ADHD transporter running backwards

Author:  Neil Majithia
Institution:  Virginia Commonwealth University
Date:  July 2008

A dysfunctional variant in the brain's dopamine transporters might be responsible for the hyperactive symptoms that characterize ADHD (Attention-deficit hyperactivity disorder), suggests a study conducted by Vanderbilt University. The findings, published last week in the Journal of Neuroscience, describe patterns of brain activity similar to those found in people who are taking amphetamine, or speed.'

ADHD is a common mental health disorder, affecting around 5 percent of school-age children in the United States. It is characterized by hyperactivity, forgetfulness, impulsivity, and general distractibility. Although the disorder can result from trauma or toxic exposure, there is also a strong genetic component involved, and it is this heritability that claimed the focus of the Vanderbilt team's investigation.

The team's work yielded two major results. The first was the discovery of a gene coding for a dopamine transporter that has an altered function in patients with ADHD. The second finding was that dopamine, a neurotransmitter involved in various neuropsychological signaling pathways, might play a role in the disorder.

The researchers found that the faulty transporter works backwards, pushing dopamine out of brain cells into the surrounding environment instead of bringing them into the cell, as they are designed to do. This behavior mimics the activity seen when the same transporters (of an individual without ADHD) are treated with amphetamine. Speed causes hyperactivity, paranoia, and psychosis.

"It's like these kids are on amphetamine all the time," said Aurelio Galli, an investigator working on the project.

Dopamine's role in attention, motor function, reward, and cognition has been well-established, and it has long been suspected to play some part in ADHD. In fact, many drugs currently administered to treat ADHD work by targeting dopamine receptors. Because the dopamine transporter is a key player in the dopamine signaling pathway, the Vanderbilt team initiated their study by carrying out an in-depth analysis of the dopamine transporter in patients with ADHD.

The first set of data did not suggest any suspicious differences in the transporters. Only when the investigators used a small carbon fiber to "listen in" on the transporter at work did they discover that dopamine was being pushed backwards out of the cell.

"We think this activity would short circuit the normal synaptic transmission process," said Randy Blakely, director of the Center for Molecular Neuroscience and lead author of the study. "Instead of the precise pop-pop-pop' of dopamine being released from vesicles (tiny packets of neurotransmitter), there's a cloud of dopamine bleeding out, and the dopamine signaling system is not as sharp as it should be. We believe that this is important evidence that ADHD can be caused by a functional deficit in the brain's dopamine signaling pathway."

Blakely's team also has a hunch that backwards-running transporters might be a more general phenomenon, involved in a variety of neuropsychological disorders. "Millions of patients have taken drugs that block transporter proteins, such as those that handle brain norepinephrine and serotonin, to treat anxiety and depression," Blakely said. "We used to think that the only thing these drugs could do is block uptake – now we wonder if reducing the backward leak of neurotransmitter is a key component of their utility."

Written by Neil Majithia

Reviewed by Falishia Sloan, Pooja Ghatalia

Published by Pooja Ghatalia.