High dopamine transporter levels not linked to attention-deficit hyperactivity disorder

Dec 2 2006

Results from a brain-imaging study conducted at the U.S. Department of Energy's Brookhaven National Laboratory in collaboration with Mount Sinai School of Medicine in New York indicate that levels of a brain protein proposed as a diagnostic marker for attention-deficit hyperactivity disorder (ADHD) are not positively correlated with the disease.

In fact, the study found lower levels of these "dopamine transporter" proteins in certain brain regions of ADHD patients compared with controls.

The study, which will be published in an upcoming issue of the journal Neuroimage and is now available online, also found that for any given level of dopamine transporters in the brain, ADHD patients experienced much higher levels of inattention compared with control subjects.

"These results suggest that dopamine transporter levels alone cannot account for the severity of symptoms of inattention in ADHD," said Nora Volkow, Director of the National Institute on Drug Abuse and the lead author of the study. Added Gene-Jack Wang, who led Brookhaven's role in the research, "It is clear from these results that clinical measures of dopamine transporters should not be used as a basis for a diagnosis of ADHD."

ADHD is the most frequently recognized psychiatric disorder in children, with some 3 million children younger than 18 currently receiving treatment in the U.S. Yet the mechanism underlying this disorder and its treatment are still poorly understood. One prominent theory of ADHD is that there is a dysfunction in brain circuits that depend on the neurotransmitter dopamine to modulate attention, motivation, and interest. If, for example, ADHD subjects have elevated levels of dopamine transporters — proteins on dopamine-producing cells that take up excess dopamine — they could end up with depleted dopamine levels and reduced motivation/attention.

Four independent studies have reported that ADHD subjects have higher than normal levels of dopamine transporters in a brain region called the striatum. But the magnitude of the increase has varied widely, ranging from 70 percent to 5 percent elevations in transporter levels. Two other studies found no elevation of transporter levels, though one found a decrease in dopamine transporter levels in a different brain region.

"Because these discrepancies could reflect differences in medication or drug-abuse histories among subjects, we designed the current study to investigate dopamine transporter levels in ADHD subjects and control subjects while excluding these potentially confounding factors," Wang said.

The researchers measured dopamine transporter levels in 20 adult ADHD subjects who had never received medication, never abused drugs (except nicotine), and had no past or present history of mental or neurological disease or other medical conditions that could affect cerebral function. They also asked subjects to respond to a questionnaire to gauge levels of inattention. The scientists ran the same tests in 25 healthy control subjects with the same exclusion criteria.

To measure dopamine transporter levels, each subject was given an injection of a radiotracer (a radioactively labeled chemical) designed to bind to dopamine transporters while lying in a positron emission tomography (PET) scanner. The PET camera picks up the radioactive signal from the tracer to precisely measure the level of dopamine transporters.

The PET scans revealed that ADHD subjects had significantly fewer dopamine transporters than control subjects in the nucleus accumbens, an area of the ventral striatum that is one of the main reward centers in the brain. In a dorsal striatum region known as the putamen, which plays an important role in habits and is also involved with attention, dopamine transporter levels did not differ between the two groups.

In both groups, levels of dopamine transporters in the putamen were positively associated with scores of inattention on the self-report questionnaire: the higher the level of transporters, the higher the score of inattention. This finding makes it clear that dopamine transporters play an important role in modulating attention in all people. Yet, for a given level of dopamine transporters, scores of inattention were, on average, five times greater for ADHD subjects than for controls in this study.

"These findings suggest that an additional variable in conjunction with dopamine transporters would be required to account for the severity of the symptoms of inattention in ADHD," Volkow said. "We speculate that this other variable may be lower levels of dopamine release in ADHD subjects."

If ADHD subjects release less dopamine to start with, they may end up with lower levels of dopamine transporters as a result of down regulation — that is, the body's attempt to compensate for lower dopamine levels by reducing the number of reuptake proteins. This would explain the positive correlation between transporter levels and inattention: as the number of reuptake proteins rises, the amount of dopamine would decline, leading to a higher level of inattention. This would also explain why control subjects, with higher dopamine release levels, had lower scores of inattention than did subjects with ADHD with similar levels of dopamine transporters.

Jeffrey Newcorn, a child and adolescent psychiatrist and lead collaborator from Mount Sinai, emphasized that ADHD is not a simple, one-type-fits-all disorder. There are very likely variations in dopamine transporter levels among and even within ADHD subgroups.

"The significant differences across studies and investigators clearly highlight the need to look for factors affecting these inconsistencies to improve our ability to diagnose and treat ADHD," he said. "Although levels of dopamine transporters alone do not determine whether an individual has ADHD, the association of inattention ratings and transporter levels in both ADHD and normal subjects is consistent with the use of treatments such as stimulant medications, which block activity of the transporter, in ADHD."

Ongoing research in adults with ADHD, currently being conducted at Brookhaven National Laboratory and Mount Sinai, is investigating the potential long-term impact of treatment with stimulants on the dopamine system.

This study was funded by the Office of Biological and Environmental Research within the U.S. Department of Energy's Office of Science and by the Intramural Research Program of the National Institutes of Health. DOE has a long-standing interest in brain-imaging studies. Brain-imaging techniques such as PET are a direct outgrowth of DOE's support of basic physics and chemistry research.