| By a nose,
worms reveal new Prozac targets.(research into how
antidepressant Prozac works)(Brief Article)
Author/s: J. Travis
Issue: Sept 25, 1999
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.
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