Although millions depend on medications such as Ritalin to quell symptoms of attention deficit hyperactivity disorder (ADHD), scientists have struggled to pinpoint how the drugs work in the brain.

But new work at the University of Wisconsin-Madison is now starting to clear up some of the mystery. Writing in the journal Biological Psychiatry, UW-Madison researchers report that ADHD drugs primarily target the prefrontal cortex (PFC), a region of the brain that is associated with attention, decision-making and an individual’s expression of personality.

The finding could prove invaluable in the search for new ADHD treatments, and comes amidst deep public concern over the widespread abuse of existing ADHD medicines.

“There’s been a lot of concern over giving a potentially addictive drug to a child [with ADHD],” says lead author Craig Berridge, a UW-Madison professor of psychology. “But in order to come up with a better drug we must first know what the existing drugs do.”

A behavioral disorder that afflicts both children and adults, ADHD is marked by hyperactivity, impulsivity and an inability to concentrate. The National Institute of Mental Health estimates that 2 million children in the U.S. suffer from the condition, with between 30 to 70 percent of them continuing to exhibit symptoms in their adult years.

Despite public anxiety over the treatment of a behavioral condition with pharmacological drugs, doctors have continued to prescribe meds like Adderall, Ritalin and Dexedrine because - quite simply - they work better than anything else.

ADHD drugs fall into a class of medications known as stimulants. ADHD stimulants boost levels of two neurotransmitters, or chemical messengers in the brain, known as dopamine and norepinephrine. Dopamine is thought to play a role in memory formation and the onset of addictive behaviors, while norepinephrine has been linked with arousal and attentiveness.

Berridge notes that scientists have learned little about how ADHD drugs work because past studies have primarily examined the effects of the medicines 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,” says Berridge. “So we asked the natural question: what are these drugs doing at clinically relevant doses?”

To answer that question, Berridge and his team monitored neurotransmitter levels in three different brain regions thought to be targeted by ADHD drugs: the PFC 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 - the UW-Madison team measured concentrations of dopamine and norepinephrine in the three different brain areas, both in the presence and absence of low-dose ADHD stimulants.

Under the influence of ADHD drugs, dopamine and norepinephrine levels increased in the rats’ PFC. Levels in the accumbens and medial septum, however, remained much the same, the scientists found.

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

In the future, Berridge and his colleagues plan to look deeper within the PFC to gain more detailed insights into how ADHD meds act on nerves to enhance cognitive ability.

Other researchers who contributed to the study include UW-Madison co-authors David Devilbiss, Matthew Andrzejewski, Ann Kelley, Brooke Schmeichel, Christina Hamilton and Robert Spencer, and Yale Medical School researcher Amy Arnsten.

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