BRAIN BUILDUP CAUSES ADDICTION

by
WILLIAM McCALL

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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