"This is an important breakthrough because it is the first time that scientists have identified discrete gene regions involved in physical dependence on (withdrawal from) alcohol or other drugs of abuse," says Kari Buck, Ph.D., assistant professor of behavioral neuroscience at OHSU and lead author of the study.
Buck's team has shown that mice carrying three gene regions are at greater risk for acute physical dependence on alcohol than mice without these genes. Using a new genetic mapping technique, Buck's team found that genes on mouse chromosomes 1, 4 and 11 lead to an increased risk for physical dependence on alcohol. Mice with different alleles within these gene regions were instead protected from alcohol withdrawal symptoms.
Buck and her colleague John Crabbe, Ph.D., researcher at OHSU and the VAMC, think the new work might someday help in understanding and treating physical dependence on alcohol and other drugs of abuse in humans.
"These studies in animal models are important because they enable us to pinpoint the chromosomal regions associated with a specific component of alcohol dependence," says Enoch Gordis, M.D., director of the National Institute on Alcohol Abuse and Alcoholism. "Because of the importance of alcohol withdrawal in clinical manifestations of alcoholism, and because of similarities between the mouse and human genomes, the study will contribute significantly to the ultimate development of new treatments."
"Alcohol dependence in humans is clearly influenced by genes as well as environmental factors," Crabbe said. "There is clearly an increased risk for severe alcohol-related problems in children of alcoholics who were adopted out, even if they have been raised without knowledge of their biological parents' problems."
Identifying the genes that lead to an increased risk of alcoholism and drug abuse in humans has been difficult, since humans express more than 100,000 genes.
"Trying to identify the few genes that are important in alcoholism is a daunting task," said Buck. "By zeroing in on the genes that govern physical dependence on alcohol in mice, we can now locate the chromosome regions that carry human versions of these genes about 80 percent of the time.
"It is hard to make a clear translation between mice and humans, but the gene regions identified in our study appear to correspond to regions of human chromosomes 1 and 5. These chromosomes may carry the human versions of genes that contribute to alcohol withdrawal."
The collaborative study on the Genetics of Alcoholism, sponsored by the National Institute on Alcohol Abuse and Alcoholism, has examined regions of human chromosomes that correspond to the genetic markers identified in mice, and also found evidence for a gene on human chromosome 1 that appears to be involved in alcohol dependence.
"A major focus of this project will now be to hone in on the specific genes contributing to an increased risk for alcohol dependence," said Buck. "It is compelling that our study identifies a discrete region of mouse chromosome 11 that contains three GABA receptor genes."
GABA is one of the brain's most important chemical messengers, carrying signals to neighboring nerve cells and docking on receptor molecules embedded in the membrane of cells. Previous studies suggest that susceptibility to alcohol withdrawal in humans and mice may involve changes in brain activity involving GABA.
"Our findings are provocative because one or more of the GABA receptor genes plausibly confers an increased risk for physical dependence on alcohol," Buck said. "Future studies will be aimed at unraveling the role of these genes in physical dependence on alcohol and other drugs of abuse."
Previous studies of humans suggest that alcoholics appear to have more brain GABA receptors.
"We know that humans have versions of these same genes," said Buck. "Some of the gene regions identified in our study also appear to contain genes that are important in physical dependence on other drugs of abuse, including pentobarbital, a barbiturate with a high potential for abuse and severe drug dependence.
"This new information could result in the targeting of treatment interventions to the most appropriate populations at risk as well as providing insights into possible preventive medical interventions before alcoholism or drug abuse behaviors become habitual."
Members of Buck's team from the Portland Alcohol Research Center at OHSU and the VAMC who made important contributions to this work include John Belknap, Ph.D.; John Crabbe, Ph.D.; and Pamela Metten, Ph.D.