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Scientists at Scripps Research Institute Describe Dangerous Cocktail of Alcohol, Brain Peptides, and Neurotransmitters

La Jolla, CA, March 4, 2004 - 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.

About The Scripps Research Institute

The Scripps Research Institute in La Jolla, California, is one of the world's largest, private, non-profit biomedical research organizations. It stands at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. TSRI is internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases and synthetic vaccine development.

For more information contact:
Jason Bardi
10550 North Torrey Pines Road
La Jolla, California 92037

Tel: 858.784.9254
Fax: 858.784.8118
jasonb@scripps.edu