The Search for Genetic Keys to Alcoholism
Scientists are beginning to unravel the complex relationship between genes and behavior to understand alcohol addiction. The hope is to design treatments to block excessive drinking.
“We have a difficult challenge,” said Dr. Enoch Gordis, director of the National Institute on Alcohol Abuse and Alcoholism, at the centennial anniversary lecture recently at Rockefeller University in Manhattan, where the first methadone program was developed in the 1960s to treat heroin addicts.
Gordis pointed out that alcohol affects every receptor system in the body, making it unlike other drugs, which target only a few key pathways. Alcoholism is very common, affecting about 12 million men and 8 million women in the U.S. A recent count of patients at Johns Hopkins Medical Institutions in Baltimore revealed that one-quarter of the beds were filled by people sickened as a consequence of their drinking.
If alcoholism can be inherited, as studies of twins and adopted children have repeatedly shown, then what exactly is passed down? Is it a gene that regulates the brain chemical dopamine that affects how one experiences pleasure? Is it a gene that makes some people less, or more, sensitive to the powerful chemicals that make up alcohol? Is it a gene that modulates preference? Is it a mix of genes and powerful environmental forces?
Scientists are focusing their search on genes that alter brain response and would make people more sensitive to alcohol.
Probably one of the best examples is a gene called aldehyde dehydrogenase 2. Variations of this gene are common in Japan, with some research indicating they can be found in almost 50% of the population. In people with these gene variations, a glass of wine causes such an uncomfortable physiological effect that they do not want to drink. Their cheeks flush, their heart pounds and they feel sick. One of the oldest antidotes to alcoholism is Antabuse, which works on the ALDH2 gene.
“Half the population of Japan is in a natural Antabuse state,” said Dr. David Goldman, a leading alcoholism researcher at the National Institute of Mental Health.
Goldman and his colleagues have spent years combing through the genes of populations at risk for alcoholism and identifying risk genes. Each gene identified--about a dozen--has a different effect on the brain and behavior, Goldman said.
These days, his sights are set on a gene called COMT that is turned on in the brain’s frontal lobes and is thought to play an important role in impulse control and cognitive function. Goldman is also focusing on genes that regulate serotonin, an important brain chemical that governs many aspects of behavior and emotion. Genes that regulate the brain chemical dopamine and endorphins also have been implicated in alcoholism and drug addiction. Dopamine pathways are active in reward and reinforcement; endorphins are brain chemicals that trigger the feeling of pleasure and reward.
Dr. John Numberger Jr. and his colleagues at the Institute of Psychiatric Research at Indiana University Medical Center identified a strong link on Chromosome 1 that affects both alcoholism and depression. They are still searching for the specific gene or genes involved.
Goldman has spent years with Southwest American Indian tribes and isolated several genes that he believes put them at great risk for alcoholism. Goldman found that the genetic contribution might be as high as 85% in males in some of the tribes he has studied.
“People are not just making lifestyle choices, or hereditability wouldn’t be so high,” Goldman said. “I don’t know why people have a problem calling [alcoholism] a disease. Clogged arteries exist because of choices made about eating Twinkies. No one says it isn’t heart disease.”
The brains of alcoholics are different, and studies are beginning to address what this may mean for diagnosis, prevention and treatment. In a new study, published in the Archives of General Psychiatry, Dr. Mark S. George and his colleagues had 10 alcoholics and 10 social drinkers take a sip of alcohol while hooked up to monitors to measure brain activity. After tasting the alcohol, they were shown pictures of alcoholic and nonalcoholic beverages. Only the alcoholics showed increased activity in the prefrontal cortex and anterior thalamus when looking at pictures of alcohol. These brain areas are involved with emotion, attention and appetite. The control subjects had increased activity in different brain regions.
Federal scientists are also finding distinct gender-related differences among alcoholics. Dr. Daniel Homer of the national alcohol institute took brain scans of men and women, all heavy drinkers, and found that women had greater decreases in the size of a portion of the brain than did men--even though the two groups drank a comparable amount.
Alcohol works on some of the same biochemical pathways involved in the stress response. In particular, a hormone called ACTH is released during the stress response. Small amounts of alcohol also trigger the release of ACTH. Many scientists and drug companies have been trying to find compounds similar to ACTH that could be used to design new treatments.
Laboratory animals behave quite like humans when it comes to alcohol consumption and stress. If 20 male rats are put in cages with two drinking tubes, one with saccharin, the other with saccharin and 10% alcohol, 20% of the rats will never drink the alcohol; another 20% will drink significant amounts; and still another 20% will consume the equivalent of a social drinker. But if these same animals are exposed to random bouts of stress, after a week they will all drink more.
Federal researchers studying the effects of early maternal separation have shown that monkeys brought up away from their mothers had twice the level of stress hormones in their blood than monkeys that were not separated from their mothers. When these same animals grew up and were given free access to alcohol, the animals that were separated at birth consumed much more than their less stressed counterparts.
“Both drinking behavior and an individual’s response to stress are determined by multiple genetic and environmental factors,” Gordis said. “If borne out in humans, these findings elucidate the alcohol-stress relationship in two ways: They confirm that early life stress can influence later alcohol consumption, and they offer a promising biological marker of risk for excessive drinking.”
Figuring out alcohol addiction seems an insurmountable task, as some studies are quick to show. In one recent experiment, genetically identical animals were distributed to labs in Albany, N.Y., Portland, Ore., and Edmonton, Canada, and those who handled the animals were trained to do so in a particular way. But it turned out that those who were fed alcohol behaved differently from those who were able to take it themselves. Different genes were turned on. Those fed alcohol drank more, at first. The animals given the choice--the freedom--to drink ended up drinking more.
“How the alcohol is administered has a profound effect on the results,” Gordis said. “We have to pay attention to these issues.”
Unfortunately, the complexities inherent in the disease process have made finding effective treatments difficult. The federal alcohol research institute has recently embarked on a study to test a combination of treatments for alcoholism. During the next two years, doctors at 11 treatment centers will enroll more than 1,300 people, who will receive one or both of two behavioral therapies and one or both of two medications (naltrexone or acamprosate) or a placebo. They will also have outpatient therapy sessions for four months and return for follow-up.
“As many as 50% of those who receive treatment for alcoholism relapse at least once, and only a fraction achieve long-term remission of the disease,” said Dr. Roger Weiss, director of McLean Hospital’s alcohol and drug treatment center in Massachusetts and one of the investigators in the federally sponsored trial. “The clinical trial may lead to better treatment.”
Many doctors are dissatisfied with current treatments. Dr. Charles O’Brien, an expert on alcohol addiction at the University of Pennsylvania, has observed for 30 years how the treatment for addictions has changed, but remains unimpressed. He and other alcohol-abuse experts say that alcoholism is a chronic disease and that long-term treatments will be necessary to help people avoid drinking throughout their lives.
