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.
Molecular psychiatry
April 1, 2026
Zijian Lv, Qifeng Xie, Kecan Li et al.
3 citations
Chronic stress changes behavior in both people and animals. By testing different chronic restraint stress (CRS) protocols in male mice, researchers identified that short, intense stress (6 hours/day for 3 days) caused persistent avoidance and repetitive behaviors, while longer, milder stress (2 hours/day for 10–14 days) progressively reduced reward-seeking and coping behaviors. A 10-day CRS protocol marked a threshold for reward-seeking deficits and served as a model combining avoidance and reward-processing impairments. The antidepressant ketamine reversed reward-seeking and coping deficits, while paroxetine alleviated both repetitive/avoidance behaviors and coping/reward-seeking deficits. These findings support CRS as a valid male mouse model of stress-related neuropsychiatric disorders.
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.