Choi I Y, Lee S, Rivier C
The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Neuroscience. 2008 Aug 26;155(3):888-901. doi: 10.1016/j.neuroscience.2008.04.081. Epub 2008 Jun 6.
Exposure to alcohol during embryonic development leads to changes in the hypothalamic-pituitary-adrenal (HPA) axis such that adult offspring release more adrenocorticotrophic hormone (ACTH) than controls when exposed to stress. In the present work, we tested the hypothesis that changes in the activity of the catecholaminergic system modulate, at least in part, this upregulation of the HPA axis. Pregnant Sprague-Dawley rats were exposed to alcohol 6 h daily during gestation days 7-18 using the vapor chamber model, which generated mean blood alcohol levels of 188.6+/-10 mg/dl. All experiments were performed on 2 to 3-month-old offspring. We first measured the ACTH response to i.c.v. injection of adrenergic receptor agonists. In rats exposed to footshocks, we then investigated the activity of corticotrophin-releasing factor (CRF) as well as indexes of catecholamine ir, namely tyrosine hydroxylase (TH) immunopositive neurons in the paraventricular nucleus (PVN), TH immunopositive neurons in the locus coeruleus, and phenylethanolamine N-methyltransferase (PNMT) immunopositive neurons in the brain stem. While adult females exposed to alcohol during fetal development (FAE) displayed the expected enhanced ACTH response to stress, there were no significant differences in response to adrenergic receptor agonists or in shock-induced CRF/TH ir and neuronal activity, as determined by c-fos colocalization. In contrast, FAE female offspring exposed to footshocks showed a significant increase in the activity of adrenergic neurons in the C1 region of the brain stem, a population of cells that project to the PVN. Collectively, these results suggest that while FAE-induced hyperactivity of the HPA axis is not accompanied by significant changes in PVN CRF or TH-ir neurons, it is characterized by an upregulation of C1 adrenergic neurons of the brain stem. This novel finding should lead to the functional characterization of this brain region in the FAE model.
胚胎发育期间接触酒精会导致下丘脑 - 垂体 - 肾上腺（HPA）轴发生变化，使得成年后代在受到应激时释放的促肾上腺皮质激素（ACTH）比对照组更多。在本研究中，我们检验了以下假设：儿茶酚胺能系统活性的变化至少部分调节了HPA轴的这种上调。使用气室模型，在妊娠第7 - 18天期间，每天让怀孕的斯普拉格 - 道利大鼠暴露于酒精6小时，该模型产生的平均血酒精水平为188.6±10mg/dl。所有实验均在2至3个月大的后代上进行。我们首先测量了促肾上腺皮质激素对脑室内注射肾上腺素能受体激动剂的反应。然后，在遭受足部电击的大鼠中，我们研究了促肾上腺皮质激素释放因子（CRF）的活性以及儿茶酚胺免疫反应性指标，即室旁核（PVN）中酪氨酸羟化酶（TH）免疫阳性神经元、蓝斑中TH免疫阳性神经元以及脑干中苯乙醇胺N - 甲基转移酶（PNMT）免疫阳性神经元。虽然胎儿发育期间接触酒精（FAE）的成年雌性表现出对应激的促肾上腺皮质激素反应增强，但在对肾上腺素能受体激动剂的反应或电击诱导的CRF/TH免疫反应性和神经元活性方面（通过c - fos共定位确定）没有显著差异。相比之下，遭受足部电击的FAE雌性后代脑干C1区域的肾上腺素能神经元活性显著增加，C1区域的细胞投射到PVN。总体而言，这些结果表明，虽然FAE诱导的HPA轴功能亢进并不伴有PVN中CRF或TH免疫反应性神经元的显著变化，但其特征是脑干C1肾上腺素能神经元上调。这一新发现应能促使对FAE模型中该脑区进行功能特性研究。
