M2-AChR Mediates Rapid Antidepressant Effects of Scopolamine Through Activating the mTORC1-BDNF Signaling Pathway in the Medial Prefrontal Cortex

Shuang Liu; Dandan Shi; Zuoli Sun; Yi He; Jian Yang; Gang Wang

doi:10.3389/fpsyt.2021.601985

M2-AChR Mediates Rapid Antidepressant Effects of Scopolamine Through Activating the mTORC1-BDNF Signaling Pathway in the Medial Prefrontal Cortex

Front Psychiatry. 2021 May 17:12:601985. doi: 10.3389/fpsyt.2021.601985. eCollection 2021.

Authors

Shuang Liu¹, Dandan Shi¹, Zuoli Sun¹, Yi He¹, Jian Yang^{1

2}, Gang Wang^{1

2}

Affiliations

¹ The National Clinical Research Center for Mental Disorder and Beijing Key Laboratory of Mental Disorder, Beijing Anding Hospital, Capital Medical University, Beijing, China.
² Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China.

Abstract

Background: Scopolamine, a non-selective muscarinic acetylcholine receptor (M1~5-AChR) antagonist, has rapid and robust antidepressant effects in humans and other species. However, which of the five M-AChRs mediates these therapeutic effects has not been fully identified. Several studies implicate M2-AChR as a potential antidepressant target of scopolamine. This study aimed to explore the role of M2-AChR in scopolamine's antidepressant-like effects and determine the underlying mechanisms. Methods: We used the classic novelty suppressed feeding test (NSFT), open field test (OFT) and forced swim test (FST) to observe antidepressant-related behaviors of normal rats, medial prefrontal cortex (mPFC) neuron silenced rats and M2-AChR knockdown rats treated with scopolamine. In a further experiment, the M2 cholinergic receptor antagonist methoctramine (MCT) was injected intracerebroventricularly into normal rats. Levels of mTORC1 and brain-derived neurotrophic factor (BDNF) in the mPFC of animals were analyzed by Western blotting. Results: Consistent with previous studies, mPFC was required for the antidepressant-like effects of scopolamine, and intracerebroventricular injection of MCT into rats could produce similar antidepressant-like effects. Use of AAV-shRNA to knock down M2-AChR in the mPFC resulted in the antidepressant-like effects of scopolamine being blunted. Furthermore, Western blotting demonstrated increased expression of mTORC1 signaling and BDNF in MCT-treated rats. Conclusion: Our results indicate that M2-AChR in the mPFC mediates the antidepressant-like effects of scopolamine by increasing the expression of BDNF and activating the mTORC1 signaling pathway.

Keywords: brain-derived neurotrophic factor; mammalian target of rapamycin complex 1; medial prefrontal cortex; muscarinic acetylcholine receptor-2; scopolamine.