The multimodal antidepressant vortioxetine is thought to mediate its pharmacological effects via 5-HT receptor agonism, 5-HT receptor partial agonism, 5-HT, 5-HT, 5-HT 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-HT receptors (in Xenopus oocytes and HEK-293 cells) and in mouse neuroblastoma N1E-115 cells with endogenous expression of 5-HT 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-HT receptor mRNA expression by in situ hybridization. Whereas, both vortioxetine and the 5-HT 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-HT receptors. Furthermore, vortioxetine's but not ondansetron's 5-HT receptor antagonistic potency varied considerably across species. Vortioxetine had the highest potency at rat and the lowest potency at guinea pig 5-HT receptors. Finally, in 5-HT receptor-expressing GABAergic interneurons from the CA1 stratum radiatum, vortioxetine and ondansetron blocked depolarizations induced by superfusion of either 5-HT or the 5-HT 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-HT receptor antagonism-dependent mechanism and thereby disinhibit pyramidal neurons and enhance glutamatergic signaling.
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