Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba.
Division of Neuronal Network, Department of Basic Medical Sciences, Institute of Medical Sciences, University of Tokyo, Tokyo.
Biol Psychiatry. 2018 Oct 15;84(8):591-600. doi: 10.1016/j.biopsych.2018.05.007. Epub 2018 May 14.
Ketamine, an N-methyl-D-aspartate receptor antagonist, exerts robust antidepressant effects in patients with treatment-resistant depression. The precise mechanisms underlying ketamine's antidepressant actions remain unclear, although previous research suggests that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) activation plays a role. We investigated whether (S)-norketamine and (R)-norketamine, the two main metabolites of (R,S)-ketamine, also play a significant role in ketamine's antidepressant effects and whether the effects are mediated by AMPAR.
Cellular mechanisms of antidepressant action of norketamine enantiomers were examined in mice.
(S)-Norketamine had more potent antidepressant effects than (R)-norketamine in inflammation and chronic social defeat stress models. Furthermore, (S)-norketamine induced more beneficial effects on decreased dendritic spine density and synaptogenesis in the prefrontal cortex and hippocampus compared with (R)-norketamine. Unexpectedly, AMPAR antagonists did not block the antidepressant effects of (S)-norketamine. The electrophysiological data showed that, although (S)-norketamine inhibited N-methyl-D-aspartate receptor-mediated synaptic currents, (S)-norketamine did not enhance AMPAR-mediated neurotransmission in hippocampal neurons. Furthermore, (S)-norketamine improved reductions in brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling in the prefrontal cortex of mice susceptible to chronic social defeat stress, whereas the tropomyosin receptor kinase B antagonist and a mechanistic target of rapamycin inhibitor blocked the antidepressant effects of (S)-norketamine. In contrast to (S)-ketamine, (S)-norketamine did not cause behavioral abnormalities, such as prepulse inhibition deficits, reward effects, loss of parvalbumin immunoreactivity in the medial prefrontal cortex, or baseline gamma-band oscillation increase.
Our data identified a novel AMPAR activation-independent mechanism underlying the antidepressant effects of (S)-norketamine. (S)-Norketamine and its prodrugs could be novel antidepressants without the detrimental side effects of (S)-ketamine.
氯胺酮是一种 N-甲基-D-天冬氨酸受体拮抗剂，对治疗抵抗性抑郁症患者具有强大的抗抑郁作用。氯胺酮抗抑郁作用的确切机制尚不清楚，尽管先前的研究表明α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的激活起作用。我们研究了（S）-去甲氯胺酮和（R）-去甲氯胺酮，（R，S）-氯胺酮的两种主要代谢物，是否也在氯胺酮的抗抑郁作用中起重要作用，以及这些作用是否由 AMPAR 介导。
在小鼠中研究了去甲氯胺酮对细胞的抗抑郁作用机制。
（S）-去甲氯胺酮在炎症和慢性社交挫败应激模型中比（R）-去甲氯胺酮具有更强的抗抑郁作用。此外，（S）-去甲氯胺酮诱导的前额叶皮层和海马中的树突棘密度和突触发生的有益作用比（R）-去甲氯胺酮更多。出乎意料的是，AMPAR 拮抗剂并未阻断（S）-去甲氯胺酮的抗抑郁作用。电生理数据表明，尽管（S）-去甲氯胺酮抑制 N-甲基-D-天冬氨酸受体介导的突触电流，但（S）-去甲氯胺酮并未增强海马神经元中 AMPAR 介导的神经传递。此外，（S）-去甲氯胺酮改善了对慢性社交挫败应激敏感的小鼠前额叶皮层中脑源性神经营养因子-原肌球蛋白受体激酶 B 信号的降低，而原肌球蛋白受体激酶 B 拮抗剂和雷帕霉素靶蛋白抑制剂阻断了（S）-去甲氯胺酮的抗抑郁作用。与（S）-氯胺酮不同，（S）-去甲氯胺酮不会引起行为异常，如前脉冲抑制缺陷、奖励效应、内侧前额叶皮质中钙调蛋白免疫反应性丧失或基线γ波段振荡增加。
我们的数据确定了（S）-去甲氯胺酮抗抑郁作用的一种新的 AMPAR 激活非依赖性机制。（S）-去甲氯胺酮及其前药可能是新型抗抑郁药，没有（S）-氯胺酮的有害副作用。
