Department of Psychiatry of Sir Run Run Shaw Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China. cuiyihui@mail.kiz.ac.cn.
2 papers in the library · 205 citations · publishing 2023-2026
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.
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.