Brain scans may become an effective way of testing whether a drug designed for attention-deficit disorder can raise dopamine levels, according to research at the Washington University School of Medicine in St. Louis.

In a previous mouse study, the same group discovered that by raising dopamine levels they could improve attention problems caused by neurofibromatosis type 1 (NF1), a disorder that affects more than 100,000 people in the United States. About 60 to 80 percent of children with NF1 have some sort of attention deficit.

“Many kids with NF1 really struggle in school, and finding ways to help alleviate attention problems is a high priority,” says David H. Gutmann, MD, PhD and Donald O. Schnuck Family Professor of Neurology. “The technique we’ve refined may make it possible to match specific treatments to the patients with NF1 and attention deficit who are most likely to benefit from those treatments.”

Symptoms of NF1 attention deficits are similar to other types of attention deficit disorders. It’s unclear, however, whether the brain differences that trigger these issues in children with NF1 are the same brain changes that underlie attention deficits in the general population.

“This mouse model may not be a perfect model for all forms of attention deficit, but it is a terrific model for one type of attention system dysfunction,” Gutmann says. “Greater understanding of what goes wrong in some children with NF1 could lead to new insights into a broader variety of attention problems.”

Gutmann, director of the Washington University Neurofibromatosis (NF) Center, and his team genetically engineered mice to develop NF1 attention problems and brain tumors.

Last year, Gutmann demonstrated that one of these strands of mice had lower levels of dopamine in part of the brain. After treating these mice with Ritalin, their dopamine levels and their attention deficits went back to normal.

“Prior to our study, there was no molecular basis for using Ritalin to treat children with NF1 and attention deficits, so its use depended on the pediatrician’s practice, the severity of the attention deficit and how comfortable the parents were with the use of medication,” Gutmann says. “In general, only the most severely affected kids are being treated, but that may change in the future.”

For the current study, Gutmann joined forces with Robert Mach, PhD, professor of radiology, who had been working with raclopride, an imaging agent that binds to dopamine receptors in the brain. Raclopride can be detected by positron emission tomography (PET) scans.

Jinbin Xu, PhD, research instructor in radiology, used raclopride to evaluate dopamine levels in untreated mice and discovered that lower levels of brain dopamine allowed for better raclopride binding, creating a stronger PET image. After Ritalin treatment, the raclopride binding decreased.

“This finding suggested that raclopride PET imaging could be used as a platform for preclinical testing of drugs that may affect brain dopamine levels,” Gutmann says. “We can get an image in an hour and assess the effects of the drug on mouse behavior in a day.”

“At some point, we envision a prescreening process that identifies children with reduced dopamine levels most likely to respond to Ritalin or other medications,” Gutmann says. “As we learn more about the different ways attention deficits arise in these children, it may be possible to use the prescreening data and preclinical drug tests in mouse models to select the best drug for each patient.”

Source: Washington University in St. Louis

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