Abstract
The selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLU, Prozac®) is commonly prescribed for depression in pregnant women. This results in SSRI exposure of the developing fetus. However, there are knowledge gaps regarding the impact of SSRI exposure during development. Given the role of serotonin in brain development and its cross-talk with sex hormone function, we investigated effects of developmental exposure to pharmacologically relevant concentrations of FLU (3 and 30 nM (measured)) on brain neurotransmitter levels, gonadal differentiation, aromatase activity in brain and gonads, and the thyroid system, using the Xenopus tropicalis model. Tadpoles were chronically exposed (8 weeks) until metamorphosis. At metamorphosis brains were cryosectioned and levels of serotonin, dopamine, norepinephrine, and their metabolites 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, and homovanillic acid were measured in discrete regions (telencephalon, hypothalamus and the reticular formation) of the cryosections using high-performance liquid chromatography. Exposure to 30 nM FLU increased the concentration of 5-hydroxyindoleacetic acid in hypothalamus compared with controls. FLU exposure did not affect survival, time to metamorphosis, thyroid histology, gonadal sex differentiation, or aromatase activity implying that the effect on the serotonergic neurotransmitter system in the hypothalamus region was specific. The FLU concentration that impacted the serotonin system is lower than the concentration measured in umbilical cord serum, suggesting that the serotonin system of the developing brain is highly sensitive to in utero exposure to FLU. To our knowledge this is the first study showing effects of developmental FLU exposure on brain neurochemistry. Given that SSRIs are present in the aquatic environment the current results warrant further investigation into the neurobehavioral effects of SSRIs in aquatic wildlife.
Highlights
Fluoxetine (FLU, ProzacH) is a selective serotonin reuptake inhibitor (SSRI), which increases extracellular serotonin levels and serotonin neurotransmission
The present study shows that chronic exposure to FLU during development impacts the serotonergic system in the developing brain
Considering that FLU is frequently prescribed to pregnant women [37,38,39], the finding that the developing serotonergic system was affected at FLU concentrations lower than the mean measured concentration in umbilical cord serum is of particular interest
Summary
Fluoxetine (FLU, ProzacH) is a selective serotonin reuptake inhibitor (SSRI), which increases extracellular serotonin levels and serotonin neurotransmission. It is commonly prescribed for depression, compulsive behaviours, and eating disorders. FLU is one of the SSRIs prescribed to pregnant women. In a study of pregnant women taking FLU the mean serum concentration was 81.4 mg/L and the mean umbilical-cord serum concentration was 60.5 mg/L which implies fetal exposure [1]. FLU is designed to interfere with the serotonin system of the adult brain, and our knowledge on the effects of developmental SSRI exposure is still very limited. Studies on the effects of FLU on neurotransmitter levels in the brain of developing individuals are highly relevant. To the best of our knowledge, effects of developmental FLU exposure on brain neurochemistry are not known
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