Growing Up to Prozac: Drug makes new neurons mature faster

Peter Pan won’t be pleased to hear the latest theory about how Prozac works. A new study shows that the antidepressant stimulates growth of neurons in the hippocampus and speeds the young brain cells toward maturity. The maturation process could be the mechanism by which the drug relieves depression.

Fluoxetine, the drug commonly known as Prozac, has been used to treat depression since the 1980s. Prozac and other SSRIs (selective serotonin reuptake inhibitors) block the ability of the neurons to take up serotonin, thereby raising levels of the active neurotransmitter in the brain. When people with depression begin taking such drugs, serotonin levels in the brain increase rapidly, but it often takes 2 to 4 weeks before they begin to feel better.

The new study, published Feb. 6 in the Journal of Neuroscience, suggests that the lag is due to the time it takes for serotonin to stimulate new neurons to grow, mature, and integrate into brain circuits.

René Hen, a neuroscientist at Columbia University, and his colleagues tested the long-term effects of Prozac treatment on a specially bred strain of nervous mice.

Inside the brains of mice treated with Prozac, the researchers found many more newborn neurons in the dentate gyrus of the hippocampus, a part of the brain involved in learning and memory.

Not only did the Prozac-treated mice have more young neurons than untreated mice, but their neurons had more branch-like extensions, called dendrites, than did neurons from untreated mice. Those branches are important for making connections with other neurons and wiring cells into the larger network of the brain.

The researchers gave the mice a behavioral test to see whether having more newly mature neurons was important for changing how the brain works. For the test, the mice don’t get any food for a day. Then researchers place the mice in unfamiliar cages with food pellets in the middle of the box. The mice usually cower in the corner, but after about 2 weeks with Prozac treatment the rodents approach the food. Neither untreated mice nor Prozac-treated mice whose hippocampi have been irradiated with X rays to prevent new neuron formation seek out the food. The result indicates that the birth and maturation of neurons in the hippocampus is important for Prozac to do its job, Hen says.

But it may not be the only way the antidepressant works, he says.

“We still don’t know, of all the effects Prozac has on young neurons, which ones are important,” Hen says.

It also isn’t clear exactly how the hippocampus figures into depression, says Randy Blakely, a neuroscientist from Vanderbilt University in Nashville, Tenn. The brain region may be peripherally involved in regulating mood through connected areas, such as the amygdala, which helps process emotions.

Antidepressants may trigger changes in the hippocampus that relieve symptoms of depression but may not target the underlying cause of the illness, Blakely says. Still, learning how antidepressants work gives clues to how the brain is wired and what goes wrong in mental illness, he says.

“We need these leads to understand the cellular and circuit changes that occur with chronic drug administration to learn what the entire system is doing,” Blakely says.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.