CESP/UMR-S 1178, Univ. Paris-Sud, Fac. Pharmacie, Inserm, Université Paris-Saclay, Chatenay-Malabry, 92290, France.
CESP/UMR-S 1178, Univ. Paris-Sud, Fac. Pharmacie, Inserm, Université Paris-Saclay, Chatenay-Malabry, 92290, France.
Pharmacol Ther. 2019 Jul;199:58-90. doi: 10.1016/j.pharmthera.2019.02.017. Epub 2019 Mar 7.
Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptor, displays a fast antidepressant activity in treatment-resistant depression and in rodent models of anxiety/depression. A large body of evidence concerning the cellular and molecular mechanisms underlying its fast antidepressant-like activity comes from animal studies. Although structural remodeling of frontocortical/hippocampal neurons has been proposed as critical, the role of excitatory/inhibitory neurotransmitters in this behavioral effect is unclear. Neurochemical and behavioral changes are maintained 24h after ketamine administration, well beyond its plasma elimination half-life. Thus, ketamine is believed to initiate a cascade of cellular mechanisms supporting its fast antidepressant-like activity. To date, the underlying mechanism involves glutamate release, then downstream activation of AMPA receptors, which trigger mammalian target of rapamycin (mTOR)-dependent structural plasticity via brain-derived neurotrophic factor (BDNF) and protein neo-synthesis in the medial prefrontal cortex (mPFC), a brain region strongly involved in ketamine therapeutic effects. However, these mPFC effects are not restricted to glutamatergic pyramidal cells, but extend to other neurotransmitters (GABA, serotonin), glial cells, and brain circuits (mPFC/dorsal raphe nucleus-DRN). It could be also mediated by one or several ketamine metabolites (e.g., (2R,6R)-HNK). The present review focuses on evidence for mPFC neurotransmission abnormalities in major depressive disorder (MDD) and their potential impact on neural circuits (mPFC/DRN). We will integrate these considerations with results from recent preclinical studies showing that ketamine, at antidepressant-relevant doses, induces neuronal adaptations that involve the glutamate-excitatory/GABA-inhibitory balance. Our analyses will help direct future studies to further elucidate the mechanism of action of fast-acting antidepressant drugs, and to inform development of novel, more efficacious therapeutics.
氯胺酮是一种 N-甲基-D-天冬氨酸（NMDA）受体非竞争性拮抗剂，在治疗抵抗性抑郁症和焦虑/抑郁的啮齿动物模型中显示出快速的抗抑郁活性。大量关于其快速抗抑郁样作用的细胞和分子机制的证据来自动物研究。尽管已经提出了前额皮质/海马神经元的结构重塑是关键的，但兴奋性/抑制性神经递质在这种行为效应中的作用尚不清楚。神经化学和行为变化在氯胺酮给药后 24 小时内保持不变，远远超过其血浆消除半衰期。因此，氯胺酮被认为引发了一系列支持其快速抗抑郁样活性的细胞机制。迄今为止，潜在的机制涉及谷氨酸释放，然后下游激活 AMPA 受体，通过脑源性神经营养因子（BDNF）和蛋白质新合成在中前额皮质（mPFC）触发哺乳动物雷帕霉素靶蛋白（mTOR）依赖性结构可塑性，mPFC 是与氯胺酮治疗效果密切相关的大脑区域。然而，这些 mPFC 效应不仅限于谷氨酸能锥体神经元，还扩展到其他神经递质（GABA、血清素）、神经胶质细胞和脑回路（mPFC/背侧中缝核-DRN）。它也可能由一种或几种氯胺酮代谢物（例如（2R，6R）-HNK）介导。本综述重点介绍了主要抑郁障碍（MDD）中 mPFC 神经传递异常的证据及其对神经回路（mPFC/DRN）的潜在影响。我们将整合这些考虑因素与最近的临床前研究结果相结合，这些研究表明，氯胺酮在抗抑郁相关剂量下诱导神经元适应，涉及谷氨酸兴奋性/GABA 抑制性平衡。我们的分析将有助于指导未来的研究，以进一步阐明快速作用抗抑郁药物的作用机制，并为新型、更有效的治疗方法提供信息。
