An evaluation of the role of 5-MT2 receptor antagonism during subchronic antipsychotic drug administration in rats

A widely postulated mechanism of action for the atypical profile of many no vel antipsychotic drugs (APDs) is their relatively high affinity for 5-HT2 receptors. The present study investigated motor function and striatal dopam ine (DA) efflux and metabolism in rats given 21 daily injections of drugs t hat differed in 5-HT2 affinity. These drugs included: risperidone (high 5-H T2A/2C/high D-2), clozapine (high 5-HT2A/2C/low D-2), haloperidol (low 5-HT 2A/2C/high D-2), haloperidol+ritanserin (selective 5-HT2A/2C), or vehicle. Rats injected with haloperidol (0.5 mg/kg) or haloperidol+ritanserin (0.5 m g/kg and 1.0 mg/kg, respectively) showed extreme catalepsy on day 1, but si gnificantly decreased catalepsy when tested again on days 7 and 21. Acute o r subchronic risperidone (0.05 or 0.5 mg/kg), clozapine (20 mg/kg), or vehi cle did not induce significant catalepsy. Microdialysis performed 24 h afte r the last injection demonstrated that rats treated with risperidone, cloza pine, or vehicle showed similar increases in DA efflux and metabolism follo wing 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 halop eridol alone group; this effect was less apparent in the haloperidol+ritans erin group. However, both of these groups showed a similar tolerance effect to the raclopride-induced increase in DA metabolites. These results sugges t that the profile seen after subchronic risperidone more closely resembles clozapine than haloperidol. While ritanserin reduced the tolerance-like ef fects of haloperidol on striatal DA efflux, the overall results demonstrate that potent 5-HT2 blockade alone may not entirely account for the distinct ive profile of novel APDs. (C) 2000 Elsevier Science B.V. All rights reserv ed.