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Rapid-acting and long-lasting antidepressant-like action of (R)-ketamine in Nrf2 knock-out mice: a role of TrkB signaling

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Abstract

The transcription nuclear factor-erythroid factor 2-related factor 2 (Nrf2) plays a key role in inflammation that is involved in depression. We previously reported that Nrf2 knock-out (KO) mice exhibit depression-like phenotypes through systemic inflammation. (R)-ketamine, an enantiomer of ketamine, has rapid-acting and long-lasting antidepressant-like effects in rodents. We investigated whether (R)-ketamine can produce antidepressant-like effects in Nrf2 KO mice. Effects of (R)-ketamine on the depression-like phenotypes in Nrf2 KO mice were examined. Furthermore, the role of TrkB in the antidepressant-like actions of (R)-ketamine was also examined. In the tail-suspension test (TST) and forced swimming test (FST), (R)-ketamine (10 mg/kg) significantly attenuated the increased immobility times of TST and FST in the Nrf2 KO mice. In the sucrose preference test (SPT), (R)-ketamine significantly ameliorated the reduced preference of SPT in Nrf2 KO mice. Decreased expression of synaptic proteins (i.e., GluA1 and PSD-95) in the medial prefrontal cortex (mPFC) of Nrf2 KO mice was significantly ameliorated after a single injection of (R)-ketamine. Furthermore, the pre-treatment with the TrkB antagonist ANA-12 (0.5 mg/kg) significantly blocked the rapid and long-lasting antidepressant-like effects of (R)-ketamine in Nrf2 KO mice. Furthermore, ANA-12 significantly antagonized the beneficial effects of (R)-ketamine on decreased expression of synaptic proteins in the mPFC of Nrf2 KO mice. These findings suggest that (R)-ketamine can produce rapid and long-lasting antidepressant-like actions in Nrf2 KO mice via TrkB signaling.

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Acknowledgements

This study was supported by the grants from AMED, Japan (to K.H., JP20dm0107119).

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Authors and Affiliations

  1. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan

    Youge Qu, Jiajing Shan, Siming Wang, Lijia Chang, Yaoyu Pu, Xingming Wang, Yunfei Tan & Kenji Hashimoto

  2. Departments of Medical Biochemistry and Respiratory Medicine, Tohoku University Graduate School of Medicine, SendaiMiyagi, Miyagi, 980-8575, Japan

    Masayuki Yamamoto

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  1. Youge Qu
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  2. Jiajing Shan
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  3. Siming Wang
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Correspondence to Kenji Hashimoto.

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Dr. Hashimoto is an inventor on a filed patent application on “The use of R-ketamine in the treatment of psychiatric diseases” by Chiba University. Other authors have no conflicts of interest.

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Qu, Y., Shan, J., Wang, S. et al. Rapid-acting and long-lasting antidepressant-like action of (R)-ketamine in Nrf2 knock-out mice: a role of TrkB signaling. Eur Arch Psychiatry Clin Neurosci 271, 439–446 (2021). https://doi.org/10.1007/s00406-020-01208-w

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