The Developmental Role of Serotonin: A Comparison of Short- and Long-term Blockade of the Serotonin Transporter on Behavioural Outcomes in Adulthood
Serotonin is an important neurotransmitter that regulates a range of processes within the brain and is implicated in several psychiatric disorders. In addition, serotonin acts as a developmental signal during critical periods of prenatal development, influencing processes such as neuronal proliferation, migration, and synaptogenesis (Gaspar et al., 2003). The serotonin transporter (5- HTT) plays a key role in regulating extracellular serotonin levels and is the main target of selective-serotonin reuptake inhibitors (SSRIs), a class of drugs that have anti-anxiety and anti- depressive activity. SSRIs cause an acute increase in extracellular serotonin and are commonly prescribed as a treatment for depression and anxiety during pregnancy (Tran & Robb, 2015). Given that these drugs alter serotonin transmission and can pass to the developing fetus via the placenta, it is vital that the outcomes of prenatal SSRI exposure are investigated. In humans, a genetic variant of the gene that codes for the 5-HTT (SLC6A4) has been linked to increased risk for developing depression and anxiety (Caspi et al., 2003). The functional consequences of this genetic polymorphism are life-long alterations in 5-HTT activity, resulting in increased extracellular levels of serotonin (Nakamura et al., 2000). Given prenatal SSRI exposure results in a time-locked blockade of 5-HTT during critical periods of development, it follows that alterations in serotonin during development might similarly result in enhanced risk for depression and anxiety later in life. Outcomes in children prenatally exposed to SSRIs are difficult to study due to confounds of pre- existing maternal depression. Therefore, the current thesis presents two experiments that aimed to further investigate the role of altered extracellular serotonin levels during development in an animal model. Experiment one aimed to develop a method of voluntary oral administration of the SSRI fluoxetine to pregnant rat dams. This method was then applied in experiment two to create a time-locked blockade of 5-HTT during critical periods of development in an animal model of life-long 5-HTT blockade. The aim of experiment two was to directly assess the contribution of short- and long-term 5-HTT blockade on anxiety and depression phenotypes in adult male offspring. In addition, maternal behaviour was assessed to determine whether fluoxetine treatment had an influence on mother-pup interactions that could confound results. To test for anxiety and depression phenotypes, the novel affective disorder test (ADT) was used to assess anxiety behaviour and the deficits in anticipatory pleasure indicative of anhedonia. In the current study, fluoxetine treatment did not have an effect on litter outcomes or mother-pup interactions. Crucially, no significant group differences were found indicating that neither short- nor long- term blockade of 5-HTT resulted in increased anxiety- or depressive-like behaviours in the current experiment. However, limitations with methodological design limit the translatability of these results to the broader literature, and validation of the ADT is required before these results can be generalised beyond this thesis.