Pubdate: Fri, 15 Jan 1999 Source: San Diego Union Tribune (ca) Contact: http://www.uniontrib.com/ Forum: http://www.uniontrib.com/cgi-bin/webx Copyright: 1999 Union-Tribune Publishing Co. THEORIES ON RITALIN REVAMPED | FOUND TO STIMULATE REGULATOR OF MOOD Millions of Americans young and old take daily doses of Ritalin and other stimulants because the drugs paradoxically seem to control their hyperactivity and inattention. Until recently, most scientists had thought that the stimulants worked by somehow shorting out the brain's sensitivity to a neurotransmitter called dopamine, which promotes arousal and activity and which stimulants rev up. But a new study published in the journal Science points to a completely different way that low doses of stimulants may act to calm hyperactivity. It appears that the drugs work by boosting production of another brain chemical -- serotonin -- which regulates mood and inhibits aggressive and impulsive behavior, say researchers at Duke University Medical Center. Although their study was limited to genetically altered mice, the scientists said they believe that the same situation exists in people. Attention deficit hyperactivity disorder is caused as much by having too little serotonin in the brain as by having too much dopamine. "This suggests that, rather than acting directly on dopamine, the stimulants create a calming effect by increasing serotonin levels," said Marc Caron, a brain researcher at the Howard Hughes Medical Institute Laboratories at Duke and a co-author of the study. Caron and his colleagues said they believe that their findings could open the way for hyperactivity disorders to be treated with a new class of drugs which selectively turn up serotonin production without using stimulants. Stimulants can have side effects and are feared by some experts to set children at risk for later drug abuse. "We've always thought of ADHD as a function of too much activity in the brain, and it is, 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," said Dr. Raul Gainetdinov, a research associate in the department of cell biology at Duke and co-author of the study. The researchers were able to identify the brain's balancing act through a series of tests involving mice which had been genetically altered so that they lack a protein which serves to mop up dopamine after it has been used to transmit impulses between nerve endings in the brain. The mice behaved in a hyper, impulsive and inattentive manner but responded with calmness and focus to a dose of Ritalin or cocaine, just as do humans with ADHD. But the same doses given to a group of normal mice made them hyperactive. When the researchers measured dopamine levels in the brains of the two groups of mice after the dosing, the normal mice had increased levels of dopamine at the impulse exchange points, but the altered mice did not. This meant that Ritalin could not be working by increasing dopamine levels. So the researchers turned to two other neurotransmitters, giving the mice various drugs known to either inactivate or enhance those signaling chemicals. The breakthrough came when the researchers gave the altered mice a dose of fluoxetine (Prozac), which is known to boost serotonin levels. The drug had a dramatic calming, focusing effect on the mice, as measured by their ability to navigate a maze that had previously stymied them. - --- MAP posted-by: Rich O'Grady