Scientists Describe Dangerous Cocktail of Alcohol, Brain
Peptides, and Neurotransmitters
By Jason Socrates Bardi
A team of scientists at The Scripps Research Institute has
described the cellular mechanism underlying the brain's response
to alcohol, which suggests a possible method for treating
alcoholism.
This work, published in the latest issue of the journal
Science, ties together the effect of the brain peptide
corticotropin releasing factor (CRF) with alcohol. Both appear
to influence neurotransmission in the amygdala, the so-called
pleasure center of the brain, by increasing the transmission
of one particular neurotransmitter called gamma amino butyric
acid (GABA).
"There is a strong relationship between drugs of abuse,
stress, and the amygdala," says Neuropharmacology Professor
George Siggins, who led the research.
The research suggests that compounds that block CRF receptors
might be a potential new therapeutic for alcoholics, who struggle
to stop drinking.
Drugs that block CRF receptors are already being looked
at by scientists as potential treatments for other psychiatric
conditions such as depression, panic disorder, and post-traumatic
stress disorder—conditions that also involve CRF in the
amygdala.
The Scourge of Alcoholism
Of all potential substances of abuse, alcohol is one of
the most readily available in American society. It is regularly
or occasionally consumed by nearly two-thirds of all American
adults, and the United States Centers for Disease Control
and Prevention estimates that four-fifths of U.S. adults have
been regular or occasional drinkers at one time.
Despite its widespread use and reputation as "social lubricant,"
alcohol extracts a heavy toll on society. Drunk driving, for
instance, is a major scourge in the United States—about
a third of the approximately 40,000 traffic fatalities every
year involve drunk drivers. Tens of thousands more Americans
die each year from alcohol poisoning, and from alcohol-related
degenerative conditions such as gastritis, cardiomyopathy,
and liver disease. Fetal alcohol syndrome, caused by alcohol
consumption by pregnant women, is the leading cause of mental
retardation in the United States. The CDC estimates that perhaps
as many as one out of every 1,000 babies born in the United
States each year suffers from fetal alcohol syndrome.
And then there is alcoholism—the chronic compulsive
use of and loss of control over alcohol intake. The direct
and indirect public health costs of alcoholism are estimated
to be in the hundreds of billions of dollars yearly. Currently,
there is no cure, and the neurobiology of the disease is not
completely understood.
A number of scientists at Scripps Research are involved
in basic biomedical research and its clinical application
to fight this disease. In 2001, the National Institute on
Alcohol Abuse and Alcoholism (NIAAA) funded a multi-year consortium
headed by professors at Scripps Research to identify the molecular
basis of alcoholism.
Scripps Research is also home to the newly established Pearson
Center for Alcoholism and Addiction Research, which aims to
discover and test new compounds that might be translated into
practical treatments for alcoholism, particularly relapse
prevention. The center will also aim to bring these compounds
rapidly to clinical trials.
Working Towards a Cure
In the latest research, Siggins and his colleagues looked
at the effect of alcohol and a common stress-related neuropeptide
on a neurotransmitter called gamma amino butyric acid (GABA).
GABA is the main inhibitory neurotransmitter in the brain,
and neurons in every brain region use GABA to fine-tune signaling
throughout the nervous system.
Scientists have known for several years that alcohol produces
many of its intoxicating actions through facilitation of GABA
receptor function, and preclinical studies of alcohol dependence
have shown that GABAergic activity decreases during alcohol
withdrawal and protracted abstinence—the initial post-acute
withdrawal period after the cessation of drinking during which
a person is especially vulnerable to relapse. These GABAergic
activity changes are probably a major cause of relapse to
alcoholism in individuals undergoing treatment.
Previous studies have also shown that alcohol enhances GABA
neurotransmission in the amygdala, the so-called pleasure
center of the brain. Interestingly, the brain corticotropin
releasing factor (CRF) stress system also increases GABA transmission
in the amygdala.
CRF is a common peptide in the brain that is responsible
for activating the hypothalamic-pituitary-adrenal stress response
and in the amygdala for activating sympathetic and behavioral
responses to stressors. CRF is found in lots of different
parts of the brain and is known to be involved in the brain
in response to stress, anxiety, and depression.
Significantly, the CRF system also seems to be central to
alcoholism, and scientists at Scripps Research and elsewhere
have shown that CRF is involved in the transition from alcohol
use to alcohol dependence. Scripps Research Professor George
Koob and his colleagues found recently that levels of CRF
increase in brains treated with alcohol. Other studies have
shown that CRF levels increase when animals are withdrawing
from alcohol as well—a situation analogous to an alcoholic's
protracted abstinence.
In their latest paper, Siggins and his colleagues show,
at the cellular level, how alcohol and CRF interact. When
neurons are exposed to alcohol, says Siggins, they release
CRF, and this causes the release of GABA in the amygdala.
And when the CRF receptor is removed altogether (by genetic
knock out), the effect of alcohol and CRF on GABA neurotransmission
is lost.
Siggins and his colleagues say that this suggests a cellular
mechanism underlying involvement of CRF in alcohol's behavioral
and motivational effects. During withdrawal, CRF levels increase
and these changes may persist for a long time.
It also suggests a possible way of treating alcoholism—using
CRF antagonists, or compounds that block the effects of CRF.
In the current study, when the scientists applied an antagonist
of CRF, they found that alcohol no longer had an effect.
"Not only did the antagonists block the effect of CRF in
enhancing GABA transmission, it also blocked the effect of
alcohol," says Siggins. "The response was totally gone—alcohol
no longer did anything."
The research article "Ethanol Augments GABAergic Transmission
in the Central Amygdala via CRF1 Receptors" is authored by
Zhiguo Nie, Paul Schweitzer, Amanda J. Roberts, Samuel G.
Madamba, Scott D. Moore, and George Robert Siggins and appears
in the March 5, 2004 issue of the journal Science.
See: http://www.sciencemag.org/.
This work was supported by the National Institute on Alcohol
Abuse and Alcoholism and the National Institute on Drug Abuse.
Send comments to: jasonb@scripps.edu
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