Effects of antipsychotic drugs on operant responding after acute and repeated administration

The current generation of atypical antipsychotic drugs represents an improvement over traditional ("typical") antipsychotics in many respects. However, a theoretical framework and adequate preclinical models have not yet been developed to predict or explain differences among the atypical antipsychotics, a necessary component of future development. The purpose of the present set of experiments was to identify differences between the acute and subchronic effects of several atypical antipsychotic drugs and the typical antipsychotic haloperidol on operant responding in rats. The effects of haloperidol and the atypical antipsychotics clozapine, olanzapine, risperidone, sertindole, quetiapine, remoxipride, and thioridazine were determined in rats trained to respond for food reward under a multiple fixed ratio 30/fixed interval 60 s schedule. A profile of the acute effects of each drug on response rates, response durations, and within-session effects were determined. Next, the dose of each drug that produced 75% suppression of response rates was administered for 16 consecutive days to determine whether or not tolerance would develop to the rate-suppressing effects of that dose. All drugs produced dose-related decreases in response rates. Only haloperidol and risperidone produced significant increases in response duration, while only haloperidol and remoxipride displayed within-session response decrements. Tolerance was evident for clozapine and to a lesser extent thioridazine. These results illustrate that the current generation of atypical antipsychotics are a heterogeneous group and that operant procedures may be useful for identifying differences preclinically. Specifically, clozapine appears to possess properties that distinguish it from other atypical antipsychotics, particularly after repeated dosing.