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PPAR agonists regulate brain gene expression: relationship to their effects on ethanol consumption.
Laura B Ferguson1, Dana Most1, Yuri A Blednov2
1Waggoner 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.
Neuropharmacology
|July 19, 2014
Summary
Peroxisome proliferator-activated receptor (PPAR) agonists reduced alcohol consumption in mice by altering gene expression in the amygdala, particularly in GABAergic interneurons. These findings reveal molecular targets for treating alcohol use disorder.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors with known anti-inflammatory and metabolic roles.
- PPAR agonists are prescribed for dyslipidemia and type-II diabetes.
- PPAR agonists have demonstrated anti-addictive properties, reducing ethanol consumption and withdrawal symptoms in preclinical models.
Purpose of the Study:
- To investigate the cellular and molecular mechanisms underlying the anti-addictive effects of PPAR agonists on ethanol consumption.
- To identify specific brain regions and gene expression changes associated with PPAR agonist-induced reduction in alcohol intake.
Main Methods:
- Three PPAR agonists (tesaglitazar, fenofibrate, bezafibrate) were tested in a two-bottle choice ethanol consumption paradigm in male C57BL/6J mice.
- Unbiased genomic profiling was performed on the prefrontal cortex (PFC), amygdala, and liver.
- Weighted gene co-expression network analysis (WGCNA) was used to identify co-expressed gene networks and functional pathways.
Main Results:
- Tesaglitazar and fenofibrate significantly decreased ethanol consumption, while bezafibrate did not.
- PPAR agonists induced a neuronal gene expression signature in the brain, contrary to expectations of targeting glial cells.
- Fenofibrate and tesaglitazar specifically targeted a subset of GABAergic interneurons in the amygdala.
- WGCNA identified neuropeptide and dopaminergic signaling pathways in the amygdala as potentially modulated by PPAR agonists.
Conclusions:
- PPAR agonists, specifically tesaglitazar and fenofibrate, reduce alcohol consumption through mechanisms involving altered gene expression in the brain.
- The anti-addictive effects appear to be mediated by targeting specific neuronal populations, such as GABAergic interneurons in the amygdala.
- These findings identify novel gene targets and signaling pathways through which PPAR agonists can influence alcohol consumption behavior, offering potential therapeutic avenues for alcohol use disorder.
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