Involvement of 5-HT1Aand 5-HT2AReceptors but Not α2-Adrenoceptors in the Acute Electrophysiological Effects of Cariprazine in the Rat Brain In Vivo

Cariprazine, an orally active and potent dopamine D3–preferring D3/D2receptor 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-HT1Areceptors and antagonism at 5-HT2Aand 5-HT2Breceptors 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-HT1Areceptor antagonist, WAY100635. In the LC, cariprazine reversed the inhibitory effect of the preferential 5-HT2Areceptor agonist, 2,5-dimethoxy-4-iodoamphetamine, on norepinephrine (NE) neurons (ED50= 66 µg/kg) but did not block the inhibitory effect of the α2-adrenergic receptor agonist, clonidine. Cariprazine, iontophorized into the hippocampus, diminished pyramidal neuronal firing through activation of 5-HT1Areceptors, while its concomitant administration did not dampen the suppressant effect of 5-HT. These results indicate that, in vivo, cariprazine acted as a 5-HT1Aautoreceptor agonist in the DRN, a 5-HT2Areceptor antagonist in modulating the firing activity of LC NE neurons, and a full agonist at 5-HT1Areceptors 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.