Jan. 18, 1999 DURHAM, N.C. -- A study using genetically engineered mice suggests a different mechanism of action than scientists have hypothesized to explain how the drug Ritalin calms humans with attention deficit hyperactivity disorder (ADHD).
If confirmed in humans, the finding could lead to more effective drugs to treat a disorder that has long baffled and frustrated parents, physicians and doctors alike.
The study results are published in the Jan. 15 issue of the journal Science by Marc Caron, a Howard Hughes Medical Institute investigator at Duke University Medical Center, and Research Associate Dr. Raul Gainetdinov of the department of cell biology.
The researchers found evidence that Ritalin works by affecting levels of the brain chemical serotonin, which helps regulate mood and inhibit aggression and impulsive behavior. Current theory holds, however, 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 "knockout" mice lacking a protein called a dopamine transporter that 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.
Since the brains of the knockout mice had dopamine levels five times normal, their neurons were firing at abnormally high rates, causing them to behave as do humans with ADHD or those using cocaine. Such mice showed hyperactivity, inattentiveness and lack of impulse control in a novel environment. This behavior was measured by their ability to complete a complicated maze that required them to remember, pay attention and respond to external cues and display appropriate behavioral responses.
However, the scientists detected no corresponding rise in dopamine to accompany the behavioral change, leading them to believe that these changes were regulated through more than just the dopamine system.
Administering Ritalin or cocaine to the hyperactive knockout mice calmed them down and made them more attentive -- the same reaction to Ritalin seen in humans with ADHD, Caron said. Conversely, the normal mice became hyperactive when given Ritalin or cocaine, just like normal humans.
To understand why the drugs had such opposite effects on the two groups of mice, the researchers measured brain dopamine levels in both groups 20 minutes after a dose of Ritalin. As expected, normal mice showed an increase of dopamine in the "synaptic clefts," or spaces between nerve cells, while the knockout mice showed no such increase.
"This finding indicated that Ritalin couldn't be working on dopamine," Gainetdinov said. "It told us that the drug had to be exerting its calming influence on systems involving the hormone norepinephrine or the neurotransmitter serotonin."
Exploring a possible norepinephrine link, the scientists gave the knockout mice a drug that inactivated their norepinephrine transporter, causing an accumulation of excess norepinephrine in their synapses. This drug had no effect on hyperactivity or inattention in the mice, eliminating norepinephrine as the mechanism through which Ritalin was acting.
Finally, the researchers administered fluoxetine, or Prozac -- which is known to inhibit reuptake of serotonin in the synapse -- to the knockout mice. The drug caused a dramatic reduction in hyperactivity, as did other drugs that either directly activated serotonin receptors or increased brain serotonin levels, the researchers found.
Based on this finding, Caron and his colleagues believe that ADHD-like symptoms in the knockout mice are caused as much by having too little serotonin in the brain as by having too much dopamine, and that restoring a balance between the two brain chemicals is the key to controlling hyperactive behavior.
"We've always thought of ADHD as a function of too much activity in the brain, and it is," said Gainetdinov. "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. Ritalin helped control behavior in these mice by boosting serotonin's calming effects on dopamine, rather than by acting directly on dopamine, as had long been assumed.
"Our findings provide the tantalizing possibility that hyperactivity in ADHD patients might be controlled through precise targeting of serotonin receptors, or even by supplementing serotonin precursors, such as dietary tryptophan" Gainetdinov said. "In other words, giving them selective serotonin drugs could have the same effect, or even better, than Ritalin or Dexedrine."
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, Caron added. Giving children medications that boost serotonin could provide both an attractive alternative therapy for children in whom these drugs are ineffective or prohibited, he said.
While theirs isn't the first study to implicate serotonin in impulse control, scientists had long assumed that the primary action of psychostimulants like Ritalin was through the dopamine system, Caron said.
According to the scientists, the new findings also raise the question of which characteristic of ADHD precedes the others. In other words, does hyperactive behavior cause a person to think and act on impulse, without taking time to pay attention? Or does lack of inhibition of thoughts and behaviors cause the person to behave hyperactively?
As with any mental disorder, many neurological defects could cause ADHD, the researchers said. However, they said, the new findings suggest that genetic defects in the dopamine transporter gene might cause some forms of ADHD in humans.
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