Developmental Fluoxetine Exposure Alters Behavior and Neuropeptide Receptors in the Prairie Vole.

Rebecca H Lawrence,Michelle C Palumbo,Caleigh D Guoynes,Karen L Bales,Sara M Freeman

doi:10.3389/fnbeh.2020.584731

Abstract

Developmental exposure to selective serotonin reuptake inhibitor (SSRI) increases the risk of Autism Spectrum Disorder (ASD), however, the underlying neurobiology of this effect is not fully understood. Here we used the socially monogamous prairie vole as a translational model of developmental SSRI exposure. Paired female prairie voles (n = 20) were treated with 5 mg/kg subcutaneous fluoxetine (FLX) or saline (SAL) daily from birth of the second litter until the day of birth of the 4th litter. This design created three cohorts of FLX exposure: postnatal exposure in litter 2, both prenatal and postnatal exposure in litter 3, and prenatal exposure in litter 4. Post-weaning, subjects underwent behavioral testing to detect changes in sociality, repetitive behavior, pair-bond formation, and anxiety-like behavior. Quantitative receptor autoradiography was performed for oxytocin, vasopressin 1a, and serotonin 1a receptor density in a subset of brains. We observed increased anxiety-like behavior and reduced sociality in developmentally FLX exposed adults. FLX exposure decreased oxytocin receptor binding in the nucleus accumbens core and central amygdala, and vasopressin 1a receptor binding in the medial amygdala. FLX exposure did not affect serotonin 1A receptor binding in any areas examined. Changes to oxytocin and vasopressin receptors may underlie the behavioral changes observed and have translational implications for the mechanism of the increased risk of ASD subsequent to prenatal SSRI exposure.

Highlights

In humans, antidepressant medication, most frequently a selective serotonin reuptake inhibitor (SSRI), is commonly prescribed to pregnant and lactating women with major depression (Boukhris et al, 2016)
We used the prairie vole as a translational model of developmental SSRI exposure
Understanding the etiology of the increased risk of Autism Spectrum Disorder (ASD) associated with developmental SSRI exposure is an area of research which can greatly benefit from animal models

Summary

Introduction

Antidepressant medication, most frequently a selective serotonin reuptake inhibitor (SSRI), is commonly prescribed to pregnant and lactating women with major depression (Boukhris et al, 2016). Developmental SSRIs in Voles may be side effects of SSRIs leading to preterm labor, altered gestational length and early delivery (Hayes et al, 2012), congenital heart malformations (Knudsen et al, 2014; Gentile, 2015a), persistent pulmonary hypertension (Grigoriadis et al, 2014), and adverse neurodevelopmental outcomes (El Marroun et al, 2014; Glover and Clinton, 2016). There is reason for concern about the effects of early exposure to SSRIs on the developing brain. SSRIs can cross the placental barrier (Hendrick et al, 2003; Rampono et al, 2009) and enter into breast milk (Kristensen et al, 1999; Rampono et al, 2000). Exposed infants show altered brain activity measured via EEG (Videman et al, 2017)

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