Asenapine sensitization from adolescence to adulthood and its potential molecular basis

Asenapine is a new antipsychotic drug that induces a long-lasting behavioral sensitization in adult rats. The present study investigated the developmental impacts of adolescent asenapine treatment on drug sensitivity and on 3 proteins implicated in the action of antipsychotic drugs (i.e. brain-derived neurotrophic factor (BDNF), dopamine D2 receptor, and ΔFosB) in adulthood. Male adolescent Sprague-Dawley rats (postnatal days, P 43-48) were first treated with asenapine (0.05, 0.10 or 0.20 mg/kg, sc) and tested in the conditioned avoidance or PCP (2.0 mg/kg, sc)-induced hyperlocomotion tasks for 5 days. After they became adults (∼P 76), asenapine sensitization was assessed in a single avoidance or PCP-induced hyperlocomotion challenge test with all rats being injected with asenapine (0.10 mg/kg, sc). Rats were then sacrificed 1 day later and BDNF, D2 and ΔFosB 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 (0.10 and 0.20 mg/kg) in adolescence made significantly fewer avoidance responses and showed a stronger inhibition of spontaneous motor activity than those previously treated with saline. However, no group difference in the levels of BDNF, D2 and ΔFosB 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, D2 and ΔFosB.