Brain epigenetic mechanisms in alcohol dependence

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DESCRIPTION (provided by applicant): Anxiety is a common early symptom of ethanol withdrawal and is considered an important factor in the continued use of alcohol by alcoholics. It is also well known that alcohol produces anxiolytic effects. How different epigenetic mechanisms are contributing to changes in neural plasticity associated with alcohol addiction is unknown. Studies have shown the role of changes in chromatin structure due to histone covalent modifications via acetylation and deacetylation in the regulation of gene expression. Histone acetylation is controlled by two groups of enzymes known as histone acetyl-transferases (HATs) and histone deacetylases (HDACs). Three distinct families of HDACs have been described and trichostatin A (ISA) is a potent inhibitor of class I and II HDACs, but not the class III HDACs [silent information regulator 2(Sir2) protein family] which requires a cofactor, nicotinamide-adenine dinucleotide (NAD), for enzymatic activity. It has been shown that phosphorylated cAMP-responsive element binding (p-CREB) regulates neuronal plasticity via recruitment of the HAT associated with CREB binding protein (CBP) to activate gene transcription. Neuropeptide Y (NPY) is one of the CREB-related genes and acts as a potent endogenous anxiolytic compound ,and plays a role in alcoholism. Our proposal is based on the hypothesis that histone modifications, due to an altered acetylation state in the amygdala, are involved in the molecular mechanisms of alcohol dependence. We have proposed several approaches to test this hypothesis specifically by examining a) the effects of acute ethanol on various components of histone acetylation mechanisms as well as NPY expression in the central (CeA), medial (MeA) and basolateral amygdala(BLA) of rats and manipulations of activities of HATs activity and Sir2 in the CeA, MeA, and BLA will also be examined on the anxiolytic properties of ethanol. b) Effects of HDACs inhibitor (Trichostatin A) challenge or intra-amygdaloid Sir 2 inhibitor infusion on anxiety-like behaviors and also on various components of histone acetylation and on NPY expression in amygdala during withdrawal after chronic ethanol exposure. We will also examine the effects of H3 acetylation on NPY mRNA levels in the amygdala during ethanol treatment and its withdrawal. The proposed studies will provide new information on epigenetic mechanisms in the neurocircuitry of the amygdala that may be involved in the process of alcohol dependence.