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

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

  • Mol Neurobiol. 2021 Oct;58(10):4944-4958. doi: 10.1007/s12035-021-02469-9.
Xiaotao Xu  # 1,  Kaixuan Wu  # 1,  Xiaqing Ma  # 1,  Wenying Wang  # 1,  Haiyan Wang 1,  Min Huang 1,  Limin Luo 1,  Chen Su 2,  Tifei Yuan 3,  Haibo Shi 4,  Ji Han 5,  Aizhong Wang 6,  Tao Xu 7 8
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, People's Republic of China.
  • 2 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.
  • 3 Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, People's Republic of China.
  • 4 Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, 200233, People's Republic of China.
  • 5 Internal medicine of TCM, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, No.164 Lanxi Road, Shanghai, 200062, China. doctorhanji@126.com.
  • 6 Department of Anesthesiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, People's Republic of China. w19680420@sohu.com.
  • 7 Department of Anesthesiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, People's Republic of China. balor@sjtu.edu.cn.
  • 8 Department of Anesthesiology, Tongzhou People's Hospital, Nantong, 226300, China. balor@sjtu.edu.cn.
  • # Contributed equally.
PMID: 34227060 DOI: 10.1007/s12035-021-02469-9
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.

Keywords

Depression; Metabotropic glutamate receptor 5; Nucleus accumbens; Pain; Stress.

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