Originally created 11/05/04

Molecule is key to nicotine addiction



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, changed body temperatures 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, Switzerland, wrote in a companion piece.

More than 4 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," McGehee said. Tampering with it "may interfere with our ability to find pleasure and joy in normal, healthy things."

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.

What wasn't clear was which mice to manipulate.

Others found answers by subtraction, erasing genes to create knock-out mice to study nicotine addiction. Lester's group made "knock-in" mice, making a single amino acid change among the millions of choices present in 30,000 mice genes.

"This is extremely clever because you're looking at it by addition," said Dr. L.W. Role, a Columbia University Medical Center professor who studies receptors sensitive to nicotine.

In the first set of mice, the genetic mutation was too pronounced. After the nicotine hits, dopamine levels were so intense the mice died, 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."

Because of that, the knock-in mice are nicotine addicted without complicating side effects. "We can now go on this molecular detective hunt" Lester said, looking for other molecules changed by nicotine dependence.

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