http://www.scienceagogo.com/news/19990105054701data_trunc_sys.shtml
5 February 1999
Serotonin May Be Better Target For ADHD Treatment
Researchers at the Howard Hughes Medical Institute (HHMI) at Duke University
have discovered that Ritalin and other stimulants exert their paradoxical
calming effects by boosting serotonin levels in the brain. Elevating serotonin
appears to restore the delicate balance between the brain chemicals dopamine
and serotonin and calms hyperactivity, says HHMI investigator Marc Caron at
Duke University Medical Center. Caron is an author of the study published in
the January 15 issue of the journal Science.
Attention deficit hyperactivity disorder (ADHD) affects three to six per cent
of school-aged children. Symptoms include restlessness, impulsiveness, and
difficulty concentrating. Stimulants commonly used to treat ADHD are so
effective that "researchers haven't really taken the time to investigate how
they work," says Caron.
Previous dogma, says Caron, held that the calming action of Ritalin works
through the neurotransmitter dopamine. Specifically, researchers believed that
Ritalin and other stimulants interact with the dopamine transporter protein
(DAT), a housekeeper of sorts for nerve pathways. After a nerve impulse moves
from one neuron to another, DAT removes residual dopamine from the synaptic
cleft-the space between two neurons-and repackages it for future use.
Caron's team suspected that dopamine wasn't the only key to understanding ADHD,
so they turned to mice in which they had "knocked out" the gene that codes for
DAT. Since there is no DAT to "mop up" dopamine from the synaptic cleft, the
brains of the mice are flooded with dopamine. The excess dopamine causes
restlessness and hyperactivity, behaviors that are strikingly similar to those
exhibited by children with ADHD.
When placed in a maze that normal mice negotiate in less than three minutes,
the knockout mice became distracted-performing extraneous activities such as
sniffing and rearing - and they failed to finish in less than five minutes. The
knockout mice also seemed unable to suppress inappropriate impulses - another
hallmark of ADHD.
Surprisingly, the knockout mice were still calmed by Ritalin, Dexedrine and
other stimulants even though they lacked the protein target on which Ritalin
and Dexedrine were thought to act. "That caused us to look for other systems
that these stimulants might affect," says Caron.
To test whether the stimulants interact with dopamine through another
mechanism, the researchers administered Ritalin to the normal and knockout mice
and monitored their brain levels of dopamine. Ritalin boosted dopamine levels
in the normal mice, but it did not alter dopamine levels in knockout mice. That
result implied that "Ritalin could not be acting on dopamine," says Caron.
They then studied whether the stimulants altered levels of the neurotransmitter
serotonin. The scientists administered Prozac - a well-known inhibitor of
serotonin reuptake - to the knockout mice. After ingesting Prozac, the knockout
mice showed dramatic declines in hyperactivity.
"This suggests that rather than acting directly on dopamine, the stimulants
create a calming effect by increase serotonin levels," Caron says.
"Our experiments imply that proper balance between dopamine and serotonin are
key," says Raul Gainetdinov, a member of Caron's research team. "Hyperactivity
may develop when the relationship between dopamine and serotonin is thrown off
balance."
The brain has 15 types of receptors that bind to serotonin, and Gainetdinov is
now trying to determine which specific serotonin receptors mediate the effects
of Ritalin.
The hope, says Caron, "is that we can replace Ritalin with a very specific
compound that targets a single subset of receptors." While Prozac calmed
hyperactivity in the knockout mice, Gainetdinov says that "Prozac isn't the
best, because it isn't very selective." Caron and Gainetdinov are optimistic
that a new generation of compounds that interact more specifically with the
serotonin system will prove to be safer and more effective for treatments for
ADHD.