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

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.