Establishment of an Animal Model of Depression: The Serotonin Transporter Knockout Rat

Major depressive disorder (MDD) is a serious and debilitating psychiatric illness found of increasing prevalence. Despite this, our current first line treatments have been shown to lack efficacy and possess a high non-response rate. Most new pharmacological developments have not shown efficacy in humans, likely due to our current models being outdated. This thesis attempts to use a range of novel approaches, integrating behavioural, physiological, and biological methods to provide support for the use of the serotonin transporter knockout (SERT-KO) rat to model components of MDD in humans. Social anhedonia is assessed through conditioned place preference and play behaviour analysis, demonstrating significantly reduced reward sensitivity in SERT-/- animals. Comorbid anxiety is assessed using a modified successive alleys test, whereby SERT-/- animals demonstrate increased anxiety behaviour, which persist over the course of the experiment. The assessment of heart rate variability, a physiological correlate of MDD was impacted by time constraints, however suggests a likely reduction to be present in the SERT-/- animals. Finally, neurogenesis was found to be significantly increased in SERT-/- animals during early development (PND7), demonstrating neurodevelopmental alterations associated with reduced SERT expression. These data demonstrate that the SERT knockout rat possesses many deficits associated with MDD, thus being a likely candidate for novel pharmacological development. A final pilot experiment was conducted using MALDI-TOF to provide a method of examining potentially thousands of compounds in brain and cardiac tissue with high spatial definition. Applications and implication of this research are discussed in detail with suggestions for future studies being presented.