title: Cariprazine exerts antimanic properties and interferes with dopamine D2 receptor β-arrestin interactions.
abstract: 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.
authors.affiliation: Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine MedCenter One, 501 East Broadway, Suite 340, Louisville, Kentucky, 40202.
authors.forename: Yonglin
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine MedCenter One, 501 East Broadway, Suite 340, Louisville, Kentucky, 40202.
authors.forename: Sean
authors.initials: S
authors.lastname: Peterson
authors.affiliation: Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine MedCenter One, 501 East Broadway, Suite 340, Louisville, Kentucky, 40202.
authors.forename: Bernard
authors.initials: B
authors.lastname: Masri
authors.affiliation: Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine MedCenter One, 501 East Broadway, Suite 340, Louisville, Kentucky, 40202.
authors.forename: M Tyler
authors.initials: MT
authors.lastname: Hougland
authors.affiliation: Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine MedCenter One, 501 East Broadway, Suite 340, Louisville, Kentucky, 40202.
authors.forename: Nika
authors.initials: N
authors.lastname: Adham
authors.affiliation: Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine MedCenter One, 501 East Broadway, Suite 340, Louisville, Kentucky, 40202.
authors.forename: Istvan
authors.initials: I
authors.lastname: Gyertyán
authors.affiliation: Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine MedCenter One, 501 East Broadway, Suite 340, Louisville, Kentucky, 40202.
authors.forename: Béla
authors.initials: B
authors.lastname: Kiss
authors.affiliation: Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine MedCenter One, 501 East Broadway, Suite 340, Louisville, Kentucky, 40202.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
authors.affiliation: Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine MedCenter One, 501 East Broadway, Suite 340, Louisville, Kentucky, 40202.
authors.forename: Rif S
authors.initials: RS
authors.lastname: El-Mallakh
keywords: Animal models; antipsychotics; arrestin; dopamine receptors; protein kinases