Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb
Shuangshuang Ma, Min Chen, Yihao Jiang, Xinkuan Xiang, Shiqi Wang, Zuohang Wu, Shuo Li, Yihui Cui, Junying Wang, Yanqing Zhu, Yan Zhang, Huan Ma, Shumin Duan, Haohong Li, Yan Yang, Christopher J Lingle, Hailan Hu
Nature October 18, 2023 DOI: 10.1038/s41586-023-06624-1 via Semantic Scholar
Summary
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.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Keywords | Medicine |
| Citations | 202 |
| Key finding | Ketamine's sustained antidepressant effects in mice result from use-dependent trapping in NMDA receptors in the lateral habenula, with the duration of action modifiable by neural activity. |
Abstract
The discrepancy between the short half-life of ketamine and its long-lasting effects is due to ketamine being trapped in NMDA receptors, and its release depends on neural activity in the lateral habenula. Ketamine, an N -methyl- d -aspartate receptor (NMDAR) antagonist^ 1 , has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects^ 2 – 4 . Although the elimination half-life of ketamine is only 13 min in mice^ 5 , its antidepressant activities can last for at least 24 h^ 6 – 9 . This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine–NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine–NMDAR interactions opens up new opportunities for the therapeutic use of ketamine.