Abstract
The negative and cognitive symptoms of schizophrenia and related disorders may be due to reduced dopaminergic tone in cortical brain areas. Alteration in the function of dopamine (DA) D3 receptors may play a role in this cortical hypofunctionality and underlie the deficits in social behaviors and cognitive functions in schizophrenia. Cariprazine is a potent DA D3-preferring D3/D2 receptor partial agonist that is approved for the treatment of schizophrenia and bipolar disorder. The objective of the study was to compare the abilities of cariprazine, aripiprazole (another DA receptor partial agonist with more D2 receptor preference), and ABT-925 (a selective DA D3 antagonist) to counteract the social deficit and neurochemical alterations induced by the D3 receptor-preferring agonist (+)-PD 128907 (PD) in rats. Administration of PD (0.16 mg/kg; s.c.) induced a marked (−72%) but short-lasting disruption of the defensive social aggregation behavior (huddling) in the first 10-min period. Cariprazine at all doses (0.1, 0.3, 1 mg/kg; p.o.) almost completely abolished the PD-induced disruption of huddling. Likewise, ABT-925 (3 mg/kg; p.o.) and to a lesser extent aripiprazole (20 mg/kg; p.o.) were effective in blocking the PD-induced disruption of huddling. As measured by microdialysis, the highest dose of cariprazine prevented a PD-induced decrease in DA levels (40–80 min post PD dose) in the medial prefrontal cortex (mPFC), whereas aripiprazole did not have a significant effect. ABT-925 significantly counteracted the effect of PD at 80 min post-dose. In the nucleus accumbens (nAcc) shell, the highest dose of cariprazine, as well as ABT-925 and aripiprazole, significantly reversed the PD-induced decrease in DA levels. Taken together, these data provide behavioral and in vivo neurochemical evidence for the preferential DA D3 receptor action of cariprazine in the rat. This property of cariprazine may offer therapeutic benefits against the cognitive deficits and negative/depressive symptoms of schizophrenia and related disorders.
Highlights
Cariprazine (Vraylar R in USA; Reagila R in Europe) is approved in the USA for the acute and maintenance treatment of schizophrenia, as well as the acute treatment of manic or mixed episodes associated with bipolar I disorder and bipolar depression in adults
Cariprazine was developed based on the hypothesis that a compound with high affinity for D3 and D2 receptors may provide benefits for treating the affective and cognitive deficits associated with schizophrenia and bipolar disorder [5, 6]
The objective of this study was to evaluate the ability of acute cariprazine administration to counteract the disruptive effect of the D3 receptor-preferring dopamine agonist, (+)-PD 129807 (PD) 128907, on huddling behavior in rats compared to the D2/D3 receptor partial agonist antipsychotic aripiprazole [32] and the selective D3 receptor antagonist ABT-925 [31]
Summary
Cariprazine (Vraylar R in USA; Reagila R in Europe) is approved in the USA for the acute and maintenance treatment of schizophrenia, as well as the acute treatment of manic or mixed episodes associated with bipolar I disorder and bipolar depression in adults. Cariprazine’s pharmacological profile differs from that of other atypical antipsychotics such as aripiprazole, clozapine, olanzapine, and risperidone, which have varying levels of in vitro affinity for D3 receptors but fail to show significant D3 receptor occupancy at doses that produce antipsychotic-like effects in rats [9] and/or at clinically relevant doses in patients with schizophrenia [10, 11]. These data indicate that cariprazine can modulate the activity of D3 receptors in vivo to a greater extent than other atypical antipsychotics in clinical use
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