The effect of acute treatment with seven atypical antipsychotic drugs and four typical antipsychotic drugs on serotonin2 (5-HT2) receptor binding sites in rat cerebral cortex was studied. Among the atypical antipsychotic drugs examined, clozapine, fluperlapine, RMI-81582 and setoperone decreased the density of 5-HT2 receptors, but ticspirone, amperozide and melperone did not. None of the drugs affected the Kd value. Among the typical antipsychotic drugs, loxapine decreased Bmax and increased the Kd of 5-HT2 receptor binding sites, whereas chlorpromazine and cis-flupenthixol had no effect. Clothiapine, a typical antipsychotic drug of the same chemical class as clozapine, decreased Bmax without increasing Kd. The downregulation of 5-HT2 receptor binding sites following a single injection of clozapine, 20 mg/kg, remained almost unchanged during the first 72 hrs and was still significantly decreased for up to 120 hrs. There was no relationship between the affinity for the downregulation of rat cortical 5-HT2 receptor binding site and 5-HT2 receptor density. Coadministration of the D1 dopamine agonist, SKF-38393, did not affect the clozapine-induced downregulation. It is suggested that rapid and prolonged downregulation of 5-HT2 receptor sites is characteristic of some but not all atypical antipsychotic drugs and is not specific to atypical antipsychotic drugs. Dibenzo-epines (clozapine, loxapine, amoxapine, chlothiapine) consistently downregulate 5-HT2 receptors in frontal cortex after acute treatment.