STUDY SHIFTS THOUGHT ON HOW RITALIN WORKS

Medicine: The drug's effect on serotonin-not dopamine-helps manage
hyperactivity, researchers say.

Millions of Americans young and old take daily doses of Ritalin and other
stimulants because the drugs paradozically seem to control their
hyperactivity and inattention.

Until recently, most scientists had thought that the stimulants worked by
somehow shorting out the brain's sensitivity to the neurotransmitter
dopamine, which promotes arousal and activity and which stimulants rev up.

But a new study published in today's journal Science points to a completely
deferent way that low doses of stimulants may act to calm hyperactivity.

It appears that the drugs actually work by boosting production of another
brain chemical - serotonin - that regulates mood and inhibits aggressive
and impulsive behavior, according to researchers at Duke University Medical
Center.

Although their study was limited to genetically altered mice, the
scientists belive the same situation exists in people. Attention deficit
hyperactivity disorder is caused as much by having too little serotonin in
the brain as by having too much dopamine.

"This suggests that rather than acting directly on dopamine, the stimulants
create a calming effect by increasing serotonin levels," said Marc Caron, a
brain researcher at the Howard Hughes Medical Institute Laboratories at
Duke and a co-author of the study.

He and his colleagues believe their findings could open the way for
hyperactivity disorders to be treated with a new class of drugs that
selectively turn up serotonin production without using stimulants, which
can have side effects and are feared by some experts to put children at
risk for later drug abuse.

"We've always thought of ADHD as a function of too much activity in the
brain, and it is. 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," said Dr. Raul Gainetdinov, a research associate
in the department of cell biology at Duke and co-author of the study.

The researchers were able to identify the brain's balancing act through a
series of tests involving mice that had been genetically altered so that
they lack a protein that serves to mop up dopamine after it has been used
to transmit impulses between nerve endings in the brain.

The mice behaved in a hyper, impulsive and inattentive manner, but
responded with calmness and focus to a dose of Ritalin or cocaine, just as
do humans with ADHD. But the same doses given to a group of normal mice
made them hyperactive.

When they measured dopamine levels in the brains of the two groups of mice
after the dosing, the normal mice had increased levels of dopamine at the
impulse-exchange points, but the altered mice did not.

That meant Ritalin couldn't be working by increasing dopamine levels. So
the researchers turned to two other neurotransmitters, giving the mice
various drugs known to either inactivate or enhance those signaling chemicals.

The breakthrough came when the researchers gave the altered mice a dose of
fluoxetine, or Prozac, which boosts serotonin levels. The drug had a
dramatic calming, focusing effect on the mice, as measured by their ability
to navigate a maze that had previously stymied them.

The same effect was obtained with several other drugs that either make
nerve cells more responsive to serotonin or boost production.