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Scientists Search for Genetic Factors at Play in Nicotine Addiction

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St. Louis Post-Dispatch


ST. LOUIS - Jennifer Breeding is afraid to die.

Jennifer, 18, is a smoker. Her whole family smokes. So do her friends. She knows the consequences - lung cancer, heart disease, death.

"That's why I want to quit," she said.

But it's hard. Really hard.

Jennifer, a junior at the Central Visual and Performing Arts High School near Fairground Park, Mo., has tried to kick the habit five times since she started smoking at 15. She's managed to go smoke-free for up to two weeks but always starts again.

The problem for Jennifer and millions of other smokers is not a lack of willpower, or even a misguided notion that they can beat the odds. In some people smoking rewires the brain, producing a powerful addiction that may never be entirely cured, experts say.

The U.S. surgeon general released a report 40 years ago linking smoking and cancer, and yet a quarter of the adult population still smokes.

"The people who could quit, quit. Now we're left with a group of really committed smokers," said Laura Bierut, a geneticist at Washington University. Bierut is trying to track down the genetic factors that contribute to alcohol and nicotine addiction.

New research by Bierut and others is only beginning to determine why people smoke, who is likely to become addicted, and why some people can stop while others never seem to be able to put the butt out.

Among the findings:

Variations in liver enzymes that break down nicotine may influence who becomes a smoker and who doesn't, and cause black smokers to puff on fewer cigarettes than their white counterparts.

People with attention deficit disorder are five times more likely to become smokers than those without it. Nicotine may help them concentrate better.

Some families have a genetic predisposition to become nicotine addicts. Other families are full of social smokers who never become dependent on the drug. Studies are under way to determine the difference.

At least two of 4,000 other chemicals - besides nicotine - in cigarette smoke may contribute to addiction. One of the chemicals is a breakdown product of alcohol and may help explain why smoking and drinking go hand in hand.

Data from the National Comorbidity Survey, 1990-1992, suggest that tobacco is more addictive than either heroin or cocaine. An estimated 32 percent of tobacco users become dependent on the drug, while 23 percent of heroin users and 17 percent of cocaine users show signs of dependence. The study was conducted by the University of Michigan Institute of Survey Research.

Tobacco kills about 430,000 people in the United States each year. That's more than die from alcohol, cocaine, heroine, homicide, suicide, car accidents, fire and AIDS combined, according to the National Institute on Drug Abuse.

Like Jennifer, most smokers know the harm tobacco can do and say they want to quit smoking. According to the recently released Missouri County-Level Study Smoking Cessation Report, about half of adult smokers have quit for a day or more in the past year, and almost 62 percent said they intend to stop smoking in the next six months.

An estimated 35 million smokers try to kick the habit each year, but only about 7 percent succeed in remaining smoke-free for more than a year. Most relapse within a few days of quitting and require multiple attempts before they can give up cigarettes, smoking cessation experts say.

The path to addiction is probably the same, whether the vehicle is nicotine, cocaine, alcohol or other drugs, brain researchers say. All drugs of addiction seem to affect a region of the brain known as the nucleus accumbens, and all in the same way - by increasing levels of a feel-good chemical called dopamine. The nucleus accumbens sits in a part of the brain responsible for organizing thoughts and emotions. It is often called the reward center of the brain.

The brain's reward for anything pleasurable is dopamine, said Dr. Nora D. Volkow, director of the National Institute of Drug Abuse, one of the National Institutes of Health.

"We do lots of things for dopamine," Volkow said. "We eat food for dopamine. We have sex for dopamine. Dopamine is the way nature motivates you to do things."

A combination of genetic factors that control the ebb and flow of dopamine in the brain also may determine whether a smoker becomes the one person in three who gets addicted to tobacco.

Preliminary results from brain imaging studies of addicted smokers suggest that nicotine leads to a rapid increase in dopamine levels in the nucleus accumbens, said Dr. Mark Mintun of Washington University.

Little spikes of drugs seem to make them more addictive, Mintun said. And smoking is tailor-made to deliver drugs to the brain quickly. A drug, such as nicotine, travels to the brain in about 10 seconds when a substance is smoked, but requires about 30 seconds when given through an intravenous injection, he said.

How long nicotine stays at high levels in an individual's blood is one of the key factors in determining who is likely to become a smoker, said Thomas C. Westfall, chairman of the Department of Pharmacological and Physiological Science at St. Louis University.

When a smoker lights up the first cigarette of the morning and takes a drag, nicotine rushes to the brain and bloodstream. In the body, a flood of adrenaline and noradrenaline constricts blood vessels and releases sugar into the blood, Westfall said.

In early studies of smoking, Westfall brought smokers into the lab for their first two cigarettes of the day. After smoking the cigarettes, the volunteers' blood pressure rose dramatically - an increase of 18 points on the systolic reading (the top number) and 10 points of the diastolic measure (the bottom number). Their pulses raced about 25 beats per minute faster than before smoking. And the temperature in their fingers and toes dropped four to five degrees as tiny blood vessels constricted in response to nicotine.

For most people the effects are short-lived, as enzymes in the liver quickly break down the nicotine. But some people have a genetic variation that decreases the amount of an enzyme called CYP2A6. The enzyme is responsible for breaking down nicotine, environmental toxins, including some found in tobacco smoke, and drugs such as the blood-thinner coumarin. People who have lower levels of the enzyme can't clear nicotine and may get nauseous, Westfall said. Those people tend not to become smokers, he said.

Howard McLeod of Washington University got interested in the enzyme because of studies that show differences in smoking habits and lung cancer rates between blacks and whites. He asked nonsmokers to chew nicotine gum for 30 minutes and then measured how quickly nicotine left the blood.

The African-Americans in the study tended to take longer to break down nicotine than their European-American counterparts, McLeod said. Genetic analysis revealed that about 5 percent of the white volunteers carried the genetic variant that lowers CYP2A6 activity, while 12 percent of the African-Americans had the variant, he said. A collaborator found that about 30 percent of Japanese people have the variation.

Those results could help explain some of the racial and ethnic differences in smoking habits, Bierut said. Black smokers tend to smoke fewer cigarettes than white smokers do. That could be because more blacks are unable to break down nicotine and need to smoke less to get the same amount of drug.

Historically, more blacks have smoked than whites, but the National Survey on Drug Use and Health, published last month by the Centers for Disease Control and Prevention, found that fewer blacks (25.7 percent) and Hispanics (23.1 percent) than whites (27.4 percent) smoked in the years 1999 to 2001. American Indians and Alaskan Natives had the highest smoking rates (40.4 percent) while Asians had the lowest (16.2 percent).

Even though blacks smoke less than whites, they suffer the negative effects of tobacco more, studies suggest.

A study at Temple University School of Medicine in Philadelphia compared records of 160 patients with chronic obstructive pulmonary disease. The researchers found that blacks smoked on average 40 pack years, said Dr. Wissam Chatila, a pulmonologist who led the study. (A pack year is determined by multiplying the number of packs of cigarettes smoked per day by the number of years a person smokes. For example, a person who smokes two packs a day for 10 years would be said to have smoked 20 pack years). Whites in the study, released in the January issue of the biomedical journal Chest, smoked 60 pack years, a third more than blacks. They also started smoking younger - at age 14 to 15 compared with age 17 for blacks.

The data did not surprise the researchers, Chatila said. Three to four times more whites than blacks get COPD, a disease that combines the effect of chronic bronchitis and emphysema to decrease the flow of air in the lungs. An estimated 32 million people in the United States have the disease, although half don't know it, Chatila said.

But blacks were not protected by their lighter smoking habits, Chatila found. Instead, they contracted the disease starting in their mid-50s, while most of the whites didn't get ill until they were more than 60 years old.

Scientists are trying to determine why cigarette smoking appears to be even more dangerous for blacks than whites.

Other groups of people have their own reasons for smoking.

A study of twins with Attention Deficit Disorder revealed that up to 70 percent of them are regular smokers, said Dr. Richard Todd, chief of child psychiatry at Washington University. The children often report that smoking helps them concentrate better, Todd said.

Children with Attention Deficit Hyperactivity Disorder, a syndrome often grouped with ADD but that Todd says has different genetic causes, were not as likely to smoke.

Todd and his colleagues examined the DNA of children with both disorders and found a genetic variation in a nicotine-receptor gene called CHRNA4. When nicotine binds to the receptors on brain cells, the cells release dopamine, which may aid concentration. The researchers are not yet sure how the variation affects the function of the nicotine-receptor. About 90 percent of the children with attention deficit carried the variant, but children with hyperactivity disorders had the variant no more often than would be expected by chance, Todd said.

The result could mean that drugs that alter the activity of some nicotine receptors could be effective treatments for attention deficit disorder, and that children with the disorder should be warned of their increased risk of becoming addicted to smoking, Todd said.

But it is not simply the amount of nicotine that reaches the brain that determines whether a person will become addicted. Dopamine levels are important, too.

Scientists also have noticed that smoking reduces the amount of an enzyme called monoamineoxidase in the brain. The enzyme degrades dopamine, so lower levels of MAO mean that dopamine stays around longer to produce rewarding feelings.

A chemical called beta-carboline, a component of cigarette smoke, inhibits the function of the dopamine-degrading enzyme, and could contribute to smoking's addictive effects, said Volkow of the National Institute on Drug Abuse.

A second chemical in smoke, acetaldehyde, also is believed to be one of the addictive substances in alcohol, Volkow said. Smoking and drinking together could reinforce the rewarding feelings that each produces in the brain, she said.

Genetic studies of alcoholic families have revealed that some regions of the human genome may contain genes that contribute to addiction to alcohol and nicotine together, while other regions have genetic variations associated with alcoholism or smoking alone, said Bierut, the Washington University geneticist. Little is known about the genes located in those parts of the genome, she said. Most have no known function and their connection with nicotine or alcohol abuse is unclear.

Many genes may make small contributions to the process of nicotine or alcohol addiction, Bierut said. She and her colleagues are beginning a study of families who are heavy smokers to find some of the genetic factors that lead to nicotine addiction.

Bierut expects to find some genes that contribute to the prevalence of smoking in these families, but the environmental factors could be equally important in determining why people start smoking or continue, she said.

Jennifer would agree. She, and more than 16 percent of high school smokers surveyed by the Missouri Department of Health and Senior Services, thought smoking was cool. But the charm soon wore off.

"I quit showing off after a while," she said.

And she started trying to quit, but it's hard to give up smoking when everyone around you does it, she said.

"I don't live in a smoke-free environment," she said.

She hopes younger students won't follow in her footsteps, she said.

"I see 10- and 11-year-olds (smoking), and it's really sad. It's going to hurt them one day."


(c) 2004, St. Louis Post-Dispatch. Distributed by Knight Ridder/Tribune News Service.


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