Stress is increasingly identified as a risk factor for brain disease, but the underlying
processes are unkown. This thesis examines the influence of raised levels of the
glucocorticoid (GC) stress hormone at different stages of life (during late gestation
and/or in adulthood) on pathways known to be altered in parkinson’s disease (PD), and
compares this with the effects of repeated adult stress. Adult stress or GC treatment
produced complex, differential sex and region specific changes in these pathways.
Notably, adult stress or GC treatment increased markers of nirosative stress in the male
but not female rat substantia nigra (SN). Prenatal GC treatment produced long term
effects on both dopamineric (DA) and noradrenergic (NA) nuclei, increasing the
number of DA neurons in the SN and ventral tegmental area, and reducing the number
of NA neurons in the locus coeruleus of adult rats. Furthermore microglial and astrocyte
populations were increased and decreased respectively in these nuclei. Interestingly
prenatal GC treatment rendered the male midbrain susceptible to a down regulation of
DA measures in response to adult challenge, whereby the number of SN DA neurons
and striatal and accumbal DA levels were attenuated. Fascinatingly adult stress or GC
treatment, but not prenatal GC treatment exacerbated 6-hydroxydopamine-induced
neurotoxicity, that was associated with increased microglial activation and protein
nitration in the SN, in males, but afforded neuroprotection in females, neither of which
were substantially altered by prenatal treatment. This is the first study to demonstrate
that prenatal GC treatment can permanentlty alter the response of the midbrain DA
pathways to adult challenge. Furthermore this is one of very few studies looking at male
and female responses in parallel and thus highlights some striking sex differences in the
response to stress and GCs. Together these novel data strongly support the premise that
stress and GCs influence the functional integrity of pathways involved in PD, thereby
potentially contributing to PD pathogenesis. The data also highlight the complex
sexually dimorphic nature of their actions. Although further work is required to
determine the functional consequences of these stress/GC related changes, these
findings may have considerable implications for the use of GCs in clinical practice.