For the past thirty years selective serotonin reuptake inhibitors, or SSRIs have offered millions of Americans a way to shed the heavy cloak of depression and attain more wholesome states of mind.

Now, a team of Rockefeller scientists has for the first time described how SSRIs initiate their action by targeting a particular type of nerve cell.

Their findings, published in the journal Neuron, may provide a path to new antidepressants that would not only be safer to use than existing ones, but that would also act more quickly.

Lucian Medrihan, a research associate in the lab of neuroscientist and Nobel laureate Paul Greengard who led the study, explains that while existing SSRIs can produce moderate effects within hours or even minutes, most people don’t really begin to feel better until they’ve been on the drugs for a significant amount of time – a major drawback when it comes to treating clinical depression. The drugs may also cause a wide range of uncomfortable side effects, including nausea, dizziness, weight gain, and sexual dysfunction.

At least 1000 types of neurons could potentially be affected by a surge in serotonin, and they don’t all respond in the same way – some get triggered, for example, while others calm down. “That’s because there are 14 types of serotonin receptors present in various combinations in different neurons,” says Yotam Sagi, a senior research associate in Greengard’s lab. How a cell reacts to the neurotransmitter depends on the particular hodgepodge of receptors it carries.

Sagi and Medrihan set out to identify the earliest molecular steps by which SSRIs curb depression. To narrow their search, they honed in on a region of the brain known as the dentate gyrus, and on a particular group of cells called cholecystokinin (CCK)–expressing neurons, which they suspected were affected by SSRI–induced serotonin changes.

Using a technique called translating ribosome affinity purification, developed at Rockefeller by Nathaniel Heintz and Greengard, Sagi was able to identify the serotonin receptors present on CCK cells. “We were able to show that one type of receptor, called 5–HT2A, is important for SSRIs’ long–term effect,” he says, “while the other, 5–HT1B, mediates the initiation of their effect.”

When a mouse’s CCK neurons were inhibited, the same neural pathways that mediate responses to SSRIs lit up. In targeting these cells, the scientists had seemingly recreated a quickened, Prozac–like response without the drug itself.

The findings, which identify CCK neurons in the dentate gyrus as the site of interest, will advance scientists’ understanding of how SSRI antidepressants work, and “should also facilitate development of new classes of potent and selective drugs,” Greengard says. Such future therapies would presumably act faster than existing SSRIs, and might also produce fewer side effects.