Epigenetic Mechanisms of Positive Affective State of Alcoholism

点击翻译按钮获取中文摘要

Dopamine is important for the rewarding and reinforcing properties of drugs of abuse, and the ventral tegmental area (VTA) is the source of dopamine to structures in the extended amygdala, including the nucleus accumbens, prefrontal cortex, amygdala and hippocampus. Alcohol-induced alterations of the physiology of neurons of the extended amygdala may underlie the alcohol craving and alcohol seeking associated with alcoholism. Chronic ethanol exposure induces a decrease in sensitivity of dopamine neurons of the VTA to inhibition by gamma aminobutyric acid (GABA) during alcohol withdrawal. Our preliminary data show that this reduction in response to GABA is reversed by treatment with histone deacetylase (HDAC) Inhibitors; this finding indicates that the alcohol-induced change in VTA neurons is maintained by epigenetic mechanisms that can be pharmacologically manipulated. Research Component Project 1 of the CARE plans to examine reduction in GABA-A function in VTA neurons from rats during ethanol withdrawal using electrophysio-^logical and molecular biological methods and to characterize the role of histone acetylation in GABA-A hypofunction during alcohol withdrawal. The goals of this project are: 1) To determine whether GABA hyposensitivity observed during withdrawal is due to increased HDAC activity and reductions in GABA-A receptor subunit expression, 2) To identify whether GABA-A subunit expression, HDAC activity, and histone acetylation are altered during withdrawal from chronic alcohol, and 3) To identify new genes that regulate GABA sensitivity during ethanol withdrawal using RNA sequencing (RNA-seq) and chromatin immunoprecipitation and DNA sequencing (ChlP-seq) in collaboration with the Epigenetic Core. Ultimately, these studies are needed to understand ethanol-induced adaptation of central nervous system neurons involved in addiction, and, with the other components of this Center, will provide a great deal of information on epigenetic mechanisms involved in maintaining alcohol-induced brain changes.