Gene Therapy Reduces Drinking In "Alcoholic" Rats

"This is a preliminary study, but when you see a rat that chooses to drink 80 to 90 percent of its daily fluid as alcohol, and then three days later it's down to 20 percent, that's a dramatic drop in alcohol intake -- a very clear change in behavior," said Panayotis Thanos, the lead researcher. "This gives us great hope that we can refine this treatment for future clinical use."

The protein in question is the so-called D2 receptor for dopamine, a chemical that transmits brain signals necessary for experiencing feelings of pleasure and reward. Without receptors for dopamine, the signals get "jammed," and the pleasure response is blunted.

Previous studies have shown that alcohol abuse and other addictive drugs increase the brain's production of dopamine. But, over time, these drugs also deplete the brain's D2 receptors. This research has suggested that alcoholics increase their intake to try to override the blunted pleasure response, and that people with low levels of D2 receptors may be predisposed to alcohol abuse. These ideas led the Brookhaven researchers to hypothesize that increasing the level of D2 receptors might decrease alcohol intake.

The researchers tested this hypothesis in experimental rats by injecting a virus that had been rendered harmless and altered to carry the D2 receptor gene directly into the rats' brains. The idea behind this gene therapy is that the virus acts as a vector or mechanism to deliver the gene to the brain cells in the nucleus accumbens, the brain's pleasure center, so the cells can make the receptor protein themselves.

To see if the D2 receptor levels actually did increase, the scientists studied the brains of one group of rats using sophisticated imaging techniques. They used a radiotracer, a signal-emitting chemical designed to bind to the D2 receptor protein, then detected the signals in brain images called autoradiographs. The strength of the signals indicated that rats injected with the D2 gene did have higher levels of D2 receptors. The levels peaked three to four days after injection and gradually returned to near baseline after eight days.

Then the scientists examined how the injected genes affected the drinking behavior of rats that had been previously trained to self-administer alcohol. Rats that showed a preference for alcohol over water during training were analyzed separately from those that had no preference.

Among the rats that initially preferred alcohol, those that had received the D2 gene showed a 43 percent drop in their preference for alcohol and drank 64 percent less alcohol than rats that received only a placebo virus with no genes. Even the rats that initially had a low preference for alcohol showed significant reductions in both their preference for and intake of alcohol after treatment with the D2 gene.

"This is the first evidence that overproduction of D2 receptors reduces alcohol intake and suggests that high levels of D2 may be protective against alcohol abuse in humans," Thanos said.

The reduction in drinking preference and behavior in both groups was transient, with both measures returning to baseline levels by eight days after treatment. But a second treatment with the D2 genes produced the same dramatic effect.

"This is just a first step," said Thanos, who is working with Brookhaven biologist Paul Freimuth to produce a better gene-delivery system that will have a longer-lasting effect.

This work was funded by the National Institute for Alcohol Abuse and Alcoholism and the U.S. Department of Energy, which supports basic research in a variety of scientific fields.

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.