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Cocaine's chemical
'switch' stays turned on
By The Associated
Press
Sept. 15, 1999
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Cocaine may be one of the
toughest addictions to cure because it triggers a buildup of a protein that
persists in the brain and stimulates genes that intensify the craving for the
drug, new research suggests.
Scientists at
the Yale School of Medicine were able to isolate the long-lived protein, called
Delta-FosB, and show that it triggered addiction when released to a specific
area of the brains of genetically engineered mice.
The
protein (pronounced fawz-bee) isn't produced in the brain until addicts have
used cocaine several times, or even for several years. But once the buildup
begins, the need for the drug becomes overpowering and the user's behavior
becomes increasingly compulsive.
''It's almost like a
molecular switch,'' said Eric Nestler, who led the research. ''Once it's
flipped on, it stays on, and doesn't go away easily.''
The
findings, to be published Thursday in the journal
Nature, were called ''elegant'' and ''brilliant'' by other
researchers who said it offered the first concrete proof that drug use triggers
a specific long-term change in brain chemistry.
The study
indicates genetics is less a factor in addiction than prolonged drug use, said
Alan Leshner, director of the National Institute on Drug Abuse, which funded
part of the study.
''Your genes
don't doom you to be an addict,'' Leshner said. ''They just make you more, or
less, susceptible. We've never found one gene that keeps you from being an
addict, or one that dictates you're going to be an addict.''
Nestler
and his colleagues combined genetic and biochemical research to isolate the
Delta-FosB protein and the area of the brain it affected, then did behavioral
studies on the mice.
Once the level
of Delta-FosB accumulates, it begins to regulate genes that control a region of
the brain called the nucleus accumbens, an area involved in addictive behavior
and pleasure responses.
They speculated
that Delta-FosB also activates other genes that produce biochemical compounds
called glutamates, which carry messages in brain cells. Receptors in the brain
cells become highly sensitive to glutamate, particularly in the nucleus
accumbens.
To test the theory, they inserted a gene associated with
glutamate into the nucleus accumbens of experimental mice. Those mice showed a
''dramatic'' increase in cocaine sensitivity, they reported.
''This is a major advance in our understanding of
addiction,'' said Francis White, chairman of cellular and molecular
pharmacology at Finch University of Health Sciences in Chicago.
Other researchers were more cautious, noting that addiction
is a complex process in humans because it is linked to learning and multiple
chemical pathways in the brain.
''It's not clear
to me that there's a separate molecular pathway that's going to be assignable
to drug abuse and not interfere with other learning,'' said Gary Aston-Jones of
the University of Pennsylvania School of Medicine.
The craving for
cocaine can be so powerful, a recovered addict who has avoided the drug for
years may start feeling his or her heart race just by seeing something
associated with drug use, such as a $100 bill or a familiar street corner,
Aston-Jones said.
''You want to
knock out the memory for the drug but you don't want to knock out the memory
for the way home,'' he said.
Steve Hyman,
director of the National Institute of Mental Health, said the study also
indicated the buildup of the Delta-FosB protein might be a factor with other
drugs, including amphetamine, morphine, heroin and nicotine.
''This is an important stepping stone but there is a long
road to travel,'' Hyman said.
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