Developmental fluoxetine exposure differentially alters central and peripheral measures of the HPA system in adolescent male and female offspring

Abstract

A significant number of women suffer from depression during pregnancy and the postpartum period. Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat maternal depression. While maternal stress and depression have long-term effects on the physical and behavioural development of offspring, numerous studies also point to a significant action of developmental exposure to SSRIs. Surprisingly, preclinical data are limited concerning the combined effect of maternal depression and maternal SSRI exposure on neurobehavioural outcomes in offspring. Therefore, the aim of the present study was to determine how maternal fluoxetine treatment affects the developing HPA system of adolescent male and female offspring using a model of maternal adversity. To do this, gestationally stressed and non-stressed Sprague–Dawley rat dams were chronically treated throughout lactation with either fluoxetine (5 mg/kg/day) or vehicle. Four groups of male and female adolescent offspring were used: (1) Prenatal Stress + Fluoxetine, (2) Prenatal Stress + Vehicle, (3) Fluoxetine alone, and (4) Vehicle alone. Primary results show that developmental fluoxetine exposure, regardless of prenatal stress, decreases circulating levels of corticosterone and reduces the expression of the glucocorticoid receptor (GR), and its coactivator the GR interacting protein (GRIP1), in the hippocampus. Interestingly, these effects occurred primarily in male, and not in female, adolescent offspring. Together, these results highlight a marked sex difference in the long-term effect of developmental exposure to SSRI medications that may differentially alter the capacity of the hippocampus to respond to stress.

Introduction

Emerging clinical and preclinical evidence is demonstrating that exposure to maternal mood disorders, maternal stress and other aspects of maternal adversity programme the developing hypothalamic–pituitary–adrenal (HPA) axis (Levine, 2005, Kapoor and Matthews, 2008; Glover et al., 2010; Harris and Seckl, 2011). In humans, maternal stress and depression have been associated with altered neonatal stress regulation (Davis et al., 2011), methylation status on the human glucocorticoid receptor (GR) gene (NR3C1) in neonates (Oberlander et al., 2008b), and elevated basal levels of salivary or urinary cortisol in infants (Field et al., 2004, Field et al., 2006, Brennan et al., 2008). Perinatal exposure to maternal adversity, particularly anxiety, also has long-lasting effects into adolescence with adolescent girls showing blunted diurnal cortisol levels and increased depressive symptoms (Van den Bergh et al., 2008). Similarly, using animal models, it has been well established that maternal adversity significantly and persistently impacts the development of the HPA system (Maccari et al., 2003, Glover et al., 2010, Green et al., 2011) through multiple facets such as changes in diurnal fluctuation in basal corticosterone, prolongation of the corticosterone response to novelty, and reductions in GR expression in the hippocampus of adult offspring (Maccari et al., 2003, Green et al., 2011).

In response to maternal adversity and maternal mood disorders, a significant number of women are prescribed selective serotonin reuptake inhibitor (SSRI) medications during pregnancy and the postpartum period (Oberlander et al., 2006, Ververs et al., 2006, Cooper et al., 2007). These medications cross the placental barrier and are also found in breast milk, therefore reaching the infant both pre- and post-natally (Hendrick et al., 2001, Gentile, 2005). SSRI medications are thought to alleviate symptoms of mood disorders in adults partly by normalizing the function of the HPA axis (Barden et al., 1995). However, physiological serotonin plays an integral part in the development and function of the HPA axis (Meaney et al., 1994, Laplante et al., 2002, Andrews and Matthews, 2004). For example, decreasing serotonin input to the hippocampus during the early postnatal period results in decreased GR expression in adult rat offspring (Mitchell et al., 1990), and in vitro work has shown that serotonin can increase GR mRNA levels in foetal hippocampal cells (Erdeljan et al., 2005). Therefore, questions have been raised about the impact of perinatal exposure to SSRIs on the developing HPA system.

Recent clinical research demonstrates that prenatal exposure to psychotropic medications, such as SSRIs, attenuates basal salivary cortisol levels (Brennan et al., 2008) and ‘blunts’ the response to acute stress (Oberlander et al., 2002, Oberlander et al., 2005) in infants. Prenatal SSRI exposure also results in increased neonatal serum corticosteroid binding globulin (CBG) levels at birth (Pawluski et al., 2012a). In animal models, treatment with fluoxetine, a popular SSRI, during gestation results in increased foetal plasma cortisol levels in sheep (Morrison et al., 2004), and fluoxetine treatment during the early postnatal period can decrease serum corticosterone response to stress in prenatally stressed mouse offspring (Ishiwata et al., 2005).

To date, most preclinical research in this area has investigated the developmental impact of perinatal SSRI exposure in healthy mothers and offspring (Cabrera-Vera et al., 1997, Olivier et al., 2011a, Olivier et al., 2011b, Pawluski et al., 2012a), and very little research has analysed the neurodevelopmental effects of perinatal fluoxetine exposure using a model of maternal adversity (Ishiwata et al., 2005, Rayen et al., 2011, Pawluski, in press). In addition, much less research has looked at how perinatal exposure to SSRI medications, via the mother, affects offspring outcomes during adolescence, a period of development characterized by marked physiological changes and increased vulnerability to stress (Romeo and McEwen, 2006, McCormick and Mathews, 2007, Romeo, 2010). Therefore, the aim of this study was to investigate the developmental effects of fluoxetine exposure, using a model of maternal adversity, on peripheral and central measures of the HPA system in adolescent rat offspring. For this work we investigated peripheral levels of corticosterone and its binding globulin, CBG, as well as hippocampal expression of the GR and mineralocorticoid receptor (MR) in adolescent male and female offspring. Furthermore, to investigate the functionality of GRs and MRs, we looked at the expression of the GR interacting protein (GRIP1), a steroid receptor coactivator, which is required for the action of GRs and MRs during transcription (Hong et al., 1996, Charlier, 2009, Tetel et al., 2009). Knowledge of the long-term effects of maternal adversity and perinatal SSRI medication exposure on the developing HPA system is fundamental to understanding how these factors affect key physiological systems later in life.