By David N. Leff

Three million Americans, nearly all of them schoolchildren, swallow daily a psychostimulant drug that's a close chemical - and behavioral - cousin of cocaine and amphetamines.

What's more, their parents, teachers and pediatricians unanimously push the hyperactive youngsters to take their medicine, methylphenidate by name, but better known as Ritalin. They don't have to push very hard.

"I think that Ritalin is effective in treating ADHD [attention deficit hyperactivity disorder]," observed neurobiochemist Marc Caron. "Because it takes a little while to take effect, the kids usually take their Ritalin before they go to school in the morning. But they're probably treated more than once a day," he added. "That's why the teachers have a supply and the kids have a supply. So that's where you see some of the problems with Ritalin being trafficked, abused by kids who really don't need it. Normal kids get a buzz from it because it's like cocaine."

However, the seductive psychostimulant also has adverse side effects, from insomnia, sadness and anorexia (loss of appetite) to headache, stomachache, and, in large doses, stunted growth.

"The use of Ritalin is widespread," Caron pointed out, "because ADHD is thought to affect 3 to 6 percent of the child population, at least in the U.S."

In that hyperactive juvenile cohort, the quixotic disorder shows itself - according to standard diagnostic criteria - in squirming, fidgeting, restlessness, jitteriness, short attention span and poor impulse control. The child is always on the go, running and climbing, can't sit still. He or she (and ADHD boys outnumber girls 10-to-1) acts before he thinks, talks nonstop, blurts answers before a question is completed, intrudes on other kids, can't stand standing in line.

Caron, a Howard Hughes Medical Institute investigator, researches brain receptors in the departments of Cell Biology and Medicine at Duke University in Durham, N.C. He is senior author of a paper in the current issue of Science, dated Jan. 15, 1999, and titled: "Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity."

"The prevailing theory of how psychostimulants work," Caron told BioWorld Today, "is that the increase of dopamine levels in the brain, in the synapses outside of the neurons, increases activity. If you treat normal people with Ritalin, cocaine or amphetamine, you get arousal, hyperactivity. So why is it when you treat ADHD kids with it you get the opposite effect? An inhibitory effect? You calm them down. This has been a great puzzle."

Dopamine is a major neurotransmitter. Its actions include regulating activity and locomotion. But Caron and his co-authors found evidence that Ritalin works by affecting levels of another neurotransmitter, serotonin, which helps regulate mood, and curbs aggressive and impulsive behavior.

Rodent Behavior Parallels Human Hyperactivity

As a surrogate for human testing, Caron turned to a unique dopamine-overload knockout mouse he and his co-authors genetically created three years ago. It lacks the gene that expresses the dopamine transporter. This protein scavenges the leftover dopamine building up in the synaptic spaces between neurons after the neurotransmitter has triggered a nerve impulse. Such transporters recycle dopamine back into neurons for reuse.

"We found these knockout [KO] mice to be hyperactive," Caron recounted, "and for a good reason. They have about five times more dopamine in the extracellular spaces, because they can't clear it after its release from the neurons."

"When we put normal mice in a novel environment that they're not habituated to," he went on, "they are initially hyperactive, but calm down very fast. But when we place our KO mice in strange surroundings, they become extremely hyper. So that led us to say," he continued, "that this is somewhat similar to what one finds in ADHD kids, because inappropriate behavior in novel environments is one of the hallmarks of people with attention disorder.

Maze Built To Test Theory

"The other interesting thing," he went on, "whether the mice have cognitive deficits, was difficult to assess." For this, the team employed a special test chamber consisting of a maze with eight radial arms. They baited each arm with a dollop of Fruit Loops, which is irresistible to rodents.

"When we put wild-type mice in there, they learned over a period of time to negotiate each arm and go retrieve the pieces of food in less than two minutes. When we put our KO mice in there," Caron went on, "they could not learn. They kept making errors, being distracted, and displayed repetitive behavior, going back to the same place they had just been even though they had eaten the food."

A normal mouse shows hyperactivity symptoms, Caron related, "by walking about and exploring its cage. But in zero to 20 or 30 minutes, it will go into a corner and sit there, licking its paws - things like that.

"When we treat that normal mouse with a psychostimulant, it will also initially explore and so on, but keep progressing more and more, eventually running in circles and across the area, because it's become hyperactive. This is what our KO mice also do in the absence of treatment," he continued. "Hyperactivity manifests itself when we put them in this novel environment. They start running around, progress, can keep it up four or five hours. Ritalin calms them down, and they look very similar to normal mice.

"Interestingly," Caron pointed out, "there are several parallels between the properties of these mice and some of the symptoms of ADHD patients."

To counter the dopamine overload in their knockouts, the co-authors treated them with psychostimulants. "When we gave them Ritalin, amphetamine and cocaine, we were able to see that these drugs calmed the activity of the animals down. When we treated normal animals with these drugs, they became hyperactive instead of hypoactive. In normal mice, these drugs increased the levels of dopamine, but in our KO mice they did not. The dopamine levels remained high because there was no transporter to remove them."

Intrigued that these drugs do two different things, in normal and KO mice, the co-authors hypothesized that instead of affecting the dopamine system, the psychostimulants might be working on serotonin.

"When we targeted the serotonin system," Caron recounted, "indeed, a different picture emerged: We were able to mimic the effects of the psychostimulants, Ritalin, amphetamine and cocaine, by treating the mice initially with Prozac - which increases serotonin levels in the brain. Then we tested compounds that mimic the action of serotonin receptor agonists, and they did the same thing.

"And the last thing that we did was to show that if we augment the brain levels of serotonin by injecting precursors to it, it effectively calmed the mice down. This really told us that in the KO mice we were able to dampen their hyperactivity by increasing the level of serotonin."

Caron suggested that this effect could be tested in humans. "I think its great potential," he observed, "is that we know serotonin binds to at least 15 different receptors in the brain. So if we are now capable of trying to decipher which of these receptors is mediating this calming effect in our KO mice, then we can go back and test this in individuals with ADHD, and see whether the same thing applies in humans.

"I think," he concluded, "that it could lead to discovery of a much more selective and safer drug, because it would eliminate all the side effects of psychostimulants, plus their potential for drug dependence and addiction." n