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.
For more information
NIH - National Institute on Alcohol Abuse and
Alcoholism
Pandey SC, et al.
Potential role of adolescent alcohol
exposure-induced amygdaloid histone modifications in
anxiety and alcohol intake during adulthood.
Neurobiology of Disease. 2015.
MDN |