Alcoholism affects millions of people and burdens society with high healthcare costs, lost work productivity and increased crime rates. There is an urgent need for improved treatments since the three that are currently approved are only modestly effective. Peroxisome proliferator activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. Recent evidence suggests that PPAR agonists possess anti-addictive characteristics and offer unexplored therapeutic intervention for treating alcoholics. PPAR agonists possess a uniquely promising pharmacologic potential for treating alcoholism since they have been demonstrated to alleviate the top four ailments confronting alcoholics: alcohol abuse, liver failure, neurodegeneration and smoking addiction. The proposed research will investigate the mechanisms that impart the anti-addictive properties of PPAR agonists.
The first aim will use immunohistochemistry and qRT- PCR to determine the baseline distribution and localization of PPAR isotypes in regions of addiction neurocircuitry. The second and third aims will use viral-mediated gene manipulation and mouse behavioral models to test the importance of PPARs in vivo for decreased alcohol consumption behavior in response to treatment with a PPAR agonist. This study will provide crucial new knowledge about a relatively new and unexplored area of addiction research. By understanding how PPAR agonists can facilitate decreased alcohol consumption, results from this project will implicate interesting new pharmacological targets and facilitate the discovery of novel genes and pathways that might contribute to the initiation, maintenance, or progression of alcoholism. By linking drug, genes, and behavior, this data may have a broader scientific significance by resolving the disparity between complex behaviors and underlying molecular changes induced by a treatment or condition. The proposed research will generate critical evidence linking the PPAR pathway on a molecular level to alcohol-related behavior, and is an important step towards repositioning PPAR agonists as treatment for alcoholism. The PPAR agonist under investigation in this study has demonstrated a reasonably favorable safety profile and is already FDA approved for dyslipidemia so could quickly become a new treatment for alcoholism without lengthy safety and efficacy trials. Furthermore, the results of this research may extend to other addictions and psychiatric disorders where PPAR agonists have demonstrated therapeutic potential, thereby increasing the quality of life for individual patients of many illnesses like Parkinson's, Alzheimer's and Huntington's disease.
Recent evidence suggests that drugs targeting PPARs, a class of nuclear hormone receptors, might be effective in treating alcoholism. This research will investigate the mechanisms by which PPAR agonists decrease alcohol consumption. This information will help us develop insights into the genes and pathways that might contribute to the transition from recreational alcohol consumption to alcoholism and provide better treatment options for alcoholics.
| Ferguson, Laura B; Harris, R Adron; Mayfield, Roy Dayne (2018) From gene networks to drugs: systems pharmacology approaches for AUD. Psychopharmacology (Berl) 235:1635-1662 |
| Warden, Anna; Truitt, Jay; Merriman, Morgan et al. (2016) Localization of PPAR isotypes in the adult mouse and human brain. Sci Rep 6:27618 |
| Blednov, Yuri A; Benavidez, Jillian M; Black, Mendy et al. (2015) Peroxisome proliferator-activated receptors ? and ? are linked with alcohol consumption in mice and withdrawal and dependence in humans. Alcohol Clin Exp Res 39:136-45 |
