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Activation of peripheral muscarinic receptors rescues depressive-like behaviors via gut-brain-axis, involving parasympathetic excitation

Acta Pharmacologica Sinica (2026) Cite this article

Abstract

Dysfunction of the autonomic nervous system (ANS) is strongly linked to the pathophysiological mechanisms of depression. Unfortunately, the correlation between depressive-like behaviors and the activation or inhibition of the sympathetic/parasympathetic nervous system has not been systematically explored. This study demonstrated that the pharmacological activation of sympathetic α-/β-adrenergic receptors increased stress susceptibility, whereas their antagonists enhanced stress resistance, thus suggesting a close correlation between sympathetic activity and depressive-like behaviors. Furthermore, arecoline, an agonist of the peripheral parasympathetic muscarinic (M) receptors, has exhibited significant antidepressant effects in multiple murine depression models, and its antidepressant effects could be blocked by the M receptor antagonist known as atropine, thus indicating that parasympathetic excitability regulates depressive-like behaviors. Moreover, arecoline acted on peripheral M receptors to activate glutamatergic neurons in the anterior cingulate cortex (ACCGlu) via the vagus nerve and nucleus tractus solitarius (NTS) in sequence. Chemogenetic manipulation confirmed that the antidepressant effect of arecoline is dependent on the activation of ACCGlu neurons, and direct activation of these ACCGlu neurons exerts an antidepressant effect. Notably, pharmacological activation of peripheral parasympathetic M receptors can regulate the activation of the nodose ganglion (NG)–NTS–ACCGlu neural axis and modulate depressive-like behaviors. For the first time, this study indicates that peripheral M receptors are promising targets for antidepressants development and proposes a potential antidepressant strategy involving the pharmacological modulation of peripheral autonomic balance.

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Fig. 1: Modulation of peripheral α- and β-adrenergic receptors directly affects stress susceptibility and resistance.
The alternative text for this image may have been generated using AI.
Fig. 2: The M receptor agonist arecoline rapidly rescues depression-like behaviors in CSDS, CUMS, and CRS-induced mouse models.
The alternative text for this image may have been generated using AI.
Fig. 3: Antidepressant effects of arecoline are involved in its peripheral exposure and the vagus nerve.
The alternative text for this image may have been generated using AI.
Fig. 4: M receptor agonists exert antidepressant effects by activating vagal afferent nerves and NTS.
The alternative text for this image may have been generated using AI.
Fig. 5: Arecoline activates ACCGlu neurons via the central neural circuit from the NTS to ACC.
The alternative text for this image may have been generated using AI.
Fig. 6: The antidepressant effect of arecoline depends on the activation of ACCGlu neurons.
The alternative text for this image may have been generated using AI.
Fig. 7: The antidepressant effect of arecoline depends on its direct activation of M receptors in the gut.
The alternative text for this image may have been generated using AI.
Fig. 8: The regulation of peripheral M receptors directly affects depression-like behaviors and the NG-NTS-ACCGlu axis in mice.
The alternative text for this image may have been generated using AI.
Fig. 9: Activation of peripheral parasympathetic M receptors by arecoline rescues depressive-like behaviors via the nodose ganglion (NG)–NTS–ACCGlu neural axis.
The alternative text for this image may have been generated using AI.

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Acknowledgements

This study was financially supported by the National Natural Science Foundation of China (82574491, 32501325 and 82321005); the National Key Project of Science and Technology for Innovation Drugs of China (2017ZX09301013); the CAMS Innovation Fund for Medical Sciences (CIFMS2021-I2M-5-011); the Jiangsu Province Science and Technology Major Project (BG2024044); and the Yangtze River Delta Science and Technology Innovation Community Joint Research Project (2023CSJZN0800). The authors thank the sharing facility platform for the use of large-scale experimental apparatuses at the State Key Laboratory of National Medicines, China Pharmaceutical University. We also sincerely acknowledge Jie Zhao and Zheng-lin Hao (Animal Experimental Center, China Pharmaceutical University) for their support in animal experiments, and Lei Dai (School of Foreign Languages, China Pharmaceutical University) for his linguistic assistance with this manuscript. The schematic diagrams were created with BioRender (https://www.biorender.com/).

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  1. Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, Research Unit of PK–PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical Sciences, China Pharmaceutical University, Nanjing, 210009, China

    Fang-fang Gao, Jing Zhang, Shi-meng Qu, Fan Xiao, Jin-qian Cheng, Zhuo-qin Yuan, Guang-ji Wang, Meng-jie Yu & Ji-ye Aa

  2. School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China

    Yi-fan Xu

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Contributions

JYA, MJY, and FFG conceptualized the manuscript structure and study framework. FFG, JZ, YFX, and JQC performed the experimental work. SMQ and FX conducted the data analysis and interpretation. FFG drafted the manuscript. ZQY and JYA reviewed and revised the manuscript for accuracy and clarity. JYA, MJY, and GJW critically revised the manuscript and were responsible for study conceptualization, supervision, editorial oversight, and funding acquisition.

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Correspondence to Guang-ji Wang, Meng-jie Yu or Ji-ye Aa.

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The corresponding author Guang-ji Wang is a member of the Editorial Board of the journal Acta Pharmacologica Sinica, but he has not been involved in the peer-review or decision-making process for this manuscript. Other authors declare no competing financial interests.

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All animal experimental procedures were approved by the Animal Welfare and Ethics Committee of China Pharmaceutical University (Ethical Approval Number: 2024-06-086).

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Gao, Ff., Xu, Yf., Zhang, J. et al. Activation of peripheral muscarinic receptors rescues depressive-like behaviors via gut-brain-axis, involving parasympathetic excitation. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-026-01834-5

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  • DOI: https://doi.org/10.1038/s41401-026-01834-5

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