Vol. 10, No. 3, 2004 Page 6

Gene therapy reduces craving for drink in 'alcoholic' rats

Researchers at Brookhaven National Laboratory report that gene therapy markedly reduces alcohol consumption in rats bred to desire large amounts of ethanol.

Panayotis Thanos and colleagues worked with two groups of rats: a normal control group, and a group genetically engineered to exhibit a strong preference for alcohol. The rats bred to prefer alcohol drank more than five grams of ethanol per kilogram of body weight per day when allowed to choose between alcohol and water, while the control rats consumed less than one gram of ethanol under the same circumstances.

Thanos et al. treated both groups of rats by inserting the gene for the dopamine D2 receptor (DRD2) into a harmless virus and then injecting it directly into the rats' nucleus accumbens. The nucleus accumbens is a key part of the brain's "reward" circuitry, and releases large amounts of dopamine—a neurotransmitter that transmits feelings of pleasure and plays a strong role in addiction—in response to alcohol ingestion.

The researchers report that following the gene insertion, the alcohol-preferring rats cut their total alcohol consumption in half, and exhibited a 37 percent reduction in their preference for alcohol over water. The control rats also reduced their alcohol consumption and preference, but to a much smaller degree. The changes were temporary, with the rats returning to their previous consumption levels by the 20th day after gene insertion.

"These findings further support our hypothesis that high levels of D2 are causally associated with a reduction in alcohol drinking, and may serve as a protective factor against alcoholism," the researchers say.

Many scientists believe that low levels of dopamine can lead directly or indirectly to "reward deficiency syndrome," in which individuals are biochemically incapable of achieving adequate levels of pleasure from normal activities and thus are vulnerable to alcoholism or drug addiction. The genetically altered rats studied by Thanos and colleagues have 20 to 25 percent fewer dopamine D2 receptors than normal rats; in future studies, Thanos et al. plan to investigate the effects of completely depleting D2 receptors in mice.


"DRD2 gene transfer into the nucleus accumbens core of the alcohol preferring and nonpreferring rats attenuates alcohol drinking," P. K. Thanos, N. B. Taintor, S. N. Rivera, H. Umegaki, H. Ikari, G. Roth, D. K. Ingram, R. Hitzemann, J. S. Fowler, S. J. Gatley, G. J. Wang, and N. D. Volkow, Alcoholism Clinical and Experimental Research, Vol. 28, No. 5, May 2004, 720-8.

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"Gene therapy reduces drinking in rats with genetic predisposition to 'alcoholism,'" news release, Brookhaven National Laboratory, May 5, 2004.

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