Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb
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.