Repeated asenapine treatment produces a sensitization effect in two preclinical tests of antipsychotic activity

Among several commonly used atypical antipsychotic drugs, olanzapine and risperidone cause a sensitization effect in the conditioned avoidance response (CAR) and phencyclidine (PCP)-induced hyperlocomotion paradigms - two well established animal tests of antipsychotic drugs, whereas clozapine causes a tolerance effect. Asenapine is a novel antipsychotic drug recently approved for the treatment of schizophrenia and manic disorders. It shares several receptor binding sites and behavioral features with other atypical antipsychotic drugs. However, it is not clear what type of repeated effect (sensitization or tolerance) asenapine would induce, and whether such an effect is transferrable to other atypicals. In this study, male adult Sprague-Dawley rats were first repeatedly tested with asenapine (0.05, 0.10 or 0.20 mg/kg, sc) for avoidance response or PCP (3.20 mg/kg, sc)-induced hyperlocomotion daily for 5 consecutive days. After 2-3 days of retraining/drug-free recovery, they were then challenged with asenapine (0.10 mg/kg, sc), followed by olanzapine (0.50 mg/kg, sc) and clozapine (2.50 mg/kg, sc). During the 5-day drug test period (the induction phase), repeated asenapine treatment progressively increased its inhibition of avoidance response and PCP-induced hyperlocomotion in a dose-dependent fashion. On the asenapine and olanzapine challenge tests (the expression phase), rats previously treated with asenapine still showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle. An increased reactivity to clozapine challenge in prior asenapine-treated rats was also found in the PCP-induced hyperlocomotion test. These findings suggest that asenapine is capable of inducing a sensitization effect and a cross-sensitization to olanzapine and clozapine (to a lesser extent). Because the behavioral profile of asenapine in both tests is similar to that of olanzapine, but different from that of clozapine, we suggest that asenapine resembles olanzapine to a greater extent than clozapine in its therapeutic and side effect profiles.