DURHAM -- Tethered to a pulse monitor, Robert Marrow sat in a tiny office and waited for the lab technician's cue. He leaned forward and placed his mouth on the filter of a lit cigarette encased in a network of glass tubes and wire.

Robert Marrow smokes a cigarette while attached to a pulse monitor at Duke University's nicotine research lab. He is participating in a study of a drug that blocks the effects of nicotine on the brain.He drew on it hard, brightening the red coal. When the technician counted down "three, two, one," Marrow exhaled, releasing smoke in a flat stream. He sat back, patiently waiting to ingest an enemy he has long known causes lung cancer, heart disease, stroke. But in this lab, Marrow learned something new. After nearly 50 years of lighting up, it's not a weak will that compelled him to rip through a pack of Marlboros each day. His brain was to blame. In a state where one in four adults still smokes, Duke University scientists are using people such as Marrow to unlock smoking's deepest molecular secrets, eager to cure an addiction linked to 14,000 deaths in North Carolina each year. Yes, smokers become physically dependent on nicotine, a drug in tobacco smoke that takes only seconds to travel from the lungs to the bloodstream and, eventually, to an influential region of the brain. But the tougher addiction, also lodged in the brain, might be the act of smoking itself, scientists say. "Addictive behaviors defy reason, not because people are irrational, but because invisible factors at work in their brain compel them to seek out substances that they know are bad for them," said Ted Slotkin, a Duke University neuropharmacologist. That explains why people like Marrow might have been most vulnerable to a lifetime cigarette addiction as teenagers, when they exposed their still-developing brains to nicotine. It explains why ex-smokers for years crave the feel of a smooth cigarette in their hands, the lighting of a match or the scratch of cigarette smoke in their throats. And it explains why, at age 62, Marrow found himself smoking for science at a nicotine research program run by Duke University and the Durham Veterans Affairs Medical Center. "I thought I was a strong-willed person," said Marrow, a former paratrooper who prides himself on his self-sufficiency. "But this is something stronger." That first smoke In ways, it's strange that anyone ever ingested nicotine. In plants, the drug acts as a pesticide, attacking the nervous systems of insects. But people have sampled countless items over the ages. Some substances, including alcohol, opiates and nicotine, have special powers. They resemble chemicals that naturally occur in the human brain. Once ingested, they corrupt the brain's normal functioning. From the first puff of a cigarette, nicotine prompts false chemical messages. Those messages tell the brain that nicotine is good, very good, and embraces any behavior that delivers more of it. New evidence at Duke suggests the teenage brain might be the most vulnerable to that process. If that's true, efforts to prevent teen smoking could become even more urgent. Marrow knew nothing about the molecular action of nicotine back in the 1950s when he tasted his first cigarettes in the woods outside Eastman High School. He grew up in rural Halifax County, tobacco country, on farmland his grandfather, Johnny Johnson, bought nearly a century ago. Smoking there was as natural as eating. "It was something everyone did," said Marrow, who today still tends a small herd of beef cattle on family land and commutes to a boiler operator job at Central Prison in Raleigh. "You were weird if you didn't smoke." When Marrow's father found out his teenager was smoking Chesterfields, he bought his son a carton of milder cigarettes, figuring they would be gentler on his throat. He had no idea that he should have worried about what was going on inside the boy's head. The brain is a tangle of specialized nerve cells, called neurons, that respond to life's events by transmitting chemical messages from one cell to another, ultimately directing a person to do everything from hug a beloved child to strike an attacker. Nicotine resembles a chemical messenger called acetylcholine that prompts the brain to fire off another of those messengers, a neurotransmitter called dopamine. Dopamine works in an influential part of the brain known as the reward pathway, which also fires when people engage in such pleasurable activities as eating or sex. On conscious and subconscious levels, people really like how that feels. And they want to feel it again. Only recently have scientists started investigating how that process affects the adolescent brain. The vast majority of long-term smokers start as teens. For years, researchers assumed that the human brain stopped developing in childhood. Now they understand that it changes into early adulthood. In the 1990s, Slotkin, the Duke neuropharmacologist, linked smoking during pregnancy to harm in the developing brains of fetuses, leaving them more vulnerable to sudden infant death syndrome. Now he is finding that adolescent rats create more microscopic receptors to put nicotine to work in their brains. He also is finding evidence of brain cell damage after exposure to nicotine, especially in females. That prompts him to wonder whether people who smoke as teenagers keep smoking, in part, to feel normal, since the dopamine-enhancing effects of nicotine could compensate for damage. "This is an affliction," Slotkin said. "People may be self-medicating themselves." Ed Levin, a behavioral pharmacologist at Duke, has watched adolescent rats learn to self-administer nicotine more quickly than adults can, prompting him to think teens might be primed to learn, and then crave, whatever it takes to get more nicotine, setting up a lifetime of dependency. "People who start earlier have the toughest time quitting," Levin said. "Looking back on it, it's strange that people didn't realize this earlier." A learned behavior As a young man, Marrow never worried about his cigarette smoking. He took cigarettes with him when he enlisted in the Army and landed a slot as a paratrooper in the First Airborne Battalion at Fort Bragg. He happily bought whole cartons of cigarettes for only $1.25 at camp stores while stationed in Germany. He enjoyed smoking in nightclubs while living in Philadelphia after his Army hitch. And he kept it up in 1972 when he returned to Halifax to be closer to his aging parents, smoking year after year, tending his small herd of beef cattle and working in a neighbor's tobacco fields. But times changed. Since the 1960s one surgeon general after another detailed smoking's harms. In time, smoking was no longer welcome in some restaurants or friends' homes. He noticed that when he carried something heavy, like bales of hay, he ran out of breath quickly. His daughter pleaded with him to stop. So 10 years ago, Marrow decided to quit. But his brain, clinging to its need for nicotine and the behaviors that delivered it, urged him to smoke. The cravings were intense, and Marrow became very irritable. So he smoked. Then he sought help. He tried nicotine-laced gum and Zyban, an antidepressant marketed as a smoking cessation aid. He even signed up for self-hypnotism lessons that drew scores of smokers to conference rooms in hotels in Raleigh and Roanoke Rapids. He can't count how many times he tried. But nothing stuck. The brain says smoke In April, in the parking lot of the nicotine research center, Marrow was still at it, fishing a smoke out of the front seat of his Nissan pickup, lighting a match with a graceful flick of his wrist and hating every minute of it. "It's an annoying, nagging desire to do something that only a cigarette will satisfy," said Marrow, who needed that first cigarette within five minutes of waking. "You're paying to kill yourself." When smokers stop ingesting nicotine, they go through withdrawal, an event scientists trace back to the brain and its appetite for continued stimulation in the reward pathway. In the 1980s, scientists such as Duke's Jed Rose, director of the nicotine research center, figured giving smokers alternative sources of nicotine would be enough to help them quit. So he helped invent the nicotine patch. But it rarely works when used alone. That's because the brain also embraces the behaviors that enable people to ingest nicotine and create sparks in the pathway. That helps explain why people experience overwhelming cravings for cigarettes years after quitting, especially if they are in settings that the brain associates with the former pleasure, whether that be a congenial wine bar or at a particularly stressful point in the day. The drive to repeat the behavior lingers long after a person musters the resolve to abstain from the drug, Rose said. "There's a drive to self-administer the drug," Rose said, of people who break down and smoke even after being weaned from nicotine, which can take only a few days. "People want more." Tying it all together These days, in offices and a former jewelry store near Duke's sprawling medical center, Rose's team conducts study after study trying to tease out all that cigarette addiction entails. The researchers perform brain scans to see which regions of smokers' brains get stimulated by cigarettes. A crew of young lab technicians gives volunteers intravenous doses of nicotine and later lets them smoke cigarettes to compare how each satisfies them. They hand out doses of mecamylamine, a drug that blocks nicotine's effects on the mid-brain, to see which cravings are diminished. They are trying to counter the effects of a second, mysterious substance in cigarette smoke that also increases dopamine levels by disarming a crucial enzyme in the brain. And they are experimenting with de-nicotinized cigarettes, most recently with a brand made with genetically altered leaf by Vector Group, the parent company of the Liggett Group, which recently moved from Durham. Those cigarettes might help wean people off the smoking habit after they start abstaining from the drug, Rose said. Marrow, who has taken more than 1 million puffs on cigarettes in his day, desperately hopes that all this scientific scrutiny will help him and others put cigarettes away forever. His life is at stake. So far, Marrow has lost four people to smoking, one family member and three old friends, to lung and throat cancers. He remembers driving one friend to East Carolina Medical Center after doctors in Rocky Mount found cancer and said they could be of no help. The man was frightened, but there was nothing Marrow could do. Like the others, the man died within months of being diagnosed. "I get angry with the tobacco companies, and the government, for letting this go on for so long," Marrow said. Marrow signed up at the Duke nicotine program after reading a newspaper ad calling on healthy smokers between the ages of 18 and 65 to help with research. After entering a hive of offices in the Erwin Square complex in West Durham, he signed up for a clinical trial testing the effects of mecamylamine, the drug that blocks nicotine's effects in the brain. He also endured lots of exercises designed to help scientists better understand smoking's effects on his brain. Before and after finishing a cigarette, he filled out lengthy questionnaires about how he felt. Then he sat in front of a computer terminal so researchers could test his dexterity and memory with puzzles they flashed on the screen. After weeks of taking white tablets that might or might not be mecamylamine, using nicotine patches and smoking low-nicotine cigarettes, Marrow smoked what he says was his last cigarette on April 25. This time, he said, the cravings were far weaker. Marrow wants whatever scientists learn from his case to help others, whether that be the teenagers who get hooked for life, the pregnant women who can't stop or people like his old friends, who literally smoked themselves to death. "The more you know about anything," he said, "the better you can help yourself."

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