How a popular antidepressant drug could rewire the brain

Summary: Fluoxetine rearranges nerve fibers in the hippocampus of mice, a new study reports.

Source: American Chemical Society

Prozac, the trade name for the drug fluoxetine, was introduced to the U.S. market for the treatment of depression in 1988. Thirty years later, scientists still don’t know exactly how the medication exerts its mood-lifting effects. Now, researchers report that, in addition to the drug’s known action on serotonin receptors, fluoxetine could rearrange nerve fibers in the hippocampus of mouse brains. They report their results in ACS Chemical Neuroscience.

Fluoxetine was the first drug in the class of compounds known as selective serotonin reuptake inhibitors (SSRIs) to be approved by the U.S. Food and Drug Administration. SSRIs are thought to work primarily by increasing the amount of the neurotransmitter serotonin that is available for signaling between neurons, but researchers suspected that other processes could be going on. In past studies, Massimo Pasqualetti and colleagues showed that genetic depletion and restoration of serotonin in mice could rearrange hippocampal nerve fibers. Now, they wanted to see if the more subtle changes in serotonin availability caused by fluoxetine treatment could have the same effect.

This shows blister packs of prozac
Fluoxetine was the first drug in the class of compounds known as selective serotonin reuptake inhibitors (SSRIs) to be approved by the U.S. Food and Drug Administration. The image is in the public domain.

To find out, the team used a mouse model that expresses green fluorescent protein (GFP) in the neurons that make serotonin in the brain. They gave these mice fluoxetine in their drinking water for 28 days and then compared the GFP signals in their brains with those of control mice that were not given the drug. The mice taking fluoxetine had serotonin-producing nerve fibers that were fewer in number and smaller in diameter than those of control mice, but only in the hippocampus. Although the consequences of this structural rearrangement are currently unknown, it could contribute to how antidepressants exert their therapeutic effect, the researchers say.

Funding: The authors acknowledge funding from the Italian Ministry of Education, University and Research, Toscana Life Sciences Foundation, the University of Pisa and Santa Lucia IRCCS Foundation.

About this neuroscience research article

American Chemical Society
Media Contacts:
Katie Cottingham – American Chemical Society
Image Source:
The image is in the public domain.

Original Research: Closed access
“Fluoxetine Induces Morphological Rearrangements of Serotonergic Fibers in the Hippocampus”. Serena Nazzi, Giacomo Maddaloni, Marta Pratelli, Massimo Pasqualetti.
ACS Chemical Neuroscience. doi:10.1021/acschemneuro.8b00655


Fluoxetine Induces Morphological Rearrangements of Serotonergic Fibers in the Hippocampus

Serotonin (5-HT)-releasing fibers show substantial structural plasticity in response to genetically induced changes in 5-HT content. However, whether 5-HT fibers appear malleable also following clinically relevant variations in 5-HT levels that may occur throughout an individual’s life has not been investigated. Here, using confocal imaging and 3D modeling analysis in Tph2GFP knock-in mice, we show that chronic administration of the antidepressant fluoxetine dramatically affects the morphology of 5-HT fibers innervating the dorsal and ventral hippocampus resulting in a reduced density of fibers. Importantly, GFP fluorescence levels appeared unaffected in the somata of both dorsal and median raphe 5-HT neurons, arguing against potential fluoxetine-mediated down-regulation of the Tph2 promoter driving GFP expression in the Tph2GFP mouse model. In keeping with this notion, mice bearing the pan-serotonergic driver Pet1-Cre partnered with a Cre-responsive tdTomato allele also showed similar morphological alterations in hippocampal 5-HT circuitry following chronic fluoxetine treatment. Moreover 5-HT fibers innervating the cortex showed proper density and no overt morphological disorganization, indicating that the reported fluoxetine-induced rearrangements were hippocampus specific. On the whole, these data suggest that 5-HT fibers are shaped in response to subtle changes of 5-HT homeostasis and may provide a structural basis by which antidepressants exert their therapeutic effect.

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