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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Since the discovery of serotonin receptor subtypes in 1957, the classification of serotonin receptors now includes 5-HT1 through 5-HT7 receptors, with further subtypes of receptors in each family. Unique among this expanding group of 5-HT receptor subtypes is the 5-HT3 receptor, which is the only known 5-HT receptor that directly gates an ion channel. The channel conducts primarily Na+ and K+, resulting in rapid depolarization followed by a rapid desensitization. The immediate consequence of neuronal depolarization resulting from 5-HT3 receptor activation is the release of stored neurotransmitter. The subsequent release of stored neurotransmitter, particularly dopamine in the mesolimbic pathways, suggest a potentially important role for this receptor system in neuronal circuitry involved in drug abuse. The following review broadly covers the structure, function and distribution of the 5-HT3 receptor system in the CNS and data addressing the potential role of this receptor system in modulating the effects of a wide variety of abused drugs. Most of the evidence indicates an association between the ability of 5-HT3 antagonists to decrease mesolimbic dopamine levels and to attenuate the psychomotor stimulant effects of drugs. However 5-HT3 receptor antagonists are less robust at attenuating other drug effects that are believed to be related to their abuse liability, such as discriminative stimulus and reinforcing effects. The one exception may be ethanol, which directly potentiates the effects of 5-HT at the 5-HT3 receptor channel complex. In addition to the implications of an interaction with the mesolimbic dopaminergic system, the ability of 5-HT3 receptor antagonists to function as anxiolytics suggest they could be useful pharmacotherapies during drug withdrawal. However, further studies are needed since currently available 5-HT3 receptor antagonists do not have uniform behavioral effects, may interact with other receptor systems, and have atypical dose-response effects.
Drug Alcohol Depend 1995 May
PMID:The role of 5-HT3 receptors in drug dependence. 767 67

The influence of ethanol (0.5, 1.0 and 2.0 g/kg i.p.) on the Bezold-Jarisch reflex in urethane-anaesthetized rats was studied. 5-Hydroxytryptamine (serotonin; 5-HT; 1, 3, 10 and 30 micrograms/kg i.v.) and capsaicin (1, 3 and 10 micrograms/kg i.v.) reflexly decreased heart rate in a dose-dependent manner. The 5-HT3 receptor antagonist ondansetron 10 micrograms/kg i.v. abolished the 5-HT- but not the capsaicin-stimulated bradycardia, indicating that 5-HT and capsaicin acted via different trigger mechanisms (5-HT3 receptor-dependent and -independent, respectively). Ethanol at 1.0 and 2.0 g/kg i.p. inhibited in a dose-dependent manner (by 20-45%) the 5-HT- but not the capsaicin-stimulated decrease in heart rate. Our results demonstrate that the inhibitory effect of ethanol on the 5-HT3 receptor-mediated Bezold-Jarisch reflex may be related to the direct effect of ethanol on 5-HT3 receptors on sensory vagal nerves in the heart.
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PMID:Inhibitory effect of ethanol on the 5-hydroxytryptamine-induced Bezold-Jarisch reflex--involvement of peripheral 5-HT3 receptors. 767 10

In the presence of substance P (SP; 10 microM), serotonin (5-HT; 1 microM) triggered a cation permeability in cells of the hybridoma (mouse neuroblastoma x rat glioma) clone NG 108-15 that could be assessed by measuring the cell capacity to accumulate [14C]guanidinium for 10-15 min at 37 degrees C. In addition to 5-HT (EC50 0.33 microM), the potent 5-HT3 receptor agonists 2-methyl-serotonin, phenylbiguanide, and m-chlorophenylbiguanide, and quipazine, markedly increased [14C]guanidinium uptake in NG 108-15 cells exposed to 10 microM SP. In contrast, 5-HT3 receptor antagonists prevented the effect of 5-HT. The correlation (r = 0.97) between the potencies of 16 different ligands to mimic or prevent the effects of 5-HT on [14C]guanidinium uptake, on the one hand, and to displace [3H]zacopride specifically bound to 5-HT3 receptors on NG 108-15 cells, on the other hand, clearly demonstrated that [14C]guanidinium uptake was directly controlled by 5-HT3 receptors. Various compounds such as inorganic cations (La3+, Mn2+, Ba2+, Ni2+, and Zn2+), D-tubocurarine, and memantine inhibited [14C]guanidinium uptake in NG 108-15 cells exposed to 5-HT and SP, as expected from their noncompetitive antagonistic properties at 5-HT3 receptors. However, ethanol (100 nM), which has been reported to potentiate the electrophysiological response to 5-HT3 receptor stimulation, prevented the effects of 5-HT plus SP on [14C]guanidinium uptake. The cooperative effect of SP on this 5-HT3-evoked response resulted neither from an interaction of the peptide with the 5-HT3 receptor binding site nor from a possible direct activation of G proteins in NG 108-15 cells. Among SP derivatives, [D-Pro9]SP, a compound inactive at the various neurokinin receptor classes, was the most potent to mimic the stimulatory effect of SP on [14C]guanidinium uptake in NG 108-15 cells exposed to 5-HT. Although the cellular mechanisms involved deserve further investigations, the 5-HT-evoked [14C]guanidinium uptake appears to be a rapid and reliable response for assessing the functional state of 5-HT3 receptors in NG 108-15 cells.
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PMID:Characteristics of [14C]guanidinium accumulation in NG 108-15 cells exposed to serotonin 5-HT3 receptor ligands and substance P. 768 66

We investigated the possible involvement of 5-HT3 receptors in the colonic motor alterations and abdominal pain evoked by rectal distension (RD) in rats, under normal and inflammatory conditions. Responses to RD were evaluated by electromyography in rats treated with 5-HT3 antagonists (ondansetron and cilansetron, 0.1 and 1 mg/kg, intraperitoneally), before and 3 days after intrarectal administration of TNB/ethanol. RD evoked a significant (P < 0.05) and gradual inhibition of the occurrence of colonic spike bursts (SB) and a gradual increase in abdominal SB from 11 mm in diameter on wards. Ondansetron and cilansetron (0.1 mg/kg) significantly reduced both the colonic (62 and 66%, respectively) and the abdominal response (28 and 61%, respectively) for an 11 mm diameter of RD. After TNB/ethanol, both colonic and abdominal responses to RD were significantly (P < 0.05) enhanced and appeared for a lower diameter (9 mm) (colon: 4.8 +/- 0.9 vs 8.4 +/- 1.1, abdomen: 7.7 +/- 1.5 vs 0.5 +/- 0.4). Cilansetron (0.1, 1 mg/kg) significantly (P < 0.05) attenuated the TNB-induced colonic motor inhibition, while ondansetron and cilansetron (0.1, 1 mg/kg) reduced the TNB-induced increase in abdominal response. We conclude that 5-HT and 5-HT3 receptors mediate RD-induced viscerosensitive alterations in rats, both in normal conditions and during TNB-induced rectocolitis. However, the relative efficacy of the 5-HT3 receptor antagonists depends on the experimental conditions (intact or inflamed bowel) and does not appear to increase with the dose.
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PMID:Influence of 5-HT3 receptor antagonists in visceromotor and nociceptive responses to rectal distension before and during experimental colitis in rats. 772 Dec 33

Pharmacological manipulations to enhance 5-HT synthesis and release have been reported to reduce alcohol intake. However, recent evidence indicates that 5-HT3 receptor antagonists may also exert a similar effect in a number of species. This report reviews the existing data which implicates a central role for 5-HT3 receptors in the control of psychoactive substance abuse.
Alcohol Alcohol Suppl 1993
PMID:The effects of 5-HT3 receptor antagonists in models of dependency and withdrawal. 774 9

There was a significant increase in potassium-stimulated release of 3H-[5-HT] from hippocampal slices taken from rats withdrawn from chronic ethanol treatment, compared with control-treated rats. The anxiogenic behaviour observed 12 h after ethanol withdrawal was inhibited by the 5-HT1A partial agonist, buspirone (200 micrograms/kg s.c.), indicating that the increased 5-HT release might underlie the anxiogenic response. The ex-ethanol treated rats showed impaired habituation of motor activity in the holeboard and a reduced exploratory response. The latter, but not the former, were reversed by the 5-HT3 receptor antagonist, ondansetron (0.01 microgram/kg i.p.). Ondansetron was without effect on working memory errors, but significantly increased the number of reference memory errors made by the ex-ethanol group. It also had a significantly anxiogenic effect in this group. These results suggest that the chronic ethanol treatment changes the 5-HT system and has long-lasting effects on the function of 5-HT3 receptors.
Alcohol Alcohol Suppl 1993
PMID:The role of 5-HT in the anxiogenic effects of acute ethanol withdrawal and in the long-lasting cognitive deficits. 774 45

The effect of acute exposure to alcohols on ion current mediated by recombinant 5-HT3RA receptors transiently expressed in human embryonic kidney 293 cells was investigated. Cells transfected with 5-HT3RA cDNA expressed receptors with pharmacological and functional properties similar to those of native 5-HT3 receptors. Potentiation of receptor-mediated cation current was observed in the presence of ethanol (10-100 mM), butanol (0.1-20 mM), isopentanol (0.01-25 mM) and trichloroethanol (0.5-25 mM). Potentiation increased in a concentration-dependent manner until saturation was achieved for all alcohols tested. The maximal efficacies of potentiation differed among the alcohols with isopentanol > butanol = trichloroethanol > ethanol. Potentiation by butanol and isopentanol appeared to show acute tolerance such that the percent increase in current amplitude was largest upon the first of a series of alcohol applications and decreased during subsequent applications. The effect of ethanol was variable with potentiation occurring in 74% of cells examined, but not in the remaining cells. These observations indicate that the potentiating action of alcohols is similar in recombinant receptors to that previously observed in neuroblastoma cells and neurons expressing native receptors. These findings indicate that this recombinant system is suitable for studying the molecular basis of alcohol actions on the 5-HT3 receptor.
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PMID:Alcohols potentiate ion current mediated by recombinant 5-HT3RA receptors expressed in a mammalian cell line. 776 Sep 80

5,7-Dihydroxytryptamine (5,7-DHT) was administered ICV to Wistar male rats. Lesioned rats displayed higher preference for ETOH than sham-lesioned animals. Among 5,7-DHT-pretreated rats 38% became high-preferring, while only 22% of sham-lesioned rats displayed this behavioural pattern (p < 0.05). Both 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; the agonist of serotonin 5-HT1A receptors) and tropisetron (ICS 205-930, the antagonist of 5-HT3 receptors) reduced ETOH consumption in high-preferring, sham-lesioned rats. However, in 5,7-DHT rats the effect of 8-OH-DPAT was completely abolished, while tropisetron retained its antipreference activity. Therefore, it seems that 5-HT1A autoreceptors are critically involved in 8-OH-DPAT action, while 5-HT3 receptor sites responsible for tropisetron action are located beyond the 5-HT system.
Alcohol
PMID:Alcohol drinking in rats treated with 5,7-dihydroxytryptamine: effect of 8-OH-DPAT and tropisetron (ICS 205-930). 794 81

Both 5-HT3 receptor antagonists and benzodiazepine receptor ligands have effects on anxiety, and alter the behavioral action of ethanol. For these reasons, we tested the ability of several 5-HT3 receptor antagonists to inhibit the ligand binding and function of the gamma-aminobutyric acidA/benzodiazepine receptor Cl- channel complex of mouse brain membranes. MDL 72222 (1-a-H-3-a-5-aH-optropan-3yl-3,5-dichlorobenzoate) and LY 278584 (1-methyl-N-(8-methyl-8-azabicyclo[3.2.1.]oct-3-yl)-1H-indazole-3- carboxamide) inhibited [3H]flunitrazepam binding with Ki values of approximately 20 microM; ICS 205-930 (3 alpha-tropanyl-1H-indole-3-carboxylic acid ester) was more potent with a Ki of 0.8 microM. ICS 205-930 (50 microM) had no effect on [3H]muscimol binding. ICS 205-930, MDL 72222, and LY 278584 all inhibited the binding of [35S]TBPS (tert-butylbicyclophosphorothionate) with Ki values of approximately 10 microM and reduced muscimol-dependent 36Cl- flux into mouse cortical microsacs by 30-45% at a concentration of 10 microM. ICS 205-930, MDL 72222, and LY 278584 (at micromolar concentrations) reduced GABA-gated chloride currents studied in Xenopus oocytes expressing human alpha 1 beta 1 gamma 2S GABAA receptor subunits. ICS 205-930 differed from the other two 5-HT3 receptor antagonists in that it induced a biphasic effect on GABA-gated currents: at concentrations from 0.1 to 5 microM it potentiated GABA responses, whereas at higher concentrations (50-100 microM) it produced inhibition. The stimulatory action induced by ICS 205-930 was due to interaction at the benzodiazepine recognition site because expression of the gamma 2 subunit was required and Ro 15-1788 (1 microM) completely prevented the potentiation caused by ICS 205-930. Thus, several 5-HT3 receptor antagonists inhibit benzodiazepine binding and affect GABAA receptor function. These actions are most pronounced for ICS 205-930 and likely involve direct affects on the GABA/benzodiazepine complex rather than interactions with 5-HT3 receptors.
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PMID:Effects of 5-HT3 receptor antagonists on binding and function of mouse and human GABAA receptors. 795 45


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