferrets receiving cisplatin, cyclophosphamide, or radiation, at much lower doses than metoclopramide and without the associated side effects. Experiments to define the site of action of ondansetron suggest that at least part of its antiemetic action is in the area postrema, though a peripheral site of action in the upper gastrointestinal tract is also a possibility.
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PMID:Pharmacological and anti-emetic properties of ondansetron. 253 94

Ondansetron is a 5-HT3 receptor antagonist which has shown activity in the prevention of nausea and vomiting resulting from cytotoxic therapy. This paper describes the results of studies evaluating the efficacy of oral ondansetron in controlling radiation-induced emesis. Initial non-randomised studies showed that doses of 4 mg q.d.s. or 8 mg t.d.s. of ondansetron achieved complete or major control of vomiting in 77-91% of patients and mild or absence of nausea in 72-77% following single exposure high-dose (8-10 Gy) radiotherapy to the upper abdomen. A subsequent double-blind, prospective, randomised trial compared ondansetron 8 mg t.d.s. with metoclopramide 10 mg t.d.s. in the prevention of emesis following single radiation doses of 8-10 Gy to the upper abdomen. On the day of radiotherapy, ondansetron achieved significantly greater control of vomiting and retching (P less than 0.001) and nausea (P = 0.001) than metoclopramide. An advantage for ondansetron was also seen on days 2 and 3 after irradiation, although this did not reach a statistically significant level. Only two patients, out of 154, in all the studies experienced side effects attributable to ondansetron: one developed headache and the other experienced headache and vertigo. These studies show that ondansetron is a safe drug, with activity in the prevention of radiation-induced emesis and significantly greater efficacy than metoclopramide in the control of nausea and vomiting following single exposure upper abdominal high-dose radiotherapy.
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PMID:Clinical studies with ondansetron in the control of radiation-induced emesis. 253 96

A putative 5-HT4 receptor-mediated depolarization of the rat isolated vagus nerve has been studied using a grease-gap extracellular recording technique. Ondansetron (1 microM) was used to block the predominant 5-HT3 receptor mediated depolarization in this preparation and the effects of the 5-HT4 receptor antagonists DAU 6285 (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl-2,3-dihydro-6-methoxy-2-oxo-1H-benzimidazole-1- carboxylate HCl); 0.3, 1.0 or 3.0 microM and SDZ 205-557 (2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino)-ethyl ester HCl); 0.1, 0.3 or 1.0 microM were studied on the residual, ondansetron-resistant, component of the response. The effects of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) and of forskolin on the ondansetron-resistant response were also studied. Both DAU 6285 and SDZ 205-557 acted as competitive antagonists of the ondansetron-resistant response to 5-HT with pA2 values of 6.8 (6.7-7.1, n = 12) and 7.1 (6.9-7.5, n = 12) respectively. The vagus nerve was depolarized by IBMX (100 microM) or forskolin (10 microM), the effects being similar to the maximum response to 5-HT. In the presence of IBMX (100 microM) or forskolin (10 microM) the ondansetron-resistant component of the response to 5-HT was enhanced and the 5-HT3 receptor-mediated component reduced. These results with DAU 6285 and SDZ 205-557 are consistent with a 5-HT4 receptor-mediated mechanism of the ondansetron-resistant depolarizing response to 5-HT.
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PMID:Further characterization of the putative 5-HT4 receptor mediating depolarization of the rat isolated vagus nerve. 747 28

The 5-HT3 receptor blocking properties of YM060, YM114 (KAE-393), granisetron and ondansetron were examined in the vagus nerve and cerebral cortex of rats. 5-HT and 2-methyl-5-HT induced dose-dependent depolarizations of rat isolated vagus nerve with EC50 values of 2.53 (1.93-3.33) x 10(-6) and 4.03 (2.87-5.66) x 10(-6) M, respectively. YM060, YM114 and granisetron dose-dependently antagonized the depolarization of the rat vagus nerve induced by 5-HT, with decreases in the slope and maximal response at higher concentrations. Apparent pA2 values for these antagonists were 10.27 +/- 0.09, 10.12 +/- 0.16 and 9.44 +/- 0.40, respectively. Ondansetron produced a clear rightward shift of the concentration-response curve to 5-HT. The pA2 value was 8.63 (8.23-9.68). YM060 and YM114 at up to 10(-5) M produced no significant depression of the depolarizing responses to DMPP and GABA. YM060, YM114, granisetron and ondansetron displaced specific binding of [3H]GR65630 to rat cortical membranes with pKi values of 10.48 (10.41-10.57), 10.24 (10.18-10.28), 9.15 (9.02-9.28) and 8.70 (8.64-8.77), respectively. An excellent correlation (r = 0.97) was obtained between pA2 values in the vagus nerve and pKi values in the cerebral cortex. YM060, YM114, granisetron and ondansetron showed low affinities for 5-HT1A, 5-HT2 receptor, adrenergic alpha 1, alpha 2, dopamine D2, muscarinic M2, mu-opioid, benzodiazepine and histamine H1 receptors. These results support the possibility that the same type of 5-HT3 receptor occurs in rat vagus nerve and cerebral cortex.
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PMID:Comparative study of the affinities of the 5-HT3 receptor antagonists, YM060, YM114 (KAE-393), granisetron and ondansetron in rat vagus nerve and cerebral cortex. 756 99

At cancer treatment, the use of antiemetics are often needed due to induction of nausea and vomiting. Some antiemetics have been shown to interact with the direct cytotoxic effects. The newly developed antiemetics have, as far as we know, not been studied in this respect. In the present study, the effects of the 5-HT3 receptor antagonists ondansetron and granisetron were evaluated on the cytotoxicity, induced by irradiation, bleomycin, epirubicin, estramustine, and cisplatin using fibroblasts (V79) and lung cancer cells (P31) in vitro. Ondansetron or granisetron (10(-5) mol/l) had no effect on the survival of irradiated cells. Granisetron (10(-5) mol/l) significantly potentiated cytotoxicity of 2.5 mg/l epirubicin on fibroblasts whereas the effect of granisetron (10(-7) mol/l) on the cytotoxic effect of 25 mg/l bleomycin, and estramustine (80 mg/l) seemed additive to lung cancer cells. Ondansetron was non-interactive with the cytotoxicity induced by any of the anti-cancer drugs. Although the encountered observation with an enhancing effect of granisetron on the epirubicin-induced cytotoxicity is seen in a specific experimental situation in vitro, the fact that 5-HT3 receptor antagonists are routinely used during cancer treatment indicate that attention should be given to a possible interaction with the antineoplastic action of cancer treatment.
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PMID:Interaction of the antiemetics ondansetron and granisetron with the cytotoxicity induced by irradiation, epirubicin, bleomycin, estramustine, and cisplatin in vitro. 757 57

To investigate further the cholinergic specificity of the effects of basal forebrain lesion-induced disruption of attentional performance, the present study examined the efficacy of various pharmacological agents in improving performance of a five-choice serial reaction time task in rats that had received lesions of the cholinergic basal forebrain. Specifically, the effects of the novel 5-HT3 receptor antagonist, ondansetron (0.3, 1, 10 ng/kg), and of nicotine (0.03, 0.06, 0.1, 0.3 mg/kg) and the anticholinesterase, physostigmine (0.05, 0.1 mg/kg), on attentional function were examined in animals which had received AMPA-induced lesions of the nucleus basalis magnocellularis (nbM). The behavioural impairments observed immediately following the lesion were a reduction were choice accuracy and an increase in correct response latency. Although these impairments showed recovery over the course of the following weeks, the deficit in choice accuracy could be reinstated by reducing the duration of the visual stimulus and thus increasing the attentional load placed on the animals. This reduction in choice accuracy could be dose dependently improved by systemic administration of either physostigmine or nicotine, suggesting that this impairment in attentional function may be attributed to disruption of cholinergic function. The pharmacological specificity of these improvements was supported by the inability of d-amphetamine to improve task performance (0.2, 0.4, 0.8 mg/kg). Ondansetron was also unable to improve accuracy of performance in lesioned animals, but was effective in reducing the anticipatory or premature responding observed in both control and lesioned animals, even when elevated (in the case of controls) by treatment with systemic d-amphetamine. The results of the present study therefore suggest that cholinergic dysfunction can lead to attentional impairments which can be ameliorated by cholinergic treatments such as physostigmine and nicotine, but that ondansetron, despite its proposed ability to release cortical acetylcholine, was unable to restore choice accuracy at the doses employed. The results further suggest a double dissociation of effects on accuracy and the disinhibition of responding.
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PMID:Reversal of visual attentional dysfunction following lesions of the cholinergic basal forebrain by physostigmine and nicotine but not by the 5-HT3 receptor antagonist, ondansetron. 759 26

The effect of the 5-HT3 antagonist ondansetron on ethanol self-administration was examined in a limited access paradigm. Acute administration of ondansetron (0.01 and 0.1 mg/kg) reduced ethanol intake in male Wistar rats by 35%, whilst water intake was unaffected. Both a lower (0.001 mg/kg) and higher dose (1 mg/kg) of ondansetron failed to modify ethanol consumption. Ondansetron did not, however, alter the pharmacokinetic profile of an orally administered dose of ethanol (1 g/kg) over the same dose range. To examine the generality of these findings and to determine if tolerance would develop to the suppressant effects of ondansetron on ethanol intake, male C57BL/6 mice were treated with ondansetron (0.001, 0.01 and 0.1 mg/kg) over 22 days, 30 min prior to scheduled access to ethanol. Both 0.01 and 0.1 mg/kg doses reduced ethanol intake; however, water intake was not altered by either dose. This finding confirms and extends the generality of the effects of 5-HT3 receptor antagonists on ethanol intake across different species and different paradigms of ethanol consumption. More importantly, the present study shows that the reduction in ethanol intake induced by ondansetron was maintained even after a prolonged period of treatment and is not due to an alteration in the absorption or metabolism of ethanol.
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PMID:Effect of the 5-HT3 antagonist ondansetron on voluntary ethanol intake in rats and mice maintained on a limited access procedure. 760 51

Psychosis, linked to chronic levodopa and other antiparkinsonian drug treatments, is a common and incapacitating complication of advanced Parkinson's disease (PD). The psychosis may be due, in part, to overstimulation of central serotonergic (5-HT) receptors. We treated 16 PD patients who had psychosis of 6 to 60 months' duration with the 5-HT3 receptor antagonist ondansetron (12 to 24 mg daily) in an open-label, short-term (4 to 8 weeks) trial. There was marked to moderate improvement (p < 0.01) in measures of visual hallucinations, paranoid delusions, confusion, and the associated global functional impairment in all but one of the patients, and there was moderate improvement in the Brief Psychiatric Rating Scale and the Nurse's Observation Scale for Inpatient Evaluation; the Mini-Mental State Examination scores remained unaltered. Ondansetron did not cause any worsening in basic PD symptoms or levodopa efficacy and was well tolerated with no major side effects. Our study suggests that pharmacologic blockade of central 5-HT receptors may become a strategy to attenuate PD psychosis without inducing motor deterioration or suppression of antiparkinsonian action of levodopa, and it lends support to the hypothesis that serotonergic mechanisms are pathogenetically important in the emergence of psychosis in PD.
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PMID:Psychosis in advanced Parkinson's disease: treatment with ondansetron, a 5-HT3 receptor antagonist. 896 Jul 64


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