The findings are reported in the January 15 issue of the Journal of Neuroscience by researchers from the U.S. Department of Energy's Brookhaven National Laboratory. The publication can be found on the Web at http://www.jneurosci.org/cgi/content/full/20014896.

Although Ritalin has been used for more than 40 years as a successful treatment for ADHD, minimal information has been gathered to date on exactly how the drug works in the brain, outside of limited animal studies. This latest study, on humans, indicates that Ritalin significantly increases levels of dopamine in the brain, thereby stimulating attention and motivational circuits that enhance one's ability to focus and complete tasks.

"For the first time, we are seeing that Ritalin given at doses commonly used to treat children with ADHD significantly increases levels of dopamine in the brain," said psychiatrist Nora Volkow, head of the research team and Associate Laboratory Director for Life Sciences at Brookhaven Lab. "This combination - the ability to increase motivation and also directly activate circuits of attention - is likely to be key to the beneficial effects of Ritalin."

Earlier animal and limited human studies had indicated that Ritalin interferes with the recycling of dopamine within the brain by blocking dopamine transporters. However, since these earlier studies involved injection of much higher doses of Ritalin, it was unclear whether the drug would increase extracellular dopamine at doses used therapeutically for children.

Using a technique called positron emission tomography, or PET, researchers at Brookhaven's Center for Imaging and Neurosciences studied dopamine levels in 11 male subjects. In two sessions, the volunteers were each given a dose of Ritalin, calculated using their body weight to correspond to the doses given to children with ADHD, or a placebo. While their brains were scanned to record dopamine levels, the subjects were asked to rate their feeling of restlessness and "high." Meanwhile, physicians monitored each subject's blood pressure and heart rate.

The results showed that brain dopamine levels increased significantly approximately 60 minutes following ingestion of the drug as compared to the placebo. "We now know that by increasing the levels of extracellular dopamine, you can activate these motivational circuits and make the tasks that children are performing seem much more exciting," said Volkow. "By raising that level of interest, you can significantly increase the ability of the child to focus on the task."

Volkow added that Ritalin also works to suppress "background" firing of neurons not associated with task performance, allowing the brain to transmit a clearer signal. "Random activation of other cells can distract you, and children with ADHD are easily distracted," she said. "Ritalin suppresses that background firing and accentuates the specific activation, basically increasing the signal-to-noise ratio and increasing a child's ability to focus."

Volkow is now planning a follow-up study of subjects suffering from ADHD. "We hypothesize that we will find that ADHD sufferers have decreased function of dopamine circuits and are therefore easily distracted," she said. "The effect of Ritalin should be to normalize these levels, allowing them to focus and pay attention."

The findings also have important implications for another research area - understanding why Ritalin, which is chemically quite similar to highly addictive cocaine, is not addictive when taken in pill form. One thing in common with all drugs of abuse is that they increase dopamine levels. Since oral doses of Ritalin do not produce a "high," the Brookhaven researchers did not expect to see a significant increase in dopamine levels. Since they did see a significant increase, Volkow postulates that another factor is at work.

"We've found that for drugs of abuse to be effective, they must get into the brain very quickly, and for that reason, when injected, Ritalin can become addictive," she said. "However, when Ritalin is given in pill form it takes at least 60 minutes to raise dopamine levels in the brain. So, it is the speed at which you increase dopamine that appears to be a key element in the addiction process."

The study's authors also included Gene-Jack Wang, Laurence Maynard, Samuel Gatley, Andrew Gifford, and Dinko Franceschi of Brookhaven's Medical Department, and Joanna Fowler, Jean Logan, Madina Gerasimov, and Yu-Shin Ding of Brookhaven's Chemistry Department.

The research was funded by DOE's Office of Energy Research and by the National Institute on Drug Abuse, part of the National Institutes of Health.