Chronic mild stress (CMS)-induced 'anhedonia' is a predictive model of antidepressant activity. We assessed the reversal of CMS-induced behavioral changes by asenapine, the antidepressant imipramine, and the atypical antipsychotics otanzapine and risperidone. Secondarily, the ability of these agents to facilitate intracranial self-stimulation (ICSS) was assessed to ensure that any attenuation of CMS-induced anhedonia was not associated with an overt hedonic profile. After 2 weeks of CMS, male Wistar rats were administered asenapine (0.06-0.6 mg/kg), olanzapine (2 mg/kg), risperidone (0.5 mg/kg), or imipramine (10 mg/kg) by intraperitoneal injection over 5 weeks to examine their ability to reverse CMS-induced reductions in the intake of a sucrose solution. For the ICSS study, rats were trained to deliver an electrical stimulus to the ventral tegmental area. The effects of acute doses of subcutaneous asenapine (0.01-0.3 mg/kg), otanzapine (0.3 and 1 mg/kg), risperidone (0.1 and 0.3 mg/kg), and intraperitoneal imipramine (3-30 mg/kg), cocaine (5.0 mg/kg), or amphetamine (1.0 mg/kg) on ICSS were then examined. CMS significantly reduced sucrose intake (P < 0.001). All active agents (0.6 mg/kg asenapine, 2 mg/kg olanzapine, 0.5 mg/kg risperidone, and 10 mg/kg imipramine) reversed the effect of CMS (all P < 0.001). In the ICSS protocol, asenapine (0.01 and 0.03 mg/kg), olanzapine (1 mg/kg), and risperidone (0.3 mg/kg) impaired ICSS performance, whereas positive controls (5 mg/kg cocaine, 1 mg/kg amphetamine) facilitated ICSS. Asenapine reversed CMS-induced anhedonia without facilitating ICSS, providing support for a role of asenapine in treating bipolar disorder and aspects of negative and/or affective symptoms in schizophrenia.
