Further characterization of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in C57BL/6 mice: role of 5-HT2A serotonergic and a1 adrenergic antagonism

• Published in: Psychopharmacology 2009-04, Vol.203 (2), p.303-315
• Main Authors: Philibin, Scott D, Walentiny, DMatthew, Vunck, Sarah A, Prus, Adam J, Meltzer, Herbert Y, Porter, Joseph H
• Format: Article
• Language: English
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-008-1385-3

Rationale: The discriminative stimulus properties of the atypical antipsychotic drug (APD) clozapine (CLZ) have recently been studied in C57BL/6 mice, a common background strain for genetic alterations. However, further evaluation is needed to fully characterize CLZ's discriminative cue in this strain of mice. Objectives: The objectives of the study were to confirm the previous findings using a shorter pretreatment time and to further characterize the receptor mechanisms mediating the discriminative stimulus properties of CLZ by testing APDs, selective ligands, and N-desmethylclozapine (CLZ's major metabolite) in C57BL/6 mice. Materials and methods: C57BL/6 male mice were trained to discriminate 2.5 mg/kg CLZ (s.c.) from vehicle in a two-lever drug discrimination task. Results: Generalization testing with CLZ yielded an ED50=1.19 mg/kg. Substitution testing with APDs showed that the atypical APDs quetiapine, sertindole, zotepine, iloperidone, and melperone fully substituted for CLZ (.80% CLZ-appropriate responding), but aripiprazole did not. The typical APDs chlorpromazine and thioridazine substituted for CLZ (fluphenazine and perphenazine did not). The serotonin (5-HT) 2A antagonist M100907 and the a1-adrenoceptor antagonist prazosin fully substituted for CLZ. The H1 histaminergic antagonist pyrilamine, dopamine agonist amphetamine, and the selective serotonin reuptake inhibitor fluoxetine did not substitute for CLZ. While N-desmethylclozapine did not substitute for CLZ when tested alone, N-desmethylclozapine plus a low dose of CLZ combined in an additive manner produced full substitution. Conclusions: CLZ's discriminative cue in C57BL/6 mice is a 'compound' cue mediated in part by antagonism of 5-HT2A and a1 receptors.