浙江大学Hailan Hu研究团队近期取得突破性进展，他们研究提出，氯胺酮通过NMDAR捕获LHb发挥持续的抗抑郁作用。相关研究成果2023年10月18日在线发表于《自然》杂志上。

据介绍，氯胺酮是一种N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂，由于其强大、快速和持续的抗抑郁作用，已经彻底改变了抑郁症的治疗方法。尽管氯胺酮在小鼠中的消除半衰期只有13分钟，但其抗抑郁活性可持续至少24小时。这种巨大的差异提出了一个有趣的基本生物学问题，并具有强烈的临床意义。

研究人员证明了单次全身注射后，氯胺酮继续抑制突发放电，并阻断外侧缰核（LHb）中的NMDAR长达24小时。NMDAR的这种长期抑制不是由于内吞作用，而是取决于氯胺酮在NMDAR中的使用依赖性捕获。释放的速度是由神经活动调节的。通过激活LHb并在不同血浆氯胺酮浓度下打开局部NMDAR，利用氯胺酮与NMDAR相互作用的动态平衡，研究人员能够缩短或延长氯胺酮在体内的抗抑郁作用。这些结果为氯胺酮持续抗抑郁作用的因果机制提供了新的见解。

总之，这一研究基于氯胺酮与NMDAR相互作用的生物物理特性调节氯胺酮作用持续时间的能力，为氯胺酮的治疗应用开辟了新的机会。

附：英文原文

Title: Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb

Author: Ma, Shuangshuang, Chen, Min, Jiang, Yihao, Xiang, Xinkuan, Wang, Shiqi, Wu, Zuohang, Li, Shuo, Cui, Yihui, Wang, Junying, Zhu, Yanqing, Zhang, Yan, Ma, Huan, Duan, Shumin, Li, Haohong, Yang, Yan, Lingle, Christopher J., Hu, Hailan

Issue&Volume: 2023-10-18

Abstract: Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist1, has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects2,3,4. Although the elimination half-life of ketamine is only 13min in mice5, its antidepressant activities can last for at least 24h6,7,8,9. This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine–NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine–NMDAR interactions opens up new opportunities for the therapeutic use of ketamine.

DOI: 10.1038/s41586-023-06624-1

Source: https://www.nature.com/articles/s41586-023-06624-1