Repeated Asenapine Treatment Produces A Sensitization Effect In Two Preclinical Tests Of Antipsychotic Activity And Its Potential Molecular Basis

Asenapine is a novel antipsychotic drug recently approved for the treatment of schizophrenia and manic disorders. It shares several receptor binding and behavioral features with other atypical antipsychotic drugs. Repeated administration of atypical antipsychotic drugs often causes either a sensitization effect (in the case of olanzapine and risperidone) or a tolerance effect (in the case of clozapine) in various behavioral tests, however, it is not clear what long-term effect (sensitization or tolerance) that asenapine would induce, and whether such an effect is transferrable to other atypicals. The present study addressed these issues by testing asenapine in the conditioned avoidance response (CAR) and phencyclidine (PCP)-induced hyperlocomotion paradigms-two well established animal tests of antipsychotic activity. Male adult Sprague-Dawley rats were first repeatedly tested with asenapine (0.05,0.10or0.20mg/kg, sc) for avoidance response or PCP (3.20mg/kg, sc)-induced hyperlocomotion daily for5consecutive days. After2-3days of retraining/drug-free recovery, they were then challenged with asenapine (0.10mg/kg, sc), followed by olanzapine (0.50mg/kg, sc) and clozapine (2.50mg/kg, sc). During the5-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 profile. Asenapine is a new antipsychotic drug that induces a long-lasting behavioral sensitization in adult animals. The present study investigated the developmental impacts of adolescent asenapine treatment on drug sensitivity and on3proteins implicated in the action of antipsychotics (i.e. Brain-derived neurotrophic factor (BDNF), dopamine D2receptor, and AFosB) in adulthood. Male adolescent Sprague-Dawley rats (postnatal days, P43-48) were first treated with asenapine (0.05, or0.10and0.20mg/kg, sc) and tested in the conditioned avoidance or PCP (2.00mg/kg, sc)-induced hyperlocomotion tasks for5days. After they became adults (-P76), asenapine sensitization was assessed in a single avoidance or PCP-induced hyperlocomotion challenge test with all rats being injected with asenapine (0.10mg/kg, sc). Rats were then sacrificed1day later and BDNF, D2and AFosB in the prefrontal cortex, striatum and hippocampus were examined using Western blotting. In adolescence, repeated asenapine treatment produced a persistent and dose-dependent inhibition of avoidance response, spontaneous motor activity and PCP-induced hyperlocomotion. In the asenapine challenge test, adult rats treated with asenapine (0.10and0.20mg/kg) in adolescence made significantly fewer avoidance responses and showed a stronger inhibition of spontaneous motor activity than those previously treated with vehicle. However, no group difference in the levels of BDNF, D2and AFosB expression was found. These findings suggest that although adolescent asenapine treatment for a short period of time induces a robust behavioral sensitization that persists into adulthood, such a long-term effect is not likely to be mediated by BDNF, D2and AFosB.Part I Repeated asenapine treatment produces a sensitization effect in two preclinical tests of antipsychotic activityObjective To determine what long-term effect (sensitization or tolerance) that asenapine would induce, and whether such an effect is transferable to other atypical antipsychotic drugs.Methods Testing asenapine in the conditioned avoidance response (CAR) and phencyclidine (PCP)-induced hyperlocomotion paradigms-two well established animal tests of antipsychotic activity. Male adult Sprague-Dawley rats were first repeatedly tested with asenapine (0.05,0.10or0.20mg/kg, sc) for avoidance response or PCP (3.20mg/kg, sc)-induced hyperlocomotion daily for5consecutive days. After2-3days of retraining/ drug-free recovery, they were then challenged with asenapine (0.10mg/kg, sc), followed by olanzapine (0.50mg/kg, sc) and clozapine (2.50mg/kg, sc).Results During the5-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.Part II Asenapine sensitization from adolescence to adulthood and its molecular basisObjective To investigated the developmental impacts of adolescent asenapine treatment on drug sensitivity and on3proteins implicated in the action of antipsychotics (i.e. Brain-derived neurotrophic factor (BDNF), dopamine D2receptor, and AFosB) in adulthood.Methods Male adolescent Sprague-Dawley rats (postnatal days, P43-48) were first treated with asenapine (0.05, or0.10and0.20mg/kg, sc) and tested in the conditioned avoidance or PCP (2.00mg/kg, sc)-induced hyperlocomotion tasks for5days. After they became adults (-P76), asenapine sensitization was assessed in a single avoidance or PCP-induced hyperlocomotion challenge test with all rats being injected with asenapine (0.10mg/kg, sc). Rats were then sacrificed1day later and BDNF, D2and AFosB in the prefrontal cortex, striatum and hippocampus were examined using Western blotting.Results In adolescence, repeated asenapine treatment produced a persistent and dose-dependent inhibition of avoidance response, spontaneous motor activity and PCP-induced hyperlocomotion. In the asenapine challenge test, adult rats treated with asenapine (0.10and0.20mg/kg) in adolescence made significantly fewer avoidance responses and showed a stronger inhibition of spontaneous motor activity than those previously treated with vehicle. However, no group difference in the levels of BDNF, D2and AFosB expression was found. Conclusions1. 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 profile.2. These findings suggest that although adolescent asenapine treatment for a short period of time induces a robust behavioral sensitization that persists into adulthood, such a long-term effect is not likely to be mediated by BDNF, D2and ΔFosB.