Vortioxetine (VOR) is a 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 beneficial effects on cognitive dysfunction in major depressive patients. Here we compared the effects of 14-day treatments with VOR and escitalopram (ESC, selective serotonin reuptake inhibitor) on neuronal activity in the medial
prefrontal cortex (mPFC). Ten groups of rats (5 standard, 5 depleted of 5-HT with p-chlorophenylalanine-pCPA-, used as model of cognitive impairment) were fed with control food or with two doses of VOR-containing food. Four groups were implanted with minipumps delivering
vehicle or ESC 10 mg/kg·day s.c. The two VOR doses enable occupation by VOR of SERT+5-HT3-R and all targets, respectively, and correspond to SERT occupancies in patients treated with 5 and 20 VOR 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 neuronal discharge in standard and 5-HT-depleted conditions, with a greater effect of the low VOR dose in standard rats. VOR increased neuronal discharge in infralimbic (IL) and prelimbic (PrL) cortices. Hence, oral VOR doses evoking 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 SSRIs in animal modelsSupported by Lundbeck A/S and grants: SAF2015-68346-P (Spanish Ministry of Economy and Competitiveness, co-financed by European Regional Development Fund (ERDF)) and PI12/00156 (Instituto de Salud Carlos III, co-financed by European Regional Development Fund (ERDF)). Support from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) and Generalitat de Catalunya Grup de Recerca Consolidat, 2014SGR798 is also acknowledgedPeer reviewe
