This study examined regional changes of 5-HT(2A and 2C) receptor mRNA expression in the rat brain after chronic administration of clozapine (1.5 mg/kg/day) and haloperidol (2.0 mg/kg/day) for 36 days. 5-HT(2A and 2C) receptor mRNA expression and distributions were detected by in situ hybridization after rats were sacrificed either 2 or 48 h after the last drug administration to examine both immediate and delayed effects following drug withdrawal. Following 2 h of drug withdrawal, it showed that clozapine administration significantly decreased 5-HT(2A) receptor mRNA, predominantly in the nucleus accumbens (65%), hippocampus (80%), lasteral septal nucleus (61%) and striatum (68%) compared to controls, whilst rebound increases were observed in most of these regions 48 h later. In contrast, no change in 5-HT(2A) receptor mRNA expression was found in the haloperidol treated groups either 2 h or 48 h after drug withdrawal. Clozapine also decreased 5-HT(2C) receptor mRNA expression in the posteromedial cortical amygdala (32%) and substantia nigra (35%) 2 h after the last drug administration, while rebound effects were also observed 48 h later. 5-HT(2C) receptor mRNA was only decreased in the substantia nigra at both 2 h (42%) and 48 h (54%) after the last haloperidol administration. Alterations in serotonin receptor expression in limbic system region such as the nucleus accumbens, hippocampus and lateral septal nucleus as well as the striatum may represent the specific regional targets that mediate the clinical effects of antipsychotics via the serotonin system.