Abstract
Major depression disorder is a severe and recurrent neuropsychological disorder characterized by lowered mood and social activity and cognitive impairment. Owing to unclear molecular mechanisms of depression, limited interventions are available in clinic. In this study we investigated the role of dynorphin/κ opioid receptor system in the development of depression. Mice were subjected to chronic social defeat stress for 14 days. Chronic social defeat stress induced significant social avoidance in mice characterized by decreased time duration in the interaction zone and increased time duration in the corner zone. Pre-administration of a κ opioid receptor antagonist norBNI (10 mg/kg, i.p.) could prevent the development of social avoidance induced by chronic social defeat stress. Social avoidance was not observed in κ opioid receptor knockout mice subjected to chronic social defeat stress. We further revealed that social defeat stress activated c-fos and ERK signaling in the amygdala without affecting the NAc, hippocampus and hypothalamus, and ERK activation was blocked by systemic injection of norBNI. Finally, the expression of dynorphin A, the endogenous ligand of κ opioid receptor, was significantly increased in the amygdala following social defeat stress; microinjection of norBNI into the amygdala prevented the development of depressive-like behaviors caused by social defeat stress. The present study demonstrates that upregulated dynorphin/κ opioid receptor system in the amygdala leads to the emergence of depression following chronic social defeat stress, and sheds light on κ opioid receptor antagonists as potential therapeutic agents for the prevention and treatment of depression following chronic stress.
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18 November 2022
A Correction to this paper has been published: https://doi.org/10.1038/s41401-022-01016-z
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Acknowledgements
This research was supported by the National Natural Science Foundation of China 81130087, 81671322, 82030112 (to JGL), 81771188 (to ZQL), 81773710 (to YJW), 81801321 (to GYZ), by the Science and Technology Commission of Shanghai Municipality 19401930500 (to ZQL), by the Youth Innovation Promotion Association of the Chinese Academy of Sciences 2017334 (to YJW), and by the China Postdoctoral Science Foundation 2018M640423 (to GYZ). The authors would like to thank Dr. Xin Xie, Shanghai Institute of Materia Medica, for providing KOR knockout mice with detailed gene phenotype identification protocol.
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ZQL, QLL, and GYZ designed the experiments. GYZ and XS performed the experiments with the assistance of YJW, RL, CYW, JRC, and LBG. GYZ and XS performed data statistical analysis. GYZ wrote the manuscript and JGL, ZQL, QLL, and WJD revised it.
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Zan, Gy., Sun, X., Wang, Yj. et al. Amygdala dynorphin/κ opioid receptor system modulates depressive-like behavior in mice following chronic social defeat stress. Acta Pharmacol Sin 43, 577–587 (2022). https://doi.org/10.1038/s41401-021-00677-6
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DOI: https://doi.org/10.1038/s41401-021-00677-6
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