12/11/2009 - Researchers at Vanderbilt University Medical Center have found evidence that genetic variations affecting three different brain chemicals may contribute to the three types of attention-deficit hyperactivity disorder (ADHD).
The researchers previously have found a link between a variant of the norepinephrine transporter gene and the predominantly “inattentive” type of ADHD, and a link between a variant in the dopamine transporter gene and the predominantly “hyperactive and impulsive” type.Now, in this month's Journal of Neurodevelopmental Disorders, Randy Blakely, Ph.D., and colleagues report that a variation in the choline transporter gene is associated with the “combined” type, characterized by both inattention and hyperactivity/impul-sivity.
Choline is the precursor to acetylcholine, which, along with norepinephrine and dopamine, transmits messages across the synapse, or gap between nerve cells. Transporters regulate the supply of these and other brain chemicals in the synaptic gap to ensure proper signaling.
“Our findings raise the question as to whether the three subtypes of ADHD derive from deficits in three distinct chemical signals in the brain,” said Blakely, director of the Vanderbilt Center for Molecular Neuroscience.
“They do suggest that going forward, we might target (the chemicals) individually depending on the subtype of ADHD the individual has,” he said.
Hyperactivity is often treated with drugs like Ritalin, which are thought to act primarily by blocking the dopamine transporter to increase the supply of dopamine in the synapse.
A newer ADHD drug that blocks the norepinephrine transporter, Strattera, seems to be particularly good at improving attention.
Currently there's no FDA-approved drug that targets the acetylcholine pathway and which has been shown to be effective in treating ADHD, but Blakely said he and Alicia Ruggiero, Ph.D., instructor in Pharmacology, are developing choline transporter-targeted agents that could lead to new medications.
In the meantime, he discouraged parents from “genotyping” their children with ADHD to find out if they have a genetic variation in the dopamine, norepinephrine or choline transporter.
“We still have work to do to see if genotyping ADHD subjects can accurately predict disease subtypes,” Blakely said. “These are complex disorders, and I'm sure that (genetic variation) is only one of the risk factors that these kids may have.”
Environmental influences also may play a role. For example, prenatal exposure to nicotine, cocaine and environmental pollutants has been implicated in the later development of ADHD, and chronic sleep deprivation paradoxically produces hyperactivity in children.
Nevertheless, the latest genetic finding is significant, as it is the first reported association between choline transporter function and a brain disorder, Blakely said. “It's a bit of a foot in the door,” he added, “but we hope it's a big foot.”
Brett English, graduate student in Pharmacology, is the paper's first author.
Other co-authors: Maureen Hahn, Ph.D., Michelle Mazei-Robison, Ph.D., Angela Steele and Daniel Kurnik, M.D., all from Vanderbilt; Ian Gizer, Ph.D., from the University of North Carolina at Chapel Hill; Mark Stein, Ph.D., from the University of Illinois at Chicago; and Irwin Waldman, Ph.D., from Emory University.©2014 Vanderbilt University Medical Center