Scientists shed light on nicotine addiction

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 has tried to kick the habit five times since she started smoking at 15.

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.

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 nicotine, 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, heroin, homicide, suicide, car accidents, fire and AIDS combined, according to the National Institute on Drug Abuse.

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 such drugs 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 that organizes 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 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 with an intravenous injection, he said.

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.

Smoking and drinking

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.

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 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. Their pulses raced about 25 beats per minute faster. And the temperature in their fingers and toes dropped four to five degrees as tiny blood vessels constricted in response to nicotine.

Enzyme may be a key

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 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 have the variation.

Those results could help explain some 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 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 fewer blacks (25.7 percent) and Hispanics (23.1 percent) than whites (27.4 percent) smoked from 1999 to 2001. American Indians and Alaska Natives had the highest rates (40.4 percent) while Asians had the lowest (16.2 percent).

Other groups of people have their own reasons for smoking.

A study of twins with attention-deficit disorder (ADD) found 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 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.

Mystery genes

Genetic studies of alcoholic families also 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. Most of the genes 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, she said.