





Current medications for addictions are not universally effective; many either mimic the addictive substance to help people get through withdrawal periods or block the substance to prevent its effects. For stimulants, such as methamphetamines, there are no therapies yet, Boettiger said.

"What's exciting about this study is that it suggests a new approach to therapy. We might prescribe medications, such as those used to treat Parkinson's or early Alzheimer's disease, or tailor cognitive therapy to improve executive function," said Boettiger, who led the study as scientist at the University of California, San Francisco's Gallo Clinic and Research Center.

"I am very excited about these results because of their clinical implications," said Dr. Howard Fields, a professor of neurology at UCSF and an investigator in the Gallo Center.

"The genetic findings raise the hopeful possibility that treatments aimed at raising dopamine levels could be effective treatments for some individuals with addictive disorders," said Fields, who is senior author of the study.

Most addiction imaging studies have focused on the brain response to drug-related stimuli.

Boettiger used functional magnetic resonance imaging (fMRI), which shows brain activity while a subject performs a function, to see what happened inside their heads when sober alcoholics and people in a non-alcoholic control group made decisions between immediate and delayed rewards.

Boettiger recruited 24 subjects; 19 provided fMRI data, nine were recovering alcoholics in abstinence and 10 had no history of substance abuse. Another five were included in the genotyping analysis.

At the fMRI research facility at the University of California, Berkeley, the subjects were asked to decide between receiving a small monetary award immediately or wait for a larger payoff. The scenarios were hypothetical, but the tasks measured rational thinking and impulsivity; sober alcoholics chose the "now" reward almost three times more often than the control group, reflecting more impulsive behavior.

While decisions were being made the imaging detected activity the predicted individual choice in regions associated with decision making -- the posterior parietal cortex, the dorsal prefrontal cortex, the anterior temporal lobe and the orbital frontal cortex.

People who sustain damage to the orbital frontal cortex generally suffer impaired judgment; they manage money poorly and act impulsively. Boettiger's study revealed reduced activity in the orbital frontal cortex in the brains of subjects who preferred "now"over "later," most of whom had a history of alcoholism.

The orbital frontal cortex activity may be a neural equivalent of long-term consequences. "Think of the orbital frontal cortex as the brakes," Boettiger said. "With the brakes on, people choose for the future; without the brakes they choose for the short-term gain."




The COMT gene has two common variants with a single amino acid difference at position 158; valine (Val) or methionine. The Val form of the gene is associated with lower dopamine levels, and Boettiger's study showed that people with two copies of the Val allele (resulting in the lowest dopamine levels) had significantly higher frontal and parietal activity and chose now over later significantly more often.

"We have a lot to learn," Boettiger said. But the data take a significant step toward being able to identify subtypes of alcoholics, which could help tailor treatments, and may people who are at risk for developing addictions and provide earlier intervention.

The bigger picture, Boettiger said, is that her study provides more evidence that addiction is a disease, something even some of her peers do not yet believe.

"It's not unlike chronic diseases, such as diabetes," she said. "There are underlying genetic and other biological factors, but the disease is triggered by the choices people make."
