Developmental fluoxetine and prenatal stress effects on serotonin, dopamine, and synaptophysin density in the PFC and hippocampus of offspring at weaning.

Selective serotonin reuptake inhibitor medication exposure during the perinatal period can have a long term impact in adult offspring on neuroplasticity and the serotonergic system, but the impact of these medications during early development is poorly understood. The aim of this study was to determine the effects of developmental exposure to the SSRI, fluoxetine, on the serotonergic system, dopaminergic system, and synaptophysin density in the prefrontal cortex and hippocampus, as well as number of immature neurons in the dentate gyrus, in juvenile rat offspring at weaning. To model aspects of maternal depression, prenatal restraint stress was used. Sprague-Dawley rat offspring were exposed to either prenatal stress and/or fluoxetine. Main findings show that developmental fluoxetine exposure to prenatally stressed offspring decreased 5-HT and 5-HIAA levels and altered the dopaminergic system in the hippocampus. Prenatal stress, regardless of fluoxetine, increased synaptophysin density in the PFC. This work indicates that early exposure to maternal stress and SSRI medication can alter brain monoamine levels and synaptophysin density in offspring at weaning.

Stress and the pregnant female: Impact on hippocampal cell proliferation, but not affective-like behaviors.

Fifteen percent of women worldwide develop postpartum depression; however, many women also suffer from mood disorders during pregnancy. Our knowledge of how these stress-related disorders affect the neurobiology of the mother is very limited. In animal models, depressive-like behavior is often associated with repeated stress and alterations in adult neurogenesis in the hippocampus. However, research has yet to investigate the effect of stress on affective-like behavior and hippocampal neurogenesis in the pregnant female. The aim of the present study was to determine whether stress during gestation alters affective-like behaviors, corticosterone levels, and hippocampal cell proliferation and new cell survival in the pregnant female, and whether these effects differ from virgin females. Age-matched pregnant and virgin Sprague-Dawley rats were divided into two conditions: 1) stress and 2) control. Females in the stress condition were repeatedly restrained during gestation, and at matched time points in virgin females. Affective-like behaviors were assessed at the end of gestation, and at matched time points in virgin females. Results demonstrate that regardless of repeated restraint stress, pregnant females have increased anxiety-like behavior, decreased depressive-like behavior, and lower corticosterone levels, compared to non-stressed, and at times stressed, virgin females. In addition, stressed virgin females have lower levels of depressive-like behavior compared to control virgin females. Interestingly, hippocampal cell proliferation was increased in both virgin and pregnant females after stress. Understanding how stress affects the female during different reproductive states will aid in improving the health and well being of the mother and child.

Gestational stress and fluoxetine treatment differentially affect plasticity, methylation and serotonin levels in the PFC and hippocampus of rat dams.

Women are more likely to develop depression during childbearing years with up to 20% of women suffering from depression during pregnancy and in the postpartum period. Increased prevalence of depression during the perinatal period has resulted in frequent selective serotonin reuptake inhibitor (SSRI) antidepressant treatment; however the effects of such medications on the maternal brain remain limited. Therefore, the aim of the present study is to investigate the effects of the SSRI medication, fluoxetine, on neurobiological differences in the maternal brain. To model aspects of maternal depression, gestational stress was used. Sprague-Dawley rat dams were exposed to either gestational stress and/or fluoxetine (5mg/kg/day) to form the following four groups: 1. Control+Vehicle, 2. Stress+Vehicle, 3. Control+Fluoxetine, and 4. Stress+Fluoxetine. At weaning maternal brains were collected. Main findings show that gestational stress alone increased synaptophysin and serotonin metabolism in the cingulate cortex2 region of the cortex while fluoxetine treatment after stress normalized these effects. In the hippocampus, fluoxetine treatment, regardless of gestational stress exposure, decreased both global measures of methylation in the dentate gyrus, as measured by Dnmt3a immunoreactivity, as well as serotonin metabolism. No further changes in synaptophysin, PSD-95, or Dnmt3a immunoreactivity were seen in the cortical or hippocampal areas investigated. These findings show that gestational stress and SSRI medication affect the neurobiology of the maternal brain in a region-specific manner. This work adds to a much needed area of research aimed at understanding neurobiological changes associated with maternal depression and the role of SSRI treatment in altering these changes in the female brain.

Developmental exposure to SSRIs, in addition to maternal stress, has long-term sex-dependent effects on hippocampal plasticity.

RATIONALE: During pregnancy and postpartum period, 20 % of women are affected by depression, which is a growing health concern. Selective serotonin reuptake inhibitor (SSRI) medications are popular treatments for maternal depression; however, the effect of maternal depression and perinatal SSRI exposure on offspring's neural development needs further investigation. OBJECTIVES: This study aims to determine the role of developmental fluoxetine exposure on hippocampal plasticity in the adult offspring. METHODS: Sprague-Dawley rat offspring were exposed to fluoxetine beginning on postnatal day 1. Offspring were also exposed to prenatal maternal stress. Four groups of male and female offspring were used: (1) prenatal stress + fluoxetine, (2) prenatal stress + vehicle, (3) fluoxetine alone, and (4) vehicle alone. Hippocampi were analyzed for levels of cell proliferation, immature neurons, and new cell survival (3 weeks after 5-bromo-2-deoxyuridine injection) in the granule cell layer, as well as synaptophysin density in the CA3 region and granule cell layer. TPH staining was assessed in the dorsal raphe nucleus. RESULTS: Developmental fluoxetine exposure to prenatally stressed offspring reversed the effect of prenatal stress or fluoxetine exposure alone on the number of immature neurons. Prenatal stress alone, regardless of developmental exposure to fluoxetine, markedly decreased hippocampal cell proliferation and tended to decrease new cell survival. Furthermore, in adult female offspring, developmental fluoxetine exposure greatly increased new cell survival and significantly decreased synaptophysin density in the granule cell layer. CONCLUSIONS: There are long-term effects of developmental SSRI exposure on hippocampal plasticity that is differentially affected by expose to maternal adversity and offspring sex.

Developmental fluoxetine exposure facilitates sexual behavior in female offspring.

RATIONALE: A growing number of infants are being exposed to selective serotonin reuptake inhibitor (SSRI) medications during the perinatal period. SSRIs target the serotoninergic system and are a popular treatment for maternal mood disorders. Serotonin itself plays a key role in the sexual differentiation through its role in the development of the hypothalamic-pituitary-gonadal axis, and previous research has shown that developmental SSRI exposure has an effect on sexual behavior in male offspring. OBJECTIVES: Our aim was to determine the role of developmental exposure to a popular SSRI medication, fluoxetine, on sexual differentiation of the brain and behavior in female offspring using a rodent model of maternal adversity. METHODS: Stressed and non-stressed Sprague-Dawley rat dams were chronically treated with either fluoxetine (5 mg/kg/day) or vehicle beginning on postnatal day 1. Four groups of female offspring were used: (1) control + vehicle, (2) control + fluoxetine, (3) prenatal stress + vehicle, and (4) prenatal stress + fluoxetine. RESULTS: Primary results show that in adult female offspring, developmental fluoxetine exposure facilitates proceptive and receptive behaviors with a significant increase in the number of proceptive behaviors, a significant increase in the lordosis quotient, and a significant decrease in the rejection quotient. CONCLUSIONS: This research contributes in the understanding of the long-term impact developmental fluoxetine exposure on the hypothalamus-pituitary-gonadal (HPG) system in adult female offspring.

Developmental fluoxetine exposure and prenatal stress alter sexual differentiation of the brain and reproductive behavior in male rat offspring.

Depression during pregnancy and postpartum is a significant health problem and affects up to 20% of women. While selective serotonin reuptake inhibitor (SSRI) medications are the drug of choice for treatment of maternal depression, the combined effect of maternal depression and perinatal SSRI exposure on offspring development is poorly investigated. Our aim was to determine the role of exposure to fluoxetine during development on sexual behavior and sexually dimorphic brain structures in male offspring using a rodent model of maternal adversity. Sprague-Dawley rat dams were stressed during gestation and were chronically treated throughout lactation with either fluoxetine or vehicle beginning on postnatal day 1. Four groups of offspring were used: (1) Control+Vehicle, (2) Control+Fluoxetine, (3) Prenatal Stress+Vehicle, and (4) Prenatal Stress+Fluoxetine. We show here that developmental fluoxetine treatment decreases the anogenital distance in juvenile male offspring. In adult male offspring, maternal fluoxetine treatment results in a decrease in the number of intromissions, a longer latency to the first intromission, and a longer latency to the first ejaculation. Furthermore, developmental fluoxetine and/or prenatal stress decrease the area of the sexually dimorphic nucleus of the preoptic area (SDN-POA). Prenatal stress, but not exposure to developmental fluoxetine, decreases the number of tyrosine hydroxylase (TH)-positive cells in anteroventral periventricular nucleus (AVPv) and the volume of the posterior bed nucleus of the stria terminalis (pBST) in male offspring. These results provide important evidence for the long-term impact of maternal adversity and maternal fluoxetine use on the development of primary endocrinology systems in juvenile and adult male offspring.

Developmental fluoxetine exposure normalizes the long-term effects of maternal stress on post-operative pain in Sprague-Dawley rat offspring.

Early life events can significantly alter the development of the nociceptive circuit. In fact, clinical work has shown that maternal adversity, in the form of depression, and concomitant selective serotonin reuptake inhibitor (SSRI) treatment influence nociception in infants. The combined effects of maternal adversity and SSRI exposure on offspring nociception may be due to their effects on the developing hypothalamic-pituitary-adrenal (HPA) system. Therefore, the present study investigated long-term effects of maternal adversity and/or SSRI medication use on nociception of adult Sprague-Dawley rat offspring, taking into account involvement of the HPA system. Dams were subject to stress during gestation and were treated with fluoxetine (2×/5 mg/kg/day) prior to parturition and throughout lactation. Four groups of adult male offspring were used: 1. Control+Vehicle, 2. Control+Fluoxetine, 3. Prenatal Stress+Vehicle, 4. Prenatal Stress+Fluoxetine. Results show that post-operative pain, measured as hypersensitivity to mechanical stimuli after hind paw incision, was decreased in adult offspring subject to prenatal stress alone and increased in offspring developmentally exposed to fluoxetine alone. Moreover, post-operative pain was normalized in prenatally stressed offspring exposed to fluoxetine. This was paralleled by a decrease in corticosteroid binding globulin (CBG) levels in prenatally stressed offspring and a normalization of serum CBG levels in prenatally stressed offspring developmentally exposed to fluoxetine. Thus, developmental fluoxetine exposure normalizes the long-term effects of maternal adversity on post-operative pain in offspring and these effects may be due, in part, to the involvement of the HPA system.

Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence.

Depression during pregnancy and the postpartum period is a growing health problem, which affects up to 20% of women. Currently, selective serotonin reuptake inhibitor (SSRIs) medications are commonly used for treatment of maternal depression. Unfortunately, there is very little research on the long-term effect of maternal depression and perinatal SSRI exposure on offspring development. Therefore, the aim of this study was to determine the role of exposure to fluoxetine during development on affective-like behaviors and hippocampal neurogenesis in adolescent offspring in a rodent model of maternal depression. To do this, gestationally stressed and non-stressed Sprague-Dawley rat dams were treated with either fluoxetine (5 mg/kg/day) or vehicle beginning on postnatal day 1 (P1). Adolescent male and female offspring were divided into 4 groups: 1) prenatal stress+fluoxetine exposure, 2) prenatal stress+vehicle, 3) fluoxetine exposure alone, and 4) vehicle alone. Adolescent offspring were assessed for anxiety-like behavior using the Open Field Test and depressive-like behavior using the Forced Swim Test. Brains were analyzed for endogenous markers of hippocampal neurogenesis via immunohistochemistry. Results demonstrate that maternal fluoxetine exposure reverses the reduction in immobility evident in prenatally stressed adolescent offspring. In addition, maternal fluoxetine exposure reverses the decrease in hippocampal cell proliferation and neurogenesis in maternally stressed adolescent offspring. This research provides important evidence on the long-term effect of fluoxetine exposure during development in a model of maternal adversity.