Long-term administration of cariprazine increases locus coeruleus noradrenergic neurons activity and serotonin 1A receptor neurotransmission in the hippocampus

Abstract

Background:

Cariprazine, the novel dopamine (DA) D₃-preferring D₃/D₂ and serotonin (5-HT)_1A receptor partial agonist, has activity as an adjunctive therapy in major depressive disorder (MDD).

Aims:

This study aims to investigate the effects of chronic cariprazine administration in combination with the selective serotonin reuptake inhibitor escitalopram on the activity of monoaminergic systems.

Methods:

Rats received cariprazine alone and in adjunct to escitalopram for 2 and 14 days and the firing activity of dorsal raphe nucleus 5-HT, locus coeruleus norepinephrine (NE) and ventral tegmental area DA neurons was assessed. 5-HT and NE neurotransmission in hippocampus pyramidal neurons was evaluated by assessing tonic activation of their 5-HT_1A, and α₁- and α₂-adrenergic receptors, using their selective antagonists.

Results:

Two and 14-day cariprazine regimens increased the firing rate of NE, but not 5-HT and DA neurons. Addition of cariprazine to escitalopram reversed the inhibitory effect of escitalopram on NE but not 5-HT and DA neurons. In the hippocampus, there was an increase in neurotransmission at 5-HT_1A receptors in cariprazine-treated rats, but no change in overall NE transmission by either regimen.

Conclusion:

Cariprazine increased NE neuronal firing and reversed the escitalopram-induced inhibition of these neurons. Despite a lack of effect on 5-HT neuronal firing activity, there was an increase in tonic activation of hippocampus 5-HT_1A receptors by cariprazine alone but not with the combination. These effects provide a possible rationale for the clinical efficacy of cariprazine as an adjunctive strategy in patients with MDD.