Atypical antipsychotics produce within-session decrements on self-stimulation of the rat medial prefrontal cortex

It has been described that "typical" antipsychotic drugs (APDs) induce characteristic within-session response decrements in operant behaviors, including intracranial self-stimulation (ICSS). In contrast, recent reports have shown that in food operant behavior, clozapine and a number of "atypical" APDs do not give rise to within-session effects. However, to elucidate whether or not this is a common property of atypical APDs, their effects on other operant models need to be studied. To address this question we investigated the temporal pattern of ICSS responding, after systemic administration of five atypical APDs and the typical antipsychotic, haloperidol. Rats were trained to lever press for electrical stimulation at the medial prefrontal cortex (mPFC), and response rates were recorded during each 3-min period of the 15-min session. Significant within-session response decrements on mPFC ICSS were observed with haloperidol, risperidone, sertindole and olanzapine but not with clozapine or ziprasidone. The magnitude of within-session decline produced by the APDs tested was positively correlated with their affinity for dopamine D2 receptors. The results show for the first time that atypical APDs are capable to induce within-session decrements on ICSS behavior, and suggest that this particular temporal pattern of responding is not exclusively characteristic of typical APDs. The results are also consistent with the hypothesis that the ability of APDs to induce greater within-session effects may be related, in part, to potent D2 antagonism.