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Study May Explain How ADHD Treatments Work
PET scans show drugs' effect on the brain

  Tuesday, June 6, 2006


TUESDAY, June 6 (HealthDay News) -- Commonly prescribed drugs to treat attention deficit hyperactivity disorder (ADHD) seem to have an effect on dopamine released in the brain of people with the disorder.

New German research shows that different amounts of dopamine, which is related to positive reinforcement-based learning and behavior, are released in the brains of people treated for ADHD, compared with those untreated for their disorder.

"The significant difference we found between treated and untreated ADHD patients provides an important hint on the effect of the most commonly prescribed drug for this disease, which has long baffled and frustrated parents and physicians," Felix M. Mottaghy, a research fellow at the University of Ulm, said in a prepared statement. Mottaghy added that this is the first study to identify the positive effect that ADHD drugs have on the brain's dopamine system -- although that's long been a theory.

"This is a very preliminary, basic science study... however, future studies of the dopamine system could aid differential diagnosis in hyperactive children," said Mottaghy.

Researchers tested individuals with ADHD, both treated and untreated, with a PET scan of the brain and 18F-DOPA, a drug related to dopamine. Then, the brain images that resulted were statistically mapped.

"The most affected seemed to be the dopaminergic system. Until now, most studies focused on the so-called postsynaptic or receiving part of this system," said Mottaghy. "Our study shows that the beneficial effect of methylphenidate is received via 'normalization' of the dopamine system."

Results of the study were to be presented at this week's annual meeting of the Society of Nuclear Medicine, in San Diego.

"We demonstrated that the brain's dopamine system -- including midbrain, the striatum and the amygdala -- is differentially modulated in treated and untreated ADHD patients with respect to healthy normal controls," Mottaghy said.

   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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