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Report: Key to nicotine addiction found
Researchers isolated single molecule they think to blame
WASHINGTON (AP) -- 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 sensitiz
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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Copyright 2004 The Associated Press. All rights reserved.This
material may not be published, broadcast, rewritten, or
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http://www.cnn.com/2004/HEALTH/11/04/nicotine.study.ap/index.html
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