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NEW THEORY MAY EXPLAIN RITALIN ACTION IN HYPERACTIVITY

DURHAM, N.C. - A study using genetically engineered mice
suggests a different mechanism of action than scientists have
hypothesized to explain how the drug Ritalin calms humans with
attention deficit hyperactivity disorder (ADHD).

If confirmed in humans, the finding could lead to more
effective drugs to treat a disorder that has long baffled and
frustrated parents, children and doctors alike.

The study results are published in the Jan. 15 issue of the
journal Science by Marc
Caron, a Howard Hughes Medical Institute investigator at Duke
University Medical Center, and Research Associate Dr. Raul
Gainetdinov of the department of cell biology.

The researchers found evidence that Ritalin works by
affecting levels of the brain chemical serotonin, which helps
regulate mood and inhibit aggression and impulsive behavior.
Current theory holds, however, that Ritalin calms people with
ADHD by affecting the level of the brain chemical dopamine,
whose actions include regulation of activity and locomotion.
Both dopamine and serotonin are neurotransmitters, chemicals
which are launched by neurons, or brain nerve cells, to trigger
nerve impulse in neighboring neurons.

Caron and Gainetdinov made their discovery by genetically
creating "knockout" mice lacking a protein called a dopamine
transporter that scavenges the dopamine remaining in the spaces
between neurons after the chemical has triggered a nerve
impulse. Such transporters are a key part of the machinery for
recycling neurotransmitters back into neurons for reuse.

Since the brains of the knockout mice had dopamine levels
five times normal, their neurons were firing at abnormally high
rates, causing them to behave as do humans with ADHD or those
using cocaine. Such mice showed hyperactivity, inattentiveness
and lack of impulse control in a novel environment. This
behavior was measured by their ability to complete a
complicated maze that required them to remember, pay attention
and respond to external cues and display appropriate behavioral
responses.

However, the scientists detected no corresponding rise in
dopamine to accompany the behavioral change, leading them to
believe that these changes were regulated through more than
just the dopamine system.

Administering Ritalin or cocaine to the hyperactive knockout
mice calmed them down and made them more attentive -- the same
reaction to Ritalin seen in humans with ADHD, Caron said.
Conversely, the normal mice became hyperactive when given
Ritalin or cocaine, just like normal humans.

To understand why the drugs had such opposite effects on the
two groups of mice, the researchers measured brain dopamine
levels in both groups 20 minutes after a dose of Ritalin. As
expected, normal mice showed an increase of dopamine in the
"synaptic clefts," or spaces between nerve cells, while the
knockout mice showed no such increase.

"This finding indicated that Ritalin couldn't be working on
dopamine," Gainetdinov said. "It told us that the drug had to
be exerting its calming influence on systems involving the
hormone norepinephrine or the neurotransmitter serotonin."

Exploring a possible norepinephrine link, the scientists
gave the knockout mice a drug that inactivated their
norepinephrine transporter, causing an accumulation of excess
norepinephrine in their synapses. This drug had no effect on
hyperactivity or inattention in the mice, eliminating
norepinephrine as the mechanism through which Ritalin was
acting.

Finally, the researchers administered fluoxetine, or Prozac
-- which is known to inhibit reuptake of serotonin in the
synapse -- to the knockout mice. The drug caused a dramatic
reduction in hyperactivity, as did other drugs that either
directly activated serotonin receptors or increased brain
serotonin levels, the researchers found.

Based on this finding, Caron and his colleagues believe that
ADHD-like symptoms in the knockout mice are caused as much by
having too little serotonin in the brain as by having too much
dopamine, and that restoring a balance between the two brain
chemicals is the key to controlling hyperactive behavior.

"We've always thought of ADHD as a function of too much
activity in the brain, and it is," said Gainetdinov. "But it
also appears to be a function of the brain's failure to inhibit
impulses and thoughts that we all have, but which we are
typically able to control. Ritalin helped control behavior in
these mice by boosting serotonin's calming effects on dopamine,
rather than by acting directly on dopamine, as had long been
assumed.

"Our findings provide the tantalizing possibility that
hyperactivity in ADHD patients might be controlled through
precise targeting of serotonin receptors, or even by
supplementing serotonin precursors, such as dietary tryptophan"
Gainetdinov said. "In other words, giving them selective
serotonin drugs could have the same effect, or even better,
than Ritalin or Dexedrine."

Although these commonly prescribed drugs are effective in
treating ADHD, the use of such psychostimulants in children is
controversial due to well-known side effects of this class of
drugs, Caron added. Giving children medications that boost
serotonin could provide both an attractive alternative therapy
for children in whom these drugs are ineffective or prohibited,
he said.

While theirs isn't the first study to implicate serotonin in
impulse control, scientists had long assumed that the primary
action of psychostimulants like Ritalin was through the
dopamine system, Caron said.

According to the scientists, the new findings also raise the
question of which characteristic of ADHD precedes the others.
In other words, does hyperactive behavior cause a person to
think and act on impulse, without taking time to pay attention?
Or does lack of inhibition of thoughts and behaviors cause the
person to behave hyperactively?