Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb

Abstract 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…

• NN
  National Natural Science Foundation of China

  Awards: 2021ZD0203001, STI2030, 2018B030334001, 31830032, 82288101, 2021ZD0203000, 2018B030331001
• ZU
  Zhejiang University

  Award: SN-ZJU-SIAS-002
• NI
  National Institute of General Medical Sciences

  Award: R35GM118114