Carrying a gene variant that affects the release of
a specific brain protein may put one at greater risk
of developing an alcohol use disorder, according to
the results of a recent animal study. The study was
led by Professor Dorit Ron, PhD, Endowed Chair of
Cell Biology of Addiction, Department of Neurology,
University of California, San Francisco.
Scientists found that mice carrying the Met68BDNF
gene variant, which reduces the release of
brain-derived neurotrophic (BDNF) factor, would
consume excessive amounts of alcohol, despite
negative consequences.
BDNF plays a role in the survival of existing
neurons and the growth of new neurons and synapses,
the junctures through which cell-to-cell
communication occurs. The human form of this gene
variant, Met66BDNF, leads to a reduction in the
normal function of BDNF in the brain and is
associated with several psychiatric disorders,
including schizophrenia and depression.
In an animal study reported earlier this year, NIAAA-supported
scientists found that adolescent binge drinking was
linked to lower levels of brain-derived neurotrophic
factor, and these changes persisted into adulthood.
“Genetic factors play a role in determining who
develops alcohol problems,” said Dr. George Koob,
PhD, NIAAA Director. “By understanding the genetic
underpinnings of alcohol use disorder, we will be
better able to develop targeted treatment and
prevention strategies.”
In the study, published in Biological Psychiatry,
researchers tested the role of BDNF in alcohol
addiction by creating a “knock-in” mouse carrying
Met68BDNF. In this variant, the amino acid valine
(Val) is replaced by methionine (Met) in a specific
position within the protein sequence of BDNF,
resulting in reduced activity-dependent BDNF
release.
These “knock-in” mice drank more alcohol, even when
the alcohol was treated with bitter-tasting quinine.
This suggests Met68BDNF carriers compulsively drink
alcohol despite aversive consequences.
The effect of the genetic mutation seemed to be
specific to alcohol consumption since the mice did
not differ in their consumption of other fluids, or
exhibit differences in levels of anxiety or
compulsive behaviors.
Significantly, researchers were able to reverse
compulsive alcohol drinking in the mice using gene
delivery and pharmacology. Increasing levels of BDNF
in the ventromedial portion of the prefrontal
cortex, a brain region involved in compulsive drug
and alcohol seeking, returned the mice to moderate
levels of alcohol intake.
In addition, by administering a pharmaceutical
compound developed to mimic the action of BDNF,
researchers were also able to put a stop to
compulsive drinking behaviors. This compound
(LM22A-4) may have potential as a therapeutic for
humans. It appears to reduce compulsive alcohol
drinking without a generalized effect on motivation.
Knowing whether patients carry a gene that results
in decreased BDNF function could help in tailoring
alcohol prevention and treatment strategies in the
future.
The study was funded by the National Institute on
Alcohol Abuse and Alcoholism, part of the National
Institutes of Health.
For more information
The
National Institutes of Health (NIH)
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