Murray, John Fraser; (2006) Biochemical, Behavioural and Cellular Studies of Chronic Antidepressant and Corticosterone Administration. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Despite the fact that major depressive disorder (MDD) is expected to become the single largest cause of injury and illness in the world by 2020 little is known regarding the underlying cause of the disease or the mechanism of action of antidepressants although the HPA axis and neurogenesis may be of importance in both processess. In this thesis I have attempted to further elucidate the links between the mechanism of action of antidepressants, disruption of the HPA axis and neurogenesis with particular focus on members of the Bcl-2 family of pro- and anti-apoptotic proteins. Results showed that disruption of the HPA axis in mice by elevating corticosterone via a pellet implant method caused robust behavioural changes in the forced swim test (FST) (following acute and 7 day administration but not 14 or 21 day administration) and the light/dark box (following chronic but not acute administration which was normalised following corticosterone withdrawal) indicative of a "depressed phenotype". Chronic corticosterone treatment also significantly decreased hippocampal neurogenesis (attenuated by antidepressant treatment) but failed to alter expression of the anti- or pro-apoptotic proteins Bcl-2 and BAX respectively indicating a role for a disrupted HPA axis in reduced hippocampal neurogenesis but not in increased apoptosis via changes in Bcl-2 or BAX expression. Conversely, antidepressants increased hippocampal neurogenesis and selectively increased hippocampal Bcl-2 without a corresponding change in BAX. Treatment with receptor subtype selective 5-HT antagonists indicated the involvement of the 5-HT1A and 5-HT2C receptor subtypes in the effects on Bcl-2. Central administration of Bcl-2 and BAX peptide fragments modulated monoamine systems increasing 5-HT metabolism and produced an antidepressant effect in the FST. Taken together results suggest a potential involvement for the Bcl-2 family of proteins in the mechanism of action of antidepressants and further supports the suggestion that chronically disrupted HPA axis function influences hippocampal neurogenesis.

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