Gallo Center Scientists Identify Potential New Mechanism For
Treating Problem Drinking
Date: February 19, 2013
A study by researchers at the Ernest Gallo Clinic and Research
Center at UC San Francisco identified a potential new approach for
reducing problem drinking: a new family of drugs with the ability to
manipulate DNA structure without changing it.
The drugs, already approved for human use for other indications, reduced
drinking and alcohol-seeking behavior using pre-clinical models in mice and
rats trained to drink large quantities of alcohol.
The animals in the study, published today in the advance online publication of
Translational Psychiatry, were
trained to mimic so-called “problem drinkers,” not yet full blown alcoholics, said
senior author Dorit Ron, PhD,
a Gallo Center investigator and a professor of neurology at UCSF.
“They consumed large quantities of alcohol and drank in binges, but were not yet
physically dependent on alcohol,” she said. “In humans, these drugs could represent
a promising new direction in preventing drinkers from going on to become fully addicted.”
The drugs which inhibit enzymes called DNMT and HDAC are currently being used to treat
several types of cancer and show promise as medications for the treatment of mood disorders.
The study presents “a potential new mechanism to control excessive drinking,” said Ron.
The drugs act by modifying the structure of chromatin – a combination of DNA and proteins known
as histones -- without affecting the composition of DNA itself, Ron said.
“Normally, changes on the DNA sequence called methylation lead to tightening of the chromatin
structure, which prevents the expression of certain genes,” she said. “Conversely, a change in histones
called acetylation leads to the opening of the DNA structure, allowing certain genes to be expressed.” DNMT
inhibitors, which prevent methylation, and HDAC inhibitors, which promote acetylation, both act to loosen DNA
structure, which in turn allows gene expression.
In the study, Ron and her research team trained mice to drink a solution of 20 percent alcohol. Mice that
were given DNMT inhibitor called 5-AzaC or HDAC inhibitors drank significantly less than mice that were not
given DNMT.
Rats were also trained to self-administer drinks of alcohol by pressing a lever. Rats given SAHA, an HDAC
inhibitor, showed significantly less alcohol-seeking behavior.
Importantly, in both mice and rats, the consumption of water, saccharine solution and sugar solution remained
unchanged. “This means that these drugs specifically target alcohol without affecting the pleasure centers of the
brain,” said Ron. “For people who have problems with alcohol, this would be a real improvement over current abuse
medications, which suppress pleasure in general, leading to problems with compliance.”
Ron noted that alcohol use disorders represent a significant threat to public health worldwide, causing or
being associated with a wide variety of physical and psychiatric illnesses. She called the study “an important
example of pre-clinical, translational research, where findings in basic science lead straight to the possibility
of clinical studies.”
Co-authors of the study are Vincent Warnault, PhD, and Emmanuel Darcq, PhD, of the Gallo Center and UCSF; Amir
Levine, MD, of Columbia University; and Segev Barak, PhD, who was with Gallo and UCSF at the time of the study.
The study was supported by funds from the National Institutes of Health and the State of California through
UCSF.
The UCSF-affiliated Ernest Gallo Clinic and Research Center is one of the world’s preeminent academic centers
for the study of the biological basis of alcohol and substance use disorders. Gallo Center discoveries of
potential molecular targets for the development of therapeutic medications are extended through preclinical and
proof-of-concept clinical studies.
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research,
graduate-level education in the life sciences and health professions, and excellence in patient care.
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