DIFFERENTIAL REGULATION OF RAT 5-HT2A AND 5-HT2C RECEPTORS AFTER CHRONIC TREATMENT WITH CLOZAPINE, CHLORPROMAZINE AND 3 PUTATIVE ATYPICAL ANTIPSYCHOTIC-DRUGS

Interactions with 5-HT2A and 5-HT2C receptors may be important for the actions of atypical antipsychotic drugs, such as clozapine (CLOZ). In this study we characterized the interaction of chlorpromazine (CPZ) a nd three putative atypical antipsychotic drugs, risperidone (RIS), amp erozide (AMP), and ORG 5222 (ORG) with the 5-HT2A and the 5-HT2C recep tor. CLOZ was used as a reference agent. These agents had 5-HT2C recep tor-binding affinities (K-i values) in the following rank order: ORG ( 0.9 nM) > CLOZ (13.2 nM) greater than or equal to CPZ (27.1 nM) > RIS (112 nM) > > AMP (2580 nM). RIS (1.9 nM) and AMP (75.6 nM) had clearly higher affinities for the 5-HT2A than the 5-HT2C receptor; otherwise the 5-HT2A and 5-HT2C receptor affinities were approximately the same. Phosphoinositide hydrolysis studies in the rat choroid plexus reveale d that all these agents were 5-HT2C receptor antagonists, with an appr oximately similar rank order of potency compared to the 5-HT2C recepto r-binding data. Quantitative receptor autoradiography was used to stud y the regulation of 5-HT2A and 5-HT2C receptors after chronic treatmen t (14 days, SC injections once a day) with CLOZ (25 mg/kg), CPZ (15 mg /kg), RIS (0.3 mg/kg), AMP (5 mg/kg), and ORG (0.1 mg/kg). In the dose s used, CLOZ, CPZ, and ORG decreased the frontal cortical 5-HT2A recep tor binding of [H-3]ketanserin and [I-125]DOI by 40% to 60%. AMP also significantly decreased 5-HT2A receptor [H-3]ketanserin binding by 30% , whereas XIS did not affect 5-HT2A receptor binding. In contrast to 5 -HT2A receptors, only CLOZ significantly (by about 50%) decreased 5-HT 2C receptor [H-3]mesulergine and [I-125]DOI binding in the choroid ple xus. For comparison, CPZ was the only drug to significantly upregulate striatal D-2 receptor-binding sites, whereas none of the drugs affect ed striatal D-1 receptors. The main finding in this study is that 5-HT 2A and 5-HT2C receptors are differentially regulated after chronic tre atment with CLOZ, CPZ, RIS, AMP, and ORG.