Effects of prenatal ethanol exposure on basal limbic-hypothalamic-pituitary-adrenal regulation: role of corticosterone.
BACKGROUND
Rats prenatally exposed to ethanol (E) exhibit hypothalamic-pituitary-adrenal (HPA) hyperresponsiveness and changes in central HPA regulation following exposure to stressors. Whether ethanol-induced alterations in basal HPA regulation play a role in mediating HPA hyperresponsiveness remains unclear. We utilized adrenalectomy (ADX), with or without corticosterone (CORT) replacement, to investigate basal HPA function and the role of CORT in mediating ethanol-induced alterations.


METHODS
Adult males and females from prenatal E, pair-fed (PF), and ad lib-fed control (C) groups were terminated at the circadian peak, 7 days following sham surgery or ADX, with or without CORT replacement. Plasma levels of CORT and adrenocorticotropin (ACTH), and mRNA levels of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) in the paraventricular nucleus, CRH Type 1 receptor (CRH-R1) and pro-opiomelanocortin (POMC) in the anterior pituitary, and mineralocorticoid (MR) and glucocorticoid (GR) receptors in the dorsal hippocampus were determined.


RESULTS
Adrenalectomy resulted in significantly greater plasma ACTH elevations in E and PF males, and parallel CRH mRNA elevations in both E and PF males and females compared with their C counterparts. In contrast, pituitary CRH-R1 mRNA levels were lower in E compared with C males, with no differences in POMC. In addition, in response to ADX, E females showed a greater MR mRNA response, and E males showed a greater GR mRNA response compared with their C counterparts, and CORT replacement was ineffective in normalizing ADX-induced alterations in ACTH levels in E and PF females, hippocampal MR mRNA levels in E males, and AVP mRNA levels in PF males and females.


CONCLUSIONS
Together, these data indicate that the prenatal ethanol exposure induces HPA dysregulation under basal conditions at multiple levels of the axis, resulting in alterations in both HPA drive and feedback regulation and/or in the balance between drive and feedback. While some effects may be nutritionally mediated, it appears that the mechanisms underlying basal HPA dysregulation may differ between E and PF animals rather than occurring along a continuum of effects on the same pathway. Altered basal HPA tone may play a role in mediating the HPA hyperresponsiveness to stressors observed in E offspring.
Glavas
Maria M
MM
Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.
Ellis
Linda
L
Yu
Wayne K
WK
Weinberg
Joanne
J
D000315:Adrenalectomy; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D002492:Central Nervous System Depressants / Q000009:adverse effects / Q000494:pharmacology*; D003345:Corticosterone / Q000097:blood / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D000431:Ethanol / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology*; D008032:Limbic System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008901:Mineralocorticoids / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D010902:Pituitary Gland / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D014667:Vasopressins / Q000378:metabolism; D000099052:CRF Receptor, Type 1
D002492:Central Nervous System Depressants; D008901:Mineralocorticoids; D018019:Receptors, Corticotropin-Releasing Hormone; D011965:Receptors, Glucocorticoid; D014667:Vasopressins; D000431:Ethanol; D000099052:CRF Receptor, Type 1; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone