ARTICLE IN BRIEF
Investigators reported that PET scans show that people with attention deficit-hyperactivity disorder have fewer dopamine receptors and dopamine transporters in the nucleus accumbens and the midbrain.
New evidence supports the theory that attention deficit-hyperactivity disorder (ADHD) is caused by abnormal chemical activity in the dopamine reward pathway of the brain. In a Sept. 9 paper in JAMA, investigators at Brookhaven National Laboratory in Upton, NY, reported that the brains of people with ADHD have fewer dopamine receptors and dopamine transporters in a cerebral region that regulates reward and motivation.
Fewer dopamine signals may make it harder for a person to see something as pleasurable and worth the effort (an intrinsic reward) to carry out the particular task, they said.
“These deficits in the brain's reward system may help explain clinical symptoms of ADHD, including the inattention and reduced motivation,” said Nora Volkow, MD, director of the NIH National Institute on Drug Abuse and a collaborator on the study. Dr. Volkow spent decades at the Long Island laboratory before moving to the NIH.
The mesoaccumbens dopamine pathway, which projects from the ventral tegmental area in the midbrain to the nucleus accumbens, is involved in reward and motivation and has been hypothesized to underlie the reward and motivational deficits observed in ADD, the study authors wrote. They noted that functional MRI studies have shown decreased accumbens activation with reward processing in people with ADHD. But no one had directly measured synaptic markers in the accumbens region of people with ADHD.
So the investigators set out to do just that. In the years 2000-2007, they conducted PET scans on 53 adults with ADHD who had never taken stimulants and had no history of drug abuse, as well as 44 healthy controls with no history of ADHD or drug abuse.
One PET ligand was used to measure dopamine receptors and the other tracked dopamine transporters. They found clear differences in the brains of people with ADHD and controls without symptoms. In the nucleus accumbens and the midbrain, those with ADD had much lower levels of both dopamine receptors — D2/D3 receptor — and dopamine transporters (DAT).
What connection would the lowered dopamine levels have to ADHD symptoms? The theory is that ADD patients respond abnormally to reward processing. The nucleus accumbens and the midbrain are pathways where learning is paired with various rewards, that is, people expect a sense of reward at the end of the behavior. But if there is a deficit in this system — not enough receptors or transporters — the person doesn't learn that a given act will have a motivating consequence. There is insufficient dopamine to pair a response to a reward.
The lower than normal [availability of] D2/D3 receptors and DAT in the accumbens and midbrain supports the hypothesis of an impairment of the dopamine reward pathway in ADHD, the investigators wrote.
Stimulants shift the balance and offer up more dopamine receptors and transporters, according to study co-author Gene-Jack Wang, MD, who is chairman of the Brookhaven medical department. Dr. Wang said that the finding could explain why people with ADHD are also more prone to drug use and overeating — two behaviors that also increase dopamine in the reward pathway. Dr. Wang and his colleagues have conducted studies with drug users and obese people that show that their addictive behavior may in fact be a strategy to compensate for the lack of dopamine in the brain by ramping up the brain's D2 system with drugs or food. Many scientists are working on ways to fix the abnormal reward system.
Dr. Wang said that it was important to conduct the studies on large groups of ADD patients who had not been treated with stimulants. Earlier this year, they reported preliminary results at a meeting of the Society for Nuclear Medicine showing that there is an upregulation of dopamine transporters when they give stimulants to their study volunteers with ADD. “We have no idea what happens to the D2 receptor density when people receive stimulants,” said Dr. Wang.
“This [NEJM] paper is a tour de force,” said F. Xavier Castellanos, MD, the Brooke and Daniel Neidich Professor of Child and Adolescent Psychiatry and director of the Phyllis Green and Randolph Cowen Institute for Pediatric Neuroscience at the New York University Child Study Center.
“There has been a theory that dopamine transporters are increased in ADHD,” Dr. Castellanos said. “The initial 1999 report in The Lancet had six patients and a large effect size. Subsequent papers failed to confirm this finding or reported much smaller effects. This study reports the opposite result with a much larger sample size and more reliable methods. The bottom line is that it confirms an important role for dopamine deficiencies in a specific circuit that we have all suspected for some time.”
• Volkow ND, Wang G-J, Kollins SH, et al. Evaluating Dopamine Reward Pathway in ADHD. JAMA
• Dougherty DD, Bonab AA, Fischman AJ, et al. Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet
Castellanos FX. Toward the dimensionome: Parsing reward-related processing in attention-deficit/hyperactivity disorder. Biol Psychiatry