Finding: Ritalin calms by working on serotonin levels in brain
Theory that it affects dopamine now debunked

Web posted at 18-Jan-99 01:26 Central European Time

DURHAM, N.C. - 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, and not dopamine levels, as was previously thought. If confirmed in humans, this finding could lead to more effective medications to treat hyperactivity.

Stimulant medications such as Ritalin are often prescribed to children and adults with ADHD (hyperactivity), including people with both autism and hyperactivity features.

Previous theory holds 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 mice lacking the "dopamine transporter" protein (DAT) which 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. (Photo courtesy Duke News Service)

According to the new theory, elevating serotonin appears to restore the delicate balance between the brain chemicals dopamine and serotonin and calms hyperactivity. So says HHMI investigator Marc Caron at Duke University Medical Center. Caron is an author of the study published in the January 15, 1999, issue of the journal Science.

Findings could lead to safer and less controversial treatment

Speaking of Ritalin and similar medications, Caron said: "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".

"Giving children medications that boost serotonin could provide an attractive alternative therapy for children in whom these drugs are ineffective or prohibited", he added.

Genetically engineered mice provided clues

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 the Dopamine Transporter Protein (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.

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," said 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 increasing 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 study results are published in the January 15 issue of the journal Science.

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