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Brain DNA 'remodeled' in alcoholism
http://www. physorg. com/ news126353910. html
April 02, 2008
The remodeling of DNA scaffolding in the brain that controls gene expression may play a major role in alcohol withdrawal syndrome, particularly anxiety, making it difficult for alcoholics to stop using alcohol.
This discovery was reported by researchers from the University of Illinois at Chicago (UIC) and the Jesse Brown VA Medical Center in the April 2 issue of the Journal of Neuroscience.
DNA can undergo functional group changes without altering the sequence of inheritance or the genetic code. These "epigenetic" changes are secondary chemical modifications of chromosomes (tightly packed DNA and histones).
"This is the first time someone has found epigenetic changes related to chromatin remodeling in the brain during alcohol addiction," said Dr. Subhash C. Pandey, professor and director of neuroscience and alcoholism research at the UIC College of Medicine and the Jesse Brown VA Medical Center, and the lead author of the study.
Chemical modifications of histones can alter the way DNA is wound up with histones. Histone acetyltransferases (HATs) are enzymes that add acetyl groups to histones, loosening their binding and promoting gene expression. On the other hand, histone deacetylases (HDACs) remove acetyl groups from histones, causing them to wrap DNA more tightly, reducing gene expression.
UIC researchers previously demonstrated in an animal model that the concentration of neuropeptide Y (NPY) in the amygdala regulates anxiety and drinking behavior. In this new study, they observed HDAC activity, histone acetylation, and NPY gene expression in the amygdala, as well as anxiety-like behaviors associated with withdrawal from long-term alcohol use.
Pandey and colleagues found that acute exposure to alcohol reduces HDAC activity; increases histone acetylation; increases NPY levels—and reduces anxiety in animals.
Conversely, during withdrawal from long-term alcohol exposure, anxiety-like behaviors were associated with increased HDAC activity, decreased histone acetylation, and reduced NPY levels.
Importantly, during alcohol withdrawal, blocking the observed increase in HDAC activity with HDAC inhibitors enhanced histone acetylation and NPY expression in the amygdala and prevented the development of anxiety-like behaviors.
"Our findings suggest that HDAC inhibitors may have potential as therapeutic agents for treating alcoholism," Pandey said.
The researchers also found that the binding protein CREB, which has HAT enzyme activity, increases with acute alcohol exposure but decreases during ethanol withdrawal.They concluded that enzymes involved in chromosomal remodeling play a significant role in the anxiety accompanying alcohol withdrawal and in the anti-anxiety effects of acute alcohol use.
"We need new strategies for treating alcoholism that can be directed toward avoiding withdrawal syndrome," Pandey said. "Anxiety associated with alcohol withdrawal is a key factor in maintaining alcohol addiction."
Source: http://only- perception. blogspot. com/ 2008/ 04/ dna. html
DNA Remodeling in Alcoholics' Brains
http://www. physorg. com/ news126353910. html
April 02, 2008
The remodeling of DNA scaffolding in the brain that controls gene expression may play a major role in alcohol withdrawal syndrome, particularly anxiety, making it difficult for alcoholics to stop using alcohol.
This discovery was reported by researchers from the University of Illinois at Chicago (UIC) and the Jesse Brown VA Medical Center in the April 2 issue of the Journal of Neuroscience.
DNA can undergo functional group changes without altering the sequence of inheritance or the genetic code. These "epigenetic" changes are secondary chemical modifications of chromosomes (tightly packed DNA and histones).
"This is the first time someone has found epigenetic changes related to chromatin remodeling in the brain during alcohol addiction," said Dr. Subhash C. Pandey, professor and director of neuroscience and alcoholism research at the UIC College of Medicine and the Jesse Brown VA Medical Center, and the lead author of the study.
Chemical modifications of histones can alter the way DNA is wound up with histones. Histone acetyltransferases (HATs) are enzymes that add acetyl groups to histones, loosening their binding and promoting gene expression. On the other hand, histone deacetylases (HDACs) remove acetyl groups from histones, causing them to wrap DNA more tightly, reducing gene expression.
UIC researchers previously demonstrated in an animal model that the concentration of neuropeptide Y (NPY) in the amygdala regulates anxiety and drinking behavior. In this new study, they observed HDAC activity, histone acetylation, and NPY gene expression in the amygdala, as well as anxiety-like behaviors associated with withdrawal from long-term alcohol use.
Pandey and colleagues found that acute exposure to alcohol reduces HDAC activity; increases histone acetylation; increases NPY levels—and reduces anxiety in animals.
Conversely, during withdrawal from long-term alcohol exposure, anxiety-like behaviors were associated with increased HDAC activity, decreased histone acetylation, and reduced NPY levels.
Importantly, during alcohol withdrawal, blocking the observed increase in HDAC activity with HDAC inhibitors enhanced histone acetylation and NPY expression in the amygdala and prevented the development of anxiety-like behaviors.
"Our findings suggest that HDAC inhibitors may have potential as therapeutic agents for treating alcoholism," Pandey said.
The researchers also found that the binding protein CREB, which has HAT enzyme activity, increases with acute alcohol exposure but decreases during ethanol withdrawal.They concluded that enzymes involved in chromosomal remodeling play a significant role in the anxiety accompanying alcohol withdrawal and in the anti-anxiety effects of acute alcohol use.
"We need new strategies for treating alcoholism that can be directed toward avoiding withdrawal syndrome," Pandey said. "Anxiety associated with alcohol withdrawal is a key factor in maintaining alcohol addiction."
Source: http://only- perception. blogspot. com/ 2008/ 04/ dna. html