title: Hypothalamic-specific proopiomelanocortin deficiency reduces alcohol drinking in male and female mice.
abstract: Opioid receptor antagonist naltrexone reduces alcohol consumption and relapse in both humans and rodents. This study investigated whether hypothalamic proopiomelanocortin (POMC) neurons (producing beta-endorphin and melanocortins) play a role in alcohol drinking behaviors. Both male and female mice with targeted deletion of two neuronal Pomc enhancers nPE1 and nPE2 (nPE-/-), resulting in hypothalamic-specific POMC deficiency, were studied in short-access (4-h/day) drinking-in-the-dark (DID, alcohol in one bottle, intermittent access (IA, 24-h cycles of alcohol access every other day, alcohol vs. water in a two-bottle choice) and alcohol deprivation effect (ADE) models. Wild-type nPE+/+ exposed to 1-week DID rapidly established stable alcohol drinking behavior with more intake in females, whereas nPE-/- mice of both sexes had less intake and less preference. Although nPE-/- showed less saccharin intake and preference than nPE+/+, there was no genotype difference in sucrose intake or preference in the DID paradigm. After 3-week IA, nPE+/+ gradually escalated to high alcohol intake and preference, with more intake in females, whereas nPE-/- showed less escalation. Pharmacological blockade of mu-opioid receptors with naltrexone reduced intake in nPE+/+ in a dose-dependent manner, but had blunted effects in nPE-/- of both sexes. When alcohol was presented again after 1-week abstinence from IA, nPE+/+ of both sexes displayed significant increases in alcohol intake (ADE or relapse-like drinking), with more pronounced ADE in females, whereas nPE-/- did not show ADE in either sex. Our results suggest that neuronal POMC is involved in modulation of alcohol 'binge' drinking, escalation and 'relapse', probably via hypothalamic-mediated mechanisms, with sex differences.
authors.affiliation: Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: INGEBI/CONICET, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Rubinstein
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Low
authors.affiliation: Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Kreek
mesh_terms: D000309:Adrenal Insufficiency / Q000235:genetics / Q000378:metabolism*; D000428:Alcohol Drinking / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D005838:Genotype; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009271:Naltrexone / Q000494:pharmacology; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D000431:Ethanol; D009271:Naltrexone; D011333:Pro-Opiomelanocortin
keywords: Alcohol deprivation effect; drinking-in-the-dark; hypothalamic-specific POMC-deficient mice; intermittent access drinking; naltrexone; sex differences