Muscone Exerts Rapid Antidepressant Effects Through Modulating Glutamatergic Neural Transmission in the Anterior...

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.