THE MOOD MOLECULE

Monday, Sep. 29, 1997 By MICHAEL D. LEMONICK

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It is also not surprising that serotonin deficits can give rise to very different illnesses, depending on what part of the brain is affected. Obsessive-compulsive disorder, for example, probably arises in the striatum, a part of the brain that controls voluntary movements. Princeton's Jacobs believes that, based on experiments with cats, repetitive motor activity--walking, chewing, breathing--stimulates the release of serotonin, which improves mood. That might explain why people are soothed by gum chewing and why obsessive-compulsives perform such ritualistic acts as hand washing over and over; they may simply be self-medicating to overcome a serotonin deficit.

Anxiety disorders, on the other hand, probably reflect serotonin deficits in the amygdala, the part of the brain that processes fear and other emotions. For depression, bulimia, obesity and the rest of the serotonin-related disorders, however, no one knows for sure what part of the brain is involved or exactly why the drugs work. "There is," says Hyman, "a bit of mystery here."

More than a bit. In fact, the entire history of serotonin and of drugs that affect it has been largely a process of trial and error marked by chance discoveries, surprise connections and unanticipated therapeutic effects. The chemical was not even first discovered in the brain. It was stumbled on in the late 1940s by U.S. and Italian researchers, working independently, in blood platelets and in the intestines, respectively. The Italians called it enteramine, the Americans serotonin (sero for blood, tonin for muscle tone)--and when the two groups compared notes, they found their compounds were identical.

At first, the effects of serotonin seemed confined to the body alone: it was found to trigger contractions in the muscles and intestines and to regulate blood pressure by forcing blood vessels to constrict. But experiments at the National Institutes of Health in the 1950s revealed that compounds that depressed serotonin levels depressed patients as well. Not long after, researchers found two more clues to the serotonin-depression connection. The first was that reserpine, an anti-blood-pressure medicine that depresses serotonin levels, can sometimes trigger depression. The second came from iproniazid, originally developed as an anti-tuberculosis agent. The medicine worked against TB, which naturally made patients happy. When the euphoria did not wear off, however, scientists began to suspect that it was not entirely natural.

They were right. Iproniazid is what is known as a monoamine oxidase inhibitor (MAO). In the brain, scientists have subsequently learned, monoamine oxidase's job is to destroy leftover neurotransmitters that are floating around loose after they have done their work. By inhibiting the action of monoamine oxidase, drugs like iproniazid let neurotransmitters circulate and keep stimulating neurons longer than they normally would. An extended soaking in serotonin and norepinephrine evidently made for a happier patient, and MAO inhibitors became the first antidepressants.