Clinical studies have shown the therapeutic efficacy of an increase in dopamine (DA) transmission in treatment of major depressive disorder (MDD). In the present study, we investigated whether blockade of DA transporters in addition to serotonin (5-HT) and norepinephrine (NE) produced additional adaptations of monoaminergic systems. In vivo electrophysiological recordings were carried out in male anesthetized rats. Vehicle, the 5-HT reuptake inhibitor escitalopram, the NE/DA reuptake blocker nomifensine and their combination (triple reuptake inhibition; TRI) were delivered for 2 or 14 days. Firing activity of NE, 5-HT and DA neurons was assessed. Tonic activation of 5-HT_1A receptors and α₁- and α₂-adrenoceptors was determined in the hippocampus and extracellular DA levels in the nucleus accumbens (NAc). Unlike escitalopram, nomifensine and TRI administration increased the tonic activation of α₂-adrenoceptors in the hippocampus despite decreasing NE neuronal firing activity after 2 and 14 days of administration. The firing activity of 5-HT neurons was increased after prolonged nomifensine and TRI regimens, while addition of nomifensine to escitalopram prevented the early 2-day suppression of firing by 5-HT reuptake inhibition. The tonic activation of 5-HT_1A receptors was enhanced only with escitalopram. Whereas escitalopram and nomifensine decreased firing activity of DA neurons after a 2-day administration, their combination normalized it to baseline level after 14 days; this was accompanied by a robust increase in extracellular DA levels in the NAc. In summary, these results indicate that TRI increases NE and DA but not 5-HT transmission, suggesting a differential efficacy profile in MDD patients.

临床研究表明，增加多巴胺 (DA) 传输在治疗重度抑郁症 (MDD) 中具有疗效。在本研究中，我们调查了除血清素 (5-HT) 和去甲肾上腺素 (NE) 之外的 DA 转运蛋白的阻断是否会产生单胺能系统的额外适应性。在雄性麻醉大鼠中进行体内电生理记录。载体、5-HT 再摄取抑制剂依他普仑、NE/DA 再​​摄取阻滞剂诺米芬辛及其组合（三重再摄取抑制；TRI）递送 2 或 14 天。评估了 NE、5-HT 和 DA 神经元的放电活动。5-HT _1A受体和α ₁ - 和α _{2 的}强直激活β-肾上腺素能受体在海马体和伏隔核 (NAc) 中的细胞外 DA 水平上测定。与依他普仑不同，诺米芬辛和 TRI 给药增加了海马中 α _{2 -}肾上腺素能受体的强直激活，尽管在给药 2 天和 14 天后降低了 NE 神经元放电活动。在延长诺米芬辛和 TRI 方案后，5-HT 神经元的放电活动增加，而将诺米芬辛添加到依他普仑中可防止 5-HT 再摄取抑制引起的早期 2 天放电抑制。5-HT _1A的滋补激活受体仅用依他普仑增强。艾司西酞普兰和诺米芬辛在给药 2 天后降低了 DA 神经元的放电活动，但它们的组合在 14 天后使其恢复到基线水平；这伴随着 NAc 中细胞外 DA 水平的强劲增加。总之，这些结果表明 TRI 增加 NE 和 DA 但不增加 5-HT 传输，表明 MDD 患者的疗效不同。