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.

The Diverse Roles of Arrestin Scaffolds in G Protein–Coupled Receptor Signaling

“…Locomotor hyperactivity induced by the dopaminergic drug apomorphine, a D2 receptor agonist, is reduced in b-arrestin2 null mice, implicating arrestin-dependent signaling in D2 receptor-dependent behaviors, and the mood stabilizer lithium acts by destabilizing the b-arrestin2-PP2A-AKT-GSK3b complex, which enhances AKT-dependent inhibition of GSK3b (Beaulieu et al, 2008). Strikingly, the clinical efficacy of nearly all mood-stabilizing drugs correlates better with their ability to inhibit b-arrestin2-dependent signaling than with their effects on D2 receptor-G protein signaling (Masri et al, 2008;Gao et al, 2015). Although different classes of antipsychotics vary in D2 receptor-G protein agonist/antagonist efficacy, they share the ability to block b-arrestin2 recruitment to D2 receptors.…”

Cariprazine for the Treatment of Bipolar Disorder

“…These are symptoms that may be targets in both bipolar illness and the negative symptoms of schizophrenia (Fountoulakis, Kelsoe, & Akiskal, ; Gross, Wicke, & Drescher, ). True to these predictions, cariprazine has demonstrated efficacy in animal models that examine cognition (Gyertyán et al., ; Zimnisky et al., ), depression (Papp et al., ), and mania (Gao et al., ).…”

Functional selectivity – chance for better and safer drugs?

“…Stwierdzono także, że lit wykazuje hamujący wpływ na kinazę GSK-3, zarówno w mechanizmie bezpośrednim, jak i pośrednim, prowadząc do destabilizacji kompleksu sygnalizacyjnego β-arestyna 2/Akt/GSK-3 aktywowanego przez receptory D 2 [53,54]. Ostatnio zasugerowano też, że aktywność kariprazyny wobec ścieżki sygnalizacji Akt/GSK-3 może odgrywać zasadniczą rolę w jej skuteczności antymaniakalnej [55].…”

“…Lithium was found to inhibit GSK-3, both directly and through an indirect mechanism that destabilizes the D2R-mediated β-arrestin 2/Akt/GSK-3 signaling complex [53,54]. More recently, the effects of cariprazine on Akt/GSK-3 signaling were suggested to play a role in its anti-manic efficacy [55].…”