|Fruit Fly Study Identifies Gene Mutation That
Regulates Sensitivity to Alcohol
Researchers at the University of California, San Francisco (UCSF)
have discovered a gene mutation in fruit flies that alters sensitivity
to alcohol. The findings, reported in the October 6 issue of the
journal Cell, may have implications for human studies
seeking to understand innate differences in people’s tolerance
for alcohol. The research was supported by the National Institute
on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute
on Drug Abuse (NIDA) of the National Institutes of Health (NIH),
part of the U.S. Department of Health and Human Services.
The study was authored by Adrian Rothenfluh, Ph.D., and colleagues
in the laboratory of Ulrike Heberlein, Ph.D., at UCSF, in collaboration
with researchers at the Ernest Gallo Clinic & Research Center.
The scientists examined the behavior of fruit flies (Drosophila)
exposed to alcohol. Ordinarily, at low doses of alcohol fruit flies
increase their activity, while high doses have a sedative effect.
However, the researchers found some fruit flies were much more
resistant to alcohol sedation. These flies continued to move about
much longer than typical fruit flies exposed to the same amount
of alcohol. The scientists subsequently identified key differences
in a particular gene associated with this behavior. The mutation
also altered the flies’ sensitivity to cocaine and nicotine as
well. Because this gene variant affected the behavioral response
to substances of abuse, the researchers dubbed it white rabbit — a
reference to the title of a 1960s song about drug-induced changes.
“This study describes key molecular pathways and gene interactions
that control alcohol sensitivity,” said NIAAA Director Ting-Kai
Li, M.D. “These significant clues about the fruit fly’s behavioral
response may translate into useful tools to advance the search
for human genes involved in sensitivity to alcohol. Insights about
sensitivity, or acute tolerance, are especially important because
we know that people who are less sensitive to alcohol’s impact
are at greater risk for becoming alcohol dependent,” he said.
The researchers exposed fruit flies to vaporized alcohol and monitored
their behavior and motion patterns with sensitive tracking instruments.
They isolated the flies that were less sensitive to alcohol’s sedative
effects. By breeding subsequent populations of mutant flies, the
scientists identified the particular genetic mutation.
The researchers further showed that the white rabbit mutation
disrupted the function of the RhoGAP18B gene. They also
isolated a number of gene variants of RhoGAP18B, each
of which had a distinctly different effect on the response to alcohol.
Manipulating these genetic variants, the researchers generated
flies with greater and lesser sensitivity to alcohol’s sedative
and stimulant effects.
The research team also detailed how signaling proteins encoded
by the RhoGAP18B gene variants played an important role in reorganizing
components of the adult fruit fly’s central nervous system, which
in turn affected the flies’ behavior. Dr. Rothenfluh said the research
team concluded that the RhoGAP18B gene is intimately involved in
regulating behavioral responses to alcohol exposure.
The findings have implications for researchers seeking corresponding
genes and molecular pathways in other animal models and humans.
Antonio Noronha, Ph.D., director of NIAAA’s Division of Neuroscience
and Behavior, said, “If we can characterize similar genetic differences
and neurobehavioral responses that underlie acute tolerance in
humans, that could potentially provide new targets for the development
of drugs to treat alcohol dependence.”
NIAAA 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 and disseminates
research findings to general, professional, and academic audiences.
Additional alcohol research information and publications are
available at www.niaaa.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.