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mGluR5-Mediated eCB Signaling in the Nucleus Accumbens Controls Vulnerability to Depressive-Like Behaviors and Pain After Chronic Social Defeat Stress

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Abstract

Stress contributes to major depressive disorder (MDD) and chronic pain, which affect a significant portion of the global population, but researchers have not clearly determined how these conditions are initiated or amplified by stress. The chronic social defeat stress (CSDS) model is a mouse model of psychosocial stress that exhibits depressive-like behavior and chronic pain. We hypothesized that metabotropic glutamate receptor 5 (mGluR5) expressed in the nucleus accumbens (NAc) normalizes the depressive-like behaviors and pain following CSDS. Here, we show that CSDS induced both pain and social avoidance and that the level of mGluR5 decreased in susceptible mice. Overexpression of mGluR5 in the NAc shell and core prevented the development of depressive-like behaviors and pain in susceptible mice, respectively. Conversely, depression-like behaviors and pain were exacerbated in mice with mGluR5 knockdown in the NAc shell and core, respectively, compared to control mice subjected to 3 days of social defeat stress. Furthermore, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), an mGluR5 agonist, reversed the reduction in the level of the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) in the NAc of susceptible mice, an effect that was blocked by 3-((2-methyl-1, 3-thiazol-4-yl) ethynyl) pyridine hydrochloride (MTEP), an mGluR5 antagonist. In addition, the injection of CHPG into the NAc shell and core normalized depressive-like behaviors and pain, respectively, and these effects were inhibited by AM251, a cannabinoid type 1 receptor (CB1R) antagonist. Based on these results, mGluR5-mediated eCB production in the NAc relieves stress-induced depressive-like behaviors and pain.

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Data Availability

All the data supporting the findings of this study are available within the article and its Supplementary Information files and from the corresponding author upon reasonable request.

Abbreviations

MDD:

Major depressive disorder

CSDS:

Chronic social defeat stress

NAc:

Nucleus accumbens

eCB:

Endocannabinoid

2-AG:

2-Arachidonoylglycerol

CHPG:

(RS)-2-chloro-5-hydroxyphenylglycine

MTEP:

3-((2-Methyl-1,3-thiazol-4-yl)ethynyl) pyridine hydrochloride

CB1R :

Cannabinoid type 1 receptor

mGluR5:

Metabotropic glutamate receptor 5

mPFC:

Medial prefrontal cortex

AEA :

Anandamide

LTD:

Long-term depression

SPT:

Sucrose preference test

TST:

Tail suspension test

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Funding

This work was supported by a grant from the Natural Science Foundation of Shanghai to T.X. (21ZR1448400), the Interdisciplinary Program of Shanghai Jiao Tong University to T.X. (grant no. YG2021ZD23), a grant from the Natural Science Foundation of China to C.S. (81901141), and grants-in-aid from Shanghai Municipal Commission of Science and Technology (18DZ2260200).

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Author notes

  1. Xiaotao Xu, Kaixuan Wu, Xiaqing Ma and Wenying Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, People’s Republic of China

    Xiaotao Xu, Kaixuan Wu, Xiaqing Ma, Wenying Wang, Haiyan Wang, Min Huang, Limin Luo, Aizhong Wang & Tao Xu

  2. Department of Anesthesiology, Tongzhou People’s Hospital, Nantong, 226300, China

    Tao Xu

  3. Department of Anesthesiology and Pain Medicine, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, 410013, People’s Republic of China

    Chen Su

  4. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, People’s Republic of China

    Tifei Yuan

  5. Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, 200233, People’s Republic of China

    Haibo Shi

  6. Internal medicine of TCM, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, No.164 Lanxi Road, Shanghai, 200062, China

    Ji Han

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  1. Xiaotao Xu
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Contributions

X.X., K.W., X.M., W.W., data curation, investigation, and methodology; H.W., M.H., methodology and software; H.S. and T.Y., formal analysis; S.C., visualization and funding acquisition; J.H., A.W. and T.X., writing and supervision.

Corresponding authors

Correspondence to Ji Han, Aizhong Wang or Tao Xu.

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All experiments and procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (Eighth Edition) published by the National Research Council (USA) and were approved by the Institutional Animal Care and Use Committee of Sixth People’s Hospital Affiliated with Shanghai Jiao Tong University.

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Highlights

• Chronic social defeat stress-induced depressive-like behaviors and pain by decreasing mGluR5 levels in the nucleus accumbens.

• Overexpression or activation of mGluR5 in the nucleus accumbens prevented the development of depressive-like behaviors and pain following stress.

• The enhancement of endocannabinoid signaling in the NAc by targeted pharmacological activation of mGluR5 in the NAc alleviates depressive-like behaviors and relieves pain in mice exposed to stress.

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Xu, X., Wu, K., Ma, X. et al. mGluR5-Mediated eCB Signaling in the Nucleus Accumbens Controls Vulnerability to Depressive-Like Behaviors and Pain After Chronic Social Defeat Stress. Mol Neurobiol 58, 4944–4958 (2021). https://doi.org/10.1007/s12035-021-02469-9

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