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Methamphetamine Delivers One-Two Punch to the Brain

Mechanism may knock out brain’s ability to “just say no.”

UPTON, NY — A new brain-imaging study at the U.S. Department of Energy’s Brookhaven National Laboratory reveals that, compared with people who don’t use drugs, people who abuse methamphetamine have fewer receptors for dopamine, a brain chemical associated with feelings of reward and pleasure. Furthermore, in the drug abusers, low dopamine receptor levels were linked with reduced metabolic activity in a brain region that regulates motivation and “drive.”

“These findings mirror those from a similar Brookhaven study on cocaine abusers, and may help explain why drugs addicts lose control and take drugs compulsively,” said Nora Volkow, the lead researcher. The new results appear in the December issue of the American Journal of Psychiatry.

Abuse of methamphetamine — also known as “speed” or “crank” — has risen dramatically over the past decade in several areas of the United States and around the world. “It has become a significant public health problem,” said Volkow, whose team has worked for years to uncover the neurological mechanisms of addiction.

Previous imaging studies at Brookhaven and elsewhere have shown that a common abnormality in drug-addicted subjects — including alcoholics, cocaine abusers, and heroin abusers — is a lower-than-normal level of so-called dopamine D2 receptors. The Brookhaven scientists have also shown that, in cocaine abusers, dopamine D2 receptor levels are linked with lower metabolic activity in the orbitofrontal cortex of the brain.

“Disruption of the orbitofrontal cortex is associated with obsessive and compulsive behaviors,” Volkow said. “So we hypothesized that disruption of this brain region, resulting from depletion of dopamine receptors, could lead to compulsive cocaine intake.”

The Study

To find out if the same mechanism might be at work in methamphetamine abusers, the scientists measured dopamine D2 receptor levels and orbitofrontal cortex activity in 15 methamphetamine abusers — who were not taking drugs at the time of the study — and 20 non-drug-abusing comparison subjects.

To measure D2 receptor levels, each study volunteer was given an injection of a radiotracer, a radioactive chemical “tag” designed to bind to the D2 receptors in the brain. The researchers then scanned the subjects’ brains using a positron emission tomography (PET) camera. The PET camera picks up the radioactive signal of the tracer and shows where it is bound to receptors. The strength of the signal indicates the concentration of receptors.

To measure metabolic activity in the orbitofrontal cortex, a similar PET study was performed, this time using a radiotracer designed to bind to glucose, the brain’s metabolic “fuel.” Higher levels of glucose on PET scans indicate higher metabolic activity.

The Results

As hypothesized, the methamphetamine abusers had significantly lower levels of D2 receptors than the control subjects. And the lower the number of D2 receptors, the lower the metabolic activity in the orbitofrontal cortex.

The blunted orbitofrontal cortex activity in these drug abusers “reduces the ability of all other stimuli to trigger a reward response,” said Volkow. “Ordinary stimuli are not strong enough to activate the circuits.”

Administration of methamphetamine, however, releases such an enormous amount of dopamine, that all available dopamine receptors are activated, no matter how few there are. This very strong dopamine signal then becomes the only stimulus capable of boosting activity in the orbitofrontal cortex, Volkow said, making it very hard for the addict to resist the drug.

This work was funded by the U.S. Department of Energy, which supports basic research in a variety of scientific fields; the National Institute on Drug Abuse, part of the National Institutes of Health; and the Office of National Drug Control Policy.

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