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Zooming in on how antidepressants work.

Posted Oct 22 2008 6:15pm

According to a new article on the Nature website, antidepressants act as a "roadblock" to certain brain chemicals as they're trying to enter neurons. In a way, this isn't really news -- we already know that antidepressants reduce the degree to which serotonin, for instance, binds with serotonin receptors. But the studies cited in the article are the first time anyone's been able to document what the process looks like on a molecular level. From the article:

Antidepressants work by preventing neurons in the brain from importing certain chemicals, such as dopamine and serotonin, which are used to pass messages from cell to cell. The route by which these chemicals are imported depends on passageways in the outer membrane of the cells called transporter proteins, and it is on these passageways that the antidepressants exert their influence. But how exactly they hold up the process has remained a mystery since the drugs were discovered 45 years ago, says Les Iversen, a pharmacologist at the University of Oxford, UK.

To resolve the mystery, both teams — one led by Eric Gouaux of Oregon Health and Science University in Portland and the other based at New York University and led by Da-Neng Wang — set out to understand what happens when antidepressants lock onto a transporter at the most fundamental level. They zoomed in on the transporters' molecular structures as revealed at atomic resolution through X-ray crystallography.

...Their results provide the first glimpse of the mechanism by which the drugs block the transporters. Both groups agree on what's happening: the drug binds to the outside of the transporter, changing its shape. This traps the brain chemical inside the tunnel like a cork in a bottle, preventing it from passing through to the inside of the neuron. They published their results almost simultaneously in Nature1 and Science2 this week.

More on the science of antidepressants here.

CLARIFICATION: The antidepressants used in these studies were tricyclics. Don't know whether these findings hold true for MAOIs, SSRIs, or other anti-D drugs.
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