Hofmann Candace E, Ellis Linda, Yu Wayne K, Weinberg Joanne
Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Alcohol Clin Exp Res. 2007 Feb;31(2):345-55. doi: 10.1111/j.1530-0277.2006.00316.x.
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.
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.
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.
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.
孕期乙醇暴露会改变下丘脑 - 垂体 - 肾上腺（HPA）轴的发育，导致成年后HPA对应激源的反应过度。孕期乙醇暴露还会改变血清素能（5 - HT）系统的发育和活性。我们之前已经表明，5 - HT（1A）和5 - HT（2A/C）受体介导的行为和生理功能在胎儿乙醇暴露的后代中发生了改变。由于HPA轴和5 - HT系统之间存在广泛的相互作用，本研究检验了以下假设：孕期乙醇暴露会改变5 - HT（1A）和5 - HT（2A/C）受体介导的HPA功能。
将5 - HT（1A）激动剂8 - 羟基 - 2 - （二正丙基氨基）四氢萘（8 - OH - DPAT；0.2 mg/kg）、5 - HT（2A/C）激动剂（ + ） - 1 - （2,5 - 二甲氧基 - 4 - 碘苯基） - 2 - 氨基丙烷盐酸盐（DOI；0.3 mg/kg）或溶剂（1 mL/kg）给予孕期乙醇暴露（E）、配对喂养对照（PF）和自由摄食对照（C）母鼠的成年雌性和雄性后代。在注射后0、15、30、60和120分钟测定促肾上腺皮质激素（ACTH）和皮质酮（CORT）的血浆浓度。此外，通过原位杂交分别测定下丘脑室旁核中促肾上腺皮质激素释放激素（CRH）mRNA的表达，以及海马和前额叶皮质中5 - HT（1A）和5 - HT（2A/C）受体mRNA的表达。
与PF和C组雌性相比，乙醇暴露的雌性在15和30分钟时对8 - OH - DPAT的ACTH反应减弱，相反，在注射后所有时间点对DOI的ACTH反应增强。E、PF和C组雄性之间的差异未达到显著水平。然而，在中枢方面，与C组雌性相比，DOI导致E组和PF组雌性的CRH mRNA水平有降低趋势，但与对照雄性相比，E组的CRH mRNA水平更高。在8 - OH - DPAT或DOI处理后，前额叶皮质中5 - HT（2A）受体表达在各孕期组之间没有差异。然而，在8 - OH - DPAT处理后，E组雌性CA1区海马5 - HT（1A）受体表达高于PF组雌性，CA2区E组雌性表达高于C组雌性有趋势，而在DOI处理后，通过孕期组与亚区相互作用表明，与C组雌性相比，E组和PF组在CA1区和齿状回的5 - HT（1A）mRNA水平较低。
这些数据首次证明孕期乙醇暴露对雌性和雄性5 - HT（1A）介导和5 - HT（2A）介导的神经内分泌功能有不同的长期影响，并表明乙醇诱导的HPA轴与血清素系统之间相互作用存在性别特异性改变。
