Perinatal fluoxetine has enduring sexually differentiated effects on neurobehavioral outcomes related to social behaviors

Abstract

Selective serotonin reuptake inhibitor medications (SSRIs) are prescribed to up to 10% of pregnant women to treat maternal mood disorders. Exposure to these medications in-utero has raised concerns about altered neurobehavioral outcomes; most recently those related to peer-to-peer social interactions and play. While clinical data show that both perinatal SSRIs (pSSRI) and maternal stress can contribute to social behavioral changes in children, minimal animal work has investigated the effects of pSSRIs in relevant models of maternal stress or the long-term implications of these effects. Therefore the aim of this work was to investigate the long-term effects of pSSRI exposure to fluoxetine on social behaviors, the hypothalamic pituitary adrenal system (HPA) and hippocampal plasticity in adult male and female rat offspring using a model of pre-gestational maternal stress. Adult Sprague-Dawley female and male rat offspring from the following four groups were utilized: 1.Control + Vehicle, 2. Control + Fluoxetine, 3.Pre-gestational Stress + Vehicle, 4. Pre-gestational Stress + Fluoxetine (n=8-16/female/age groups, n=8-14/male/age groups). Main findings show pSSRIs increased social investigation in adult females and increased social play (pouncing, nape attacks) in adult males. Perinatal SSRIs also had sexually differentiated effects on hippocampal neurogenesis and GR density. Pre-gestational stress had enduring effects by decreasing social investigation and hippocampal neurogenesis in adult males. Thus pSSRIs, as well as pre-gestational maternal stress, have significant long-term effects on social neurobehavioral outcomes which differ in males and females. This suggests that it would be valuable to consider fetal-sex specific treatments for maternal mental illness.

Third-party prosocial behavior in adult female rats is impaired after perinatal fluoxetine exposure

“…In terms of social interaction at adulthood, the findings are more controversial. Some studies have indicated that developmental SSRI exposure decreases social interaction in either male offspring [25,27] or female offspring [31], while others found an increase in sniffing behavior towards conspecifics [32,33]. When looking at the motivation for social interaction in particular, the majority found that SSRI exposure negatively affects the motivation to start social contact [26,28,29,34].…”

Gestational Factors throughout Fetal Neurodevelopment: The Serotonin Link

“…Studies showing a decrease in an offspring's 5-HT levels in response to maternal stress suggest alterations within the prefrontal limbic circuitry. Pregestational and prenatal stress reduced hippocampal neurogenesis and reduced synaptic plasticity (synaptophysin and PSD-95 densities) in the mPFC and hippocampus of adolescent rats [150,151,155,160]. Moreover, prenatal chronic unpredictable stress caused hippocampal structural modifications (decreases in ventral hippocampal sub-region volume together with a decrease in number of neurons; increases in dorsal hippocampal sub-region volume) [153].…”

“…Different maternal stress models increased fetal and adult offspring plasma and serum (baseline and stress-induced) corticosterone levels, corticotrophin releasing factor, and the hormone adrenocorticotropic and increased amygdala corticotrophin releasing factor gene expression [148,153,154,158,159]. Furthermore, diminished hippocampal glucocorticoid receptor levels and density were detected [158,160]. Of note, maternal stress-induced fetal changes in serum corticosterone and corticotrophin releasing factor have been suggested to cause the discussed 5-HT-ergic modifications.…”

“…Prenatal restraint stress and pregestational chronic unpredictable stress, respectively, decreasing and increasing offspring's 5-HT metabolism, reduced social behavior in juvenile and adult offspring. Mechanisms underlying these behavior alterations probably include the above discussed reduced hippocampal plasticity and over-activated HPA-axis function [150,152,160]. Reduced social behavior has been suggested to be a potential indicative for the development of ASD-like behaviors [152].…”

“…Bond et al [227] Maloney et al [226] (social preference) Ehrlich et al [218] Khatri et al [205] Olivier et al [209] Rodriguez-Porcel et al [228] Simpson et al [229] Silva et al [222] Yu et al [223] Zimmerberg & Germeyan [224] Houwing et al [230] Gemmel et al [150] (normalised stress effect) Gemmel et al [160] (irrespective of stress effect) Ko et al [206] Maloney et al [226] (social interaction) Meyer et al [221] Svirsky et al [231] Zaidan et al [232] A few studies investigated the effects of gestational SSRI exposure on the 5-HT system of the offspring. Offspring of pregnant mice that were perinatally treated with fluoxetine and sertraline or prenatally with escitalopram exhibited whole brain decreases in MAOA expression and whole brain increases in cortical expression of TPH2, 5-HTT, and 5-HT 1A/2A/C receptors [218,221,227].…”