Megens, A.A.H.P., C.J.E. Niemegeers, and F.H.L. Awouters: Antipsychotic profile and side-effect liability of haloperidol, risperidone, and ocaperidone as predicted from their differential interaction with amphetamine in rats. Drug Dev. Res. 26:129-145, 1992. Motor activity effects of haloperidol, risperidone, and ocaperidone were studied in rats challenged with amphetamine. At a low dose of amphetamine, the compounds were about equipotent in reducing amphetamine-induced hyperactivity to normal values (lowest ED, , s: 0.01 5-0.023 mg/kg). Haloperidol completely blocked motility at a slightly higher dose (0.14 mgikg). In contrast, much higher doses of risperidone and ocaperidone were required for complete blockade of motility (ED, , s: 2.0 and 1.7 mg/kg, respectively). With increasing dose of amphetamine, risperidone became considerably less potent than haloperidol in reducing hyperactivity; ocaperidone remained at least as potent as haloperidol in this respect. Moreover, risperidone lost, while ocaperidone maintained, its high margin towards complete blockade of motility. The compounds were also equipotent (lowest ED, , s: 0.0075-0.0089 mg/kg) in reversing amphetamine-induced behavioral withdrawal (stationary stereotypy) to more environment directed behavior (active exploration). However, this "disinhibitory" effect was maintained over a much wider dose range with risperidone than with haloperidol and ocaperidone. The observed differences in interaction with amphetamine are presumably related to relative serotonin 5HT2/dopamine D , antagonistic activity and suggest important differences in therapeutic profile and side-effect liability of the
