BACKGROUND: Cariprazine, a D3-preferring dopamine D2/D3 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 D3 receptors.
METHODS: Wild-type and D3-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 D3-knockout mice, suggesting that the 
cariprazine antidepressant-like activity is mediated by dopamine D3 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 D3 
receptor-dependent mechanism of action that may be beneficial in the treatment 
of schizophrenia, bipolar disorder, and major depressive disorder.