Adolescent binge drinking can disrupt gene regulation and brain development in ways that promote anxiety and excessive drinking behaviors that can persist into adulthood, according to a new study supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health. A report of the study, conducted in animals by researchers at the University of Illinois at Chicago College of Medicine, appears online in the journal Neurobiology of Disease.

"These findings are an important contribution to our understanding of the alcohol-induced brain changes that make alcohol problems in adulthood more likely among young people who abuse alcohol," said NIAAA Director George F. Koob, Ph.D.

Previous studies have shown that people who start drinking before the age of 15 are four times more likely to meet the criteria for alcohol dependence at some point in their lives, and young people consume more than 90 percent of their alcohol by binge drinking.

Researchers led by Subhash C. Pandey, Ph.D., professor of psychiatry and director of neuroscience alcoholism research at the University of Illinois at Chicago and a Research Career Scientist at Jesse Brown Veteran Affairs Medical Center in Chicago, investigated the effects of intermittent binge alcohol exposure during the adolescent stage of development in rats. To model adolescent binge-drinking in humans, the researchers gave 28-day-old rats alcohol for two days in a row, followed by two days off, and repeated this pattern for 13 days. Some rats were followed into adulthood and observed for abnormal behaviors. They were offered both alcohol and water, and their alcohol-drinking behavior was monitored.

Rats exposed to alcohol during adolescence exhibited changes in behavior that lasted into adulthood, long after their adolescent binge exposure to alcohol had ended. For example, they showed increased anxiety-like behaviors and drank more alcohol in adulthood.

Prior research has implicated a brain structure known as the amygdala in anxiety and alcohol-drinking behaviors. When Dr. Pandey and his colleagues analyzed the amygdala of alcohol-exposed rats in their study, they found that the complex of DNA and histone proteins within the amygdala cell nuclei appeared to be tightly wrapped. They also found increased levels of a protein called HDAC2, which modifies histones in a way that causes DNA to be wound tighter around them. Collectively, these kinds of changes to DNA or its associated proteins that change its function but do not affect the DNA sequence are referred to as epigenetic changes.

"Genes that lie within DNA that is tightly wrapped around the histones are less active than they are if the DNA is loosely wrapped," explains Dr. Pandey. "The looser the DNA is coiled, the more accessible are the genes to the cellular machinery that makes relevant proteins."

Dr. Pandey and his team found that the epigenetic changes they observed in alcohol-exposed rats were linked to lowered expression of two genes - brain-derived neurotrophic factor and activity-regulated cytoskeleton-associated -- that nerve cells need to form new connections with each other. The diminished expression of the genes persisted in adulthood, even if alcohol exposure was stopped weeks before, and the researchers observed diminished nerve connectivity in the amygdala of these affected adult rats. But they then showed that a drug that blocks the activity of HDAC2 could loosen the coiling of DNA in amygdala cell nuclei of alcohol-exposed rats, and increased the expression of the gene needed for nerve cell connectivity in those animals. The animals then also exhibited less anxiety and reduced alcohol intake.

The researchers plan additional studies of this target and other epigenetic drugs to investigate their possible use in reversing the persistent harmful effects of adolescent alcohol exposure.

The National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health, is the primary U.S. agency for conducting and supporting research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems. NIAAA also disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at http://www.niaaa.nih.gov.


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