Nearly everyone knows someone who's quit smoking. And someone else who keeps puffing.

"Some people have a harder time than others, and nobody knows why," says Jon-Kar Zubieta. As part of a University of Michigan research team, he pores over bright blue, red and green images, trying to find answers in the intricate effects of nicotine on the human brain. Nicotine is the magnet that makes 47 million Americans smoke, even though 70 percent want to quit. But curiously, the addictive agent in tobacco has remained mysterious, compared to dozens of better-studied cancer-causing and blood-flow-constricting chemicals smokers inhale. Now though, scientists at the U-M and elsewhere are actively exploring nicotine's effects on the body. The team Zubieta is part of uses positron emission tomography, or PET, to look at nicotine's minute-by-minute effects on the brains of cigarette-deprived smokers. And in the U-M Nicotine Research Laboratory, psychologists explore a burning question: Do genes and related psychological traits help explain why smoking hooks some people and not others? In both cases, increased knowledge should lead to smarter, more effective ways to help people quit smoking and help reduce the 430,000 tobacco-related deaths each year, researchers say. By understanding the parts of smokers' brains that are key to pleasure and dependency, "we can target specific drugs to these locations," Zubieta says. What's more, the new focus on nicotine promises to shed light on the common factors that may underlie many kinds of addiction. Zubieta, a psychiatrist, is interested in whether nicotine and other substances known for their addictive properties, such as heroin and cocaine, produce similar effects in the brains of habitual users. There's another reason to learn more about nicotine's effects. Companies are hustling to market modified tobacco products in which they say disease-causing chemicals are reduced or absent. To give users pleasure and motivate them to buy more, these products are likely to contain nicotine. The National Institute of Medicine recently issued a report urging thorough analysis of products being developed as healthier alternatives to cigarettes. It sets out regulatory principles that would require manufacturers to prove new products reduce harm. Increased knowledge about nicotine is also pertinent for people using nicotine patches and gum as quitting aids or as cigarette substitutes. Nicotine is not known to cause cancer in humans, though University of Minnesota researchers recently reported that when nicotine is metabolized, a precursor chemical to a lung cancer agent, NNK, is produced. (See related story for recent findings about nicotine's negative and beneficial effects.) Peering into smokers' brains In the past five years, there's been a big upswing in interest in imaging the human brain to show effects of nicotine and other addictive substances, Zubieta says. The National Institute on Drug Abuse is funding research to discover which parts of the human brain influence cravings. In this effort, the U-M is one of a handful of centers nationally using PET imaging to trace what regions of the brain are aroused by nicotine. Zubieta is part of a research team headed by pharmacologist Ed Domino, who has studied nicotine's effects for years. Domino says first he's out to pin down whether the majority opinion among experts that nicotine addicts smokers is indeed correct. "Secondly, I want to know if nicotine is like cocaine or methamphetamine, or is it quite different? The rat research literature seems to say yes. I'm saying, is that true in humans?" The team so far has measured blood flow and glucose metabolism in the brains of habitual smokers as they inhale a nicotine spray after 12 hours without a cigarette. That's the time when smokers report their peak pleasure. PET scans make color images of which areas of the brain become less active or more active during these moments, by picking up signals from a radioactive tracer. So far the team has found that blood flow and glucose metabolism increase in the thalamus, a part of the brain associated with the ability to concentrate and other mental performance tasks such as the ability to date things. The tests also showed heightened activity in a part of the brain that controls visual functions. Activity decreased in some other parts of the brain as the craving was satisfied. "Our next thought is to look specifically in particular areas of the brain and specific neurotransmitters that relate to craving and euphoria," says Sally Guthrie, a U-M pharmacologist and team member. Zubieta, like Guthrie, is excited at the prospects for significant discoveries using PET to reveal how nicotine affects different neural messaging networks in the brain. They plan to apply for funding for that next step soon. In related studies, Zubieta is studying two neurotransmitters and their receptors which are important in any drug addiction, including alcohol. He's intrigued with the idea that a number of substances may work through similar pathways in the brain, helping to explain why many people use more than one addictive substance. Many cocaine users, heroin users and alcoholics are also smokers, for instance. He's convinced that insights into specific neurostransmitter systems and better knowledge of the role genes play will lead to effective treatments. Designers of future substitutes for cigarettes or smoking cessation products should find insights into smokers' initial rush important, Guthrie says. "We could block specific pathways so they won't get that rush, or come up with (safe) products that would cause the same effects." Quitting methods: One size may not fit all Devising safer alternatives to cigarettes and better quitting methods for the 25 to 30 percent of Americans who continue to smoke will be tricky, says Ovide Pomerleau, director of U-M's behavioral medicine program, which includes the Nicotine Research Laboratory. That's because those smokers tend to have complicating factors that aren't yet well understood. "The easy quitters have quit," he says. "If we're going to keep making progress, we need to look at individual differences." Some people are more likely than others to become dependent on nicotine because of genetic and other reasons. They may be more susceptible to nicotine's addictive pull. On top of that, some people may smoke to alleviate symptoms of mental conditions such as depression, attention deficit hyperactivity disorder and anxiety disorders, research at the U-M Nicotine Research Laboratory and elsewhere suggests. "They learn its benefits: It focuses attention, brightens their mood, and may relieve anxiety," says Pomerleau. "For those people it's going to be a real bear to give it up. It is a challenge to come up with different methods." He sees promise in approaches tailored to each smoker's profile. These will become easier to design as knowledge grows about brain neurochemistry and certain groups of genes thought to predispose some people to be nicotine dependent. Pomerleau and other U-M researchers now are working with Pharmacia to see if some currently available drugs and experimental drugs designed to reduce cravings can be effective in helping smokers quit. On another front, the Nicotine Research Laboratory, directed by Cynthia Pomerleau, Ovide Pomerleau's wife, has launched the Great Lakes Smoker Sibling Registry, funded by the National Cancer Institute, to examine the role certain genes play in making some people susceptible to nicotine dependence. Benefiting from the human genome project and advances in computing power, they want to discover what relationships may exist between the activity of certain genes that regulate nicotine receptors in the brain and smoking patterns among smoking and non-smoking siblings and their parents.

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