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-HT1A, 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-HT1A 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-HT1A 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.

Effects of the acute administration of delta-opioid receptor ligands on the excitability of rat hippocampal glutamate and brainstem monoamine neurons in vivo

“…Pyramidal CA1/3 neurons were identified based on the following criteria: large amplitude (0.5-1.2 mV), long-duration (0.8-1.2 ms) simple action potentials alternating with complex spike discharges (Fig. 1A) (Kandel and Spencer 1961;El Mansari et al 2020). The 5-HT DRN neurons were identified by bi-or tri-phasic action potentials with a rising phase of long duration (0.8-1.2 ms) and regular firing rate of 0.5-5.0 Hz (Fig.…”

Ketamine promptly normalizes excess norepinephrine and enhances dopamine neuronal activity in Wistar Kyoto rats

“…Altogether, these data imply that ketamine normalized phasic NE neuronal firing in WKY rats, and increased tonic NE transmission found in SD rats, which may underlie at least in part the rapid antidepressant action of ketamine. A similar augmentation in NE transmission is also achieved with standard antidepressant treatments, but only after chronic administration (El Mansari et al, 2020).…”

“…For instance, the NE/DA releaser bupropion re-established normal firing in rats subjected to olfactory bulbectomy, which caused dampened firing activity (Dong and Blier, 2001;El Mansari et al, 2014). Normalization of 5-HT neuronal firing that is dampened following acute administration of an SSRI/ selective norepinephrine reuptake inhibitor (SNRI) was, however, observed in SD rats that received an adjunct medication such as DA/ 5-HT modulators (Seager et al, 2004;Chernoloz et al, 2009;El Mansari et al, 2020). In addition, some antidepressant strategies for MDD such as vagus nerve stimulation, agomelatine, mirtazapine, bupropion, and pramipexole all enhance the firing activity of 5-HT neurons above their baseline in naïve SD rats (Blier and El Mansari, 2013).…”

Inhibition of cytochrome P450 with proadifen alters the excitability of brain catecholamine-secreting neurons

“…We had previously reported that SKF525 decreased the firing rate of 5-HT neurons of the DRN, which might result in decreased 5-HT transmission (Grinchii et al 2018). We had previously found that the increase in extracellular 5-HT, induced by the selective 5-HT reuptake inhibitor escitalopram, led to decrease in the firing rate and bursting activity of noradrenalin neurons (Dremencov et al 2007a(Dremencov et al , 2007bEl Mansari et al 2020). It is therefore possible that the enhancing effect of SKF525 on the bursting activity of noradrenalin neurons is secondary to the suppressing effect of this compound on the excitability of 5-HT neurons.…”