Cariprazine Exhibits Anxiolytic and Dopamine D3 Receptor-Dependent Antidepressant Effects in the Chronic Stress Model

Abstract

BackgroundCariprazine, a D3-preferring dopamine D2/D3 receptor partial agonist, is a new antipsychotic drug recently approved in the United States for the treatment of schizophrenia and bipolar mania. We recently demonstrated that cariprazine also has significant antianhedonic-like effects in rats subjected to chronic stress; however, the exact mechanism of action for cariprazine’s antidepressant-like properties is not known. Thus, in this study we examined whether the effects of cariprazine are mediated by dopamine D3 receptors.MethodsWild-type and D3-knockout mice were exposed to chronic unpredictable stress for up to 26 days, treated daily with vehicle, imipramine (20 mg/kg), aripiprazole (1 and 5 mg/kg), or cariprazine (0.03, 0.1, 0.2, and 0.4 mg/kg), and tested in behavioral assays measuring anhedonia and anxiety-like behaviors.ResultsResults showed that cariprazine significantly attenuated chronic unpredictable stress-induced anhedonic-like behavior in wild-type mice, demonstrating potent antidepressant-like effects comparable with aripiprazole and the tricyclic antidepressant imipramine. This antianhedonic-like effect of cariprazine was not observed in D3-knockout mice, suggesting that the cariprazine antidepressant-like activity is mediated by dopamine D3 receptors. Moreover, cariprazine significantly reduced drinking latency in the novelty-induced hypophagia test in wild-type mice, further confirming its antianhedonic-like effect and showing that it also has anxiolytic-like activity.ConclusionsIn combination with previous studies, these results suggest that cariprazine has a unique pharmacological profile and distinct dopamine D3 receptor-dependent mechanism of action that may be beneficial in the treatment of schizophrenia, bipolar disorder, and major depressive disorder.

Lentiviral-mediated let-7d microRNA overexpression induced anxiolytic- and anti-depressant-like behaviors and impaired dopamine D3 receptor expression

“…The potential implication of the D3R in the effects of antidepressants, such as imipramine, amitriptyline, citalopram and mianserin, was suggested by several reports indicating that when administered repeatedly, such drugs enhance the responsiveness of D3R, probably via an increase in the density and/or binding of these receptors ( Lammers et al, 2000;Maj et al, 1998 ). In addition, the D3R is a clinically relevant therapeutic target for anxietyand depression-related behaviors as clinically-used D3Rpreferring agonists, aripiprazole, pramipexole, cariprazine, and ropinirole, have all been shown to have anxiolytic and/or antidepressant effects in humans and animal models ( Duric et al, 2017;Rogers et al, 2000;Rogoz et al, 2004;Zarate et al, 2004 ). However, studies using D3R transgenic mice yielded conflicting results.…”

<p>Negative Symptoms in Schizophrenia: A Review and Clinical Guide for Recognition, Assessment, and Treatment</p>

“…[33][34][35][36][37] This hypothesis has been supported by findings from animal models, which have suggested that antagonism and partial agonism at dopamine D 3 receptors can mediate improvements in social interaction, novel object recognition, as well as displaying D 3 -receptor mediated anti-anhedonic and procognitive effects in rodents. [38][39][40] The mechanism by which these effects may occur is not clear, although it is possible that antagonism of D 3 receptors in the midbrain (eg, ventral tegmental area) could enhance dopamine neurotransmission to the prefrontal cortex 41,42 and the nucleus accumbens, [43][44][45] two areas of the brain where hypodopaminergic functioning has been linked to negative symptoms and mood deficits. 46,47 This normalization of dopamine release in the prefrontal cortex could result in increased activation of D 1 receptors, which in turn could mediate improvements in cognition and negative symptoms.…”

International Union of Basic and Clinical Pharmacology CIV: The Neurobiology of Treatment-resistant Depression: From Antidepressant Classifications to Novel Pharmacological Targets

“…Studies in animal models of depression, such as CMS, revealed potent antidepressant and antianhedonic-like activity of cariprazine (Papp et al, 2014). Interestingly the antianhedoniclike effects of cariprazine were not observed in D 3 -knockout mice, suggesting that these effects are mediated by dopamine D 3 receptors (Duric et al, 2017). A first phase II randomized, double-blind, placebo-controlled trial (NCT01469377) demonstrated the efficacy and safety of cariprazine (2-4.5 mg/day) as adjunctive therapy in patients with MDD who have inadequate response to standard "monoaminergic" antidepressant therapy (Durgam et al, 2016).…”