Building on Success:
Cindy Ehlers Extends Innovative Research on Alcoholism

By Mika Ono

Despite the difficult funding environment these days, Scripps Research Institute Associate Professor Cindy Ehlers is winning grants. Her c.v. lists eight—most recently a rare and prestigious MERIT award from the National Institute of Alcohol Abuse and Alcoholism (NIAAA) providing her with 10 years of research support.

Even a quick look at Ehlers' track record makes it easy to see why funding agencies want more. Over the past decades, Ehlers has brought us dramatic new insights into alcoholism and substance abuse—problems that affect many millions of Americans, not to mention their families and communities. In the process, Ehlers has routinely challenged us to rethink what we thought we knew. 

At the heart of Ehlers research is one critical question—why do some people become dependent on alcohol or other substances while others escape their grip? To shed light on the answers, Ehlers has applied an innovative approach, conducting both human and animal studies and drawing techniques from disciplines as wide-ranging as physiology, genetics, and epidemiology.

One of her strategies has been focusing on minority populations at relatively high or low risk for alcoholism. The recent MERIT (an acronym for Method to Extend Research in Time) grant is a case in point, as the research seeks to tease apart risk and protective factors in Southwest California Indians, who have a five-fold greater risk for developing alcohol dependency than the general population.

"In this population, the lifetime alcohol dependence rate is about 70 percent," says Ehlers. "That means that only about a third of the population escapes developing alcohol dependence in their lifetime. In the study, I'm looking at factors—both environmental and genetic—that may be causing this increase."

Ehlers is no stranger to this group of Southwest California Indians in San Diego County, collectively known as Mission Indians, whom she has been working with for more than 15 years. While the research has provided a treasure trove of information, few other investigators have ventured to reach out to this population. "It takes a lot of work," acknowledges Ehlers, who spends one day a week building relationships by visiting the reservations or helping with community-based issues.

The Teenage Brain

But Ehlers' tenacity has paid off, most recently in insights into the dangers and opportunities of adolescence.

Drinking during this period of development can prime the body for alcohol dependence. And, importantly, avoiding alcohol during these years can protect against developing the condition.

"If you are a member of this Native American population and start drinking—and I mean just getting intoxicated, not necessarily drinking regularly—before the age of 13, the chance of becoming alcohol dependent is 85 percent," Ehlers says. "And if you wait until after age 17, it drops to about 15 percent."

These results, published last November in Alcoholism: Clinical and Experimental Research, also showed that drinking at an earlier age was associated with a shorter time to the onset of alcohol dependence. No heritability was found in the age of first intoxication—pointing to this as an environmental, rather than genetic, factor.

Additional studies suggest that adolescence is key for other groups and for other substances of abuse as well. National surveys have correlated the age of onset of drinking with development of alcohol dependence in the general population, and Ehlers has found this effect extends to a group of Mexican Americans in San Diego County. Adolescence is also critical for marijuana use—Ehlers recently published a study funded by the National Institute of Drug Abuse (NIDA) showing early marijuana use by Southwest California Indians was strongly associated with abuse and dependence.

Animal models further confirm the importance of this period of development. Ehlers has demonstrated long-lasting neurobehavioral consequences of adolescent alcohol exposure in rodents. She also found adolescent exposure to nicotine also has life-long effects on rodent brain function.

"Adolescence is a time when drugs are very toxic, not unlike fetal development," she says. "The brain is going through its final level of development, a process called brain pruning, where all the connections between the brain's neurons start reducing to their final form as an adult. When you think about it, teenagers wake up every day as a different person. They're trying to find out who they are and how to cope with stress. But if drugs come in, particularly early in the process, that process can be hijacked so that these individuals become focused on drugs."

This research has striking implications for both parents and policy makers, suggesting the prevention of underage drinking and drug use should be of the highest priority.

"I think there should be a zero tolerance policy for drugs and alcohol under the age of 16," says Ehlers. "We need to educate parents about the risks."

Ehlers is currently leading a joint project with the Indian Health Council, which serves as the primary healthcare facility for the nine north San Diego County reservations, and the Pacific Institute for Research and Evaluation's Prevention Research Center to help develop the community's capacity to address the problem of underage drinking.

Challenging Conventional Wisdom

Over the years, Ehlers and her team have confronted a number of myths about the causes of alcohol dependence in the Native American population. "I call it exploding the myth of firewater," says Ehlers.

One common view is that Native Americans have a weakness for alcohol and that if they drink even small amounts they lose control. In fact, just the opposite is true—these individuals tend to have a less intense responsive to alcohol, which enables them to drink prodigious amounts. This increased exposure to alcohol raises the risk of developing alcohol dependence.

Ehlers' research also challenges the conventional wisdom that depression and poverty contributes to the high rate of alcoholism among Native Americans.

"A lot of people think that Native Americans drink more because they are depressed or because the environment is less than adequate," she says. "We found that in fact they have lower rates of depression than the general population and that depression and anxiety do not account for this alcohol dependence. We've also looked at acculturation and stress—and those also don't seem to have an impact on the development of alcohol dependence in these Native Americans."

Interestingly, though, stress does seem to play a role in the development of alcoholism in another population—second and third generation Mexican-Americans. Ehlers is studying this group under the auspices of the Alcohol Research Center, which she co-directs with Scripps Research Professor George Koob. These young Mexican American adults, who are in the country legally and speak English, have double the risk for alcohol dependence compared with the general population. While first-generation immigrants have lower-than-average rates of alcohol dependence, this protection does not extend to their children and children's children.

"We did find an association between alcohol dependence and stress in our Mexican American population," says Ehlers. "We also found higher rates of depression and anxiety, and a physiologically increased response to auditory stress stimuli as measured in the lab. We believe that the excess risk for alcoholism may have something to do with their stress responses."

It's worth noting that the differences among groups that Ehlers has uncovered have practical consequences, pointing to the utility of targeted intervention programs.

Genetics of Metabolism

Ehlers' study of ethnic groups has also illuminated genetic factors that can provide protection against alcoholism. 

Here, enzymes that control alcohol metabolism can play a role. Normally, when a person drinks, a set of enzymes called alcohol dehydrogenase converts ethanol into the toxic intermediate acetaldehyde. Acetaldehyde dehydrogenase then converts this intermediate into the non-toxic acetyl-CoA. However, in some individuals genetic variations make this process less efficient.

In the early 1990s, Ehlers conducted some of the first clinical work with Asians. About 40 percent of all Chinese, Japanese, and Koreans have a change in the acetaldehyde dehydrogenase gene ALDH2, which affects alcohol metabolism. Ehlers and colleagues conducted an "alcohol challenge" test on a group of young men with and without this genetic variation. The researchers examined how consumption of precise amounts of alcohol affected blood pressure, heart rate, brain waves, and other physiological measures, as well as more subjective factors, such as how drunk the men said they felt.

"Compared to young men who did not have the allele, these men had a more intense response to alcohol," says Ehlers. "They basically feel more drunk, so they tend to drink less."

Interestingly, the study also found the response to alcohol varied not only depending on whether an individual had the genetic variation or not, but also whether he had one or two copies of the variant gene. Individuals who had two copies (in other words, who were homozygous for the trait) were alcohol intolerant. "Two drinks were enough to cause practically a medical emergency, with lower blood pressure, rapid heart beat, and a really large body stress response," notes Ehlers. Those with one copy of the gene (who were heterozygous for the trait) still had a relatively intense response to alcohol, with facial flushing and increased heart rate and blood pressure, but one that was not necessarily perceived as negative by the participant.

More recently, Ehlers has turned her attention to another group that demonstrates a genetic variation in the metabolism of alcohol, individuals of African descent. In this case, the variant is a gene coding for one of the alcohol dehydrogenase enzymes, ADH1B*3.

To conduct this research, Ehlers has been working with a population in San Diego and also on the island of Trinidad. The people of this island provide a unique opportunity for study, since they have been genetically isolated for a number of generations (a "population isolate"). About half of the population in Trinidad is of African ancestry and about half is of Indian ancestry.

In the February 2007 issue of Alcoholism: Clinical & Experimental Research, Ehlers and colleagues published results showing that the ADH1B*3 variation in Afro-Trinidadians is associated with protection from the development of alcohol dependence. The researchers also found, however, the same variation could increase the risk of liver disease if these individuals choose to drink.

A Construct of Consumption

In addition to insights into the protective effects of some genetic variations, Ehlers has provided some tantalizing clues to a genetic link between increased risk for alcohol dependence and disorders such as obesity.

"One of the factors that seems to be important seems to be what I call a 'consumption gene,' which appears to code for an increased appetite for alcohol as well as for foods," says Ehlers. "In one of our studies, we showed there's an overlap in the genetic location for risk of drug dependence and a high body mass index [an indicator of obesity]… When you think about it, alcohol abuse is a consumption disorder. Not unlike overeating, it occurs when you lose control over stopping a behavior."

This relationship may involve a compound called neuropeptide Y (NPY), which recently made headlines after a study indicated it was part of a mechanism by which stress activates weight gain in mice. Ehlers had suggested ties between NPY and alcohol consumption almost 10 years ago, showing that rats selectively bred for increased consumption of alcohol had increased levels of NPY in their brains.

Ehlers is currently following up on these and other findings. She is working with colleagues to find the exact location of genes associated with risk of alcohol and drug dependence in Native Americans. She is looking at changes in brain structure in this same group. She is planning an "alcohol challenge" test in a group of African Americans. And she is conducting research into the relationship between sleep and alcoholism, as sleep disturbance is one of the biggest risk factors for relapse in alcohol dependence.

Thanks to Ehlers' initiative, a dedicated team of lab members, colleagues, and community participants, and her bevy of grants from NIAAA and NIDA, Ehlers will continue to expand our understanding of drug and alcohol dependence—and how we might prevent and treat the disorders.

For more information on Ehlers research, see the Ehlers lab web site.

Send comments to: mikaono[at]scripps.edu

Associate Professor Cindy Ehlers examines both environmental and genetic factors that influence the risk of developing dependence on alcohol or other substances.

"Adolescence is a time when drugs are very toxic."

—Cindy Ehlers

"Not unlike overeating, [alcohol abuse] occurs when you lose control over stopping a behavior."

—Cindy Ehlers