Sex specific modulation of LC neuronal activity in a binge drinking mouse model

Binge drinking substantially elevates the risk of developing alcohol use disorder, with pronounced sex-specific differences observed. However, there is a limited understanding of the underlying sex differences in the neural mechanisms that underpin binge drinking. The present study utilized the Drinking in the Dark (DID) paradigm, in combination with electrophysiology and chemogenetics, to reveal the critical role of the locus coeruleus (LC) in regulating sexually dimorphic binge-like drinking behavior. Electrophysiological analysis revealed that after three weeks of DID modeling, female mice showed accelerated repolarization of action potential in LC norepinephrine (NE) neurons, whereas male mice exhibited reduced frequency and amplitude of miniature inhibitory postsynaptic current (mIPSC) in LC NE neurons. Chemogenetic activation of LC-NE neurons suppressed ethanol preference specifically in males, whereas it reduced overall fluid intake in females. Taken together, LC NE neurons exhibit significant sexual dimorphism in regulating alcohol consumption behavior and may serve as a key node in the negative feedback circuit, providing a critical avenue for developing targeted intervention strategies.