The role of M1 muscarinic cholinergic receptors in the discriminative stimulus properties of N-desmethylclozapine and the atypical antipsychotic drug clozapine in rats

The discriminative stimulus properties of clozapine (CLZ) have been studied for decades because it remains the prototype for atypical antipsychotic drug effects and yet is unique in many ways, including increased efficacy in treatment-resistant schizophrenia and in reducing suicidality. Recent studies have indicated that the active CLZ metabolite N-desmethylclozapine (NDMC) may play a role in mediating the cognitive efficacy of CLZ and may also have atypical antipsychotic properties. The present study sought to determine if NDMC has discriminative stimulus properties similar to that of its parent drug CLZ. Rats were trained to discriminate 1.25 mg/kg CLZ from vehicle in a two-choice drug discrimination task. Although NDMC (2.5-20.0 mg/kg) failed to substitute for CLZ, the combination of NDMC (5.0 and 10.0 mg/kg) with a low dose (0.3125 mg/kg) of CLZ produced full substitution (> 80% CLZ-appropriate responding) for the 1.25 mg/kg CLZ training dose. Co-administration of the M1-preferring receptor antagonist trihexyphenidyl (6.0 mg/kg) with a 5.0 mg/kg dose of NDMC produced partial substitution (> 60% to < 80% CLZ-appropriate responding) for CLZ, while administration of trihexyphenidyl alone (0.3-12.0 mg/kg) failed to substitute for CLZ. These findings suggest that NDMC produces discriminative stimulus effects that are different from those elicited by its parent drug CLZ. This difference may be due to the agonist properties of NDMC at M-1 muscarinic cholinergic receptors.