Stimulants appear to improve symptoms of attention deficit hyperactivity disorder (ADHD) by modulating neurotransmitter levels in the prefrontal cortex, according to an article published online June 22 by Biological Psychiatry.

"There's been a lot of concern over giving a potentially addictive drug to a child [with ADHD]," said lead author Craig Berridge, PhD, a University of Wisconsin professor of psychology. "But in order to come up with a better drug we must first know what the existing drugs do."

The National Institute of Mental Health estimates that 2 million American children have the disorder, with between 30 to 70 percent of them continuing to have symptoms in adulthood.

Almost all drugs used to treat the disorder are stimulants. Stimulants boost levels of dopamine and norepinephrine. Dopamine is thought to play a role in memory formation and onset of addictive behaviors, whereas norepinephrine has been linked with arousal and attentiveness.

Berridge noted that scientists have learned little about how the drugs work because past studies have primarily examined drug effects at high doses. High-dose stimulants can cause dramatic spikes in neurotransmitter levels in the brain, which can in turn impair attention and heighten the risk of developing addiction.
"It is surprising that no one was looking at low-dose [ADHD] drugs because we know that the drugs are most effective only at low doses," said Berridge. "So we asked the natural question: what are these drugs doing at clinically relevant doses?"

The researchers monitored neurotransmitter levels in three different brain regions thought to be targeted by the drugs: the prefrontal cortex and two smaller brain areas known as the accumbens, which has been linked with processing rewards, and the medial septum, which has been implicated in arousal and movement.

Working with rats, the researchers conducted laboratory and behavioral tests to ensure that animal drug doses were functionally equivalent to doses prescribed in humans. Then, using a type of brain probe - a process known as microdialysis - investigators measured concentrations of dopamine and norepinephrine in the three different brain areas, both in the presence and absence of low-dose stimulants commonly used to treat the disorder.

Under the influence of drugs, dopamine and norepinephrine levels increased in the rats' prefrontal cortex. Levels in the accumbens and medial septum, however, remained much the same.

"Our work provides pretty important information on the importance of targeting the prefrontal cortex when treating ADHD," added Berridge. "In particular it tells us that if we want to produce new ADHD drugs, we need to target [neurotransmitter] transmission in the prefrontal cortex."

In the future, Berridge and colleagues plan to look deeper within the prefrontal cortex to gain more detailed insights into how the medications act on neurons to enhance cognitive ability.