Discriminative stimulus properties of the atypical antipsychotic clozapine and the typical antipsychotic chlorpromazine in a three-choice drug discrimination procedure in rats.

RATIONALE: The atypical antipsychotic drug (APD) clozapine elicits a robust discriminative cue that is generally selective for other atypical APDS in two-choice drug discrimination (DD) procedures.

OBJECTIVES

The present study determined whether a three-choice DD procedure with the atypical APD clozapine (CLZ) versus the typical APD chlorpromazine (CPZ) versus vehicle (VEH) could provide greater selectivity between atypical and typical APDs.

METHODS

Sprague-Dawley rats were trained to discriminate 5.0 mg/kg CLZ from 1.0 mg/kg CPZ from VEH in a three-lever DD task with an FR30 food reinforcement schedule.

RESULTS

Generalization testing with CLZ produced CPZ-appropriate responding at lower doses (ED50=0.103 mg/kg) and CLZ-appropriate responding at higher doses (ED50=1.69 mg/kg). Generalization testing with the atypical APD olanzapine produced similar results. In contrast, the atypical APD risperidone and the typical APDs CPZ and haloperidol produced only CPZ-appropriate responding. The muscarinic antagonist scopolamine produced CPZ-appropriate responding at lower doses and CLZ-appropriate responding at higher doses in a manner similar to CLZ and olanzapine. The co-administration of haloperidol (0.00625 mg/kg) with scopolamine shifted the dose-response curve for CLZ-appropriate responding to the left. The 5-HT(2A/2C) antagonist ritanserin and the H1 histamine antagonist pyrilamine did not substitute for either CLZ or CPZ. The alpha1 adrenergic antagonist prazosin did not substitute for CLZ, but produced full substitution for CPZ.

CONCLUSIONS

The three-choice DD procedure clearly distinguished the atypical APDs CLZ and olanzapine from the typical APDs CPZ and haloperidol; however, the stimulus properties of the atypical APD risperidone were similar to CPZ, but not to CLZ. These findings further suggest that CLZ, as well as CPZ, elicits a compound cue.