Persistent changes in gene expression may mediate many alcohol effects including reward learning, tolerance and dependence, suggesting that agents effective at changing alcohol-induced gene expression should be considered as therapeutic agents. Drugs targeting gene expression through inhibition of enzymes that regulate chromatin structure (epigenetic drugs) have been widely used in cancer research and recently emerged as potential therapeutics for neurodegenerative disorders and drug addiction. The main goals of this project are: 1) to identify epigenetic drugs that affect alcohol reward through testing their effects on alcohol consumption and conditioned place preference (CPP) and 2) to investigate the effects of selected epigenetic drugs on gene expression and cellular physiology in the reward pathway including ventral tegmental area (VTA) and the nucleus accumbens (NA). The overall hypothesis is that some epigenetic drugs will reduce the rewarding properties of alcohol through changes in gene expression and cellular physiology in the reward pathway. To address this research problem, we will use a combination of pharmacological, behavioral, genomic and electrophysiological approaches. Alcohol will be delivered via voluntary consumption using a mouse model of binge drinking or via systemic injections to produce CPP. Epigenetic drugs will be delivered via systemic injections prior to alcohol. We will use laser capture microdissections to dissect VTA and NA. We will measure global gene expression in these regions after different combinations of epigenetic drugs, vehicle and alcohol. VTA dopamine neurons will be tested using electrophysiological techniques in parallel with gene expression. Microarray results will be validated using qRT-PCR and epigenetic assays. Integration of electrophysiological and gene expression data will elucidate the drug's mechanisms of action and identify novel targets for drug development. This research will provide initial mechanistic evidence for the therapeutic potential of epigenetic drugs in treating alcohol addiction.
There is clearly a need for more effective and more specific medications for treatment of alcoholism. Epigenetic drugs offer unique advantages in treating diseases through chromatin-dependent changes in gene expression. Completion of this project will provide initial mechanistic evidence for the therapeutic potential of epigenetic drugs in treating alcohol addiction. The ultimate goal of this line of research is to promote the development of new therapies for human alcoholism.
| Scott, Luisa L; Iyer, Sangeetha; Philpo, Ashley E et al. (2018) A Novel Peptide Restricts Ethanol Modulation of the BK Channel In Vitro and In Vivo. J Pharmacol Exp Ther 367:282-290 |
| Most, Dana; Salem, Nihal A; Tiwari, Gayatri R et al. (2018) Silencing synaptic MicroRNA-411 reduces voluntary alcohol consumption in mice. Addict Biol : |
| McCarthy, Gizelle M; Warden, Anna S; Bridges, Courtney R et al. (2018) Chronic ethanol consumption: role of TLR3/TRIF-dependent signaling. Addict Biol 23:889-903 |
| Ferguson, Laura B; Zhang, Lingling; Kircher, Daniel et al. (2018) Dissecting Brain Networks Underlying Alcohol Binge Drinking Using a Systems Genomics Approach. Mol Neurobiol : |
| Mayfield, R Dayne (2017) Emerging roles for ncRNAs in alcohol use disorders. Alcohol 60:31-39 |
| Scott, L L; Brecht, E J; Philpo, A et al. (2017) A novel BK channel-targeted peptide suppresses sound evoked activity in the mouse inferior colliculus. Sci Rep 7:42433 |
| Tulisiak, Christopher T; Harris, R Adron; Ponomarev, Igor (2017) DNA modifications in models of alcohol use disorders. Alcohol 60:19-30 |
| Harris, R Adron; Bajo, Michal; Bell, Richard L et al. (2017) Genetic and Pharmacologic Manipulation of TLR4 Has Minimal Impact on Ethanol Consumption in Rodents. J Neurosci 37:1139-1155 |
| Cornelison, Garrett L; Daszkowski, Anna W; Pflanz, Natasha C et al. (2017) Interactions between Zinc and Allosteric Modulators of the Glycine Receptor. J Pharmacol Exp Ther 361:1-8 |
| Ponomarev, Igor; Stelly, Claire E; Morikawa, Hitoshi et al. (2017) Mechanistic insights into epigenetic modulation of ethanol consumption. Alcohol 60:95-101 |
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