Treating alcoholics, one at a time - The Rockefeller University Scientist

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Treating alcoholics, one at a time

The latest study from the Kreek lab suggests that new addiction treatments can be custom-tailored to individuals

BY JOSEPH BONNER

Mary Jeanne Kreek has a hypothesis about alcohol addiction: alcohol abusers are forever chasing the “good feeling” that non-alcoholics get from drinking a single drink. Studies have shown that the alcohol-dependence treatment naltrexone may mimic this good feeling by activating part of the stress responsive system, and thus reduce the craving for that second and third drink that alcoholics seek. Now, new research may explain why some alcohol abusers do better with naltrexone than others.

The key lies in a gene variant, or single nucleotide polymorphism (SNP), of the much studied mu opioid receptor gene, called A118G. In 1998, Kreek’s lab identified A118G, as well as four other SNPs of the coding region of the mu opioid receptor gene. Each SNP derives from a single difference in how the building blocks of DNA pair with one another. Some of these differences may change the gene’s protein products in ways that may confer susceptibility — or protection — against diseases.

In the new study, published in Neuropsychopharmacology, Kreek and first author Gavin Bart, director of clinical research in Kreek’s lab, obtained DNA samples from 539 people living in central Sweden: 389 were dependent on alcohol, the remainder were healthy volunteers. The researchers chose central Sweden because this population has had a limited influx of non-Swedish immigrants and therefore has remained genetically stable for the last several hundred years.

In collaboration with Jürg Ott, head of the Laboratory of Statistical Genetics, the scientists embarked on a molecular and statistical analysis of the DNA samples from the alcohol-dependent and control groups to calculate the attributable risk of A118G in developing alcoholism. Attributable risk estimates the extent to which a disease can be explained by having a specific SNP, in this case A118G.

What Ott found was surprising: the attributable risk for A118G in this population was 11 percent. A similar study by the Kreek and Ott labs of heroin addicts in central Sweden published last summer in Molecular Psychiatry showed that the attributable risk with the A118G variant for developing heroin addiction was 21 percent for people with two Swedish parents and 18 percent overall.

“Together, these two findings may indicate that the A118G variant contributes to a common susceptibility for developing two different addictive diseases,” says Kreek. “This makes sense because all addictions probably share some genetic load, but also have unique variants.”

This human genetic research has implications for developing new, customized treatments that target these unique variants. “We know that if a person drinks a shot, the levels of certain stress hormones in the HPA axis — the body’s fight or flight center — increase,” says Kreek. “In chronic alcoholics, this increase is lost. We hypothesize that alcoholics are chasing that increase in stress hormones, so they keep drinking in an attempt to get it.”

Kreek cites a study she performed in collaboration with Stephanie O’Malley at Yale University that shows naltrexone, which can reduce the urge to drink alcohol in some patients, mimics alcohol’s activation of the HPA axis. Kreek and Bart believe this effect may explain why patients with the A118G SNP may respond better to naltrexone treatments than people without this SNP.

November 19, 2004

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