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 consumption in rat models and are promising therapeutics in the treatment of drug addictions. We studied the effects of different classes of PPAR agonists on chronic ethanol intake and preference in mice with a genetic predisposition for high alcohol consumption and then examined human genome wide association data for polymorphisms in PPAR genes in alcohol-dependent subjects. Methods Two different behavioral tests were used to measure intake of 15% ethanol in C57BL/6J male mice: 24-hour two-bottle choice and limited access (3-hour) two-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 ethanol intake and preference. Fenofibric acid, the active metabolite of fenofibrate, was quantified in mouse plasma, liver, and brain by LC-MS/MS. Data from a human genome wide association study (GWAS) completed in the Collaborative Study on the Genetics of Alcoholism (COGA) was then used to analyze the association of single nucleotide polymorphisms (SNPs) in different PPAR genes (PPARA, PPARD, PPARG, and PPARGC1A) with two phenotypes: DSM-IV alcohol dependence (AD) and the DSM-IV criterion of withdrawal. Results Activation of two isoforms of PPARs, α and γ, reduced ethanol intake and preference in the two different consumption tests in mice. However, a selective PPARδ agonist or a pan agonist for all three PPAR isoforms did not decrease ethanol 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 ethanol 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.

Promising Pharmacogenetic Targets for Treating Alcohol Use Disorder: Evidence from Preclinical Models

“…Because of the strong preclinical pharmacology and genetic data linking PPAR signal ing with alcohol intake, a clinical trial is currently underway to determine if the PPAR agonist fenofi brate will decrease craving for alcohol following cue exposure and reduce the number of drinks consumed in alcoholdependent subjects (ClinicalTrial.gov trial number: NCT02158273). A recent study demon strated that SNPs in PPARG and PPARGC1A were associated with alcohol dependence in EuropeanAmerican alcoholics [155]. Moreover, these authors also reported that PPARA and PPARG were associated with a DSMIV criterion for an alcohol withdrawal pheno type.…”

“…PPARs are nuclear proteins that regulate gene expres sion and control neuroimmune responses and inflam mation [152]. Expression of PPARD (PPARδ subunit) and PPARGC1A (PPARγ coactivator) are altered in the basolateral and central amygdala of alcoholics [111], and PPAR agonists show promise in preclinical mod els of alcohol drinking, stressinduced relapse and withdrawal [153][154][155][156][157]. Because of the strong preclinical pharmacology and genetic data linking PPAR signal ing with alcohol intake, a clinical trial is currently underway to determine if the PPAR agonist fenofi brate will decrease craving for alcohol following cue exposure and reduce the number of drinks consumed in alcoholdependent subjects (ClinicalTrial.gov trial number: NCT02158273).…”

Genetic studies of alcohol dependence in the context of the addiction cycle

“…It is logical to assume that PECR and PPAR are part of the same biological pathway and thus likely have cooperative/complementary functions. PPAR agonists, including tesaglitazar and fenofibrate, reduce voluntary alcohol consumption, withdrawal severity and stress-induced relapse in rodents (Blednov et al, 2015, 2016; Stopponi et al, 2013; Stopponi et al, 2011). Re-analysis of GWAS data focusing only on SNPs within PPAR genes found an association of SNPs in PPARA and PPARG with alcohol withdrawal and PPARGC1A with alcohol dependence (Blednov et al, 2015).…”

“…PPAR agonists, including tesaglitazar and fenofibrate, reduce voluntary alcohol consumption, withdrawal severity and stress-induced relapse in rodents (Blednov et al, 2015, 2016; Stopponi et al, 2013; Stopponi et al, 2011). Re-analysis of GWAS data focusing only on SNPs within PPAR genes found an association of SNPs in PPARA and PPARG with alcohol withdrawal and PPARGC1A with alcohol dependence (Blednov et al, 2015). Reduced alcohol consumption by tesaglitazar and fenofibrate may be associated with signaling at GABAergic interneurons, neuropeptide systems and dopaminergic signaling pathways which ultimately regulate stress-related neurocircuitry (Ferguson et al, 2014).…”

Neuroimmune Pathways in Alcohol Consumption: Evidence from Behavioral and Genetic Studies in Rodents and Humans

“…One study, however, showed that clofibrate increased voluntary alcohol consumption in male spontaneous hypertensive rats, although a very high ethanol concentration was used (30% ethanol, v/v) (Schlicht, 1987). The PPARα agonist, fenofibrate, and the dual PPARα/γ agonist, tesaglitazar, selectively decreased voluntary alcohol consumption and preference in mice (Blednov et al, submitted; Ferguson et al, 2014). Gene expression profiling revealed that fenofibrate and tesaglitazar changed the transcriptome of mouse amygdala and prefrontal cortex (Ferguson et al, 2014), two important brain areas for reward and dependence.…”