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The Journal of Neuroscience, April 2, 2008, 28(14):3729-3737; doi:10.1523/JNEUROSCI.5731-07.2008

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Behavioral/Systems/Cognitive
Brain Chromatin Remodeling: A Novel Mechanism of Alcoholism

Subhash C. Pandey,1,2,3 Rajesh Ugale,1,3 Huaibo Zhang,1,3 Lei Tang,1,3 and Anand Prakash1,3

Departments of 1Psychiatry and 2Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois 60612, and 3Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612

Correspondence should be addressed to Dr. Subhash C. Pandey, Department of Psychiatry, University of Illinois at Chicago and Jesse Brown Veterans Affairs Medical Center, 820 South Damen Avenue, M/C 151, Chicago, IL 60612. Email: scpandey{at}uic.edu

The treatment of alcoholism requires the proper management of ethanol withdrawal symptoms, such as anxiety, to prevent further alcohol use and abuse. In this study, we investigated the potential role of brain chromatin remodeling, caused by histone modifications, in alcoholism. We found that the anxiolytic effects produced by acute alcohol were associated with a decrease in histone deacetylase (HDAC) activity and increases in acetylation of histones (H3 and H4), levels of CREB (cAMP-responsive element binding) binding protein (CBP), and neuropeptide Y (NPY) expression in the amygdaloid brain regions of rats. However, the anxiety-like behaviors during withdrawal after chronic alcohol exposure were associated with an increase in HDAC activity and decreases in acetylation of H3 and H4, and levels of both CBP and NPY in the amygdala. Blocking the observed increase in HDAC activity during alcohol withdrawal with the HDAC inhibitor, trichostatin A, rescued the deficits in H3 and H4 acetylation and NPY expression (mRNA and protein levels) in the amygdala (central and medial nucleus of amygdala) and prevented the development of alcohol withdrawal-related anxiety in rats as measured by the elevated plus maze and light/dark box exploration tests. These results reveal a novel role for amygdaloid chromatin remodeling in the process of alcohol addiction and further suggest that HDAC inhibitors may be potential therapeutic agents in treating alcohol withdrawal symptoms.

Key words: alcoholism; anxiety; amygdala; histone acetylation; HDAC inhibitors; NPY

Received Dec. 27, 2007; revised Feb. 21, 2008; accepted Feb. 26, 2008.

Correspondence should be addressed to Dr. Subhash C. Pandey, Department of Psychiatry, University of Illinois at Chicago and Jesse Brown Veterans Affairs Medical Center, 820 South Damen Avenue, M/C 151, Chicago, IL 60612. Email: scpandey{at}uic.edu






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