Involvement of 5-HT3 receptors in the action of vortioxetine in rat brain: focus on glutamatergic and GABAergic neurotransmission

The antidepressant vortioxetine is a 5-HT3-R, 5-HT7-R and 5-HT1D-R antagonist, 5-HT1B-R partial agonist, 5-HT1A-R agonist, and serotonin (5-HT) transporter (SERT) inhibitor. Vortioxetine occupies all targets at high therapeutic doses and only SERT and 5-HT3-R at low doses. Vortioxetine increases extracellular monoamine concentrations in rat forebrain more than selective serotonin reuptake inhibitors (SSRI) and shows pro-cognitive activity in preclinical models. Given its high affinity for 5-HT3-R (Ki = 3.7 nM), selectively expressed in GABA interneurons, we hypothesized that vortioxetine may disinhibit glutamatergic and monoaminergic neurotransmission following 5-HT3-R blockade. Here we assessed vortioxetine effect on pyramidal neuron activity and extracellular 5-HT concentration using in vivo extracellular recordings of rat medial prefrontal cortex (mPFC) pyramidal neurons and microdialysis in mPFC and ventral hippocampus (vHPC). Vortioxetine, but not escitalopram, increased pyramidal neuron discharge in mPFC. This effect was prevented by SR57227A (5-HT3-R agonist) and was mimicked by ondansetron (5-HT3-R antagonist) and by escitalopram/ondansetron combinations. In microdialysis experiments, ondansetron augmented the 5-HT-enhancing effect of escitalopram in mPFC and vHPC. Local ondansetron in vHPC augmented escitalopram effect, indicating the participation of intrinsic mechanisms. Since 5-HT neurons express GABAB receptors, we examined their putative involvement in controlling 5-HT release after 5-HT3-R blockade. Co-perfusion of baclofen (but not muscimol) reversed the increased 5-HT levels produced by vortioxetine and escitalopram/ondansetron combinations in vHPC. The present results suggest that vortioxetine increases glutamatergic and serotonergic neurotransmission in rat forebrain by blocking 5-HT3 receptors in GABA interneurons.This work was supported by a grant from Lundbeck A/S and by grants SAF 2012-35183 and SAF 2015-68346-P from the Spanish Ministry of Economy and Competitiveness, co-financed by European Regional Development Fund (ERDF) and grant 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 acknowledged. FA and PC are PI and co-PI from a grant from Lundbeck A/S to examine the mechanism of action of vortioxetine. FA has also received lecture and consultation fees from Lundbeck A/S and is scientific advisor to Neurolixis. CS is a Lundbeck A/S employee.Peer reviewe