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Effects of foetal ethanol exposure on hypothalamic-pituitary adrenal axis function and behaviour on the elevated plus maze

University of British Columbia

This thesis investigated effects of prenatal ethanol exposure on hypothalamicpituitary- adrenal (HPA) axis function and on behaviour on the elevated plus maze (+- maze). Male and female Sprague-Dawley rats from prenatal ethanol (E), pair-fed (PF) and ad lib-fed control (C) treatment groups, were tested in adulthood in all studies. The hormonal studies investigated the hypothesis that a deficit in feedback inhibition of the HPA axis may underlie the hormonal hyperresponsiveness seen in E rats. The effects of dexamethasone (DEX) blockade on corticosterone (CORT) levels and adrenocorticotrophin (ACTH) levels were examined over a 36 hour (h) period. Following DEX, E males and females had significantly higher stress CORT levels and/or ACTH than PF and C animals, and showed differential responsiveness following DEX administration depending upon the time of day tested. At the trough of the circadian rhythm, E males did not differ from PF and C males, whereas E females had increased stress CORT levels compared to PF and C females. In contrast, at the peak of the circadian rhythm, E males showed increased stress CORT levels but not ACTH, whereas E females showed increased stress CORT and ACTH levels. These data- support the hypothesis that E animals may exhibit deficits in HPA feedback inhibition. Two other possible mechanisms for HPA hyperresponsiveness were investigated during the trough of the CORT circadian cycle. First, adrenal sensitivity to exogenous ACTH was examined. No significant differences were found among prenatal treatment groups in adrenal sensitivity to ACTH. Second, corticotrophin releasing factor (CRF) mRNA expression in the hypothalamus was measured in DEX suppressed animals 1 h after exposure to ether vapor. E males showed a trend toward higher CRF mRNA levels and E females demonstrated significantly higher CRF mRNA levels than their respective controls. These data suggest that HPA hyperresponsiveness seen in E animals is not due to increased adrenal sensitivity to ACTH but may be due to increased synthesis of CRF. The behavioural studies investigated the hypothesis that alterations in behaviour seen in E animals is in part mediated by alterations in the GABA-ergic system or increased sensitivity to central CRF. Both E males and females demonstrated behavioural hyperactivity and alterations in fear on the +-maze. In addition, the hyperactivity seen in E animals appeared to be reduced by prior exposure to the open field. Furthermore, E males and females demonstrated increased sensitivity to the effects of benzodiazepine on the +-maze compared their with respective controls. Due to methodological issues, the studies on central CRF sensitivity were inconclusive. These data suggest that E animals may exhibit differential responses to aversive environments but the underlying dysfunction may be altered by prior experience to aversive stimuli. Further, the data suggest that prenatal ethanol exposure may have long lasting effects on the GABA-ergic system.

Thesis/Dissertation

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2009-04-02

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http://hdl.handle.net/2429/6745

Neuroscience

University of British Columbia

UBCV

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