Brain Buildup Causes Addiction
By WILLIAM McCALL
02:01 PM ET 09/15/99
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.
