Subchronic vortioxetine treatment -but not escitalopram- enhances pyramidal neuron activity in the rat prefrontal cortex

Abstract

Vortioxetine (VOR) is a new multimodal antidepressant drug. VOR is a 5-HT3-R, 5-HT7-R and 5-HT1D-R antagonist, 5-HT1B-R partial agonist, 5-HT1A-R agonist, and serotonin transporter (SERT) inhibitor. VOR shows pro-cognitive activity in animal models and major depressive patients. Here we compared the effect of 14-day treatments with VOR and escitalopram (ESC, serotonin selective reuptake inhibitor) on neuronal activity in medial prefrontal cortex (mPFC). Ten groups of rats (5 standard, 5 depleted of 5-HT with pCPA, used as model of cognitive impairment) were fed with control food or with two doses of VOR-containing food. Two groups were implanted with minipumps delivering vehicle or ESC 10 mg/kg·day s.c.. The two VOR doses occupy SERT+5-HT3-R and all targets, respectively, and correspond to SERT occupancies in patients treated with 5 and 20 mg/day, respectively. Putative pyramidal neurons (n=985) were recorded extracellularly in the mPFC of anesthetized rats. Sub¿chronic VOR administration (but not ESC) significantly increased the discharge of putative pyramidal neurons in standard and 5-HT-depleted conditions, with a greater effect of the low dose in standard rats. VOR increased neuronal discharge in both the infralimbic (IL) and prelimbic (PrL) subdivisions of mPFC, with a slightly greater effect in IL. Hence, oral VOR doses evoking a SERT occupancies similar to those in treated patients increase mPFC neuronal discharge. The effect in 5-HT-depleted rats cannot be explained by an antagonist action of VOR at 5-HT3-R and suggests a non-canonical interaction of VOR with 5-HT3-R. These effects may underlie the superior pro-cognitive efficacy of VOR compared with SSRI.