EPA-0579 – At Antipsychotic-Like Effective Doses, Cariprazine Displays Potent Dopamine D3 and D2 Receptor Occupancy in Vivo and Efficacy Across Animal Models

Abstract

Introduction:

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.

Objective:

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

Aims:

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

Methods:

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.

Results:

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.

Conclusion:

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.