March 7, 2001
Treatment Blocks Environment-Triggered Craving
Treatment may help
diminish addicts' tendency to relapse
UPTON, N.Y. -- Anecdotal reports suggest that addicts crave drugs when they visit places where they've routinely used drugs. Now, a new study funded by the U.S. Department of Energy and conducted at Brookhaven National Laboratory shows that, in animals, such environmental cues trigger measurable increases in dopamine, a brain chemical closely linked with addiction. Even more important, lab scientists demonstrate that a therapeutic agent they've been studying as a potential treatment for addiction completely blocks this environmentally triggered increase in dopamine.
These findings extend the potential value of this therapeutic agent, known as GVG (or gamma-vinyl GABA), which the Brookhaven team has previously shown to be effective at blocking the neurochemical and behavioral effects of addictive drugs such as cocaine, nicotine, methamphetamine, and alcohol.
"This is the first therapeutic agent that successfully combats three major components of drug addiction -- the neurochemical and behavioral effects of the drug itself and the neurochemical changes triggered by drug-related environmental cues," says Stephen Dewey, the Brookhaven neuroanatomist who led the study. This research will be published in the March 7, 2001 issue of the European Journal of Pharmacology.
All addictive drugs elevate dopamine levels in the parts of the brain associated with reward and reinforcement. It is thought that this reinforcing effect is the primary biochemical explanation foraddiction. GVG indirectly depletes dopamine. It works by inhibiting an enzyme that normally breaks down gamma amino butyric acid (GABA), a dopamine-modulating enzyme. The resulting excess GABA breaks down the excess dopamine.
Previously, Dewey's group has shown that GVG can block drug-triggered increases in dopamine and drug-craving behavior in animals. But they wondered whether environmental cues, such as being in a drug-related environment, might trigger increases in dopamine in the absence of the drug. Both would provide a biochemical mechanism for craving, and another potential target for treatment by GVG.
To find out, they measured brain dopamine levels in laboratory rats that had been trained to expect cocaine in a given environment and rats that received no treatment and no cocaine (the controls). When the animals trained to expect cocaine later entered the "drug" environment, their dopamine levels increased by about 25 percent as compared to the controls, even when no cocaine was given. If cocaine-trained animals were first given GVG before entering the drug environment, however, their dopamine levels remained normal.
This demonstrates that environmental cues that lead to drug craving do trigger increases in dopamine, and that GVG can block this effect in addition to the direct biochemical effects of the drug. "No other drug has been tested as extensively for substance abuse treatment as GVG," says Dewey. "And no other drug has been tested for substance abuse treatment using these simultaneous biochemical and behavioral tests."
Dewey's proposed GVG treatment protocol was recently awarded U.S. Patent No. 6,057,368, based on previous animal studies. But before it can be implemented in this country, GVG must undergo clinical testing to ensure its safety and effectiveness for human use. Manufactured by the French company Aventis, GVG (also known as Sabril® or vigabatrin) is currently used for the treatment of epilepsy in children in more than 65 other countries, but it is not approved for use in the United States.
As noted, the current study was funded by the U.S. Department of Energy joined by the National Institute of Mental Health, part of the National Institutes of Health. It was done in collaboration with researchers from St. John's University, Albert Einstein College of Medicine, New York University School of Medicine, and Chirotech Technology Ltd.
The U.S. Department of Energy's Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies. Brookhaven also builds and operates major facilities available to university, industrial, and government scientists. The Laboratory is managed by Brookhaven Science Associates, a limited liability company founded by Stony Brook University and Battelle, a nonprofit applied science and technology organization.