Abstract

Depression associated with peripheral inflammation is characterized by severe symptoms and high relapse rates, highlighting the urgent need for rapid-acting antidepressants. Here, we demonstrate that muscone, the principal bioactive component of musk, exerts rapid antidepressant effects in murine models of peripheral inflammation-induced depression [lipopolysaccharide (LPS) challenge; dextran sulfate sodium-induced colitis] rather than in chronic restraint stress-induced depression. Acute muscone administration did not possess innate anti-inflammatory activity but selectively suppressed the hyperactivation of glutamatergic neurons within the anterior cingulate cortex (ACC), a crucial mood-regulatory hub. Chemogenetic activation or inhibition of ACC glutamatergic neurons abolished or mimicked the anti-depressive behavioral effects of muscone. Mechanistically, muscone induced presynaptic inhibition of excitatory transmission in ACC glutamatergic neurons through activation of the cannabinoid CB1 receptor. These findings identify muscone as a promising rapid-onset therapeutic candidate for treating inflammation-associated depression.