Schizophrenia is a multifactorial disease requiring treatment that manages a broad spectrum of symptoms. Cariprazine is a dopamine D3 and D2 receptor partial agonist antipsychotic candidate with preferential D3 receptor binding.

Evaluate the pharmacological/behavioral profile of cariprazine in animal models.

To determine the activity and receptor occupancy of cariprazine in rat models at doses that confer antipsychotic-like efficacy.

Cariprazine was evaluated in rat paradigms that model symptoms of schizophrenia, mania, and depression. Occupancy of cariprazine, aripiprazole, and risperidone at D3 and D2 receptors was also compared.

Cariprazine showed antipsychotic-like efficacy on conditioned avoidance response and amphetamine-induced motor activity tests (ED50: 0.8 and 0.1 mg/kg) with potencies similar to risperidone (ED50: 0.9 and 0.2 mg/kg) and greater than aripiprazole (ED50: 18 and 3.9 mg/kg). While all 3 compounds displayed high in vivo occupancy of D2 receptors, only cariprazine displayed potent in vivo occupancy of D3 receptors at antipsychotic-like doses (ED50 [% inhibition]: cariprazine, 0.43 mg/kg [99.3]; aripiprazole, >30 mg/kg [26.4]; risperidone: ~2.3 mg/kg [53.4]). At or below antipsychotic-like doses, cariprazine demonstrated antimanic-like, antidepressant-like, anxiolytic-like, and procognitive effects in rats. As determined using D3 receptor knockout mice, procognitive and antidepressant-like effects of cariprazine were shown to be mediated via the D3 receptor.

At antipsychotic-like effective doses in rats, cariprazine demonstrated balanced and significant occupancy at both dopamine D2 and D3 receptors; other antipsychotics displayed relatively low D3 receptor occupancy. Additionally, at antipsychotic-like doses cariprazine demonstrated efficacy in different rat models of mania, mood, anxiety, and cognition.