The multimodal antidepressant vortioxetine may facilitate pyramidal cell firing by inhibition of 5-HT3 receptor expressing interneurons: An in vitro study in rat hippocampus slices

• Published in: Brain research Vol. 1689; pp. 1 - 11
• Main Authors: Dale, Elena, Grunnet, Morten, Pehrson, Alan L., Frederiksen, Kristen, Larsen, Peter H., Nielsen, Jacob, Stensbøl, Tine B., Ebert, Bjarke, Yin, Haolan, Lu, Dunguo, Liu, Huiquing, Jensen, Thomas N., Yang, Charles R., Sanchez, Connie
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 15.06.2018
• Subjects: Antidepressant; Interneurons; Pyramidal cells; Serotonin receptors; Antidepressant; Interneurons; MDD; fMRI; SSRI; serotonin; SERT; SNRI; IPSC; Pyramidal cells; Serotonin receptors; GABA; BOLD; SR
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2017.12.025

•Hypothesis: Vortioxetine disinhibits glutamate transmission by GABA modulation.•Vortioxetine is a potent 5-HT3 receptor antagonist across species.•Vortioxetine blocks 5-HT3 mediated depolarizations of hippocampal interneurons.•Vortioxetine inhibits GABA neurotransmission through a 5-HT3-dependent mechanism. The multimodal antidepressant vortioxetine is thought to mediate its pharmacological effects via 5-HT1A receptor agonism, 5-HT1B receptor partial agonism, 5-HT1D, 5-HT3, 5-HT7 receptor antagonism and 5-HT transporter inhibition. Here we studied vortioxetine’s functional effects across species (canine, mouse, rat, guinea pig and human) in cellular assays with heterologous expression of 5-HT3A receptors (in Xenopus oocytes and HEK-293 cells) and in mouse neuroblastoma N1E-115 cells with endogenous expression of 5-HT3A receptors. Furthermore, we studied the effects of vortioxetine on activity of CA1 Stratum Radiatum interneurons in rat hippocampus slices using current- and voltage-clamping methods. The patched neurons were subsequently filled with biocytin for confirmation of 5-HT3 receptor mRNA expression by in situ hybridization. Whereas, both vortioxetine and the 5-HT3 receptor antagonist ondansetron potently antagonized 5-HT-induced currents in the cellular assays, vortioxetine had a slower off-rate than ondansetron in oocytes expressing 5-HT3A receptors. Furthermore, vortioxetine’s but not ondansetron’s 5-HT3 receptor antagonistic potency varied considerably across species. Vortioxetine had the highest potency at rat and the lowest potency at guinea pig 5-HT3A receptors. Finally, in 5-HT3 receptor-expressing GABAergic interneurons from the CA1 stratum radiatum, vortioxetine and ondansetron blocked depolarizations induced by superfusion of either 5-HT or the 5-HT3 receptor agonist mCPBG. Taken together, these data add to a growing literature supporting the idea that vortioxetine may inhibit GABAergic neurotransmission in some brain regions via a 5-HT3 receptor antagonism-dependent mechanism and thereby disinhibit pyramidal neurons and enhance glutamatergic signaling.