Cariprazine Exhibits Anxiolytic and Dopamine D(3) Receptor-Dependent Antidepressant Effects in the Chronic Stress Model

BACKGROUND: Cariprazine, a D(3)-preferring dopamine D(2)/D(3) receptor partial agonist, is a new antipsychotic drug recently approved in the United States for the treatment of schizophrenia and bipolar mania. We recently demonstrated that cariprazine also has significant antianhedonic-like effects in rats subjected to chronic stress; however, the exact mechanism of action for cariprazine’s antidepressant-like properties is not known. Thus, in this study we examined whether the effects of cariprazine are mediated by dopamine D(3) receptors. METHODS: Wild-type and D(3)-knockout mice were exposed to chronic unpredictable stress for up to 26 days, treated daily with vehicle, imipramine (20 mg/kg), aripiprazole (1 and 5 mg/kg), or cariprazine (0.03, 0.1, 0.2, and 0.4 mg/kg), and tested in behavioral assays measuring anhedonia and anxiety-like behaviors. RESULTS: Results showed that cariprazine significantly attenuated chronic unpredictable stress-induced anhedonic-like behavior in wild-type mice, demonstrating potent antidepressant-like effects comparable with aripiprazole and the tricyclic antidepressant imipramine. This antianhedonic-like effect of cariprazine was not observed in D(3)-knockout mice, suggesting that the cariprazine antidepressant-like activity is mediated by dopamine D(3) receptors. Moreover, cariprazine significantly reduced drinking latency in the novelty-induced hypophagia test in wild-type mice, further confirming its antianhedonic-like effect and showing that it also has anxiolytic-like activity. CONCLUSIONS: In combination with previous studies, these results suggest that cariprazine has a unique pharmacological profile and distinct dopamine D(3) receptor-dependent mechanism of action that may be beneficial in the treatment of schizophrenia, bipolar disorder, and major depressive disorder.