Sigma-1 receptor activation mediates the sustained antidepressant effect of ketamine in mice via increasing BDNF levels

Hui Ma1, Jin-feng Li1,2, Xin Qiao1, Yue Zhang3, Xiao-juan Hou4, Hai-xia Chang1, Hong-lei Chen5, Yong Zhang6,7,8, Yun-feng Li1,9
1 Beijing Institute of Basic Medical Sciences, Beijing 100850, China
2 School of Life Sciences, Tsinghua University, Beijing 100084, China
3 Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
4 Hebei North University, Zhangjiakou 075000, China
5 Graduate Collaborative Training Base of Academy of Military Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China
6 Department of Neurobiology, School of Basic Medical Sciences and Neuroscience Research Institute, Peking University, Beijing 100083, China
7 Key Laboratory for Neuroscience, Ministry of Education/National Health Commission of the People’s Republic of China, Beijing 100083, China
8 IDG/McGovern Institute for Brain Research at Peking University, Beijing 100083, China
9 Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing 100850, China
Correspondence to: Yong Zhang:, Yun-feng Li:,
DOI: 10.1038/s41401-023-01201-8
Received: 31 August 2023
Accepted: 15 November 2023
Advance online: 14 December 2023


Sigma-1 receptor (S1R) is a unique multi-tasking chaperone protein in the endoplasmic reticulum. Since S1R agonists exhibit potent antidepressant-like activity, S1R has become a novel target for antidepression therapy. With a rapid and sustained antidepressant effect, ketamine may also interact with S1R. In this study, we investigated whether the antidepressant action of ketamine was related to S1R activation. Depression state was evaluated in the tail suspension test (TST) and a chronic corticosterone (CORT) procedure was used to induce despair-like behavior in mice. The neuronal activities and structural changes of pyramidal neurons in medial prefrontal cortex (mPFC) were assessed using fiber-optic recording and immunofluorescence staining, respectively. We showed that pharmacological manipulation of S1R modulated ketamine-induced behavioral effect. Furthermore, pretreatment with an S1R antagonist BD1047 (3 mg·kg−1·d−1, i.p., for 3 consecutive days) significantly weakened the structural and functional restoration of pyramidal neuron in mPFC caused by ketamine (10 mg·kg−1, i.p., once). Ketamine indirectly triggered the activation of S1R and subsequently increased the level of BDNF. Pretreatment with an S1R agonist SA4503 (1 mg·kg−1·d−1, i.p., for 3 consecutive days) enhanced the sustained antidepressant effect of ketamine, which was eliminated by knockdown of BDNF in mPFC. These results reveal a critical role of S1R in the sustained antidepressant effect of ketamine, and suggest that a combination of ketamine and S1R agonists may be more beneficial for depression patients.

Keywords: Sigma-1 receptor; ketamine; antidepressant effect; BDNF; combination treatment; mPFC

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