Hypothalamic-pituitary-adrenal responses to 5-HT1A and 5-HT2A/C agonists are differentially altered in female and male rats prenatally exposed to ethanol.
BACKGROUND
Prenatal ethanol exposure alters the development of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in HPA hyper-responsiveness to stressors in adulthood. Prenatal ethanol exposure also alters the development and activity of the serotoninergic (5-HT) system. We have previously shown that 5-HT(1A) and 5-HT(2A/C) receptor-mediated behavioral and physiological function are altered in fetal ethanol-exposed offspring. As there are extensive interactions between the HPA axis and the 5-HT system, the present study tested the hypothesis that prenatal ethanol exposure would alter 5-HT(1A) and 5-HT(2A/C) receptor-mediated HPA function.


METHODS
The 5-HT(1A) agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.2 mg/kg), and the 5-HT(2A/C) agonist, (+)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI; 0.3 mg/kg), or vehicle (1 mL/kg) were administered to adult female and male offspring from prenatal ethanol-exposed (E), pair-fed control (PF), and ad libitum-fed control (C) dams. The plasma concentration of adrenocorticotropin (ACTH) and corticosterone (CORT) were determined at 0, 15, 30, 60, and 120 minutes postinjection. In addition, corticotropin releasing hormone (CRH) mRNA expression in the paraventricular nucleus of the hypothalamus, and 5-HT(1A) and 5-HT(2A/C) receptor mRNA expression in the hippocampus and prefrontal cortex, respectively, were determined by in situ hybridization.


RESULTS
Ethanol-exposed females showed a blunted ACTH response to 8-OH-DPAT at 15 and 30 minutes, and conversely, an increased ACTH response to DOI at all time points postinjection, compared with PF and C females. Differences among E, PF, and C males failed to reach significance. Centrally, however, DOI resulted in a trend toward lower CRH mRNA levels in E and PF compared with C females, but higher CRH mRNA levels in E compared with control males. There were no differences among prenatal groups in 5-HT(2A) receptor expression in the prefrontal cortex following either 8-OH-DPAT or DOI treatment. However, following 8-OH-DPAT, hippocampal 5-HT(1A) receptor expression was higher in E than in PF females in CA1, with a trend toward higher expression in E than in C females in CA2, whereas following DOI, a prenatal group by subfield interaction suggests lower 5-HT(1A) mRNA levels in E and PF compared with C females in CA1 and the dentate gyrus.


CONCLUSIONS
These data are the first to demonstrate that prenatal ethanol exposure has differential long-term effects on 5-HT(1A)-mediated and 5-HT(2A)-mediated neuroendocrine function in females and males, and suggest a sex-specific ethanol-induced alteration in the interaction between the HPA axis and the serotonin system.
Hofmann
Candace E
CE
Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Ellis
Linda
L
Yu
Wayne K
WK
Weinberg
Joanne
J
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000502:physiology; D008297:Male; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D012727:Sex Characteristics
D002492:Central Nervous System Depressants; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D000431:Ethanol; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone