title: PPAR agonists regulate brain gene expression: relationship to their effects on ethanol consumption.
abstract: Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. Although prescribed for dyslipidemia and type-II diabetes, PPAR agonists also possess anti-addictive characteristics. PPAR agonists decrease ethanol consumption and reduce withdrawal severity and susceptibility to stress-induced relapse in rodents. However, the cellular and molecular mechanisms facilitating these properties have yet to be investigated. We tested three PPAR agonists in a continuous access two-bottle choice (2BC) drinking paradigm and found that tesaglitazar (PPARα/γ; 1.5 mg/kg) and fenofibrate (PPARα; 150 mg/kg) decreased ethanol consumption in male C57BL/6J mice while bezafibrate (PPARα/γ/β; 75 mg/kg) did not. We hypothesized that changes in brain gene expression following fenofibrate and tesaglitazar treatment lead to reduced ethanol drinking. We studied unbiased genomic profiles in areas of the brain known to be important for ethanol dependence, the prefrontal cortex (PFC) and amygdala, and also profiled gene expression in liver. Genomic profiles from the non-effective bezafibrate treatment were used to filter out genes not associated with ethanol consumption. Because PPAR agonists are anti-inflammatory, they would be expected to target microglia and astrocytes. Surprisingly, PPAR agonists produced a strong neuronal signature in mouse brain, and fenofibrate and tesaglitazar (but not bezafibrate) targeted a subset of GABAergic interneurons in the amygdala. Weighted gene co-expression network analysis (WGCNA) revealed co-expression of treatment-significant genes. Functional annotation of these gene networks suggested that PPAR agonists might act via neuropeptide and dopaminergic signaling pathways in the amygdala. Our results reveal gene targets through which PPAR agonists can affect alcohol consumption behavior.
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712, United States; The Institute for Neuroscience (INS), The University of Texas at Austin, Austin, TX 78712, United States. Electronic address: laurazeavin@gmail.com.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Ferguson
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712, United States; The Institute for Neuroscience (INS), The University of Texas at Austin, Austin, TX 78712, United States.
authors.forename: Dana
authors.initials: D
authors.lastname: Most
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712, United States.
authors.forename: Yuri A
authors.initials: YA
authors.lastname: Blednov
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712, United States.
authors.forename: R Adron
authors.initials: RA
authors.lastname: Harris
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy* / Q000503:physiopathology; D000476:Alkanesulfonates / Q000494:pharmacology; D000679:Amygdala / Q000187:drug effects* / Q000503:physiopathology; D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology; D002491:Central Nervous System Agents / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D004326:Drinking / Q000187:drug effects; D060766:Drinking Water / Q000008:administration & dosage; D000431:Ethanol / Q000008:administration & dosage; D011345:Fenofibrate / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000378:metabolism; D010666:Phenylpropionates / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000503:physiopathology; D055697:Taste Perception / Q000187:drug effects / Q000502:physiology
chemical_list: D000476:Alkanesulfonates; D002491:Central Nervous System Agents; D002492:Central Nervous System Depressants; D060766:Drinking Water; D047492:Peroxisome Proliferator-Activated Receptors; D010666:Phenylpropionates; D000431:Ethanol; C501413:tesaglitazar; D011345:Fenofibrate; D001629:Bezafibrate
keywords: Alcohol; Amygdala; Mice; Microarray; PPAR; Prefrontal cortex