Muscone Exerts Rapid Antidepressant Effects Through Modulating Glutamatergic Neural Transmission in the Anterior Cingulate Cortex Against Peripheral Inflammation-induced Depression
Xiaoyun Qiu1 · Xiaojie Zhang1 · Yuanzhi Yang1 · Minjuan Sun1 · Xiaoli Da1 · Jiaying Liu1 · Rui Wang1 · Jingjia Liang1 · Xuhong Jiang1 · Gang Tian1 · Qiyuan Shan1 · Yu Du1 · Lihong Li1 · Li Cheng1 · Yi Wang1 · Zhong Chen1 · Cenglin Xu1
1 Zhejiang Collaborative Innovation Center for the Brain Diseases with Integrative Medicine, Zhejiang Key Laboratory of Neuropsychopharmacology, The Second Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Xinhua Hospital), School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
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.
Keywords
Muscone; Inflammation; Depression; Anterior cingulate cortex; CB1 receptor; Glutamatergic transmission
