An evaluation of the role of 5-HT(2) receptor antagonism during subchronic antipsychotic drug administration in rats.

A widely postulated mechanism of action for the atypical profile of many novel antipsychotic drugs (APDs) is their relatively high affinity for 5-HT(2) receptors. The present study investigated motor function and striatal dopamine (DA) efflux and metabolism in rats given 21 daily injections of drugs that differed in 5-HT(2) affinity. These drugs included: risperidone (high 5-HT(2A/2C)/high D(2)), clozapine (high 5-HT(2A/2C)/low D(2)), haloperidol (low 5-HT(2A/2C)/high D(2)), haloperidol+ritanserin (selective 5-HT(2A/2C)), or vehicle. Rats injected with haloperidol (0.5 mg/kg) or haloperidol+ritanserin (0.5 mg/kg and 1.0 mg/kg, respectively) showed extreme catalepsy on day 1, but significantly decreased catalepsy when tested again on days 7 and 21. Acute or subchronic risperidone (0.05 or 0.5 mg/kg), clozapine (20 mg/kg), or vehicle did not induce significant catalepsy. Microdialysis performed 24 h after the last injection demonstrated that rats treated with risperidone, clozapine, or vehicle showed similar increases in DA efflux and metabolism following an acute injection of a selective DA D(2/3) antagonist (raclopride, 0.5 mg/kg). DA efflux showed an attenuated response to raclopride in the haloperidol alone group; this effect was less apparent in the haloperidol+ritanserin group. However, both of these groups showed a similar tolerance effect to the raclopride-induced increase in DA metabolites. These results suggest that the profile seen after subchronic risperidone more closely resembles clozapine than haloperidol. While ritanserin reduced the tolerance-like effects of haloperidol on striatal DA efflux, the overall results demonstrate that potent 5-HT(2) blockade alone may not entirely account for the distinctive profile of novel APDs.