Rapid recovery of self-stimulation from depression produced by the atypical neuroleptic risperidone is not prevented...

Behavioral effects of the antipsychotic drug risperidone were tested in rats responding for variable-interval stimulation of the ventral tegmental area (VTA). Risperidone (0-0.9 mg/kg) produced a dose-dependent depression of responding in the 60 min after injection. Self-stimulation tests delayed for 30 or 120 min after injection showed that inhibition of responding by risperidone was limited in duration, with response rates recovering to pre-injection levels in a time-dependent manner. Recovery occurred regardless of opportunity to engage in self-stimulation, and was virtually complete at a time when receptor occupancy has been shown to be almost undiminished. The atypical properties of risperidone have been ascribed to its potent antagonist activity at 5-HT2 receptors; however, spontaneous recovery from the effects of risperidone was not prevented by simultaneous administration of a selective 5-HT2 agonist (DOI), even though DOI when given alone produced a 50-70% reduction in response rates. These results show that the inhibitory effect of risperidone on operant performance may be self-limiting in a manner that is not accounted for by its pharmacokinetic properties nor by its antagonist activity at central 5-HT2 receptors.