Effect of typical and atypical antipsychotic drugs on 5-HT₂ receptor density in rat cerebral cortex

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 tiospirone, amperozide and melperone did not. None of the drugs affected the K_d value. Among the typical antipsychotic drugs, loxapine decreased B_max and increased the K_d 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 B_max without increasing K_d. 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.