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

• Published in: Genes, brain and behavior Vol. 16; no. 4; pp. 449 - 461
• Main Authors: Zhou, Y., Rubinstein, M., Low, M. J., Kreek, M. J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2017; John Wiley & Sons, Inc
• Subjects: Adrenal Insufficiency - genetics; Adrenal Insufficiency - metabolism; Alcohol deprivation effect; Alcohol Drinking - drug therapy; Alcohol Drinking - genetics; Alcohol Drinking - metabolism; Alcohol use; Animals; drinking‐in‐the‐dark; Ethanol - pharmacology; Female; Females; Gender differences; Genotype; hypothalamic‐specific POMC‐deficient mice; Hypothalamus - drug effects; Hypothalamus - metabolism; intermittent access drinking; Male; Mice; Mice, Knockout; naltrexone; Naltrexone - pharmacology; Narcotics; Obesity - genetics; Obesity - metabolism; Pro-Opiomelanocortin - deficiency; Pro-Opiomelanocortin - genetics; Pro-Opiomelanocortin - metabolism; Rodents; sex differences; Sexes; drinking-in-the-dark; naltrexone; Alcohol deprivation effect; sex differences; intermittent access drinking; hypothalamic-specific POMC-deficient mice
• ISSN: 1601-1848; 1601-183X
• DOI: 10.1111/gbb.12362

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. In this study, we provide genetic and pharmacological evidence that proopiomelanocortin (POMC) within the hypothalamus plays an essential role in alcohol drinking and relapse. Using site‐specific transgenic mouse model and pharmacological validation experiments, we show that POMC expressed in the hypothalamic neurons (but not pituitary cells) plays an important role in the alcohol deprivation effect (the increase in alcohol intake after a period of abstinence), with impact on ‘binge’‐like and escalation drinking. Medications targeting hypothalamic POMC by selective alteration of the region‐ and cell‐specific POMC might have therapeutic efficacy.