| Summary: | Rats prenatally exposed to ethanol (E) exhibit a hyperresponsive hypothalamic-pituitary-adrenal
(HPA) axis, demonstrated by increased and/or prolonged elevations of
adrenocorticotropic hormone (ACTH) and/or corticosterone (CORT) following stress; however,
basal levels are normal. The major objective of this thesis was to elucidate the underlying
mechanisms of HPA hyperresponsiveness in E rats. We hypothesized that HPA
hyperresponsiveness in E rats is mediated, in part, by enhanced HPA drive and/or by alterations
in CORT feedback regulation. In all studies, male and female Sprague-Dawley offspring from E,
pair-fed (PF) and control (C) groups were tested in adulthood at 90-120 d of age.
The mechanisms mediating HPA hyperresponsiveness in E rats and the role of CORT in
mediating any alterations were investigated using several manipulations: adrenalectomy (ADX)
with or without CORT replacement, CORT receptor blockade and restraint stress. ADX revealed
that E males exhibit enhanced biosynthesis of corticotropin-releasing hormone (CRH) in the
paraventricular nucleus (PVN) and elevated plasma ACTH levels independent of CORT
alterations, indicating that HPA hyperresponsiveness in E animals is not due solely to altered
CORT feedback. Enhanced CRH synthesis also occurred in sham-operated E females. Measures
of CRH Type 1 receptor and pro-opiomelanocortin mRNA suggested that hyperresponsiveness
in E animals is likely not mediated by enhanced pituitary sensitivity to CRH. CORT receptor
(mineralocorticoid receptors, MRs, and glucocorticoid receptors, GRs) mRNA levels in the
hippocampus indicated that E males may have a decreased sensitivity to CORT feedback
regulation of these genes in response to ADX with CORT replacement. As well, in response to
MR or GR blockade, E females exhibited greater HPA activity compared to controls, indicative
of enhanced HPA drive.
Taken together, these studies indicate that prenatal ethanol exposure permanently reprograms
the HPA axis of the rat such that HPA drive is enhanced into adulthood. Although some compensatory mechanisms appear to be in place to maintain normal basal ACTH and CORT
levels, in response to challenge these mechanisms break down and alterations are revealed. HPA
dysregulation in E rats appears to be mainly suprapituitary, mediated by enhanced drive to the
hypothalamus as reflected by increased CRH biosynthesis. === Medicine, Faculty of === Graduate
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