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:
Laura B Ferguson, Dana Most, Yuri A Blednov, R Adron Harris
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:
Laura B Ferguson, Dana Most, Yuri A Blednov, R Adron Harris
Genes with particular expression in the Orbital area, ventrolateral part, layer 1. Data represent fold expression difference in structure versus grey matter average expression.
Genes associated with Rattus norvegicus that interact with the MeSH term 'furan' (C039281). Incorporates data from 1 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Rattus norvegicus that interact with the MeSH term 'vinclozolin' (C025643). Incorporates data from 12 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Rattus norvegicus that interact with the MeSH term 'bisphenol A' (C006780). Incorporates data from 3 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Cerebellum Gene Expression Correlates for SHAKE measured in BXD RI Males obtained using SJUT Cerebellum mRNA M430 (Mar05) RMA. The SHAKE measures Morphine - wet dog shakes under the domain Morphine. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
Genes with particular expression in the Periventricular zone. Data represent fold expression difference in structure versus grey matter average expression.
Genes with particular expression in the Main olfactory bulb, glomerular layer. Data represent fold expression difference in structure versus grey matter average expression.
Genes with particular expression in the Main olfactory bulb, outer plexiform layer. Data represent fold expression difference in structure versus grey matter average expression.
Genes with particular expression in the Supraoptic nucleus. Data represent fold expression difference in structure versus grey matter average expression.
Genes with particular expression in the Medial amygdalar nucleus, posteroventral part. Data represent fold expression difference in structure versus grey matter average expression.
Genes with particular expression in the Main olfactory bulb. Data represent fold expression difference in structure versus grey matter average expression.
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