title: Peroxisome proliferator-activated receptors α and γ are linked with alcohol consumption in mice and withdrawal and dependence in humans.
abstract: 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 consumption tests in mice. However, a selective PPARδ agonist or a pan agonist for all 3 PPAR isoforms did not decrease EtOH consumption. Fenofibric acid, the active metabolite of the PPARα agonist fenofibrate, was detected in liver, plasma, and brain after 1 or 8 days of oral treatment. The GWAS from COGA supported an association of SNPs in PPARA and PPARG with alcohol withdrawal and PPARGC1A with AD but found no association for PPARD with either phenotype.
  
  
  CONCLUSIONS
  We provide convergent evidence using both mouse and human data for specific PPARs in alcohol action. Reduced EtOH intake in mice and the genetic association between AD or withdrawal in humans highlight the potential for repurposing FDA-approved PPARα or PPARγ agonists for the treatment of AD.
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas.
authors.forename: Yuri A
authors.initials: YA
authors.lastname: Blednov
authors.forename: Jillian M
authors.initials: JM
authors.lastname: Benavidez
authors.forename: Mendy
authors.initials: M
authors.lastname: Black
authors.forename: Laura B
authors.initials: LB
authors.lastname: Ferguson
authors.forename: Grant L
authors.initials: GL
authors.lastname: Schoenhard
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.forename: Leah
authors.initials: L
authors.lastname: Wetherill
authors.forename: Victor
authors.initials: V
authors.lastname: Hesselbrock
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.forename: R Adron
authors.initials: RA
authors.lastname: Harris
mesh_terms: D000328:Adult; D000428:Alcohol Drinking / Q000188:drug therapy / Q000235:genetics*; D000437:Alcoholism / Q000188:drug therapy / Q000235:genetics*; D000476:Alkanesulfonates / Q000627:therapeutic use; D000818:Animals; D001629:Bezafibrate / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism; D005260:Female; D011345:Fenofibrate / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D055106:Genome-Wide Association Study; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics*; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics*; D010666:Phenylpropionates / Q000627:therapeutic use; D000077205:Pioglitazone; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013844:Thiazoles / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000627:therapeutic use; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D000476:Alkanesulfonates; D001629:Bezafibrate; D011345:Fenofibrate; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates; D000077205:Pioglitazone; D013844:Thiazoles; D045162:Thiazolidinediones; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C501413:tesaglitazar
keywords: C57BL/6J; Fenofibrate; Fenofibric Acid; Genome-Wide Association Study; Pioglitazone; Tesag-litazar; Two-Bottle Choice