This research, led by Dr. Henry Lester of the California Institute of Technology, and his colleagues at the Institute of Behavioral Genetics at the University of Colorado, is published in the November 5, 2004 issue of the journal Science.

"Nicotine addiction is the largest cause of preventable mortality in the world, leading to more than 4 million smoking-related deaths annually," says NIDA Director Dr. Nora D. Volkow. "Recent findings also have shown that the act of smoking cigarettes can affect biochemical systems within multiple organs that are far removed from the lungs and upper airways. While we have a number of treatments that have proven effective for many people, clinicians do need more options."

This new strain of mice, created through a process in which the researchers altered only one amino acid through what they call "knock-in" technology, is exceptionally sensitive to nicotine. The scientists have shown that these mice display addiction-related behaviors, including reward, tolerance, and sensitization to the drug. Furthermore, they report, these actions are powerful and occur at remarkably low nicotine doses.

"Previous work in this area of nicotine addiction has focused on creating 'knock-out' mice, in which specific genes are removed from the animals, which then produce less dopamine in response to stimulation," says Dr. Lester. "But we thought that instead of eliminating the response to nicotine, we would accentuate it by making a hypersensitive nicotinic acetylcholine receptor that would emphasize the pleasure pathway and allow us to study behaviors that play roles in nicotine abuse and addiction. Thus, we developed a 'knock-in' mouse."

Nicotine bears a molecular resemblance to the nerve chemical acetylcholine and this allows it to bind to receptors on nerve cells called the nicotinic acetylcholine receptors. The act of binding causes the cells on which the receptors reside to release dopamine, a chemical involved in the brain's pleasure/reward system.

"Studies like this are not only helping us to unravel the complexities of nicotine addiction, but they are providing innovative ideas and technologies that can be applied to other areas of drug abuse and addiction," says Dr. Volkow. "But, as with other drugs, our best treatment is prevention. We need to strengthen our programs designed to keep people from beginning to smoke."

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