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. The lateral habenula is known to regulate alcohol drinking behaviors in mice. Here, the authors show that a single dose of propofol reduces voluntary alcohol drinking in mice via hyperactivity of neurons in the lateral habenula, and through propofol interaction with the 5-HT2C receptor.