By a nose, worms reveal new Prozac targets.

The scrunched-up noses of worms swimming in a solution of Prozac could help explain the popular antidepressant's side effects, such as insomnia, sexual dysfunction, and nausea. They may even challenge the current theory of how the drug lifts spirits.

Although millions of people each year receive prescriptions for Prozac, a debate continues about how it and related antidepressants work. The prevailing hypothesis holds that these drugs correct a deficiency of the brain chemical serotonin by binding to and interfering with cell-surface proteins, the serotonin reuptake transporters, that mop up the neurotransmitter.

Some investigators, however, contend that Prozac doesn't battle depression much better than placebo pills or talk therapy. Others accept the drug's value but dispute the evidence that serotonin deficiency causes depression.

"It's not that the drugs don't help some people--I think they do--but I don't think we know why," says Elliot S. Valenstein of the University of Michigan in Ann Arbor, a critic of the serotonin hypothesis. "There's so much that contradicts this simple theory, but we don't know what to turn to."

To explore the workings of Prozac, Robert K.M. Choy and James H. Thomas of the University of Washington and the Fred Hutchinson Cancer Center, both in Seattle, chose the humble nematode Caenorhabditis elegans. While its nervous system is extremely simple, the worm's nerve cells employ many of the same molecules, such as serotonin and its transporters, that the human brain does.

When bathed in Prozac, C elegans responds in two obvious ways. First, the drug triggers the female worms to lay eggs. Second, it induces muscle contractions, most dramatically in the muscles around the olfactory cells at the worm's tip.

Investigators had previously shown that the egg-laying response stems from Prozac's interactions with the serotonin system. Choy and Thomas, however, found that the nose-muscle contractions occur independently of the drug's inhibition of serotonin transporters. This suggests that Prozac has other molecular targets in the worm, and possibly in people as well, says Choy.

By exposing C. elegans to a mutation-causing chemical, the scientists created several strains of worms that in response to Prozac, lay eggs but don't wrinkle their noses. The researchers have now identified two genes--and continue to search for more--that when mutated confer resistance to Prozac's effect on the nematode nose. The genes encode novel cell-membrane proteins and are part of a larger family of genes, the scientists report in the current (August) MOLECULAR CELL.

Choy and Thomas haven't yet found comparable genes in people or shown that Prozac and similar antidepressants interact directly with the worm cell-membrane proteins. Only then, says Choy, can scientists address whether these proteins play any role in Prozac's antidepressant actions.

While he favors the prevailing serotonin hypothesis, neuroscientist Randy D. Blakely of the Vanderbilt University Medical Center in Nashville suspects that Choy and Thomas have uncovered interesting new targets of Prozac and related antidepressants. "They do make a very strong case that some side effects of these agents may be mediated through interactions with these proteins," he says.

In the future, scientists may bathe worms in drugs other than Prozac. Blakely, for example, plans to expose C. elegans to antipsychotic drugs that affect transporters for the brain chemical dopamine.

"Drugs have historically been effective tools for investigating how worm neurons work; worm neurons may prove equally effective for investigating how drugs work," notes William R. Schafer of the University of California, San Diego in a commentary in the Sept. 3 CELL.