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
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
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DOI：
10.1016/j.brainres.2017.12.025
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发表时间：
2018-06-15
期刊：
影响因子：
2.9
通讯作者：
Sanchez, Connie
中科院分区：
文献类型：
--
作者：
Dale, Elena;Grunnet, Morten;Sanchez, Connie
多模式抗抑郁药vortioxetine被认为通过5-HT1A受体激动作用、5-HT1B受体部分激动作用、5-HT1D、5-HT3、5-HT7受体拮抗和5-HT转运体抑制介导其药理作用。本研究通过异种表达5-HT3A受体（爪蟾卵母细胞和HEK-293细胞）和内源性表达5-HT3A受体的小鼠神经母细胞瘤N1E-115细胞的细胞实验，研究了vortioxetine对不同物种（犬、小鼠、大鼠、豚鼠和人）的功能影响。此外，我们还采用电流和电压夹持法研究了vortioxetine对大鼠海马CA1辐射层中间神经元活性的影响。随后用生物细胞素填充修补后的神经元，原位杂交证实5-HT3受体mRNA的表达。然而，在细胞实验中，沃替西汀和5-HT3受体拮抗剂昂丹西酮都能拮抗5-HT3诱导的电流，在表达5-HT3A受体的卵母细胞中，沃替西汀的关闭率比昂丹西酮慢。此外，沃替西汀而不是昂丹司琼的5-HT3受体拮抗效力在不同物种之间差异很大。沃替西汀对大鼠的效价最高，对豚鼠5-HT3A受体的效价最低。最后，在CA1辐射层中表达5-HT3受体的gaba能中间神经元中，vortioxetine和ondansetron阻断了由5-HT或5-HT3受体激动剂mCPBG的灌注诱导的去极化。综上所述，这些数据增加了越来越多的文献支持vortioxetine可能通过5-HT3受体拮抗依赖机制抑制gaba能神经传递在某些大脑区域，从而去抑制锥体神经元并增强谷氨酸能信号传导的观点。(C) 2017 Elsevier B.V.版权所有
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. (C) 2017 Elsevier B.V. All rights reserved.