Septo-hypothalamic regulation of binge-like alcohol consumption by the nociceptin system
Harold Haun,
Raul Hernandez,
Luzi Yan,
Meghan Flanigan,
Olivia Hon,
Sophia Lee,
Hernán Méndez,
Alison Roland,
Lisa Taxier,
Thomas Kash
Affiliations
Harold Haun
Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Raul Hernandez
Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Morgan Community College, Fort Morgan, CO 80701, USA
Luzi Yan
Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Meghan Flanigan
Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Olivia Hon
Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Sophia Lee
Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Hernán Méndez
Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Alison Roland
Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Lisa Taxier
Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Thomas Kash
Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Corresponding author
Summary: 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 (LSPnoc) displayed increased excitability during withdrawal from binge-like alcohol drinking. LSPnoc activation promoted active avoidance and potentiated binge-like drinking behavior, whereas silencing of this population reduced alcohol drinking. LSPnoc 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. LSPnoc 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.
