Propofol induces sustained suppression of alcohol drinking via habenular activation in mice

Targeting the lateral habenula (LHb), a key brain region regulating alcohol consumption, presents a promising framework for reducing drinking. LHb neurons exhibit high sensitivity and responsiveness to the intravenous anesthetic propofol. However, whether and how propofol-activated habenular neurons regulate alcohol drinking remains unknown.

Here, we show that a single dose of propofol rapidly and persistently reduces alcohol consumption in mice for approximately six days. This effect is mediated by sustained hyperactivity of the habenular ensemble activated by propofol. Furthermore, this ensemble is enriched in 5-HT2C receptors, and we identify the V209 site as the specific binding site through which propofol induces ensemble activation.

Disrupting this binding abolishes both the propofol-induced activation of the habenular ensemble and the subsequent reduction in alcohol drinking. Our findings pinpoint a locus of 5-HT2C receptor action within the LHb through which propofol suppresses alcohol consumption, offering a mechanistic framework for understanding alcohol drinking behavior. Wu for expert assistance, and Q.C.

Yin for technical support (all from Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China). The Sci-Tech Innovation 2030 - Major Project 2021ZD0203100 (J.-L.C.). National Natural Science Foundation of China 81720108013, 82293641, 82130033 (J.-L.C.).

National Natural Science Foundation of China 82371536 (S.Z.). National Natural Science Foundation of China 82271263 (H.-L.D.). National Natural Science Foundation of China 82501532 (Z.X.).

Natural Science Foundation of Jiangsu Province BK20251043 (Z.X.). Jiangsu Basic Research Programs BK20243035 (J.-L.C.). The Key Technologies R&D Program of Guangdong Province 2023B0303020003 (J.-L.C.).