New pieces filling in addiction puzzle

By Beth Azar
Monitor staff

Lou, the oldest of three brothers, smoked from his early 20s until a quadruple bypass in his late 50s forced him to quit. Even then it took him several tries, and even years after quitting, he complained of terrible cravings.

Joe, the middle brother, began smoking in his teens, going through two packs a day at one point. He quit cold turkey in his early 50s when he realized how much money he was spending on cigarettes.

Bob, the youngest, bummed cigarettes off his friends now and then, but never took up the habit.

These three brothers demonstrate the complexity of the smoking addiction puzzle. Their environment-living above their father's smoky bar in an urban neighborhood-gave them plenty of exposure to cigarettes, which, during their formative years in the 1940s and 1950s, were hip and mainstream. Yet each responded differently.

Researchers must account for the experiences of all three brothers if they are to piece together a biobehavioral model of smoking that accounts for environmental as well as genetic factors.

And recent studies have brought them tantalizingly close to having enough pieces of the puzzle: Over the past year, several studies have begun to pinpoint specific genes associated with smoking. The trick now becomes combining that information with what researchers know about the environment.

The ultimate model will not only help researchers better understand addiction, but it will also allow them to design smoking-cessation programs tailored to individual needs. The key to building such a model will be cooperation among psychologists, epidemiologists and geneticists, says Gary Swan, PhD, director of the Center for Health Sciences at SRI International in Menlo Park, Calif.

Many genes, small effects

Researchers already know that about half the blame for smoking goes to environmental factors, including parents and friends who smoke, society's acceptance of smoking, the availability of cigarettes and the abundance of cigarette advertising. The other half can be blamed on heredity, according to studies that show identical twins are far more likely to share a smoking habit than fraternal twins.

In addition, as with most behavioral traits, there are likely many genes that contribute to one's proclivity to smoke. And each gene likely wields a relatively small effect and interacts not only with the other genes but also with the environment, says Swan.

In their search for "smoking genes" researchers are using what they know about how the brain processes nicotine to sift through genes already identified as playing a role in that process.

For example, variations in genes for proteins known to metabolize nicotine might make people react differently to nicotine. And differences in genes known to be involved in the brain's reward system-which is triggered by nicotine-might make people more or less vulnerable to addiction.

Messing with metabolism.

Rachel Tyndale, PhD, and her colleagues at the University of Toronto aimed their sights at a gene that encodes the enzyme CYP2A6, which breaks down nicotine when it enters the liver. There are several forms, or alleles, of the CYP2A6 gene, at least one of which produces an inactive form of the enzyme. People who carry this inactive form of the gene, researchers speculate, keep nicotine in their bodies longer than people with the active form of the enzyme. Such a scenario may increase nicotine's adverse effects, making some people less likely to become regular smokers. And in people who do smoke, longer-lasting nicotine would limit the number of cigarettes needed to maintain a preferred nicotine dose.

In fact, Tyndale and her colleagues find that nonsmokers are twice as likely than smokers to have a defective allele for CYP2A6. And smokers who have the defective allele smoke significantly fewer cigarettes than smokers with active forms of the gene. These findings were published last year in the journal Nature (Vol. 393, p. 750).

Other researchers have yet to replicate the Toronto researchers' findings. But they're intriguing, say some, indicating a possible mechanism that makes some people more or less vulnerable to nicotine addiction.

"Understanding the critical role this enzyme plays in nicotine addiction gives a new target for developing more effective medications to help people stop smoking," said National Institute on Drug Abuse Director Alan Leshner, PhD, when the study was released.

.and wrecking reward

Other researchers are concentrating on the brain's reward system as a potential area for finding genes associated with smoking. In particular, they are looking at genes related to the neurotransmitter dopamine-a major player in the reward system-which may influence people's inclination to smoke, according to the results of several studies.

Most recently, two research teams report in this month's issue of Health Psychology (Vol. 18, No. 1) a connection between smoking and the gene for a dopamine transporter-a protein that sweeps up dopamine after it's released by a nerve cell. The studies link the presence of a form of the gene, called the SLC6A3 "9-repeat allele," to whether people smoke and the ease with which smokers can quit. Other studies have linked the 9-repeat allele to increased levels of dopamine, indicating that the transporter the gene encodes is less efficient at clearing out excess dopamine than other forms of the transporter.

In one study comparing 289 smokers with 233 nonsmokers, psychologist Caryn Lerman, PhD, of Georgetown University Medical Center, and her colleagues found that people with the 9-repeat allele were less likely to be smokers than people with other forms of the dopamine transporter gene. This relationship was particularly strong if people also carried another gene related to dopamine-a form of the D2 dopamine receptor that provides plenty of places for dopamine to "dock" when excess dopamine is left by the inefficient transporter. In fact, people with both genes were half as likely to be smokers as people without the genes, the researchers report.

The National Cancer Institute's (NCI) Sue Sabol, PhD, Dean Hamer, PhD, and their colleagues also found a link between the 9-repeat allele and smoking. In particular, among 1,107 nonsmokers, current smokers and former smokers, former smokers were more likely than current smokers to have the 9-repeat allele, says Hamer. This finding implies that the allele may boost people's ability to quit

How? Perhaps through a connection with the personality trait known as "novelty seeking," says Hamer. He and his colleagues found that people with the 9-repeat allele scored low on novelty seeking, which was also the most significant predictor of whether people quit smoking. The 9-repeat allele, they hypothesize, increases the amount of dopamine in the brain and reduces people's need for novelty and reward through external stimuli such as smoking.

These connections among personality, genes and smoking must be examined carefully in the context of other environmental factors, including cultural and societal views of smoking, says Hamer. It may turn out that a trait that put people at risk for smoking 50 years ago is protective today. For example, during the 1940s and 50s, smoking was related to sociability, extroversion and affability. But today it is "clearly antisocial," says Hamer. So if genes contributing to sociability are related to smoking, they would have the opposite effect today than they had 50 years ago.

Proceed with caution

The overlap between the two dopamine transporter studies "is very encouraging," says Lerman. But it's important to note that it is difficult to draw conclusions from these early studies because they are looking at relatively small groups of people, and ethnic differences within and between study populations may affect the results.

"It may turn out that all of this is wrong," adds NCI researcher Peter Shields, PhD, one of Lerman's coauthors. "But we have good reason to think that it is right. Our data are fairly tight and consistent."

It's also important to note that with any complex behavior, including smoking, the contribution of any single gene is likely to be very small, says Lerman.

For example, researchers know from studies of twins that genes account for at least half the variance in smoking, says Lerman. But within that are multiple genes, each exerting a small effect on smoking and interacting with environmental, cultural and psychological factors.

"The next step is to see how these genetic effects relate to psychological, social and environmental factors and to develop a comprehensive model of addiction," Lerman says. "These are the preliminary studies to lay the foundation for those more complex studies."

The easy part is finding genes, adds Swan. The hard part is sorting through the gene-environment interactions. And that's where behavioral researchers, in tight collaboration with geneticists and biologists, will be critical.

In addition, these multidisciplinary research teams will need to collaborate among themselves, as some have already begun to do, to move the field of smoking susceptibility research forward and avoid the pitfalls of some other areas of research, says Swan.

In the area of obesity, for example, researchers have not cooperated, he says, and they now have many potential genes but no coherent model of how they interact with each other or the environment to cause obesity. The same could easily happen in the area of smoking unless researchers work together to form a coherent and cooperative research program, he says.

"I don't want to be looking back 20 years from now having all the genes and no where to go," Swan says. "The public health imperative of the smoking problem almost demands that we put aside the traditional way of doing things and work in a focused, energetic and supportive environment relatively free of competition among team members."



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