Prenatal fluoxetine exposure induces life-long serotonin 5-HT3 receptor-dependent cortical abnormalities and anxiety-like behaviour

Selective serotonin reuptake inhibitors (SSRIs) are the first choice of drugs to treat depression and anxiety during pregnancy. However, there is evidence that in utero exposure to SSRIs leads to adverse effects in offspring. Here we show that in mice, the adverse effects of the widely used antidepressant and SSRI fluoxetine are critically dependent on the 5-HT3 receptor, the only ligand-gated ion channel in the family of serotonin receptors. In utero exposure to fluoxetine induces anxiety-like behavior in wildtype, but not in mice lacking the 5-HT3 receptor. In addition to this behavioral phenotype, these mice show life-long abnormalities of cortical cytoarchitecture, which can be reversed in vitro by pharmacological block of 5-HT3 receptors. Moreover, the effect of fluoxetine on the development of cortical neurons is absent in 5-HT3 receptor knockout mice. These findings pinpoint the pivotal role of serotonergic signaling during development and provide a novel basis to investigate the adverse effects of the use of fluoxetine during pregnancy.This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.

► Prenatal exposure to fluoxetine induces morphological abnormalities in the cortex.
► These abnormalities last life-long, but can be reversed in vitro.
► In addition, fluoxetine induces anxiety-like behavior in offspring.
► These adverse effects of fluoxetine critically depend on the 5-HT3 receptor.