||NIDA News Release
|FOR RELEASE, September 15, 1999
||Contact: Beverly Jackson|
Scientists Identify Brain Chemicals Involved in
"Switching On" Cocaine Addiction
Scientists supported by the National Institute on Drug Abuse (NIDA)
have identified two chemicals in the brains of mice that appear to play a
major role in the addiction process. Their study appears in the September
16 issue of Nature.
Cocaine users may take the drug anywhere from several times to several
years before they become addicted. However, at a certain point, their use
becomes compulsive and they have great difficulty quitting.
Determining what happens in the brain at this point has been a major
goal for scientists seeking to understand the mechanisms of cocaine
"It seems that prolonged drug use eventually causes a 'switch' to be
thrown in the brain, symbolizing the onset of addiction," says NIDA
Director Dr. Alan I. Leshner. "With this new research, we are beginning to
understand exactly what that switch is and how it works, and this should
help us develop medications to turn the switch off."
One component of the switch appears to be the activation of a gene that
codes for the production of a protein called delta-FosB. Researchers have
known for several years that prolonged administration of cocaine or other
drugs of abuse increases the production of this protein in the nucleus
accumbens, an area important for the perception of pleasure. They also
knew that delta-FosB belongs to a class of chemicals that turn on other
genes. However, which genes delta-FosB was activating and how this
contributed to addiction was a mystery.
To learn more about the role of delta-FosB in the addiction process,
researchers at Yale University, Harvard Medical School, and Northwestern
University developed mice with an extra delta-FosB gene that, when
activated, produced large quantities of the chemical in the nucleus
accumbens. They figured that studying the effects of high delta-FosB
levels on the animals' responses to cocaine would shed light on its role
in cocaine's effects and why long-term cocaine administration increases
production of this protein.
The researchers found that adding the extra delta-FosB gene caused the
mice to become more sensitive to the pleasurable, or rewarding, effects of
cocaine, a change that is thought to play an important role in the
development of cocaine craving and addiction. This suggested that the
increase in delta-FosB levels that occurs during long-term cocaine
administration may be at least partially responsible for the increase in
But how does delta-FosB make cocaine more rewarding? The researchers
speculated that delta-FosB might be activating one of the genes that
produces components, or subunits, of brain chemicals called glutamate
receptors. Glutamate is one of the compounds that carries messages among
neurons (nerve cells) in the brain. After being released by certain
neurons, glutamate binds to glutamate receptors on the surface of
receiving neurons, thereby affecting their activity, which in turn affects
brain function. Studies have suggested that changes in glutamate
receptors, perhaps involving changes in individual components or subunits
of the receptors, may be important in cocaine addiction.
The scientists found that switching on the delta-FosB gene increased
the production of one glutamate receptor subunit designated GluR2.
Furthermore, this increase occurred specifically in the nucleus accumbens.
To determine whether an increase in GluR2 production might increase
sensitivity to cocaine reward, the researchers used viral vectors to
transfer a GluR2 gene directly into the nucleus accumbens of one group of
mice, which increased GluR2 production in this region. For comparison,
they also transferred genes for other glutamate receptor subunits and
other proteins into other groups of mice.
They found that inserting the GluR2 gene but not the other genes
dramatically enhanced sensitivity to cocaine reward. This suggested that
changes in glutamate receptors in the nucleus accumbens may be the second
component in the addiction switch. The next step, according to the
scientists, is to determine how these changes lead to the abnormal brain
responses to cocaine that constitute addiction.
Note: The full text of the paper, "Expression
of the Transcription Factor delta-FosB in the Brain Controls Sensitivity
to Cocaine," can be found in Nature, Volume 401, Number 6750,
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