Credit: Brookhaven National Laboratory
Brain fix: In previous studies, a gene therapy that cuts alcoholic behavior in rats proved to increase dopamine receptors in part of the brain (left) compared to non-treated parts (right)
Gene therapy has been shown to reduce alcohol consumption in "alcoholic" rats, a finding that could help treat drug and alcohol addiction in humans.

As a follow up to previous work showing that gene therapy can reduce drinking in rats trained to prefer alcohol, researcher Panayotis Thanos at Brookhaven National Laboratory in Uptown, New York used the same technique to cut drinking in rats genetically engineered to prefer alcohol.

"Though we are still early in the process, these results improve our understanding of the mechanism or mechanisms of alcohol addiction and strengthen our hope that this treatment approach might one day help people addicted to alcohol," says Thanos.

Dopamine delivery

Alcoholism is a chronic disease with genetic, psychological and environmental factors influencing its development and manifestation.

Gene therapy is an approach to preventing or treating disease by inserting genes into a person's DNA, usually to replace or influence defective genes.

A carrier molecule called a vector—usually a disabled virus into which DNA is packaged—is used to deliver therapeutic genes to target cells.

In a previous study, Thanos used gene therapy to boost the number of brain receptors for dopamine.

Dopamine, a neurotransmitter that's important for feelings of pleasure and reward, is known to play a role in addiction.

Researchers have hypothesized that people with low levels of a dopamine receptor called D2 may be predisposed to alcohol abuse.

Thanos found that overproduction of D2 receptors reduces alcohol intake, suggesting that having lots of D2 receptors might have a protective effect in humans.

Genetic predisposition

In the current study, Thanos used rats genetically predisposed to prefer alcohol.

These rats are better models for human alcoholism than rats trained to drink, says Thanos.

Without any training, the engineered alcohol-preferring rats drank, on average, more than five grams of alcohol per kilogram of body weight per day when given a choice between alcohol and water.

Rats not engineered to prefer alcohol, in contrast, typically consume less than one gram of alcohol per kilogram of body weight per day.

Both groups of rats were treated with gene therapy to increase D2 receptor levels.

Thanos and colleagues first inserted the gene into a harmless virus, and then injected the virus into the rats' brain pleasure center, the nucleus accumbens.

After treatment, the alcohol-preferring rats exhibited a 37% reduction in their preference for alcohol and cut their total alcohol consumption in half.

The other rats also reduced their drinking preference and intake after gene treatment, but not nearly as much.

As an additional measure, the researchers used positron emission tomography—a scanning mechanism that provides images of the brain's activity—to assess the effects of chronic alcohol consumption on D2 receptor levels in alcohol-preferring and non-preferring rats.

They measured D2 levels seven weeks after the gene therapy treatment and found that D2 receptor levels in alcohol-preferring rats were about 16% lower than in non-preferring rats.

Protective factor

Next, Thanos and colleagues plan to examine the D2 connection using transgenic mice that have no D2 receptors.

In addition, they plan to develop a second generation D2 vector approach that will provide a longer period of treatment.

"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," says Thanos.

The research is reported in the journal Alcoholism: Clinical and Experimental Research.