Sep. 16, 1999 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 addiction.
"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 cocaine reward.
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, Pages 272-276.
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