Millions of individuals diagnosed with attention deficit hyperactivity disorder (ADHD) are helped by methylphenidate, the stimulant better known as Ritalin. Now researchers at the University of Wisconsin-Madison have pinpointed the area of the brain in which Ritalin does its work.
"These drugs are highly effective at controlling the symptoms of attention deficit and hyperactivity disorder for the great majority of patients," says Craig Berridge, a UW psychology professor. "And they've been around since the 1930s, which makes it all the more amazing that we didn't understand until recently how they worked in the brain."
A study conducted by Berridge and graduate student Robert Spencer has identified the upper portion of the brain's prefrontal cortex as the key area in which the drug works.
Spencer delivered Ritalin to rats through tiny needles routed directly into different parts of the prefrontal cortex and into parts of the nearby striatum. The striatum is linked to the prefrontal cortex as part of the frontostriatal circuit, a neural pathway vital to motor and cognitive function.
"Brain imaging studies show that both the prefrontal cortex and striatum aren't responding normally in ADHD patients, and there was much speculation that the striatum plays a role in the way Ritalin worked," says Berridge, whose newest research was published online recently by the journal Biological Psychiatry. "This is the first study to show unambiguously that the drug acts in the prefrontal cortex to improve cognition."
Rats in the study performed much better in a maze that tests working memory after small Ritalin doses were applied to the top of the prefrontal cortex, but larger doses and other entry points for the drug failed to help the rats.
"This mirrors what we see with oral administration of this drug to ADHD patients," Berridge says.
This cognition-enhancing action was only observed when infused into the upper region of the prefrontal cortex. No significant changes were found when Ritalin was introduced in the lower prefrontal cortex, an area that processes emotional information.
Earlier studies showed the striatum receiving direction from the prefrontal cortex. And when Spencer deactivated the striatum, the animals could not complete the working memory task at all. However, despite the striatum's importance to cognitive function, Ritalin added directly to the striatum also resulted in no improvement in the maze.
The study provides new information about how methylphenidate works to produce therapeutic effects, which may well be useful for developing new treatments.
"In particular, when we're screening new compounds to treat ADHD, we will want to know if they are acting on the prefrontal cortex," says Berridge, whose work is funded by the National Institute of Mental Health. "And we know that if [the compounds] are acting outside the prefrontal cortex, they have the potential for addictive or other deleterious effects."
Though most people with attention deficit symptoms benefit a great deal from Ritalin, the drug has a sketchy reputation. It is popular without prescription as a "study aid" - sharpening the focus of people without ADHD issues. And it is a powerful stimulant that, at doses higher than those used to treat ADHD, can have addictive and detrimental effects.
"There is concern with prescribing an addictive medication to children," Berridge says. "However, our work and work of others indicates that at clinically relevant doses, Ritalin acts fundamentally different than when used at higher doses associated with drug abuse. At these lower doses, it boosts cognition dependent on the prefrontal cortex and appears to be quite safe and effective."