Scientists have known for some time that people vary considerably in their drinking behavior and in their sensitivity to the effects of alcohol. The rate of alcohol metabolism can vary as much as threefold among people with similar drinking habits, and recent studies indicate that the development of alcoholism is influenced by both genetic and environmental factors. "It appears that the development of alcoholism is not a case of genetics versus the environment; it is one of genetics and the environment," says Dr. Ting-Kai Li, distinguished professor of medicine and biochemistry at the Indiana University School of Medicine in Indianapolis. Li heads the Indiana Alcohol Research Center, an interdisciplinary group that includes colleagues on the IU Bloomington campus and at Purdue University. His current work is one of twelve research projects on alcohol at the IU School of Medicine, all funded by the National Institutes of Health.
The quest for genes that influence alcohol abuse follows two paths. One goal is to locate genes that predispose a person to alcoholism. The other is to identify genes that help to prevent this from happening. Li and his coworkers have made important advances in this latter category. "We have identified two genes that protect against heavy drinking, and these are particularly prevalent among Asians," Li says. "We have shown that Native Americans, who have a high rate of alcoholism, do not have these protective genes. The one that is particularly effective is a mutation of the gene for the enzyme aldehyde dehydrogenase, which plays a major role in metabolizing alcohol. The mutation is found very frequently in Chinese and Japanese populations but is less common among other Asian groups, including Koreans, the Malayo-Polynesian group, and others native to the Pacific Rim. "We've also looked at Euro-Americans, Native Americans, and Eskimos, and they don't have that gene mutation," says Li. Thus, incidentally, the study of genetic mutations and alcoholism links native North-American populations to central Asian ancestors, not to those from China and Japan.
Alcohol is metabolized principally in the liver, where it is converted first to acetaldehyde by the enzyme alcohol dehydrogenase. Acetaldehyde is then converted to acetate by the enzyme aldehyde dehydrogenase. Acetaldehyde produces unpleasant physiological reactions even at low concentration, so the presence or absence of the gene mutation affecting aldehyde dehydrogenase in turn affects drinking behaviors. When acetaldehyde is not rapidly converted to acetate the results are dramatic: a rapid increase in blood flow to the skin of the face, neck, and chest, rapid heartbeat, headache, nausea, and extreme drowsiness occur. "As expected, this aversive reaction affects drinking behavior," Li says, "and the mutant gene therefore serves as a protection against heavy drinking and alcoholism. " Li's current research is investigating the occurrence of mutations involving alcohol dehydrogenase. Variant forms of alcohol dehydrogenase can provide some protection against heavy drinking, though not as effectively as the specific aldehyde dehydrogenase mutation identified thus far.
The alcohol-deterrent drug disulfiram works as a deterrent by producing a similar "flush reaction." Disulfiram inactivates aldehyde dehydrogenase in a person who carries the normal gene for that enzyme, in effect producing the same situation as in the Asians who have the inactive, mutant form of the gene. Again acetaldehyde increases in the blood flow quickly, and the resulting discomfort serves as an effective deterrent to further drinking. The only problem is that disulfiram therapy requires the cooperation of the patient. If the patient decides not to take the disulfiram before drinking, the deterrent effect is lost. " Research is needed to define additional types of therapeutic agents, such as those that decrease craving and could be used adjunctively to improve treatment outcomes."
Identifying an agent that diminishes the rewarding effects of alcohol could provide a potentially effective form of alcoholism therapy. For example, drugs currently under investigation include agents that increase serotonin and dopamine levels in the brain, or drugs that block the efficacy of brain "opioids," which produce some of the pleasurable responses to alcohol consumption. At the IU School of Medicine, Li and his colleagues have bred strains of rats especially for studying the effects of drugs on alcohol drinking. Once a drug is demonstrably effective in curtailing drinking among rats bred to prefer alcohol to water, drug trials among humans can begin.
Li's work with rats that he has specially bred for studies of alcoholism has greatly influenced studies of alcoholism in humans and earned him an international reputation, even though it was his clincial experience with alcoholics that convinced him of the need to develop an animal model of alcoholism. "I was trained as an enzymologist and protein chemist," he explains. "When I was doing postdoctoral research, I found that there were different forms of alcohol dehydrogenase and that there were genetic variants that one could identify in different populations. The variant forms all have different functional properties, and these differences are reflected in differences in alcohol metabolic rate. So that is one of the genetic bases for differences among individuals in their ability to metabolize alcohol."
However, working in an alcoholism clinic in Boston at that time convinced Li that he also needed to study the brain in a laboratory setting. "It became evident to me that individual differences in the enzymes that metabolize alcohol are not in themselves sufficient to understand the biology of the disorder alcoholism." There appeared to be very large individual variations in how the brain responds to a given concentration of alcohol. "Since we cannot easily study the function of the human brain in chemical terms, I needed to develop an animal model that would at least have some relevance to the human condition."
After coming to the IU School of Medicine in 1971, Li, with his colleague Dr. Lawrence Lumeng, began a genetic breeding program to select for rats that like to drink alcohol and to select for rats that avoid or have no such preference for alcohol. Their initial goal was "to prove that one can develop a pharmacological model of alcoholism in rats based on free-choice drinking," he recalls, "and we did indeed show that." The selectively bred rats that choose an unpalatable alcoholic solution (ten percent alcohol in water) is now widely accepted by the research community. "People all over the country request these animals from us. Once we had convinced the scientific community that this was good science, we received federal funding to start a better selection study based on a genetically better foundation stock. Now we have another two sets of animals that are also selected for alcohol preference."
By comparing the high- and low-alcohol preferring strains of rats, Li not only can identify genes that are important for drinking behavior, but can also study in these animals the neurobiological basis for why they like to drink or do not like to drink. Then, for example, suspecting something wrong with the serotonin system among high-alcohol preferring strains, he can subject these rats to a drug that influences their serotonin system and observe subsequent alterations in their drinking behavior. "An interesting, important feature is that our alcohol-preferring animals are innately less sensitive to the effects of alcohol. They develop tolerance more rapidly to the behavioral impairment produced by alcohol. This seems to be the case in humans as well. So now we are seeing parallels in humans and animals that point to the same kinds of mechanisms, and I think these are very important in our understanding of the condition of alcoholism."
Li's laboratory and others at the IU Medical Center are working in collaboration with five other university medical centers to identify the genes responsible for abnormal drinking behavior in humans. "This will allow us to identify individuals who are genetically at high risk for alcoholism. If we are able to show who is at risk, then I think we can do things to help those people. Alcoholism, like diabetes or hypertension, is a complex condition influenced by both environment and genes. If we can identify those who are genetically vulnerable, we can modify the environment to help them."
Little is known about the specific biological processes and pathways involved in problem drinking and alcoholism in humans. But twin and family studies have convincingly shown that there is a strong genetic influence on susceptibility to alcoholism. Genetically based individual differences also exist in such areas as drinking behavior, sensitivity and tolerance to alcohol, and alcohol elimination rates. Analysis of those differences may help scientists to understand better the possible biological antecedents of problem drinking. Animal models are important research tools in this effort because they allow for controlled analysis of many of these biological characteristics in humans, facilitating the analysis of potential genetic determinants for alcoholism.