University of Ottawa, Institute of Mental Health Research, Ottawa, ON, Canada.
Int J Neuropsychopharmacol. 2011 Mar;14(2):211-23. doi: 10.1017/S1461145710000076. Epub 2010 Feb 11.
Triple reuptake inhibitors represent a potential new class of antidepressant drugs that block norepinephrine (NE), dopamine (DA) and serotonin [5-hydroxytryptamine (5-HT)] transporters. The present in-vivo electrophysiological study was undertaken to determine the effects of the triple reuptake inhibitors SEP-225289 and DOV216303 on the neuronal activities of locus coeruleus (LC) NE, ventral tegmental area (VTA) DA and dorsal raphe (DR) 5-HT neurons. Administered acutely, SEP-225289 and DOV216303 dose-dependently decreased the spontaneous firing rate of LC NE, VTA DA and DR 5-HT neurons through the activation of α₂, D₂ and 5-HT(₁A) autoreceptors, respectively. Both compounds predominantly inhibited the firing rate of LC NE neurons while producing only a partial decrease in VTA DA and DR 5-HT neuronal discharge. SEP-225289 was equipotent at inhibiting 5-HT and NE transporters since it prolonged to the same extent the time required for a 50% recovery (RT₅₀) of the firing activity of dorsal hippocampus CA3 pyramidal neurons from the inhibition induced by microiontophoretic application of 5-HT and NE. Finally, in the presence of WAY100635, a 5-HT(₁A) receptor antagonist, SEP-225289 activated 5-HT neurons at doses that normally did not inhibit them. Taken together, the present results indicate that reciprocal interactions among NE, DA and 5-HT inputs need to be considered to anticipate the net effect of triple reuptake inhibitors on the enhancement of brain monoamine transmission. The results also suggest that the therapeutic action of triple reuptake inhibitors may be potentiated by antagonizing the cell body 5-HT(₁A) autoreceptors.
三重再摄取抑制剂代表了一类有潜力的新型抗抑郁药物，它们可以阻断去甲肾上腺素（NE）、多巴胺（DA）和 5-羟色胺[5-羟色胺（5-HT）]转运体。本活体电生理学研究旨在确定三重再摄取抑制剂 SEP-225289 和 DOV216303 对蓝斑核（LC）NE、腹侧被盖区（VTA）DA 和中缝背核（DR）5-HT 神经元的神经元活动的影响。急性给予 SEP-225289 和 DOV216303 可剂量依赖性地通过激活 α₂、D₂ 和 5-HT(₁A)自受体，分别降低 LC NE、VTA DA 和 DR 5-HT 神经元的自发放电率。这两种化合物主要抑制 LC NE 神经元的放电率，而对 VTA DA 和 DR 5-HT 神经元的放电只有部分抑制作用。SEP-225289 对 5-HT 和 NE 转运体具有同等的抑制作用，因为它同样延长了通过微电泳应用 5-HT 和 NE 诱导的背海马 CA3 锥体神经元放电活动恢复到 50%（RT₅₀）所需的时间。最后，在 WAY100635（一种 5-HT(₁A)受体拮抗剂）存在的情况下，SEP-225289 在通常不会抑制它们的剂量下激活 5-HT 神经元。总之，目前的结果表明，需要考虑 NE、DA 和 5-HT 输入之间的相互作用，以预测三重再摄取抑制剂对增强大脑单胺传递的净效应。结果还表明，通过拮抗细胞体 5-HT(₁A)自受体，三重再摄取抑制剂的治疗作用可能得到增强。
