Abstract
Cariprazine, an orally active and potent dopamine D3-preferring D3/D2 receptor partial agonist, is approved to treat adults with schizophrenia (in the United States and Europe) and manic or mixed episodes associated with bipolar I disorder (in the United States). Cariprazine also displays partial agonism at serotonin [5-hydroxytryptamine (5-HT)] 5-HT1A receptors and antagonism at 5-HT2A and 5-HT2B receptors in vitro. The study objective was to determine whether cariprazine leads to functional alterations of monoamine systems in vivo via electrophysiological recordings from anesthetized rats. Dorsal raphe nucleus (DRN), locus coeruleus (LC), and hippocampus pyramidal neurons were recorded, and cariprazine was administered systemically or locally through iontophoresis. In the DRN, cariprazine completely inhibited the firing activity of 5-HT neurons, which was fully reversed by the 5-HT1A receptor antagonist, WAY100635. In the LC, cariprazine reversed the inhibitory effect of the preferential 5-HT2A receptor agonist, 2,5-dimethoxy-4-iodoamphetamine, on norepinephrine (NE) neurons (ED50 = 66 µg/kg) but did not block the inhibitory effect of the α 2-adrenergic receptor agonist, clonidine. Cariprazine, iontophorized into the hippocampus, diminished pyramidal neuronal firing through activation of 5-HT1A receptors, while its concomitant administration did not dampen the suppressant effect of 5-HT. These results indicate that, in vivo, cariprazine acted as a 5-HT1A autoreceptor agonist in the DRN, a 5-HT2A receptor antagonist in modulating the firing activity of LC NE neurons, and a full agonist at 5-HT1A receptors mediating the electrophysiological effect of 5-HT on pyramidal neurons. The modulatory actions of cariprazine on these monoaminergic systems may contribute to its therapeutic effectiveness in patients with depressive episodes.
Highlights
Cariprazine is a novel dopamine (DA) D3–preferring D3/D2 receptor and serotonin [5-hydroxytryptamine (5-HT)] 5-HT1A receptor partial agonist that has been approved to treat schizophrenia and manic or mixed episodes associated with bipolar I disorder
5-HT1A receptors, while its concomitant administration did not dampen the suppressant effect of 5-HT. These results indicate that, in vivo, cariprazine acted as a 5-HT1A autoreceptor agonist in the Dorsal raphe nucleus (DRN), a 5-HT2A receptor antagonist in modulating the firing activity of locus coeruleus (LC) NE neurons, and a full agonist at 5-HT1A receptors mediating the electrophysiological effect of 5-HT on pyramidal neurons
In the DRN, cariprazine fully inhibited the firing activity of 5-HT neurons. This effect was reversed by the selective 5-HT1A receptor antagonist WAY100635, which indicated that cariprazine acted as an agonist in vivo at the 5-HT1A autoreceptors in this brain structure
Summary
Cariprazine (in the United States: Vraylar; in Europe: Reagila) is a novel dopamine (DA) D3–preferring D3/D2 receptor and serotonin [5-hydroxytryptamine (5-HT)] 5-HT1A receptor partial agonist that has been approved to treat schizophrenia (in the United States and Europe) and manic or mixed episodes associated with bipolar I disorder (in the United States). Cariprazine has shown efficacy in improving symptoms of depressive episodes in patients with bipolar I disorder (Durgam et al, 2016b) Unlike aripiprazole, another DA receptor partial agonist indicated for the treatment of schizophrenia and bipolar disorder, cariprazine acts as a D3/D2 receptor partial agonist with higher binding affinity and selectivity (5- to 8-fold) for D3 versus D2 receptors and as a more potent antagonist at 5-HT2A receptors in vitro (Lawler et al, 1999; Kiss et al, 2010; Maeda et al, 2014). Activation of 5-HT1A receptors by selective agonists such as 8-OH-DPAT increases DA release in the prefrontal cortex (Arborelius et al, 1993; Li et al, 2004; Assié et al, 2005)
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