Mouse Model Links Alcohol Intake to Marijuana-Like Brain
New Pathway Presents Target for Medication Development
Brain molecules similar to the active compound in marijuana help to regulate
alcohol consumption, according to new reports by scientists at the National
Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, Maryland, and
a separate NIAAA-supported group at several New York state research institutions.
In studies conducted with a strain of mice known to have a high preference
for alcohol, the scientists found greatly reduced alcohol intake in mice specially
bred to lack CB1, the brain receptor for innate marijuana-like substances
known as endocannabinoids. The effect was age dependent, the Bethesda group
found. The New York scientists showed that the endocannabinoid system activates
a brain region known as the nucleus accumbens, which plays a major role in
mediating the rewarding effects of alcohol. Both groups had shown that alcohol
intake among normal mice of the same alcohol-preferring strain could be reduced
by treating the animals with a drug that blocks CB1 receptors in the brain.
The new reports appear in the early online versions of the Proceedings
of the National Academy of Sciences, Volume 20, Number 3, at www.pnas.org
and the Journal of Neurochemistry, Volume 24, Number 4, at www.http://www.blackwell-synergy.com/servlet/useragent?func=showIssues&code=jnc
in the week beginning January 20, 2003 (specific dates to be determined).
"These are important findings," notes NIAAA Director Ting-Kai Li, M.D. "Implicating
yet another neurochemical mechanism in alcohol consumption opens another potential
avenue for the development of new pharmacologic agents to prevent and treat
The brain’s multiple communication pathways employ a wide variety of signaling
molecules known as neurotransmitters to relay messages from one brain cell
to another. Researchers have found that alcohol affects numerous neurotransmitters
and that a variety of brain pathways are involved in alcohol abuse and dependence.
Determining precisely how alcohol interacts with brain cells and affects brain
chemistry is an ongoing focus of research. Knowledge gained through this research
helps scientists develop drugs to diminish the desire to consume alcohol and
to counteract alcohol’s effects.
Since their discovery in the early 1990’s, endocannabinoids and endocannabinoid
receptors have been studied intensely by alcohol and drug abuse researchers.
Recent animal studies have suggested that the so-called "endocannabinoid system"
is involved in some of the pharmacologic effects of alcohol and in drinking
In one of the current studies, researchers led by George Kunos, M.D., Ph.D.,
Scientific Director of NIAAA’s Division of Intramural Biological and Clinical
Research, found that, among the normal, alcohol-preferring mice that
is, those with intact CB1 receptors the animals’ appetite for both
alcohol and food decreased with age. This occurred even though levels of endocannabinoids
and the density of CB1 receptors were found to be similar in the brains of
young and old mice.
"Although unexpected," says Dr. Kunos, "the observed age-dependent decline
in alcohol preference in mice parallels observations in humans, in that only
some teenage binge drinkers become alcoholics as adults, and that the onset
of alcoholism declines with age."
The researchers found a possible explanation for this phenomenon by comparing
the efficiency of the signal sent by the CB1 receptors in different regions
of the brain in young and old mice. In old mice, they found diminished CB1
signaling in an area known as the limbic forebrain. The part of the limbic
forebrain known as the nucleus accumbens plays a major role in mediating the
rewarding properties of alcohol and cannabinoids and also is thought to help
regulate appetite. The nucleus accumbens exerts its effects through the release
of the neurotransmitter dopamine. Alcohol ingestion typically elicits a robust
release of dopamine from the nucleus accumbens.
The second report by NIAAA-supported scientists led by Basalingappa L. Hungund,
Ph.D., of the New York State Psychiatric Institute and Nathan Kline Institute
for Psychiatric Research in Orangeburg, New York, complements the findings
of the Kunos research team. Dr. Hungund and colleagues found that, in addition
to showing a dramatic reduction in alcohol intake, alcohol-preferring mice
that lack CB1 receptors release no dopamine from the nucleus accumbens after
they drink alcohol. In mice with intact CB1 receptors, the researchers were
able to abolish alcohol-induced release of dopamine from the nucleus accumbens
by treating the animals with a drug that blocks CB1 receptors.
"Our results," says coauthor Balapal Basavarajappa, Ph.D., "clearly suggest
that the CB1 receptor system is involved in ethanol-induced dopamine release
in the nucleus accumbens and indicate that activation of the limbic dopamine
system is required for the reinforcing effects of alcohol. They further suggest
an interaction between the cannabinoidergic and dopaminergic systems in the
reinforcing properties of drugs of abuse, including alcohol."
"Taken together," adds Dr. Kunos, "these findings provide unequivocal evidence
for the role of endocannabinoids and CB1 in alcohol drinking behavior in rodents,
and suggest that the CB1 receptor may be a promising pharmacotherapy target."
For interviews with Dr. Kunos, please telephone the NIAAA Press Office at
301/443-0595. For an interview with Dr. Hungund, please telephone 845/398-5452
after January 20. Coauthor Csaba Vadasz, Ph.D., also is available to discuss
the Journal of Neurochemistry article at 845/398-5536. For additional information
about alcohol research, please visit www.niaaa.nih.gov.
The National Institute on Alcohol Abuse and Alcoholism, a component of
the National Institutes of Health, U.S. Department of Health and Human Services,
conducts and supports approximately 90 percent of U.S. research on the causes,
consequences, prevention, and treatment of alcohol abuse, alcoholism, and
alcohol problems. NIAAA disseminates research findings to scientists, practitioners,
policy makers, and the general public.