Cariprazine exerts antimanic properties and interferes with dopamine D2 receptor β-arrestin interactions

Activation of dopamine D2 receptors (D2R) modulates G protein/cAMP-dependent signaling and also engages Akt-GSK-3 signaling through D2R/β-arrestin 2 scaffolding of Akt and PP2A. This G protein-independent pathway may be important in mediating the antimanic effects of mood stabilizers and antipsychotics. The mood stabilizer lithium influences behavior and Akt/GSK-3 signaling in mice and many antipsychotics have been shown to more potently antagonize the activity of the β-arrestin-2 pathway relative to the G protein-dependent pathway. Cariprazine, an antipsychotic with potent D3R/D2R partial agonist activity and preferential binding to D3R, was investigated for its effects on the mediators of D2R pathways in vitro and its efficacy in animal models of mania. Effects on G protein-dependent activity were measured via inhibition of isoproterenol-induced cAMP production; effects on D2R/β-arrestin 2 signaling were determined using bioluminescence resonance energy transfer (BRET). Cariprazine was tested in vivo for antimanic-like activity, using the ouabain-induced hyperactivity model in rats. Cariprazine was more potent than aripiprazole in inhibiting isoproterenol-induced cAMP although both compounds showed similar maximum efficacy. In assays of D2R/β-arrestin 2-dependent interactions, cariprazine showed very weak partial agonist activity, unless the levels of receptor kinase were increased; as an antagonist it showed similar potency to haloperidol and ∼fivefold greater potency than aripiprazole. In an animal model of mania, cariprazine showed similar efficacy as lithium in attenuating the effects of ouabain-induced hyperactivity. In summary, the differential effects of cariprazine on D2R G protein and β-arrestin 2 mediators of signal transduction pathways could contribute to its potent antimanic-like activity.