Document Type
Article
Publication Date
6-15-2018
Journal / Book Title
Brain Research
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., Stensbøl, T. B., Ebert, B., Yin, H., Lu, D., Liu, H., Jensen, T. N., Yang, C. R., & 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. https://doi.org/10.1016/j.brainres.2017.12.025
