Behavioral disinhibition and depression in amphetaminized rats: a comparison of risperidone, ocaperidone and...

The mixed serotonin-2/dopamine-D2 antagonists risperidone and ocaperidone were compared with the specific D2 antagonist haloperidol for their ability to antagonize amphetamine (10 mg/kg, s.c.)-induced stereotypy in rats. Four successive stages of amphetamine antagonism were differentiated: 1) disinhibition: reversal of stationary stereotypy into the hyperactivity normally observed with lower doses of amphetamine; 2) inhibition: the first significant reduction of activity; 3) normalization: reduction of activity to the level of nonamphetaminized rats; and 4) suppression: reduction of activity to 50% of the level of nonamphetaminized rats. Ocaperidone and risperidone were equipotent with haloperidol for disinhibition (0.0062-0.011 mg/kg). However, the disinhibition was maintained over a wider dose range with risperidone (factor 84) than with haloperidol (9.0) and ocaperidone (4.1) and was also more pronounced in magnitude with risperidone. Ocaperidone was equipotent with haloperidol for inhibition (0.013-0.025 mg/kg) and normalization (0.074-0.080 mg/kg) but 4.4 times less potent for suppression of activity (0.71 vs. 0.16 mg/kg). Risperidone became progressively less potent than haloperidol: 4.4 times for inhibition, 9.6 times for normalization and 22 times for suppression of activity. The present data are consistent with the hypothesis that serotonin-2 antagonism compensates for the functional consequences of D2 receptor blockade. The implications for the clinical application of the compounds are discussed.