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

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.

SUBMITTER: Liu S

PROVIDER: S-EPMC8176437 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:We previously reported that serotonergic transmission plays an important role in antidepressant effects of ketamine. However, detailed mechanisms have not been elucidated. Among the serotonin receptor subtypes, the serotonin1A receptor in the medial prefrontal cortex has an important role in depression. Here, we investigated the role of the medial prefrontal cortex serotonin1A receptor and its signaling mechanism in the antidepressant effects of ketamine. Methods:The role of serotonin1A receptor-mediated signaling mechanism (phosphoinositide-3 kinase/Akt) in the medial prefrontal cortex was examined in the mouse forced swimming test and western blotting. Results:Ketamine exerted antidepressant effects that lasted for 24 hours, and the sustained antidepressant effects were attenuated by intra-medial prefrontal cortex injection of a serotonin1A receptor antagonist, WAY100635. The sustained antidepressant effects were mimicked by intra- medial prefrontal cortex, but not systemic, administration of a serotonin1A receptor agonist, (±)-8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT). The sustained antidepressant effects of ketamine and 8-OH-DPAT were abrogated by intra- medial prefrontal cortex injection of a phosphoinositide-3 kinase inhibitor. Ketamine increased the phosphorylation of Akt in the medial prefrontal cortex at 60 minutes after administration, which was blocked by a serotonin1A receptor antagonist and a phosphoinositide-3 kinase inhibitor. Furthermore, the sustained antidepressant effects of ketamine and 8-OH-DPAT were attenuated by pretreatment of intra-medial prefrontal cortex injection of a mechanistic target of rapamycin complex-1 inhibitor. Conclusions:These results indicate that selective stimulation of the medial prefrontal cortex serotonin1A receptor and subsequent activation of the phosphoinositide-3 kinase/Akt/mechanistic target of rapamycin complex-1 pathway may be necessary for ketamine to exert the sustained antidepressant effects, and that this mechanism could be targeted to develop a novel and effective approach for treating depression.

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

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