THEORIES ON RITALIN REVAMPED | FOUND TO STIMULATE REGULATOR OF MOOD

Millions of Americans young and old take daily doses of Ritalin and
other stimulants because the drugs paradoxically 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 a neurotransmitter
called dopamine, which promotes arousal and activity and which
stimulants rev up. But a new study published in the journal Science
points to a completely different way that low doses of stimulants may
act to calm hyperactivity. It appears that the drugs work by boosting
production of another brain chemical -- serotonin -- which regulates
mood and inhibits aggressive and impulsive behavior, say researchers
at Duke University Medical Center. Although their study was limited
to genetically altered mice, the scientists said they believe that 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.

Caron and his colleagues said they believe that their findings could
open the way for hyperactivity disorders to be treated with a new
class of drugs which selectively turn up serotonin production without
using stimulants. Stimulants can have side effects and are feared by
some experts to set 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 which
had been genetically altered so that they lack a protein which 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 the researchers 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. This meant that Ritalin could not 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 (Prozac), which is known to boost 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.