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

作　　者：Hui Ma Jin-feng Li Xin Qiao Yue Zhang Xiao-juan Hou Hai-xia Chang Hong-lei Chen Yong Zhang Yun-feng Li 

机构地区：[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

出　　处：《Acta Pharmacologica Sinica》2024年第4期704-713,共10页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82204360);STI2030-Major Projects(2021ZD0200900).

摘　　要：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.

关 键 词：Sigma-1 receptor KETAMINE antidepressant effect BDNF combination treatment MPFC 

分 类 号：R96[医药卫生—药理学]