Interaction of the atypical neuroleptic clozapine with 5-HT3 receptors in the cerebral cortex and superior cervical ganglion of the rat.
Clozapine, an atypical neuroleptic drug devoid of extrapyramidal side effects, was a moderately potent, competitive inhibitor of the binding of [3H]quaternised ICS 205-930 to 5-HT3 receptor sites in rat cortical membranes, possessing a pKi value of 7.0. In contrast, several other antipsychotic agents, including fluphenazine, alpha-flupenthixol, haloperidol, spiperone and (-)-sulpiride were essentially inactive. Clozapine also antagonised the 2-methyl 5-HT-induced depolarisation of the rat isolated superior cervical ganglion, a response known to be mediated via 5-HT3 receptors. Clozapine (0.1-1 microM) induced parallel displacements to the right of the dose-response curve to 2-methyl 5-HT in this tissue, possessing a pKb value of 7.3. These data suggest that the atypical antipsychotic profile of clozapine may be related, at least, in part to its ability to interact with central 5-HT3 receptor sites.
Watling
K J
KJ
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex, U.K.
Beer
M S
MS
Stanton
J A
JA
Newberry
N R
NR
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003024:Clozapine / Q000494:pharmacology*; D005728:Ganglia, Sympathetic / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects*; D014326:Tropanes / Q000494:pharmacology; D000077526:Tropisetron
D014150:Antipsychotic Agents; D007211:Indoles; D011985:Receptors, Serotonin; D014326:Tropanes; D000077526:Tropisetron; D003024:Clozapine; C042253:bemesetron