May 10, 2004
Dopamine Receptor Gene Therapy Decreases Rat Alcohol Cravings

Gene therapy that delivered dopamine D2 receptor genes into rats decreased their desire for alcohol.

As a follow up to previous work showing that gene therapy can reduce drinking in rats trained to prefer alcohol, scientists at the U.S. Department of Energy's Brookhaven National Laboratory have used the same technique to cut drinking in rats with a genetic predisposition for heavy alcohol consumption. The findings, along with additional results on the effects of long-term ethanol consumption on certain aspects of brain chemistry, are published in the May 2004 issue of Alcoholism Clinical and Experimental Research.

"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," said Panayotis (Peter) Thanos, who lead the study in Brookhaven Lab's medical department.

The method of gene therapy used apparently did not allow delivery of genes to locations in cells that protected the genes from being broken down. The gene therapy was not long-lasting. But surely more lasting methods of delivering gene therapy will be developed.

Genetically predisposed alcohol-preferring rats are a much better model for human alcoholism than the rats used previously, which the scientists had to train to prefer alcohol. Without any training, the genetic alcohol-preferring rats drink, on average, more than five grams of ethanol per kilogram of body weight per day when given a free choice between alcohol and plain water. Genetically non-preferring rats, in contrast, typically consume less than one gram of ethanol per kilogram of body weight per day.

In this study, both groups were treated with gene transfer to increase the level of a brain receptor for dopamine, a chemical important for transmitting feelings of pleasure and reward and known to play a role in addiction. After the gene treatment, the alcohol-preferring rats exhibited a 37 percent reduction in their preference for alcohol and cut their total alcohol consumption in half -- from 2.7 grams per kilogram of body weight before treatment to 1.3g/kg after. Non-preferring rats also reduced their drinking preference and intake after gene treatment, but not in nearly as dramatic a fashion. The greatest reductions in alcohol preference and consumption were observed within the first few days after gene treatment, and both preference and consumption returned to pre-treatment levels by day 20.

The gene administered was for the dopamine D2 receptor, a protein shown in various studies to be relevant to alcohol and drug abuse. For example, low levels of dopamine D2 receptors in the brain have been postulated to lead to a reward deficiency syndrome that predisposes certain people to addictive behaviors, including drug and alcohol abuse. The alcohol-preferring rats used in this study have about 20-25 percent lower levels of dopamine D2 receptors when compared to the non-preferring rats, which may, in part, explain their tendency toward heavy drinking.

The scientists delivered the gene by first inserting it into a virus that had been rendered harmless. They then injected the virus directly into the rats' nucleus accumbens, the brain's pleasure center. The idea behind this type of gene therapy is to use the virus as a vector to carry the gene to the brain cells, which can then use the genetic instructions to make the D2 receptor protein themselves.

As an additional measure in this study, the scientists used micro-positron emission tomography (microPET) imaging to non-invasively 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 (well after the effects of gene therapy had worn off). D2 receptor levels in alcohol-preferring rats were significantly lower (about 16 percent) compared to that in non-preferring rats. These levels were similar to previous data in nave preferring and non-preferring rats.

Other research is suggestive of the idea that gene therapy that boosts D2 dopamine receptor levels will reduce human cravings for drugs other than alcohol. For instance, one study found a negative correlation between D2 dopamine receptor concentrations and "drug-liking" to intravenous methylphenidate.

The development of gene therapy to alter dopamine receptor levels in humans would open up the possibility of personality engineering. A version of the dopamine receptor D4 is correlated with both extraversion and a tendency to abuse drugs. Will some people opt to modify their personalities to be more outgoing but at the risk of becoming more prone to become drug addicts? Dopamine receptor activity is also tied to novelty-seeking behavior and also thrill-seeking behavior. If gene therapy could be selectively targetted to up dopamine receptor concentration only in specific parts of the brain and if gene therapy could deliver different genetic variants of genes for each receptor then lasting personality modification and behavior modification become real possibilities.

Many personality-altering treatments will be developed first to treat mental illnesses, drug addictions, and other severe mental problems. But then once the treatments are available it is inevitable that people who do not have obvious mental problems will choose to use them as well.

Share |      Randall Parker, 2004 May 10 03:49 PM  Brain Addiction

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