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)

Rats were trained to discriminate the 5-HT receptor agonist m-chlorophenylpiperazine (mCPP; 1 mg/kg) from saline using a two-lever, water-reinforced drug discrimination task. The antidepressant trazodone (1-8 mg/kg), the 5-HT1B/2C receptor agonists 1-(m-trifluoromethylphenyl)piperazine (TFMPP; 0.25-1 mg/kg) and MK 212 (0.125-1 mg/kg), and the mixed 5-HT1A/B receptor agonist RU 24969 (0.25-2 mg/kg) substituted fully for mCPP. The 5-HT2A/2C receptor agonists 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 0.25-1 mg/kg) and d-lysergic acid diethylamide (LSD; 0.02-0.08 mg/kg) and the 5-HT releaser fenfluramine (0.5-2 mg/kg) also mimicked mCPP. Agonists selective for the 5-HT1A or 5-HT3 receptor or the 5-HT reuptake site produced saline-lever responding. The ergoline derivative mesulergine (0.5-4 mg/kg) produced a partial agonist/antagonist profile. The 5-HT1/2 receptor antagonist metergoline (0.125-1 mg/kg) completely blocked the mCPP cue whereas the 5-HT2A/2C receptor antagonists ketanserin and LY 53857 as well as all other 5-HT receptor antagonists failed to block the mCPP cue. The dopamine receptor antagonists SCH 23390 and haloperidol were also ineffective mCPP antagonists. Following pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (pCPA; 100 mg/kg/day) for 3 consecutive days, the discriminability of low doses of mCPP increased, whereas the effects of fenfluramine decreased. The present results suggest that the discriminative stimulus effects of mCPP in rats are mediated primarily by postsynaptic 5-HT2C receptors.
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PMID:Involvement of 5-HT2C receptors in mediating the discriminative stimulus properties of m-chlorophenylpiperazine (mCPP). 808 4

The effects of the new 5-HT3 receptor antagonist, DAU 6215, on aged rats' cognition were assessed in the Morris water maze task. Task performance of aged animals that received acutely the dose of 10 micrograms/kg IP was not different than that of their aged controls treated with the vehicle. Conversely, a repeated IP administration of 10 micrograms/kg DAU 6215 for 3 weeks significantly improved task performance of the aged animals as compared to that displayed by the old rats treated with the vehicle.
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PMID:DAU 6215, a novel 5-HT3 receptor antagonist, improves performance in the aged rat in the Morris water maze task. 829 58

1. The effects of the 5-HT3 receptor antagonists, ondansetron and tropisetron, on morphine consumption were studied in naive and morphine-dependent rats. 2. The administration of ondansetron (1 microgram kg-1, i.p. twice daily) 7 days prior to, and during a 21-day period of, morphine availability (increasing concentration from 0.1 to 0.4 mg ml-1) in 5% sucrose solution reduced opiate intake from the 9th day of morphine treatment. 3. The administration of ondansetron (0.1 microgram kg-1, i.p. twice daily) or tropisetron (0.1 microgram kg-1, i.p. twice daily) on the 14th day of the 21-day period of morphine treatment failed to reduce opiate consumption. Administration of the larger doses of tropisetron (1 microgram kg-1) or ondansetron (1 microgram kg-1) reduced morphine consumption. 4. After receiving 21 days of treatment with morphine alone or with the ondansetron or tropisetron regimens identified above, the sucrose solutions were substituted with tap water for 7 days. These detoxified rats were then allowed a free choice of sucrose or morphine for 10 days. Animals that had received concomitant treatment with ondansetron or tropisetron showed reduced morphine intake when compared with the controls treated with morphine only or with vehicle-treated controls. 5. The administration of cyproheptadine (100 or 250 micrograms kg-1, i.p. twice daily) on the 14th day of 21-day morphine treatment failed to modify morphine intake and also failed to influence the subsequent intake of the opiate in the free choice situation. 6. It is concluded that ondasetron and tropisetron can reduce morphine intake in both naive and morphine-dependent rats.
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PMID:5-HT3 antagonists reduce morphine self-administration in rats. 830 73

The aim of the present studies was to investigate the effects of serotonergic compounds on preference for isotonic saline and aversion to hypertonic saline, respectively. Twenty-two-hour water-deprived rats were divided into two groups: The first was given a choice between 0.9% saline and water in a 30-min test; the second was given a choice between 1.8% saline and water. Animals were tested following administration of d-fenfluramine, the 5-HT1C receptor agonist 6-chloro-2-(1-piperazinyl)pyrazine (MK-212), and the 5-HT3 receptor antagonist ondansetron. d-Fenfluramine (0.3-3.0 mg/kg) did not reduce 0.9% saline preference; instead, at 0.3 mg/kg there was a significant increase in saline drinking. In contrast, MK-212 (0.3-3.0 mg/kg) abolished the preference for isotonic saline whereas ondansetron (10-100 micrograms/kg) had no effect. d-Fenfluramine and MK-212 reduced hypertonic saline drinking, although at the highest dose for each drug water drinking was also reduced. These data add further to the evidence for an important serotonergic involvement in the control of saline drinking and preference in the rat.
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PMID:Effects of d-fenfluramine, MK-212, and ondansetron on saline drinking in two-choice tests in the rehydrating rat. 833 21

The effects of duodenal distension on forestomach and abomasal motility were investigated in conscious sheep chronically fitted with intraparietal electrodes, a duodenal cannula, and an intracerebroventricular cannula. Duodenal distensions with a balloon inflated with 40 ml (DD40) of water reduced the frequency of forestomach and abomasal contractions by 45 and 32%, respectively, while distension with 80 ml (DD80) induced a total inhibition. Methysergide, a mixed 5HT1-5HT2 antagonist administered intravenously (200 micrograms/kg) or intracerebroventricularly (20 micrograms/kg) suppressed the DD40-induced inhibition and reduced that induced by DD80. Spiroxatrine, a selective 5HT1A antagonist, intravenously (100 micrograms/kg) or intracerebroventricularly (10 micrograms/kg), suppressed the DD40 and DD80-induced inhibition, which was also attenuated by the 5HT2 antagonist ritanserin given intravenously (200 micrograms/kg) or intracerebroventricularly (20 micrograms/kg). Granisetron, a 5HT3 antagonist, injected intravenously (150 micrograms/kg), abolished the effects of DD40 and DD80 while it had no antagonistic action on DD40 and DD80 when given intracerebroventricularly (15 micrograms/kg). It is concluded that in sheep, duodenal distension inhibits forestomach and abomasal motility through 5HT1A and 5HT2 receptors at the level of the central nervous system and 5HT3 receptors located peripherally.
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PMID:Central and peripheral serotonergic influences on viscerovisceral inhibitory reflex during duodenal distension in sheep. 850 3

In the present studies we investigated the actions of (R)- and (S)-zacopride, potent 5-HT3 receptor antagonists with 5-HT4 receptor agonists properties, on performance in a spatial learning and memory task in rats, the Morris water maze. A significant cognitive/performance deficit, as indicated by the increased escape latency across several trials, was produced by systemic administration of the muscarinic receptor antagonist atropine (30 mg/kg, IP). (R)-zacopride (0.001-1 microgram/kg, but not 10 or 100 micrograms/kg) significantly reduced escape latency in atropine-treated animals. (S)-Zacopride was inactive over the entire dose range examined (0.001-100 micrograms/kg, i.p.). Moreover, pretreatment with (S)-zacopride (1 or 100 micrograms/kg) did not alter the procognitive effects of (R)-zacopride (1 microgram/kg). These data demonstrate that the cognition enhancing properties of zacopride in this model of cholinergic hypofunction are exclusive to its (R)-enantiomer and imply that this action is unrelated to 5-HT, receptor antagonism or 5-HT4 receptor agonism. The possibility that the procognitive effects of (R)-zacopride may be related to actions at the novel "(R)-zacopride site" is discussed.
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PMID:Stereoselective effects of (R)- and (S)-zacopride on cognitive performance in a spatial navigation task in rats. 878 7

The effects of the 5-HT3 receptor antagonists. WAY-100,579 and ondansetron (both at doses of 0.001, 0.01 and 0.1 mg/kg s.c.) and the muscarinic receptor agonist arecoline (1.0 mg/kg s.c.), on spatial learning and memory in the water maze were examined in rats after combined S-AMPA lesions to the nucleus basalis and medial septal brain regions. Lesioned rats showed substantially increased latency to find the submerged platform, and spent less time searching in the correct quadrant, and more time circling the periphery of the pool, relative to controls. Lesioned rats treated with WAY-100,579, ondansetron and arecoline exhibited marked improvement in these parameters of learning relative to lesioned animals, with arecoline-treated animals showing the most substantial recovery. Linear dose-related trends of improvement were seen with both of the 5-HT3 antagonists. In probe trials, testing retention of the platform position 24 and 72 h after the end of training, control rats exhibited substantial superiority relative to lesioned rats in accuracy of search in the training quadrant and former platform area, matched by rats treated with arecoline on the first, and by rats treated with the two higher doses of WAY-100,579 and ondansetron on the second probe trial. These results are consistent with our previous studies which demonstrated that another selective 5-HT3 receptor antagonist. WAY-100,289, significantly reversed the cognitive deficits in water maze performance induced by ibotenic acid lesions of forebrain cholinergic projection system. Therefore, selective 5-HT3 receptor antagonists may provide a novel effective therapy for treating cognitive deficits associated with degeneration of central cholinergic neurones, such as Alzheimer's disease or age-associated memory impairment.
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PMID:Comparison of the effects of the 5-HT3 receptor antagonists WAY-100579 and ondansetron on spatial learning in the water maze in rats with excitotoxic lesions of the forebrain cholinergic projection system. 878 89

The functional effects of serotonin (5-HT) drugs and toxins on regional cerebral metabolic rates for glucose (rCMRglc) have been determined in rats with the in vivo, quantitative, autoradiographic [14C]2-deoxyglucose technique. Serotonin agents produced rCMRglc patterns different and more specific that one would predict from binding studies. At low doses 5-HT1 agonists reduced rCMRglc in limbic areas and at high doses increased rCMRglc in brain motor regions. The 5-HT2 agonists dose-dependently decreased rCMRglc in proencephalic areas and increased it in thalamic nuclei. 5-HT3 receptor antagonism resulted in rCMRglc decreases in limbic, auditory and visual areas and agents with 5-HT3 receptor activity increased rCMRglc in brain regions with high 5-HT3 receptor densities. Serotonin anxiolytics (e.g. azapirones) and antidepressants (e.g. tryciclic and non-tryciclic 5-HT reuptake inhibitors) reduced rCMRglc selectively in limbic areas and in brainstem monoaminergic nuclei. Dose, time from administration, receptor affinity, behavioral and neurochemical correlates, 5-HT system lesion and circulating glucocorticoid were all relevant factors in determining the rCMRglc effects of 5-HT drugs. Acutely neurotoxic amphetamines markedly increased rCMRglc in brain regions such as the nucleus accumbens that are thought to mediate amphetamine reinforcing properties; on the long term, toxic or electrolytic lesions or chronic treatment with 5-HT agonists produced minimal rCMRglc alterations in spite of marked and persistent changes in 5-HT function. In lesioned or chronically treated rats, acute challanges with 5-HT and non 5-HT agonists demonstrated specific deficits that were not detected in a resting state. Serotonin neuromodulation has been studied in humans by using positron emission tomography with 15O-water. Sequential measurements of regional cerebral blood flow (rCBF) were obtained during combined pharmacological challange with the 5-HT1A agonist buspirone and cognitive activation. Buspirone increased a memory related rCBF activation in task specific regions. This technique can provide a strong theoretical basis for the understanding of 5-HT drug mode of action in normal human brain and in neuropsychiatric diseases. Brain metabolism studies in animals will still be needed to elucidate the factors (e.g. pharmacokinetic and pharmacodynamic) relevant to the cerebral response to 5-HT drugs in humans.
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PMID:Cerebral metabolic effects of serotonin drugs and neurotoxins. 879 99

The effects of the 5-HT3 receptor antagonists tropisetron (ICS 205-930) and ondansetron on memory and performance impairments induced by scopolamine were tested in a passive avoidance procedure and in the Morris water maze task. Pretreatment with ondansetron (0.01 and 1 microgram/kg i.p.) but not with tropisetron (1, 10, and 30 micrograms/kg i.p.) reversed scopolamine-induced memory deficits in the step-through passive avoidance task. When the effects of these 5-HT3 receptor antagonists on cognition were assessed in the Morris water maze, ondansetron (0.01, 1, and 10 micrograms/kg i.p.) did not antagonize scopolamine-induced spatial navigation deficits. On the contrary, pretreatment with tropisetron (10 and 30 micrograms/kg, and to some extent also with 1 microgram/kg i.p.) counteracted the learning and memory impairment due to scopolamine treatment. The findings suggest that it could be worthwhile to investigate whether or not different subtypes of the 5-HT3 receptor may underlie the different effects on cognition displayed by compounds that belong to the same pharmacological class.
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PMID:Different effects of tropisetron and ondansetron in learning and memory paradigms. 913 Feb 79

It has long been thought that intestinal absorption of most of the drugs proceeds by passive diffusion mechanism, in which lipid solubility of the drug molecule is a determinant factor. However, water-soluble natural compounds such as amino acids and sugars can move across cell membranes by the specialized carrier-mediated transport mechanisms. Although some drugs which are structurally analogous to natural compounds have been suggested to be absorbed by such transporters, no clear evidence for the involvement of carrier-mediated transport mechanisms has been obtained. In the present study, through the approach by means of the molecular cloning and functional expression of drug transporters as well as membrane physiological analysis for the drug transport across the intestinal epithelial cell membranes, participation of the carrier-mediated transport mechanisms for the drug absorption was clarified. They include peptide transporter, monocarboxylic acid transporter, anion antiporter, and P-glycoprotein. Most of them have a function for the uptake of drugs into epithelial cells, leading to the increased absorption of drugs, whereas P-glycoprotein excludes drugs into the lumen, thereby decreasing the apparent absorbability of drugs. A rat intestinal monocarboxylic acid-proton cotransporter, MCT1, and an anion antiporter, AE2, were suggested to contribute to the pH-dependent intestinal absorption of monocarboxylic acids such as benzoic acid, lactic acid, nicotinic acid, and valproic acid. An involvement of such pH-dependent transporters in the intestinal absorption of weak organic acids is important, because they may have an alternative mechanism against passive diffusion according to the pH-partition hypothesis. PepT1 cloned from rat intestinal epithelial cells as a peptide transporter was clarified to localize at the intestinal epithelia brush-border membrane and to function for the absorption of beta-lactam antibiotics by the proton-gradient energized mechanism. In contrast, P-glycoprotein functions for the secretion of drugs into the intestinal lumen, thereby decreasing intestinal absorption of an immunosuppressive, cyclosporin A and a 5-HT3 receptor antagonist, azasetron. These lines of studies on the clarification of carrier-mediated drug absorption mechanisms will provide new knowledge for the strategies to the enhancement of intestinal absorption of drugs.
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PMID:[Molecular characterization of intestinal absorption of drugs by carrier-mediated transport mechanisms]. 926 Dec 13


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