Cariprazine is a novel dopamine (DA) and serotonin (5-HT) partial agonist
with an in vitro receptor affinity profile that endows it with the potential to be used
successfully in the treatment of both unipolar and bipolar disorders. The objective
of this study was to determine whether in vitro findings with cariprazine lead to
functional alterations of monoamine systems in the intact rat brain. In vivo
electrophysiological recordings were carried out in male Sprague-Dawley rats
under chloral hydrate anesthesia. Dorsal raphé nucleus (DRN), locus coeruleus
(LC), and hippocampus cornu ammonis region 3 (CA3) pyramidal neurons were
recorded and cariprazine was administered systemically by intravenous injection
or locally through iontophoresis. In the DRN, cariprazine induced a complete
inhibition of the firing of 5-HT neurons, which was fully reversed by the selective
5-HT1A antagonist WAY100.635. In the LC, the inhibitory effect of the preferential
5-HT2A agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) was reversed by
cariprazine with an ED50 value of 67 µg/kg, i.v., and it did not block the inhibitory
effect of the α2-adrenergic agonist clonidine. In the hippocampus, when
cariprazine was administered by iontophoresis, it inhibited the firing of pyramidal
neurons, but it did not dampen the suppressant effect of 5-HT. These results
indicate that, in vivo, cariprazine acts as a 5-HT1A agonist in the DRN, as an
antagonist on 5-HT2A receptors controlling the firing of NE neurons, and is a full
agonist at 5-HT1A receptors located on pyramidal neurons of the hippocampus.
The modulatory actions of cariprazine on the 5-HT and NE systems may
contribute to its reported effectiveness in depressive episodes.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/36713 |
| Date | January 2017 |
| Creators | Herman, Anna |
| Contributors | Blier, Pierre |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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