1. 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
- Author
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Peter H. Larsen, Tine B. Stensbøl, Elena Dale, Connie Sanchez, Jacob Nielsen, Dunguo Lu, Bjarke Ebert, Thomas N. Jensen, Haolan Yin, Kristen Frederiksen, Morten Grunnet, Alan L. Pehrson, Huiquing Liu, and Charles R. Yang
- Subjects
0301 basic medicine ,Agonist ,Serotonin receptors ,medicine.drug_class ,Antidepressant ,Pyramidal cells ,Pharmacology ,5-HT3 receptor ,03 medical and health sciences ,Glutamatergic ,0302 clinical medicine ,Interneurons ,medicine ,Receptor ,Molecular Biology ,Vortioxetine ,biology ,Chemistry ,General Neuroscience ,Receptor antagonist ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,biology.protein ,GABAergic ,Neurology (clinical) ,Pyramidal cell ,030217 neurology & neurosurgery ,Developmental Biology - 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.
- Published
- 2018
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