Peroxisome Proliferator‐Activated Receptorsαandγare Linked with Alcohol Consumption in Mice and Withdrawal and Dependence in Humans

作者：Yuri A. Blednov, Jillian M. Benavidez, Mendy Black, Laura B. Ferguson, Grant L. Schoenhard, Alison Goate, Howard J. Edenberg, Leah Flury Wetherill, VICTOR M. HESSELBROCK, Tatiana Foroud, Robert Adron Harris · 发表于：Alcoholism Clinical and Experimental Research · 年份：2014 · DOI：10.1111/acer.12610 · 被引用次数：96 · 研究领域：Peroxisome Proliferator-Activated Receptors、Neurotransmitter Receptor Influence on Behavior、Alcohol Consumption and Health Effects

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR) agonists reduce voluntary ethanol (EtOH) consumption in rat models and are promising therapeutics in the treatment for drug addictions. We studied the effects of different classes of PPAR agonists on chronic EtOH intake and preference in mice with a genetic predisposition for high alcohol consumption and then examined human genomewide association data for polymorphisms in PPAR genes in alcohol-dependent subjects. METHODS: Two different behavioral tests were used to measure intake of 15% EtOH in C57BL/6J male mice: 24-hour 2-bottle choice and limited access (3-hour) 2-bottle choice, drinking in the dark. We measured the effects of pioglitazone (10 and 30 mg/kg), fenofibrate (50 and 150 mg/kg), GW0742 (10 mg/kg), tesaglitazar (1.5 mg/kg), and bezafibrate (25 and 75 mg/kg) on EtOH intake and preference. Fenofibric acid, the active metabolite of fenofibrate, was quantified in mouse plasma, liver, and brain by liquid chromatography tandem mass spectrometry. Data from a human genome-wide association study (GWAS) completed in the Collaborative Study on the Genetics of Alcoholism (COGA) were then used to analyze the association of single nucleotide polymorphisms (SNPs) in different PPAR genes (PPARA, PPARD, PPARG, and PPARGC1A) with 2 phenotypes: DSM-IV alcohol dependence (AD) and the DSM-IV criterion of withdrawal. RESULTS: Activation of 2 isoforms of PPARs, α and γ, reduced EtOH intake and preference in the 2 different c...