Abstract
Cariprazine (US: Vraylar®, Europe: Reagila®), an orally active and potent dopamine D3 preferring D3/D2 receptor partial agonist, is approved to treat adults with schizophrenia (US and Europe) and manic or mixed episodes associated with bipolar I disorder (US). Cariprazine also displays partial agonism at serotonin (5-HT) 5 HT1A receptors and antagonism at 5 HT2A and 5 HT 2B receptors in vitro (Kiss et al., 2010). The objective of this study was to determine whether cariprazine can lead to functional alterations of monoamine systems in vivo determined by electrophysiological recordings from anaesthetised 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 DOI on norepinephrine neurons (ED 50=65.5 μg/kg) but did not block the inhibitory effect of the α2 adrenergic receptor agonist, clonidine. Cariprazine, iontophorized into the hippocampus, diminished the pyramidal neuronal firing through activation of 5 HT1A receptors, while concomitant administration with 5-HT did not dampen the suppressant effect of the latter. These results indicate that, in vivo, cariprazine acted as a 5 HT1A receptor agonist in the DRN, as a 5 HT2A receptor antagonist in the LC, and as a full agonist at 5 HT1A receptors located on pyramidal neurons. The modulatory actions of cariprazine on these monoaminergic systems may contribute to its therapeutic effectiveness in patients with depressive episodes.
- Antipsychotics
- Bipolar disorder
- Depression
- Dopamine receptors
- Electrophysiology
- Neurotransmitters
- Schizophrenia
- Serotonin receptors
- The American Society for Pharmacology and Experimental Therapeutics