Acta pharmacologica SinicaMay 29, 2026

Activating body muscarinic receptors may improve depression-like behavior through the gut-brain connection and increased parasympathetic activity

Gut-Brain Axis Weekly Brief ↗PubMed ↗DOI ↗

Updated May 30, 2026

Abstract

Pharmacological activation of sympathetic receptors increased stress susceptibility in murine models.

Activation of sympathetic α-/β-adrenergic receptors is linked to increased stress susceptibility and depressive-like behaviors.
Antagonists of these receptors showed enhanced stress resistance, suggesting a correlation between sympathetic activity and depression.
Arecoline, a parasympathetic receptor agonist, demonstrated significant antidepressant effects in multiple mouse depression models.
The antidepressant effects of arecoline were blocked by atropine, indicating that parasympathetic receptor activity is involved in regulating depressive-like behaviors.
Arecoline activates glutamatergic neurons in the anterior cingulate cortex through the vagus nerve and nucleus tractus solitarius.
Chemogenetic manipulation confirmed that the antidepressant effects of arecoline depend on the activation of anterior cingulate cortex neurons.

Simplified

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 (ACC) 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 ACCneurons, and direct activation of these ACCneurons exerts an antidepressant effect. Notably, pharmacological activation of peripheral parasympathetic M receptors can regulate the activation of the nodose ganglion (NG)-NTS-ACCneural 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. Glu Glu Glu Glu

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Competing interests

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

PubMed

Activating body muscarinic receptors may improve depression-like behavior through the gut-brain connection and increased parasympathetic activity

Abstract

Full Text

Funding

Competing interests

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