AbstractIrregularities of the Hypothalamic Pituitary Adrenal (HPA) axis are implicated in stress-related mood disorders. The ensuing long-term elevations in circulating glucocorticoids are associated with neurobiological changes seen in depression. This thesis aims to identify some of the brain mechanisms by which exposure to chronic stress may lead to depression using a preclinical experimental approach.
The role of the serotonin system in the aetiology of mood disorders is well established, although this is not considered to be the only factor which causes these mood disorders. Interactions between the serotoninergic, peptidergic and endocannabinoid systems in response to glucocorticoids have been proposed. As all three neurotransmitter systems are involved in the regulation of the HPA axis, they are implicated in the dysfunction which is seen in depression. Furthermore, oxytocin, vasopressin and endocannabinoids are known to influence serotonergic neurotransmission and therefore it is pertinent to understand how glucocorticoids directly and indirectly impact serotonergic neurotransmission. In this thesis, the effect of chronic exposure to corticosterone on the serotonergic system is determined and also the relative contribution of the peptidergic and endocannabinoid systems to stress-induced mood disorders is considered. In addition, glucocorticoid-dependant receptor changes in these systems are related to neurotransmitter activity in brain regions involved in responses to stress. This has not previously been studied nor have the simultaneous effects of glucocorticoids on the serotonergic, peptidergic and endocannabinoid systems.
Here, preclinical approaches are applied to investigate the above mentioned receptor systems and their involvement in depression resulting from exposure to chronic stress. Administration of exogenous corticosterone (400 μg/mL) to rats for 21 days, via addition to drinking water, resulted in changes in expression of central 5-HT1A, oxytocin, vasopressin 1a and CB1 receptors. This dose was selected as it has previously shown to induce depression-like behaviour in rats and also hippocampal atrophy similar to that seen in depressed patients (Magarinos et al 1998; Donner et al., 2012). In order to understand how these changes relate to the central concentrations of endogenous ligands, the concentration of serotonin, 5-HIAA, oxytocin and vasopressin was also measured in brain tissue.
Here, circulating corticosterone concentration was increased, as it is in chronic stress and in some depressed patients. Binding of the post synaptic 5-HT1A receptor was upregulated in response to chronic stress in the form of elevated corticosterone concentration without a concomitant change in serotonin turnover suggesting that elevated corticosterone exposure modulates the 5-HT1A receptor independently of serotonin turnover. Whereas presynaptic 5-HT1A receptor binding was unaffected. In addition, chronic corticosterone exposure, as can be seen in depression, resulted in a decrease in binding to the oxytocin receptor in the hypothalamus associated with an increase in oxytocin concentration suggesting possible internalisation of the oxytocin receptor in this region. Conversely, there was an upregulation of the oxytocin receptor in the septal nuclei and raphé, with no associated change in oxytocin content in the same regions. Moreover, vasopressin 1a receptor binding was increased in septal nuclei and PODG subregion of the dorsal hippocampus, but decreased in the hypothalamus. There was no change in vasopressin content in any brain region sampled, suggesting that these may be independent of peptide concentration. For the CB1 receptor, elevated corticosterone concentration, indicative of chronic stress, resulted in a decrease in receptor binding was found in the striata and raphé after chronic corticosterone treatment.
Taken together, in particular the effect on receptor binding in the raphé, the present data suggest that elevated corticosterone exposure may modulate serotonergic neurotransmission via the oxytocin and CB1 receptor. In addition, the hypothalamic peptidergic responses imply a potential role in glucocorticoid-induced dysregulation of the HPA axis. These changes may help further elucidate their respective roles in depression and stress related mood disorders.
In conclusion, the work presented in this thesis shows that the response to glucocorticoids is multifaceted and that there are changes observed in multiple neurotransmitter systems which regulate the HPA axis. Thus, the combined effect of the neurotransmitter systems studied here is of relevance to stress related mood disorders.
|Date of Award||2013|
|Supervisor||Jolanta Opacka Juffry (Supervisor) & Ella Hirani (Supervisor)|
Effects of glucocorticoid overload on central regulatory systems involved in responses to stress – preclinical investigations into putative molecular targets in neuroimaging of stress-related mood disorders
Ahmad, R. (Author). 2013
Student thesis: Doctoral Thesis