title: Competitive antagonism of serotonin (5-HT)2C and 5-HT2A receptor-mediated phosphoinositide (PI) turnover by clozapine in the rat: a comparison to other antipsychotics.
abstract: The antagonist actions of clozapine and several other antipsychotics at 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors were studied using the in vitro model of 5-HT-induced phosphoinositide (PI) turnover in rat choroid plexus (5-HT2C) and frontal cortex (5-HT2A). While (-)-sulpiride and raclopride were inactive, clozapine and the other drugs behaved as antagonists both at 5-HT2A and at 5-HT2C receptors. Their order of potency (p Inhibitory Concentration (IC)50) was as follows. 5-HT2A receptors: risperidone (9.07) > spiperone > chlorpromazine > clozapine > thioridazine = fluphenazine > haloperidol (6.03). 5-HT2C receptors: clozapine (7.19) > chlorpromazine > risperidone > thioridazine > fluphenazine > spiperone > haloperidol (< 4.00). In each tissue, clozapine shifted the concentration-effect curve for 5-HT to the right in the absence of an alteration in slope or maximal effect. These findings indicate that clozapine acts as a competitive antagonist at 5-HT2A and 5-HT2C receptors and that its antagonist properties are shared, though less potently at 5-HT2C sites, by several, clinically active antipsychotics.
authors.affiliation: Department of Psychopharmacology, Centre de Recherches de Croissy, Paris, France.
authors.forename: H
authors.initials: H
authors.lastname: Canton
authors.forename: L
authors.initials: L
authors.lastname: Verrièle
authors.forename: M J
authors.initials: MJ
authors.lastname: Millan
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D002831:Choroid Plexus / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism; D008297:Male; D010716:Phosphatidylinositols / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000145:classification / Q000502:physiology*
chemical_list: D014150:Antipsychotic Agents; D010716:Phosphatidylinositols; D011985:Receptors, Serotonin; D003024:Clozapine