WASHINGTON -- California researchers fiddled with a single gene to create mice hypersensitive to nicotine, pointing to a single molecule partly to blame for nicotine's addictive allure.

The genetically engineered mice were tripped up by the tiniest exposure to nicotine -- 50 times less than the level of nicotine coursing through a typical smoker's blood. Once hooked, the mice experienced classic signs of nicotine dependence that keep smokers puffing, the research team reports Friday in the journal Science. "Dependence-related behaviors, including reward, tolerance and sensitization, occur strongly and at remarkably low nicotine doses" in the mice, the research team wrote. In humans, reward arrives as a pleasant little jolt of dopamine, a calming brain chemical unleashed by nicotine. The body's tolerance for the drug leads to more smoking. Sensitization means not feeling good without a nicotine fix, said Henry Lester, a biology professor at the California Institute of Technology who was among the paper's 10 authors. In mice, researchers saw evidence of a reward when mice chose nicotine hits over salt, body-temperature changes as an indication of tolerance and more running around among sensitized mice. Other researchers praised the study. The findings "not only provide direct evidence of how nicotine promotes dependence, but also raise fundamental questions about the genetics of addiction," researchers at the Centre Medical Universitaire, in Geneva, wrote in a companion piece. More than four million people around the globe die from smoking-related causes each year. If the findings in mice hold true for humans, the work points to a specific target for a new drug to attack, easing the physical and behavioral toll of nicotine addiction, others suggest. People become dependent on nicotine when it parks in nerve cell receptors designed for the chemical acetylcholine. Once nicotine fills that space, dopamine is released. By knowing the specific parking place where nicotine can exact a high toll, a drug could be fashioned to fill it. "The power lies in the ability to be so specific. In being so specific, you can treat the cause without the ramifications of the side effects," said Stephen L. Dewey, a Brookhaven National Laboratory scientist who has studied epilepsy drugs to treat nicotine addiction. Daniel McGehee, a University of Chicago neurobiologist who has studied a different subset of receptors sensitive to nicotine called it "a fantastic study" but cautioned against thinking a drug would deliver benefits without costs. Interfering with how the body experiences the rewards of nicotine could dull such experiences as eating food or drinking water. "That pathway is not there to promote tobacco use. It's there to promote healthy behaviors that lead to the survival of our species," Mr. McGehee said. Tampering with it "may interfere with our ability to find pleasure and joy in normal, healthy things." Mr. Lester has been working for years on alpha4, one of a dozen known subunits of nicotine receptor sites. The team learned how to tweak that protein, making it much more sensitive to nicotine. In one set of mice, the genetic mutation was too pronounced. After the nicotine hits, dopamine levels were so intense the mice died, Mr. Lester said. In the Science paper, they made tweaks that were just right. "What we have done is to show that a particular molecule is not only necessary for nicotine addiction, but is sufficient for nicotine addiction," he said. "When the particular alpha receptor is activated by nicotine -- and no other receptors -- that is sufficient to produce some of the effects associated with addiction." Copyright © 2004 Associated Press URL for this article: http://online.wsj.com/article/0,,SB109959299097264981,00.html Copyright 2004 Dow Jones & Company, Inc. All Rights Reserved This copy is for your personal, non-commercial use only. Distribution and use of this material are governed by our Subscriber Agreement and by copyright law. For non-personal use or to order multiple copies, please contact Dow Jones Reprints at 1-800-843-0008 or visit www.djreprints.com.

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