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The effects of prenatal ethanol exposure on hypothalamic-pituitary-adrenal stress response in Sprague-Dawley rats Leo, Joyce Mo-Ting

Abstract

Rats prenatally exposed to ethanol (E) exhibit hypothalamic-pituitary-adrenal (HPA) hyperresponsiveness to stressors. The objective of this thesis was to compare responses of E and control animals to acute and repeated stress and to determine how hormonal hyperresponsiveness is mediated by alterations in central regulation of the HPA axis. While multiple mechanisms may play a role in mediating HPA hyperresponsiveness, this thesis focused on the possible roles of increased drive from higher cortical inputs to the hypothalamus and increased anterior pituitary responsiveness to secretagogues. Previous studies have shown that following acute stress, E animals show hormonal hyperresponsiveness and alterations in central regulation primarily at the level of the PVN. In contrast, repeated stress may result in habituation as indicated by an attenuation of hormonal responses to the stressor; however, alterations in central regulation following repeated stress have not been examined in E animals. Female and male offspring from E, pair-fed (PF) and control (C) dams were tested in adulthood. Animals were terminated after 1 d or 10 d of daily 1 hr restraint stress, either prior to (basal, non-stress condition), immediately after, or 3 hr after restraint. We measured plasma levels of adrenocorticotrophin (ACTH) and corticosterone (CORT), medial parvocellular paraventricular corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) mRNA levels, CRH receptor (CRH-Rj) mRNA levels in the PVN and anterior pituitary, and proopiomelanocortin (POMC) mRNA levels in the anterior pituitary. Restraint stress increased plasma ACTH and CORT above basal levels in all prenatal, groups, and the response on d 10 was attenuated compared to d 1, indicating hormonal habituation to the stressor. Overall, females but not males exhibited increased CRH mRNA over basal levels following 1 d of restraint, with a return to basal levels following 10 d of restraint. However, CRH mRNA levels were not differentially altered in either E females or males compared to their respective controls following restraint. In contrast, E females exhibited increased AVP mRNA levels compared to PF and C females following both 1 d and 10 d of restraint, and E and PF males showed greater AVP mRNA levels compared to C males overall. Furthermore, examination of the CRH: A V P ratio indicated that E females had a lower CRH: A V P ratio compared to C females following 10 d of restraint, and overall, E and PF males had a lower CRH:AVP ratio compared to C males. E males also exhibited a lower CRH:AVP ratio compared to C males under basal conditions. These data indicate a general shift towards increased AVP mRNA levels following repeated compared to acute restraint stress in E compared to control animals. Following exposure to acute stress, both females and males in all prenatal treatment groups showed upregulated CRH-Ri mRNA levels in the PVN, and the response on d 10 was attenuated compared to d 1, again suggesting habituation to the stressor. Examination of the ld:10d ratio of CRH-Ri mRNA expression in the PVN revealed that, following stress, E females exhibited a higher ld:10d ratio of CRH-Ri mRNA expression compared to PF and C females, and E and PF males also showed a greater ld:10d ratio of CRH-Ri mRNA expression compared to C males. In contrast, no differences were seen in CRH-Ri mRNA in the anterior pituitary among E, PF and C females or males in any of the experimental conditions. It is possible that increased CRH-Ri mRNA could play a role in mediating HPA hyperresponsiveness in E animals, but further studies are needed to confirm this. Measurement of POMC mRNA indicated that females in all prenatal groups had higher POMC mRNA levels following exposure to 1 d of restraint and under basal conditions on d 10 compared to basal conditions on d 1. However, this was due primarily to increased responsiveness in PF and C females, as supported by the additional finding that overall, E females had lower POMC mRNA levels compared to PF and C females. For males, overall, POMC mRNA levels were greater under basal and stress conditions on d 10 compared to basal conditions on d 1. For E males, analyses revealed lower basal POMC mRNA levels on d 1 and d 10 compared to PF and C males. Additionally, exposure to both 1 d and 10 d of restraint stress increased POMC mRNA levels over d 1 basal conditions in E but not PF and C males, and E males also had greater POMC mRNA expression compared to C males following 10 d of restraint. In conclusion, these findings demonstrate that prenatal ethanol exposure results in altered central regulation of the HPA axis following exposure to stressors. In the paradigm utilized here, E animals do show habituation to a mild repeated stress in terms of plasma hormone levels. However, E, PF and C animals exhibit differential alterations in central regulation. Differences among E, PF and C animals following exposure to both acute and repeated stress do not appear to be mediated by CRH mRNA in the PVN or CRH-Ri mRNA in the anterior pituitary, but at least following repeated stress may in part be due to a greater shift toward AVP regulation and/or increased levels of CRH-Ri mRNA in the PVN. For E males but not females, it appears that an increase in pituitary POMC mRNA levels following stress may also play a role in HPA hyperresponsiveness. Together, these data suggest that increased HPA drive and/or increased pituitary responsiveness to secretagogues may be differentially involved in mediating HPA hyperresponsiveness in females and males prenatally exposed to ethanol. In addition, these results further suggest that differences between females and males in response to stress involve the interaction of the HPA and HPG axes.

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