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Peroxisome Proliferator‐Activated Receptors α and γ are Linked with Alcohol Consumption in Mice and Withdrawal and Dependence in Humans
Author(s) -
Blednov Yuri A.,
Benavidez Jillian M.,
Black Mendy,
Ferguson Laura B.,
Schoenhard Grant L.,
Goate Alison M.,
Edenberg Howard J.,
Wetherill Leah,
Hesselbrock Victor,
Foroud Tatiana,
Adron Harris R.
Publication year - 2015
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12610
Subject(s) - peroxisome proliferator activated receptor , fenofibrate , agonist , endocrinology , peroxisome proliferator activated receptor gamma , medicine , single nucleotide polymorphism , metabolite , pharmacology , receptor , chemistry , biochemistry , genotype , gene
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 C57 BL /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), GW 0742 (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 ( SNP s) in different PPAR genes ( PPARA , PPARD , PPARG , and PPARGC 1A ) with 2 phenotypes: DSM ‐ IV alcohol dependence ( AD ) and the DSM ‐ IV criterion of withdrawal. Results Activation of 2 isoforms of PPAR s, α and γ , reduced EtOH intake and preference in the 2 different consumption tests in mice. However, a selective PPAR δ agonist or a pan agonist for all 3 PPAR isoforms did not decrease EtOH consumption. Fenofibric acid, the active metabolite of the PPAR α 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 SNP s in PPARA and PPARG with alcohol withdrawal and PPARGC 1A with AD but found no association for PPARD with either phenotype. Conclusions We provide convergent evidence using both mouse and human data for specific PPAR s 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 PPAR α or PPAR γ agonists for the treatment of AD .