Profiling Alcoholism
A Research Update

Scientists at the Indiana Alcohol Research Center continue their pioneering work in the causes of alcoholism with the support of a third consecutive NIH grant.

Although American and international psychiatric associations list alcoholism as a diagnosis, there is a lingering question regarding its physical basis as a disease. But no one doubts that it is a killer.

There are more than 20,000 alcohol-induced deaths every year in the U.S., not including motor vehicle and other fatalities caused by behavior while intoxicated. Chronic liver disease resulting from overuse of ethanol or ethyl alcohol is the primary cause.

Lowering this death rate, and lessening the social and economic problems related to alcoholism, is the ultimate goal of scientists at the Indiana Alcohol Research Center (IARC) which is headquartered at the IU School of Medicine. If a genetic predisposition to alcoholism exists, and there are strong indications that it does, knowledge of that molecular profile may open new lines of defense for individuals and families at increased risk for ethanol dependency.

Scientists at IUSM and five other schools of medicine across the country are collaborating on determining the genetic basis of alcoholism, but finding the pieces of this genetic puzzle is especially difficult because alcoholism is proving to be a multigene problem. "It is likely that, even after areas of the chromosomes are located, there could be hundreds of genes to sort through, as there are for hereditary and familial breast cancer," says Ting-Kai Li, MD, who heads IU's IARC and is associate dean of research and distinguished professor of medicine and of biochemistry and molecular biology at IUSM.

A pioneer in alcohol research for more than three decades, Dr. Li initiated the IARC at IU in 1987 through a five-year, $5 million grant awarded by the National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health (NIH). This grant was renewed in 1992. Throwing good money after good, the NIH granted another $8.5 million last year to Dr. Li and his associates at the IARC to support a continuation of their efforts.

The School's IARC is only one of a handful to pursue both human and animal studies. Over the past two decades, with Lawrence Lumeng, MD '64, professor of medicine and of biochemistry and molecular biology, and others, Dr. Li developed lines of rats that serve as animal models of predisposition to alcoholism and animal models of a lower preference for alcoholism. These selectively bred animals allow researchers to model the alcohol dependence syndrome, study the effects of alcohol on brain chemistry, and utilize other modalities which cannot ethically be employed with humans. One outcome of this body of work, and other work with human subjects, is the identification of two genes related to alcoholism "risk" in humans, and another gene possibly related to alcohol consumption in rats.

The genes found to influence drinking behavior and alcoholism are alcohol dehydrogenase and aldehyde dehydrogenase - the principal enzymes responsible for alcohol detoxification in the liver.

Alcohol detoxification in the human liver takes place in two main stages. First, the alcohol dehydrogenase enzyme converts alcohol to acetaldehyde. Then the aldehyde dehydrogenase enzyme swiftly converts the acetaldehyde to acetate. Without this rapid elimination of acetaldehyde, the drinker suffers the "alcohol flush reaction" - a rush of blood to the skin capillaries of the face, neck and chest, accompanied by rapid heartbeat, headache, nausea and extreme drowsiness.

Pointers Toward Deterrence

The alcohol flush reaction, most common among the Chinese, Japanese and Korean populations, is associated with a tendency to avoid alcohol. Asians with this trait are five times less likely to become alcoholics. The existence of such traits may point to a medical means of alcohol deterrence. In fact, in 1989, a research team led by David Crabb, MD '78, scientific co-director of IARC and IUSM professor of medicine and of biochemistry and molecular biology, identified the genetic mutation of aldehyde dehydrogenase that causes the alcohol flush reaction as an autosomal dominant trait.

In studies of human subjects under way at IU's IARC, Sean O'Connor, MD, associate professor of psychiatry, heads an effort to test the subjective and physiological effects of alcohol on humans using a technique called rapid BrAC clamping. The subjects, who have been socially exposed to drinking but are not addicted, are infused intravenously with ethanol to raise their blood alcohol content to a level of 0.06 percent as measured by the breath alcohol content (BrAC). This level is carefully maintained for more than three hours, while the subjects undergo testing of eye movement control, eye-hand coordination, short-term memory, and motor coordination, as well as electroencephalography and other tests.

Results from these rigidly controlled tests for acute tolerance to ethanol are compared with those of individuals in a study led by Richard J. Rose, PhD, scientific co-director of IARC and professor of psychology at IU-Bloomington. Rather than receiving the alcohol intravenously, the subjects in Dr. Rose's study drink alcohol.

Studying Actual Drinking Patterns

A second project led by Dr. Rose takes these comparisons a step further by testing acute tolerance of ethanol in subjects who are following their typical drinking patterns. Most college-age adults are weekend drinkers. Thus the college community offers an opportunity for researchers to test subjects on Sunday mornings after they've been drinking over the weekend, and on Thursdays after they've abstained for three days.

The Bloomington oral alcohol challenge and Indianapolis intravenous clamping methodologies are applied to three separate groups of subjects. Both teams test sixty pairs of monozygotic (identical) twins whose family history of alcoholism is known. Twin studies offer a classic nature-versus-nurture paradigm. The IARC's twin studies also compare alcohol responses of identical to nonidentical twins and non-twin siblings to find the genetic bases for alcohol-related physiological, personality, temperament and behavioral traits.

The IARC has a bank of family history and twin studies going back twenty-five years, and all its scientists concur that alcoholism, like cancer, hypertension, diabetes and other complex diseases, likely involves a complex interaction between an individual's genetic makeup and his or her social and cultural environment.

"Alcoholism is not a simple genetic disorder," notes Dr. Rose. "Unlike Huntington's disease, for which there is a single gene that inevitably leads to the disease outcome, it is unlikely that there is a gene or set of genes that will inevitably cause alcoholism in a human being. One has to learn to drink and to drink regularly. Individuals who are at very elevated risk for developing alcoholism can totally escape that risk if they remain abstinent throughout their lives. In contrast, if one inherits the HD gene, one acquires the disease and inevitably will die from it."

If there are many pathways to alcohol use and alcohol dependency, then blocking those pathways offers an effective deterrent, say Dr. O'Connor and Dr. Rose. The flush reaction is one protective mechanism; individual and cultural beliefs and accessibility are also important protective factors.

Current drug treatments for alcoholism include Disulfiram (Antabuse (R)) which mimics the flush reaction to create an aversion to alcohol, and naltrexone hydrochloride (ReVIA (R)) which appears to reduce the craving. However, the prevention approaches most likely to work, IARC scientists say, are social rather than pharmacological.

"If people have any history of alcoholism in the family, they need to know," Dr. Li says. "Will they take action? Some will, some won't. Some people are insensitive to their BrAC climbing dangerously and have no aversion to alcohol as they drink. These individuals can be taught that they should count drinks."

Finding Behavioral Correlates

Dr. Li also notes that not everyone drinks for the euphoric effect. Some people drink to "feel normal." In fact, genetic studies by Lucinda Carr, PhD '86, associate scientist and associate professor of medicine and of pharmacology and toxicology, and colleagues have discovered a strong linkage of a chromosomal residue containing the gene for neuropeptide Y, a brain peptide that is known to be anxiolytic (anxiety-reducing) as well as increasing the appetite for food and drink. Decreasing neuropeptide Y in mice by "gene knockout" increases alcohol drinking. Conversely, increasing neuropeptide Y in transgenic mice that overexpress the gene decreases drinking.

Dr. O'Connor says some of his subjects' performance improves when they drink. They respond more quickly, are less anxious, more active and more decisive. Dr. Li sees this in some of his rats, too. In a "dysregulated homeostasis," alcohol-preferring rats deprived of ethanol for two weeks will drink more of it than usual when access to ethanol is restored.

Even animals that are not bred to prefer alcohol will drink more alcohol when stressed, Dr. Li notes. Another correlation has been shown between novelty-seeking behavior and drinking. Dr. Li says it's known that his strain of alcohol-preferring rats are more novelty-seeking than the non-alcohol-preferring strain. This opens the possibility that rats could be bred to be novelty seekers in order to learn whether they show a preference for alcohol. Although this particular line of inquiry is not one of the goals of the current grant, it will support exploration of gene loci common to selected lines of rats and mice that differ in their alcohol-seeking behavior.

Dr. Li enthusiastically heads into this latest grant program with a long list of mysteries to be solved and a skilled team of researchers to address them. In sports parlance, Dr. Li has built a deep bench and is confident that the search for genetic predisposition to alcoholism will go on for many years at IUSM. He proudly notes that eighteen IARC investigators at IU also have their own grants.