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

Acta Pharmacologica Sinica volume 45, pages 704–713 (2024)Cite this article

Abstract

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.

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Fig. 1: Pharmacological manipulation of S1R modulates the sustained antidepressant effect of ketamine.
Fig. 2: S1R is involved in ketamine-induced structural and functional restoration of mPFCPyr neurons.
Fig. 3: Analysis of interaction between ketamine and S1R.
Fig. 4: S1R plays an important role in ketamine-induced increase of BDNF.
Fig. 5: Pretreatment with S1R agonists augments the effects of ketamine via BDNF.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82204360) and STI2030-Major Projects (2021ZD0200900). The experimental designs in figures were modified from BioRender.com (https://www.biorender.com/).

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Author notes

  1. These authors contributed equally: Hui Ma, Jin-feng Li, Xin Qiao.

Authors and Affiliations

  1. Beijing Institute of Basic Medical Sciences, Beijing, 100850, China

    Hui Ma, Jin-feng Li, Xin Qiao, Hai-xia Chang & Yun-feng Li

  2. School of Life Sciences, Tsinghua University, Beijing, 100084, China

    Jin-feng Li

  3. Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China

    Yue Zhang

  4. Hebei North University, Zhangjiakou, 075000, China

    Xiao-juan Hou

  5. Graduate Collaborative Training Base of Academy of Military Medical Sciences, Hengyang Medical School, University of South China, Hengyang, 421001, China

    Hong-lei Chen

  6. Department of Neurobiology, School of Basic Medical Sciences and Neuroscience Research Institute, Peking University, Beijing, 100083, China

    Yong Zhang

  7. Key Laboratory for Neuroscience, Ministry of Education/National Health Commission of the People’s Republic of China, Beijing, 100083, China

    Yong Zhang

  8. IDG/McGovern Institute for Brain Research at Peking University, Beijing, 100083, China

    Yong Zhang

  9. Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing, 100850, China

    Yun-feng Li

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Contributions

HM, YFL, and YZ designed the study; HM, JFL, XQ, YZ, XJH, HXC, and HLC performed the research; HM, JFL, and XQ wrote the manuscript; YFL and YZ revised the manuscript. All authors approved the submitted version.

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Correspondence to Yong Zhang or Yun-feng Li.

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Ma, H., Li, Jf., Qiao, X. et al. Sigma-1 receptor activation mediates the sustained antidepressant effect of ketamine in mice via increasing BDNF levels. Acta Pharmacol Sin 45, 704–713 (2024). https://doi.org/10.1038/s41401-023-01201-8

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