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 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

A series of esters and amides of 1-alkyl-2-oxo-1,2-dihydroquinoline-4- carboxylic acid or 2-alkoxy-quinoline-4-carboxylic acid containing a basic azabicycloalkyl moiety has been synthesized and evaluated for affinity for the [3H]quipazine-labeled 5-HT3 receptors. Most of the esters exhibited 10-fold more potent activity than that of ondansetron (1; Ki = 7.6 nM). Lipophilic substituents at the 1- or 2-position of the quinoline ring enhanced affinity for the receptors. Compounds 21 and 37 showed the highest affinity (Ki = 0.32 and 0.31 nM, respectively) among them. On the other hand, most of the amides showed 100-fold lower affinity than that of the esters. Molecular modeling studies indicated that the carbonyl moiety in 19 (ester) or 31 (amide) was not coplanar to the plane of an aromatic ring (over 20 degrees deviation). Although some of the selected compounds exhibited potent activity in the Bezold-Jarisch (B-J) reflex test, good correlation was not observed between the affinity for the 5-HT3 receptors and the activity in the B-J reflex test (in vivo). From these data, it was suggested that our quinoline derivatives might interact with the 5-HT3 receptors in a different way from that of the reported 5-HT3 receptor antagonists presumably due to the presence of the heterogeneity of the 5-HT3 receptors between brain and heart.
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PMID:5-HT3 receptor antagonists. 1. New quinoline derivatives. 147 89

In the present study, we have investigated how various 5-HT agonists (m-chlorophenylpiperazine (mCPP) (0.1-1 mg/kg), 8-hydroxy 2-(di-N-propylamino) tetralin (8-OH DPAT) (0.125-2 mg/kg) and 5-HT (0.5-2 mg/kg)), the 5-HT uptake blocker sertraline (1-10 mg/kg), and the 5-HT uptake blocker and releaser dexfenfluramine (0.5-2.5 mg/kg), affect ethanol intake in a continual access paradigm using Wistar rats. By means of a drinkometer system the effect of each drug on microdrinking parameters (e.g., drink latency, number, and duration of drinking bouts) was assessed. The effect of various 5-HT antagonists (metergoline, ritanserin, ondansetron, and xylamidine) against the dexfenfluramine-induced suppression was studied. Furthermore, threshold doses for the anorectic and the suppressant effects of mCPP, sertraline and dexfenfluramine on ethanol intake were identified. From these studies, it seemed that similar mechanisms may be responsible for the suppressant effects of the various 5-HT agonists studied (direct and indirect) on ethanol and food intake. The 5-HT3 receptor antagonist, ondansetron, also reduced ethanol (but not food) intake. However, the profile of this effect may suggest an alternative means by which 5-HT3 receptors regulate ethanol intake in the rat by comparison to the various 5-HT agonists studied.
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PMID:Effect of drugs influencing 5-HT function on ethanol drinking and feeding behaviour in rats: studies using a drinkometer system. 148 Mar 50

1. Three ipsilateral (MSR, PSR, IPSI SLOW) and two contralateral segmental reflexes (CON FAST, CON SLOW) were recorded from L4 or L5 ventral roots of the neonate rat spinal cord in vitro. MSR, PSR and CON FAST were evoked from lower threshold afferents; more intense stimulation evoked IPSI SLOW and CON SLOW. 2. Kainate/AMPA receptors were involved in mediation of MSR, PSR, CON FAST, IPSI SLOW and CON SLOW and NMDA receptors in mediation of CON FAST, IPSI SLOW and CON SLOW. 3. All five reflexes were depressed by 5-HT (IC50 1.2-7.9 microM; order of sensitivity, CON SLOW > CON FAST = IPSI SLOW > MSR = PSR); and by 5-CT (IC50 1.9-8.8 nM; order of sensitivity, MSR > IPSI SLOW = CON FAST = CON SLOW > PSR). alpha-Me-5-HT also depressed all five reflexes. 4. Dipropyl-5-CT selectively depressed MSR and CON SLOW (IC50 90-170 nM) but was less potent than 5-CT. 8-OH-DPAT selectively depressed MSR (IC50 1.1 microM), IPSI SLOW and CON SLOW (IC50 5.7-7.6 microM), while methylsergide depressed only MSR (IC50 26 nM). 5. Phenyl biguanide and m-chlorophenyl biguanide (5-HT3 receptor agonists) had no significant effects on any reflex. 6. It is concluded that a 5-HT1-like receptor mediates depression of the MSR. A different receptor or a mixed population of receptors, but not 5-HT3 receptors, mediate inhibition of PSR, CON FAST, IPSI SLOW and CON SLOW.
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PMID:FAST and SLOW ipsilateral and contralateral spinal reflexes in the neonate rat are modulated by 5-HT. 148 13

1. Intracerebral microdialysis was used to determine whether 5-hydroxytryptamine (5-HT) release in the ventral hippocampus of rats anaesthetized with chloral hydrate was modulated by 5-HT3 receptors. 2. It was confirmed that 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969), a selective 5-HT1B receptor agonist, decreased 5-HT release in a dose- and concentration-related manner when administered i.p. (1 and 5 mg kg-1) or via the dialysis probe (0.1 and 1 microM) respectively. The effect of RU 24969 infusion (1 microM) was attenuated by concurrent infusion of metitepine (10 microM) into the hippocampus. 3. When infused into the hippocampus for 15 min, the selective 5-HT3 receptor agonist, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT; 0.1- 10 microM) increased dialysate 5-HT levels in a concentration-related manner; an effect which was abolished by concurrent infusion of 3-tropanyl-3,5-dichlorobenzoate (1 microM, MDL 72222), a selective 5-HT3 antagonist. 4. MDL 72222 had no effects on hippocampal 5-HT release when administered via the dialysis probe (1 or 10 microM). 5. The data show that 5-HT3 and 5-HT1B receptors have opposing roles in the control of 5-HT release in the hippocampus, with 5-HT3 receptors facilitating and 5-HT1B receptors inhibiting 5-HT efflux, respectively. They also indicate that the facilitatory 5-HT3 receptors are not tonically activated.
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PMID:Opposing roles for 5-HT1B and 5-HT3 receptors in the control of 5-HT release in rat hippocampus in vivo. 150 23

1. Tritiated derivatives of the potent and selective 5-HT3 receptor antagonists GR65630 and LY278584 were used to identify 5-HT3 recognition sites in the rat gastrointestinal tract. 2. Binding studies were carried out in homogenates of the rat oesophagus, the cardia, fundus, body and antrum of the stomach, regions of the small intestine, caecum and large intestine. The specific binding of a single concentration of GR65630 (0.5 nM) defined by granisetron (10 microM) in these areas indicated that the density of 5-HT3 recognition sites varied from 2.4 +/- 1.0 to 10.1 +/- 1.0 fmol mg-1 protein. 3. Saturable binding of [3H]-GR65630 could only be demonstrated in the terminal regions of the small intestine (Bmax in the range of 13.83 +/- 4.54-21.19 +/- 0.89 fmol mg-1 protein; mean +/- s.e. mean) and of high affinity (Kd in the range of 0.42 +/- 0.18-0.79 +/- 0.24 nM). Use of [3H]-LY278584 revealed a similar binding density (Bmax 19.54 +/- 0.26 fmol mg-1 protein) and affinity (Kd 1.04 +/- 0.07 nM) in the terminal small intestine. 4. Binding of [3H]-GR65630 and [3H]-LY278584 to the terminal region of the small intestine was inhibited by 5-HT3 receptor ligands ondansetron and S-zacopride (and 5-hydroxytryptamine), but not by 5-HT1, 5-HT2, catecholamine, gamma-aminobutyric acid and opioid receptor ligands. 5. These data demonstrate that there are regional variations in the density of 5-HT3 recognition sites within the rat gastrointestinal tract. Such data are relevant to the potential use of 5-HT3 receptor ligands to modify secretory and contraction responses in the gastrointestinal system.
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PMID:Identification and distribution of 5-HT3 recognition sites in the rat gastrointestinal tract. 150 52

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 effects of the 5-HT3 receptor antagonists, zacopride, ondansetron and ICS 205-930, were investigated in an animal model of depression, the learned helplessness test. Rats previously subjected to a session of 60 inescapable foot-shocks exhibited a deficit of escape performance in three subsequent shuttle-box sessions. The 5-HT3 receptor antagonists administered i.p. twice daily on a chronic schedule (zacopride 0.03-2 mg/kg per day; ondansetron and ICS 205-930: 0.125-2 mg/kg per day) reduced the number of escape failures at low to moderate daily doses. This effect was not observed with the highest dose(s) of zacopride, ondansetron and ICS 205-930 tested. These results indicate that 5-HT3 antagonists may have effects like those of conventional antidepressants in rats.
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PMID:5-HT3 receptor antagonists reverse helpless behaviour in rats. 153 55

The purpose of the present study was to reassess the original findings of Carboni et al. (1988) who suggested that 5-HT3 receptor antagonists may block morphine-induced place conditioning in rats. These workers used a biased protocol with treatments allocated to compartments based on initial preference. In the present study we have adopted an unbiased approach with treatments randomly assigned to conditioning compartment in a counter-balanced fashion. Thus treatments were equally paired between distinct environmental cues. Using this protocol, morphine produced a dose-related place preference (0.3-3 mg/kg SC). Thirty-minute pretreatment with the selective 5-HT3 antagonists, MDL72222 (1 mg/kg SC) and ondansetron (0.01 mg/kg SC) before morphine (1.5 mg/kg SC), significantly antagonized the place conditioning to this treatment. However, with higher doses of ondansetron (0.1-1 mg/kg SC), the antagonism of morphine-induced place preference became variable and dependent on the conditioning compartment. This was probably a reflection of the fact that ondansetron when administered alone also appeared to produce an environmentally dependent place conditioning at these doses. Therefore it is concluded that at certain doses, 5-HT3 receptor antagonists may antagonize morphine place conditioning in a manner consistent with a blockade of the appetitive effects of this drug. However, at higher doses, at least with ondansetron, this antagonism became non-specific and dependent on the training environment. It is suggested that other animal models of opioid reinforcement (e.g., self-administration) are now needed to validate the hypothesis that 5-HT3 receptor antagonists may modify opioid reward.
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PMID:Effect of the 5-HT3 receptor antagonists, MDL72222 and ondansetron on morphine place conditioning. 153 88


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