Scientists at the U.S. Department of Energy's Brookhaven National Laboratory report in the current Journal of Neurochemistry (Volume 78, Number 5) that they used gene therapy techniques to increase levels of dopamine D2 (DRD2) receptors and reduce drinking in rats previously trained to self-administer alcohol. Panayotis Thanos, Ph.D., Nora Volkow, Ph.D., and colleagues used a partially inactivated virus as a vector, or transport agent, to carry copies of the DRD2 gene to the rat nucleus accumbens, the brain area associated with the reinforcing effects of alcohol. Supplying copies of the gene in this manner enables the rat brain cells to manufacture larger amounts of DRD2 receptors than they would ordinarily. Strong evidence from pharmacologic studies in both humans and animals indicates that the dopamine pathway plays a major role in brain reward circuits, the function of which is altered by addiction. Whereas a drink of alcohol increases immediate brain production of dopamine (a chemical messenger, or neurotransmitter, involved in locomotion, alcohol reward, and the compulsion to drink) chronic drinking has been associated with decreased dopamine activity in rodents and with low levels of dopamine and its metabolites in humans. In 1996, Dr. Volkow and others showed that DRD2 receptors are depleted in human alcoholics. Whereas behavioral effects of this depletion are unclear, Drs. Thanos and Volkow hypothesize that DRD2 depletion produces a blunted pleasure response that leads alcoholics to increase their intake.
The research team performed two experiments for the current study-one to evaluate the rats' DRD2 receptor levels and one to evaluate drinking behavior at different time points following the DRD2 gene injection. To determine whether receptor levels had increased, they used a signal-emitting system designed to bind to the receptors and detected the signals in brain images known as autoradiographs. The strength of the signals indicated that rats injected with the DRD2 gene had higher receptor levels than previously and than controls. The levels peaked three to four days after injection and returned to near baseline after eight days.
Dr. Thanos and his colleagues then analyzed the drinking behavior of injected rats of two types: rats with a high alcohol preference that drank 80 to 90 percent of daily fluids as alcohol, and rats with low alcohol preference that drank 10 percent of daily fluids as alcohol. After the gene injection, the high alcohol preference rats showed a 43 percent drop in alcohol preference and drank 64 percent less alcohol than rats that received a placebo virus. Low alcohol preference rats also showed a significant drop in both alcohol preference and alcohol intake following treatment with the D2 gene.
"This is the first evidence that overproduction of D2 receptors reduces alcohol intake and suggests that increasing levels of DRD2 may protect against alcohol abuse in humans," Dr. Thanos said. "Although the reduction in drinking behavior in both groups was transient, repeating the DRD2 treatment produced the same dramatic effect." With other Brookhaven researchers, Dr. Thanos is working to develop an improved gene-delivery system that will produce a longer-lasting effect.
"Drs. Thanos and Volkow have used an imaginative approach to investigate the role of DRD2 receptors in alcohol consumption," said NIAAA Director Enoch Gordis, M.D. "Theirs is an important step in continuing work to form the scientific basis of new medications for use in alcoholism treatment."
The National Institute on Alcohol Abuse and Alcoholism, a component of the National Institutes of Health, U.S. Department of Health and Human Services, conducts and supports approximately 90 percent of U.S. research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems and disseminates research findings to science, practitioner, policy making, and general audiences.
The above story is based on materials provided by NIH/National Institute On Alcohol Abuse And Alcoholism. Note: Materials may be edited for content and length.
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