Variant of COMT gene linked to impulsive decisions

Dec 28 2007

People with clinical addictions know first-hand the ravages the disease can take on almost every aspect of their lives.

So why do they continue addictive behaviors, even after a period of peaceable abstinence?

Some answers appear rooted in regions of the brain active during decision making.

"It's perhaps not just that people are slaves to pleasure, but that they have trouble thinking through a decision," said Charlotte Boettiger, an assistant professor of psychology at the University of North Carolina at Chapel Hill, and lead author of a study in the December issue of the Journal of Neuroscience that took a novel tack in addiction imaging research.

"Our data suggest there may be a cognitive difference in people with addictions," Boettiger said. "Their brains may not fully process the long-term consequences of their choices. They may compute information less efficiently."

The study also found that a variant of the COMT gene, which controls the level of the neurotransmitter dopamine in the cortex, was associated with a tendency to make impulsive decisions and with high activity in certain brain areas during decision making.

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 dorsal prefrontal cortex and the parietal cortex often form cooperative circuits, and this study found that high activity in both is associated with a bias toward choosing immediate rewards.

The frontal and parietal cortex are also involved in working memory -- being able to hold data in mind over a short delay. When asked to choose between $18 now or $20 in a month, the subjects had to calculate how much that $18 (or what it could buy now) would be worth in a month and then compare it to $20 and decide whether it would be worth the wait.

The parietal cortex and the dorsal prefrontal cortex were much more active in people unwilling to wait. This could mean, Boettiger said, that the area is working less efficiently in those people.

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."

"It wasn't that long ago that we believed schizophrenia was caused by bad mothers and depression wasn't a disease. Hopefully, in 10 years, we'll look back and it will seem silly that we didn't think addiction was a disease, too."