Hypothalamic-specific proopiomelanocortin deficiency reduces alcohol drinking in male and female mice

RUBINSTEIN, M.; LOW, M. J.; KREEK, M. J.; ZHOU, Y.

GENES BRAIN AND BEHAVIOR

WILEY-BLACKWELL PUBLISHING, INC

Año: 2017 vol. 16 p. 449 - 461

1601-1848

Opioid receptor antagonist naltrexone reduces alcoholconsumption and relapse in both humans androdents. This study investigated whether hypothalamicproopiomelanocortin (POMC) neurons (producingbeta-endorphin and melanocortins) play a role in alcoholdrinking behaviors. Both male and female mice withtargeted deletion of two neuronal Pomc enhancers nPE1and nPE2 (nPE−/−), resulting in hypothalamic-specificPOMC deficiency, were studied in short-access (4-h/day)drinking-in-the-dark (DID, alcohol in one bottle, intermittentaccess (IA, 24-h cycles of alcohol access every otherday, alcohol vs. water in a two-bottle choice) and alcoholdeprivation effect (ADE) models. Wild-type nPE+/+exposed to 1-week DID rapidly established stable alcoholdrinking behavior with more intake in females,whereas nPE−/− mice of both sexes had less intakeand less preference. Although nPE−/− showed lesssaccharin intake and preference than nPE+/+, therewasno genotype difference in sucrose intake or preferencein the DID paradigm. After 3-week IA, nPE+/+ graduallyescalated to high alcohol intake and preference,with more intake in females, whereas nPE−/− showedless escalation. Pharmacological blockade of mu-opioidreceptors with naltrexone reduced intake in nPE+/+ ina dose-dependent manner, but had blunted effects innPE−/− of both sexes. When alcohol was presentedagain after 1-week abstinence from IA, nPE+/+ of bothsexes displayed significant increases in alcohol intake(ADE or relapse-like drinking), with more pronouncedADE in females, whereas nPE−/− did not show ADE ineither sex. Our results suggest that neuronal POMC isinvolved in modulation of alcohol ?binge? drinking, escalationand ?relapse?, probably via hypothalamic-mediatedmechanisms, with sex differences.