Alcohol dependence and relapse in abstinent alcoholics are major health problems in the United States and neurochemical pathways that modulate these disorders are currently under investigation. However, the central mechanisms involved in the regulation of non-dependent binge alcohol drinking have received far less attention. Of great concern, binge drinking during adolescent years can significantly increases the risk of developing ethanol dependence later in life. Thus, it is of paramount importance to identify the central mechanisms that modulate the effects of adolescent binge drinking on subsequent excessive ethanol intake in adulthood. The role of epigenetic factors (i.e. mechanisms that influence changes of gene expression independent of changes to the underlying DNA sequence) in ethanol consumption is a new approach to understand the mechanisms that modulate excessive ethanol drinking. Brain chromatin remodeling regulates gene expression via enzymatic restructuring of histone proteins and DNA without altering the primary genetic sequence. Recent evidence has suggested that epigenetic mechanisms contribute to ethanol-induced transcriptional changes. However, the role of histone methylation in binge-like ethanol drinking has not been addressed. An interesting possibility is that adolescent ethanol exposure facilitates changes in histone methylation in critical brain regions, and this increases the risk of excessive ethanol drinking in adult years. We have found that binge-like ethanol drinking in adult mice is associated with decreased H3 lysine 9 dimethylation (H3K9me2) in the nucleus accumbens (NAc). Therefore, the specific aims proposed below will test the guiding hypotheses that (A) H3K9me2 activity in the NAc modulates excessive ethanol drinking in adult mice, and that (B) adolescent binge-like ethanol drinking promotes robust and long- term reductions of histone dimethylation in brain regions implicated in ethanol intake, and these changes contribute to increased ethanol drinking in adulthood.
Aim 1 will test the hypothesis that deletion of H3K9me2 in the NAc will augment binge-like ethanol drinking, and that overexpression of G9a (and H3K9me2 activity) in the NAc will protect against binge-like ethanol drinking, in adult mice.
Aim 2 A will determine if a history of binge-like ethanol drinking will blunt H3K9me2 and enzymes responsible for histone dimethylation in brain regions implicated in binge-like drinking, and if this effect will be greater in adolescent than adult mice and persist into adulthood.
Aim 2 B will test the hypothesis that pharmacological inhibition of G9a in adolescent mice will increased voluntary ethanol drinking in adulthood, and determine if overexpression of G9a protects against increased voluntary ethanol intake in adulthood stemming from adolescent binge drinking. These studies will provide a set of data and proof of concept for powerful and innovative tools that will be the foundation for a future R01 application that will continue research on the role of epigenetic mechanism in modulating the neurobiological responses associated with adolescent ethanol drinking.
Adolescent binge drinking is a growing problem with numerous health consequences, including an increased risk of developing alcohol dependence later in life. Thus, it is of great importance to identify the neurobiological mechanisms that underlie the effects of adolescent ethanol drinking on subsequent excessive ethanol consumption in adulthood. This highly innovative proposal will allow us to test the hypothesis that epigenetic mechanisms (specifically histone dimethylation) play key roles, and at the same time provide insight into new tools for studying the role of H3K9me2 in adolescent binge-like ethanol drinking.
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