Nature
October 18, 2023
Shuangshuang Ma, Min Chen, Yihao Jiang et al.
202 citations
Ketamine's antidepressant effects last much longer than its short half-life because the drug becomes trapped in NMDA receptors in the lateral habenula, and its release depends on neural activity. In mice, a single injection suppressed burst firing and blocked NMDA receptors in the lateral habenula for up to 24 hours. This sustained action results from use-dependent trapping, not endocytosis. By activating the lateral habenula and opening local NMDA receptors at different plasma ketamine concentrations, the duration of antidepressant effects could be shortened or prolonged. These findings explain the mechanism behind ketamine's sustained effects and suggest ways to modulate its therapeutic duration.
Science (New York, N.Y.)
August 9, 2024
Min Chen, Shuangshuang Ma, Hanxiao Liu et al.
87 citations
Ketamine, a rapid antidepressant, works by blocking N-methyl-d-aspartate receptors (NMDARs) specifically in the lateral habenula (LHb) of the brain, not in the hippocampus. In depressive-like mice, this regional selectivity depends on local neural activity and the availability of extrasynaptic NMDARs. Activating the hippocampus or inactivating the LHb reversed this sensitivity. Removing NMDARs from the LHb prevented ketamine's antidepressant effects and blocked the drug-induced rise in serotonin and brain-derived neurotrophic factor in the hippocampus. Identifying this primary brain target should help design more precise antidepressant treatments.
Philosophical transactions of the Royal Society of London. Series B, Biological sciences
July 29, 2024
Yihao Jiang, Yiyan Dong, Hailan Hu
Ketamine, an NMDAR antagonist, has superior antidepressant efficacy compared to traditional monoamine-targeting drugs, acting faster and more potently. While substantial evidence supports an NMDAR-antagonism-based hypothesis for its mechanisms, controversial results from other NMDAR inhibitors have led to alternative arguments. This article reviews the historical development of the NMDAR-centered hypothesis, classifies NMDAR inhibitors by their mechanisms, and evaluates preclinical and clinical evidence of their antidepressant effects. It critically analyzes debates over ketamine's NMDAR-dependent and independent actions, aiming to clarify molecular targets to guide future depression treatments.