研究人员发现，在抑郁样小鼠中，氯胺酮注射特异性地阻断了外侧缰核（LHb）神经元中的N-甲基-d-天冬氨酸受体（NMDAR），而不影响海马锥体神经元。这种区域特异性依赖于氯胺酮作为通道拮抗剂的使用依赖性、局部神经活动和NMDAR的突触外储备池大小。
激活海马神经元或失活LHb神经元会改变它们对氯胺酮的敏感性。LHb中NMDAR的条件性敲除阻断了氯胺酮的抗抑郁效果，并阻碍了系统性氯胺酮引起的海马中血清素和脑源性神经营养因子的升高。对氯胺酮主要靶点与次要靶点的区分有助于设计更精确和高效的抗抑郁治疗。
据悉，氯胺酮已被发现具有快速而强效的抗抑郁活性。然而，尽管其分子靶点NMDAR在大脑中普遍表达，但氯胺酮的抗抑郁作用是否存在选择性主要靶点仍不明确。
附：英文原文
Title: Brain region–specific action of ketamine as a rapid antidepressant
Author: Min Chen, Shuangshuang Ma, Hanxiao Liu, Yiyan Dong, Jingxiang Tang, Zheyi Ni, Yi Tan, Chenchi Duan, Hui Li, Hefeng Huang, Yulong Li, Xiaohua Cao, Christopher J. Lingle, Yan Yang, Hailan Hu
Issue&Volume: 2024-08-09
Abstract: Ketamine has been found to have rapid and potent antidepressant activity. However, despite the ubiquitous brain expression of its molecular target, the N-methyl-d-aspartate receptor (NMDAR), it was not clear whether there is a selective, primary site for ketamine’s antidepressant action. We found that ketamine injection in depressive-like mice specifically blocks NMDARs in lateral habenular (LHb) neurons, but not in hippocampal pyramidal neurons. This regional specificity depended on the use-dependent nature of ketamine as a channel blocker, local neural activity, and the extrasynaptic reservoir pool size of NMDARs. Activating hippocampal or inactivating LHb neurons swapped their ketamine sensitivity. Conditional knockout of NMDARs in the LHb occluded ketamine’s antidepressant effects and blocked the systemic ketamine–induced elevation of serotonin and brain-derived neurotrophic factor in the hippocampus. This distinction of the primary versus secondary brain target(s) of ketamine should help with the design of more precise and efficient antidepressant treatments.
DOI: ado7010
Source: https://www.science.org/doi/10.1126/science.ado7010