Septo-hypothalamic regulation of binge-like alcohol consumption by the nociceptin system

High-intensity alcohol drinking during binge episodes contributes to the socioeconomic burden created by alcohol use disorders (AUDs), and nociceptin receptor (NOP) antagonists have emerged as a promising intervention. To better understand the contribution of the NOP system to binge drinking, we found that nociceptin-containing neurons of the lateral septum (LS^Pnoc) displayed increased excitability during withdrawal from binge-like alcohol drinking. LS^Pnoc activation promoted active avoidance and potentiated binge-like drinking behavior, whereas silencing of this population reduced alcohol drinking. LS^Pnoc form robust monosynaptic inputs locally within the LS and genetic deletion of NOP or microinjection of a NOP antagonist into the LS decreased alcohol intake. LS^Pnoc also project to the lateral hypothalamus and supramammillary nucleus of the hypothalamus, and genetic deletion of NOP from each site reduced alcohol drinking. Together, these findings implicate the septo-hypothalamic nociceptin system in excessive alcohol consumption and support NOP antagonist development for the treatment of AUD.