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.