Peroxisome Proliferator‐Activated Receptorsαandγare Linked with Alcohol Consumption in Mice and Withdrawal and Dependence in Humans
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Le résumé fourni par la source
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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Peroxisome Proliferator‐Activated Receptors<i>α</i>and<i>γ</i>are Linked with Alcohol Consumption in Mice and Withdrawal and Dependence in Humans
- Date Crossref
- 16/12/2014
- Éditeur
- Wiley
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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The University of Texas at Austin Waggoner Center for Alcohol and Addiction Research pays non établi dans la noticeUniversité ou école supérieure
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Cassava Sciences (United States) pays non établi dans la noticeEntreprise
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Washington University in St. Louis pays non établi dans la noticeUniversité ou école supérieure
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Indiana University School of Medicine pays non établi dans la noticeUniversité ou école supérieure
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Indiana University – Purdue University Indianapolis pays non établi dans la noticeUniversité ou école supérieure
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UConn Health pays non établi dans la noticeÉtablissement de santé
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Inc. Austin Texas Pain Therapeutics pays non établi dans la noticeEntreprise
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Department of Psychiatry Washington University School of Medicine St. Louis Missouri Department of Psychiatry pays non établi dans la noticeUniversité ou école supérieure
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University of Connecticut Health Center Farmington Connecticut pays non établi dans la noticeUniversité ou école supérieure
Waggoner Center for Alcohol and Addiction Research — The University of Texas at Austin, Cassava Sciences (United States) et Washington University in St. Louis, avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.