Document Type
Article
Publication Date
6-15-2018
Abstract
The multimodal antidepressant vortioxetine is thought to mediate its pharmacological effects via 5-HT 1A receptor agonism, 5-HT 1B receptor partial agonism, 5-HT 1D , 5-HT 3 , 5-HT 7 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 3A receptors (in Xenopus oocytes and HEK-293 cells) and in mouse neuroblastoma N1E-115 cells with endogenous expression of 5-HT 3A 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 3 receptor mRNA expression by in situ hybridization. Whereas, both vortioxetine and the 5-HT 3 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 3A receptors. Furthermore, vortioxetine's but not ondansetron's 5-HT 3 receptor antagonistic potency varied considerably across species. Vortioxetine had the highest potency at rat and the lowest potency at guinea pig 5-HT 3A receptors. Finally, in 5-HT 3 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 3 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 3 receptor antagonism-dependent mechanism and thereby disinhibit pyramidal neurons and enhance glutamatergic signaling.
DOI
10.1016/j.brainres.2017.12.025
MSU Digital Commons Citation
Dale, Elena; Grunnet, Morten; Pehrson, Alan; Frederiksen, Kristen; Larsen, Peter H.; Nielsen, Jacob; Stensbøl, Tine B.; Ebert, Bjarke; Yin, Haolan; Lu, Dunguo; Liu, Huiquing; Jensen, Thomas N.; Yang, Charles R.; and Sanchez, Connie, "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" (2018). Department of Psychology Faculty Scholarship and Creative Works. 516.
https://digitalcommons.montclair.edu/psychology-facpubs/516
Published Citation
Dale, E., Grunnet, M., Pehrson, A. L., Frederiksen, K., Larsen, P. H., Nielsen, J., ... & Sanchez, C. (2018). 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. Brain research, 1689, 1-11.