Dale Elena, Grunnet Morten, Pehrson Alan L, Frederiksen Kristen, Larsen Peter H, Nielsen Jacob, Stensbøl Tine B, Ebert Bjarke, Yin Haolan, Lu Dunguo, Liu Huiquing, Jensen Thomas N, Yang Charles R, Sanchez Connie
Brintellix Science Team, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Copenhagen, Denmark.
Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Copenhagen, Denmark.
Brain Res. 2018 Jun 15;1689:1-11. doi: 10.1016/j.brainres.2017.12.025. Epub 2017 Dec 21.
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.
多模式抗抑郁药伏硫西汀被认为通过5-羟色胺（5-HT）受体激动、5-HT受体部分激动、5-HT、5-HT、5-HT受体拮抗及5-HT转运体抑制来介导其药理作用。在此，我们通过在异源表达5-HT受体的细胞试验（非洲爪蟾卵母细胞和人胚肾293细胞）以及内源性表达5-HT受体的小鼠神经母细胞瘤N1E-115细胞中进行研究，探讨了伏硫西汀在不同物种（犬、小鼠、大鼠、豚鼠和人）中的功能效应。此外，我们使用电流钳和电压钳方法研究了伏硫西汀对大鼠海马切片中CA1辐射层中间神经元活性的影响。随后，用生物胞素填充被膜片钳记录的神经元，通过原位杂交确认5-HT受体mRNA的表达。在细胞试验中，伏硫西汀和5-HT受体拮抗剂昂丹司琼均能有效拮抗5-HT诱导的电流，但在表达5-HT受体的卵母细胞中，伏硫西汀的解离速率比昂丹司琼慢。此外，伏硫西汀而非昂丹司琼的5-HT受体拮抗效力在不同物种间有很大差异。伏硫西汀对大鼠5-HT受体的效力最高，对豚鼠5-HT受体的效力最低。最后，在CA1辐射层中表达5-HT受体的γ-氨基丁酸能中间神经元中，伏硫西汀和昂丹司琼均能阻断由5-HT或5-HT受体激动剂mCPBG灌注诱导的去极化。综上所述，这些数据进一步支持了以下观点：伏硫西汀可能通过5-HT受体拮抗依赖性机制抑制某些脑区的γ-氨基丁酸能神经传递，从而解除对锥体神经元的抑制并增强谷氨酸能信号传导。
