Year

2019

Degree Name

Doctor of Philosophy

Department

School of Medicine

Abstract

Antidepressant drugs (ADDs) are one of the most widely prescribed drug classes in the world, administered to over 10% of the population for the treatment of major depressive and anxiety-related disorders. Similarly, approximately 10% of pregnant women are prescribed ADDs for the treatment of depression. Whilst various classes of ADDs exist, selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed to pregnant women (in 80% of cases). SSRIs such as Fluoxetine bind to the serotonin transporter (SERT) blocking the reabsorption of serotonin by the presynaptic neuron resulting in increased serotonin levels at the synapse. The antidepressant properties of SSRIs are thought to be mediated largely through downstream mechanisms such as increases in brain derived neurotrophic factor (BDNF) and subsequent increases in neuroplasticity and neurogenesis related processes in the prefrontal cortex (PFC) and hippocampus (HPC). The serotonergic system and downstream signaling pathways such as that associated with brain derived neurotrophic (BDNF), are also critical for normal neurodevelopment where they play a key role in neurodevelopmental processes. Furthermore, the serotonergic system regulates the development and maturation of the brain’s primary excitatory neurotransmitter system, the glutamatergic system. This raises concerns about exposure of the developing foetus and newborns to SSRIs as it has been shown that SSRIs administered during pregnancy cross the placenta and are also excreted in breast milk. This concern is accentuated by studies demonstrating associations between abnormal development of the serotonergic, BDNF and glutamatergic systems and several psychiatric and behavioural disorders. Recent clinical studies have suggested that maternal SSRI use is associated with increased risk for neurodevelopmental and mood disorders such as Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD) and depression in exposed offspring. Conversely, several studies have reported no significant association between maternal SSRI use and offspring risk for any neurodevelopmental or psychiatric abnormalities or disorders. Furthermore, there is an inherent difficulty in discerning the effects of maternal SSRI use on offspring from that of the innate maternal depression or mood disorder, given that they generally occur together in the clinic. In addition, untreated maternal mood disorders such as depression have themselves been associated with increased risk for neurodevelopmental and psychiatric disorders in offspring. Determining the effects of maternal SSRI treatment on offspring behavior in rodent models of innate depression and understanding the neurobiological changes is important to determine the clinical risk associated with maternal SSRI use in the context of the underlying maternal psychopathology. Thus, the aim of this thesis was to investigate the effects of maternal SSRI (Fluoxetine) treatment on offspring behavior and neurobiology relevant to neurodevelopmental and psychiatric disorders. Specifically, by comparing the effects of maternal SSRI treatment in a rodent model of innate depression (Wistar-Kyoto (WKY)) to that of a standard laboratory rat strain (Sprague-Dawley (SD)), we aimed to test the hypotheses that maternal depressive phenotypes (which model depressive disorders) could influence the effects of SSRI exposure on offspring neurobiology, related behavior, and ultimately risk for neurodevelopmental disorders in the clinic. As a secondary aim, we sought to determine the neurobiological profile of the WKY rat compared to a control strain, to test the hypothesis that alterations in underlying neurobiology contribute to the strain’s depressive-like phenotype, as it does in the clinic.

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Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.