January 15, 1999
Serotonin May Hold Key to Hyperactivity Disorder
Much concern has been raised over prescribing
Ritalin® or other stimulants to control hyperactivity disorders in
children. Relatively little is known about the long-term effects of these
stimulants or how they alter brain chemistry.
Now researchers at the Howard Hughes Medical Institute 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
Caron at Duke University Medical Center. Caron is an author of the study
published in the January 15, 1999, issue of the journal
Attention deficit hyperactivity disorder (ADHD) affects three to six
percent 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,"
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.
Next, the researchers gave the knockout mice a drug that inactivates the
norepinephrine transport protein. With transport disabled, norepinephrine
levels increased as expected, but the boost in norepinephrine did not
ameliorate the symptoms of ADHD as it should. This suggested to Caron's team
that Ritalin® exerted its effects through another neurotransmitter.
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
"This suggests that rather than acting directly on dopamine, the
stimulants create a calming effect by increase serotonin levels," Caron
"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.