At-Risk Alcoholism Phenotype Shows Measureable Brain Changes


by Kayt Sukel

October 28, 2011

The National Institutes of Health estimate that nearly 18 million adults in the United States have an alcohol abuse disorder. Alcoholism is a disease that has great costs—to individuals, their families, and the public at large. While doctors are not currently able to predict who will become addicted to alcohol, research suggests that one’s level of sensitivity to it plays an important role. And a new study by scientists at the University of California, San Diego shows that this sensitivity changes how the brain processes information during a cognitive task—and may provide new information for prevention and education efforts.

A heritable disease with environmental factors

Alcohol is classified a drug, but its use is not only legal in most places but pervasive. It is  not known why one person can enjoy the occasional drink without problem while another will become in thrall to it. Two factors, however, keep popping up as potential predictors of alcohol problems.

“There are a couple of things that have shown their face here,” says Edith Sullivan, a researcher at the Stanford University School of Medicine. “Family history is a very important predictor of alcohol use disorders. And new epidemiological studies suggest that the earlier a person has his first drink, the more likely they’ll end up with a problem later.”

Both genetics and environment play a role in the development of this disease. Many researchers interested in substance abuse disorders have tried to identify and characterize genes that might affect alcoholism, fully understand that genes won’t tell the whole story. GABRA2, a gene that codes proteins for a specific GABA receptor, has been linked to alcohol dependence. And a study published in the Dec. 2010 of Alcoholism: Clinical & Experimental Research demonstrates that polymorphisms in GABRA2 can influence the way the brain perceives environmental cues like the smell of a preferred alcoholic drink. The study’s lead author, David Kareken of the department of neurology and the Alcohol Research Center at the Indiana University School of Medicine, cautions that the work is still preliminary.

“Any examination of a single gene is an oversimplification. Alcoholism is not going to be explained in and of itself by any one gene,” he says. “We know that alcoholism travels in families and that family history brings with it large pools of genes. However, we can best use these studies to understand how one gene may affect aspects of the brain’s processing of reward signals, and then over time, combine the findings of those studies to understand what the larger global effect may be.”

A question of sensitivity

Marc Schuckit, a neuroscientist at the University of California, San Diego who has dedicated his long research career to characterizing the genetic influences of alcohol dependence, will publish a study in the Jan 2012 issue of Alcoholism: Clinical & Experimental Research that highlights the importance of a person’s natural sensitivity to alcohol.

“We’ve learned that what is likely to be inherited is not the alcoholism itself but additional characteristics that play a role in its development,” he says. “Think of it like a heart attack: The genes involved in risk of heart attack may not act on the heart itself but on high blood pressure or other related factors. They increase the risk, but not directly. We were the first to propose that a person’s sensitivity to alcohol, or how many drinks it takes them to get an intoxicating effect, is a factor in whether someone has a lot of alcohol-related problems.”

Previous work in Schuckit’s lab showed that people who have lower sensitive to alcohol are much more likely to consume high doses of it when they do drink—which ups the risk for alcoholism. In this most recent study, Schuckit and colleagues wanted to know how this sensitivity influenced normal brain function. Using functional magnetic resonance imaging (fMRI), the group scanned 98 people who had been previously identified as having low or high sensitivity to alcohol. The study participants were asked to perform a standardized cognitive task called the stop-signal paradigm, once while given a placebo and a second time after having the rough equivalent of three alcoholic drinks. Researchers found that sensitivity had a significant impact on cerebral blood flow during the task depending on whether subjects had been given alcohol, although actual task performance was equal. Those with low sensitivity showed more cerebral blood flow when they were given the placebo compared with high-sensitivity peers. The opposite was shown when the two groups were given alcohol, suggesting that intoxication may provide a more “normalized” state for people who are rated with low sensitivity.

 “You have to understand that people with low sensitivity to alcohol have no other traits that otherwise characterize them. They don’t have higher rates of psychiatric disorders, dependence on other drugs or other unique personality characteristics that we can pick up,” says Schuckit. “But individuals with low sensitivity to alcohol appear to have to mobilize more brain energy when doing this cognitive task when they don’t get alcohol compared to those who are very sensitive to alcohol.”

Preventing alcoholism

Schuckit hopes that this work will help provide new information for alcoholism outreach and prevention efforts.

“I think that most of us expect to be a little muddle-headed after a few drinks. It’s possible that those with low sensitivity to alcohol don’t, and keep drinking until they do. It’s also possible that they feel more at ease after a few drinks,” he says. “If we can identify those at risk and educate them about counting their drinks and not relying on what their brain is telling them about how intoxicated they are at lower doses of alcohol, we may be able to diminish some of that extra risk.”

Sullivan agrees—and while she argues this is a ground-breaking study, she hopes that Schuckit will take it a step further to see if there were any specific physiological cues that will be predictive of later alcoholism.

“This was a striking paper because behaviorally you wouldn’t find any difference between the high and low responders. They performed just as well on the task, but their brain activity showed us physiological differences under the different alcohol conditions,” says Sullivan. “But it would be wonderful if Schuckit were in a position to see a good number of these same participants in 5 or 10 years and see how well these observations really hold up with the actual development of later alcohol-use disorders.”