COCAINE FOUND TOUGHER TO KICK AFTER PROTEIN BUILDS UP

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 today 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."

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.

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.