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

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