A growing body of literature has implicated aberrant changes in gene expression induced by drugs of abuse as possible mechanisms for long-term neuroplastic changes that likely contribute to the transition to dependence. Specifically, these changes in gene expression have been linked to the ability of drugs of abuse to induce posttranslation modifications to core histone proteins, thereby relaxing or compacting chromatin structure and increasing or decreasing gene expression, respectively. These posttranslational changes include: acetylation, phosphorylation, and methylation of histone amino acid residues. Examination of the epigenetic mechanisms of drug addiction has predominantly focused on the role of histone acetylation and phosphorylation, while histone methylation has received far less attention. Histone acetylation has been implicated in the regulation of acute responses to ethanol, development of tolerance, and withdrawal. A recent examination of the impact of cocaine on histone modifications demonstrated a role for ?FosB, a transcription factor induced by a number of drugs of abuse, in suppressing the activity of histone methyltransferases, G9a and G9a-like protein (GLP), and consequently reducing methylation of histone H3 on lysine 9 (H3K9) in the nucleus accumbens (NAc). This effect resulted in reductions of dimethylated H3K9 (H3K9me2) and the activation of numerous genes involved in dendritic plasticity. Until recently, the impact of ethanol on histone methylation has received little attention, and no published reports have examined the impact of voluntary ethanol consumption on H3K9me2 in regions of the brain associated with the maintenance of drug taking behavior. Because ethanol, like cocaine, induces ?FosB in discrete reward-related regions of the brain, it is reasonable to conceive that neuroplastic changes induced by excessive ethanol consumption might be mediated by changes in histone methylation. Therefore, the experiments outlined in this proposal are designed to test the hypothesis that ethanol consumption and the reinforcing effects of ethanol are mediated, in part, by the suppression of H3K9me2 in the NAc, and that the reinforcing effects and consumption of ethanol can be modulated by manipulating H3K9me2. We predict that ethanol consumption, in both binge-drinking and operant self- administration paradigms, will increase deltaFosB and decrease H3K9me2, G9a and GLP (Specific Aim 1). As well, we predict that regional overexpression of G9a and conditional suppression of G9a in the NAc will decrease and increase binge-like ethanol consumption, respectively (Specific Aim 2). Similarly, we predict that regional overexpression or suppression of G9a in the NAc will correspondingly alter the motivation to respond for ethanol reinforcers in an operant self-administration paradigm (Specific Aim 3). The predicted results would provide the first evidence that histone dimethylation is an epigenetic mechanism involved in binge-like ethanol consumption and operant self-administration of ethanol. Understanding these mechanisms may provide insight into more targeted treatments and prevention strategies for alcohol abuse and dependence disorders.

Public Health Relevance

Binge-like and excessive alcohol consumption are major health concerns, as these types of behaviors can lead to a host of adverse health consequences, including the development of alcoholism, which costs billions of dollars in annual healthcare expenditures and other related costs. Repeated exposure to alcohol can cause neuroadaptive changes, i.e., epigenetic changes, in key circuitry in the brain, altering the neurobiological response to alcohol and possibly contributing to the transition to alcohol dependence. Results from the proposed research will help elucidate the mechanisms underlying alcohol-induced neuroplastic changes and provide insight into the development of more targeted treatment and prevention strategies.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Postdoctoral Individual National Research Service Award (F32)
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Health Services Research Review Subcommittee (AA)
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Reilly, Matthew
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University of North Carolina Chapel Hill
Schools of Arts and Sciences
Chapel Hill
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Marshall, S Alex; McKnight, Kyle H; Blose, Allyson K et al. (2017) Modulation of Binge-like Ethanol Consumption by IL-10 Signaling in the Basolateral Amygdala. J Neuroimmune Pharmacol 12:249-259
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