Prolonged exposure to intermittent alcohol vapors blunts hypothalamic responsiveness to immune and non-immune signals
Prolonged exposure to intermittent alcohol vapors blunts hypothalamic responsiveness to immune and non-immune signals
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DOI：
10.1097/00000374-200001000-00016
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发表时间：
2000-01-01
影响因子：
3.2
通讯作者：
Rivier, C
中科院分区：
文献类型：
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作者：
Lee, S;Schmidt, D;Rivier, C
背景资料：我们以前已经表明，长期酒精治疗钝化ACI-H对酒精本身的反应，以及其他压力，并伴有垂体对加压素（VP）的反应性降低，但坚果促肾上腺皮质激素释放因子（CRF）。目前的工作旨在确定CRF和VP受体在垂体和/或CRF神经元在室旁核（PVN）的下丘脑，最直接参与ACTH release.Methods的领域的肽库的变化的相关性：完整的雄性大鼠暴露于酒精使用一种新的蒸汽输送系统，使个别大鼠住房在盒子里。每天一次（0700-1300）给予酒精治疗6小时，之后将大鼠放回其家笼，在那里它们可以自由获取食物和水。对照组大鼠被关在类似的盒子里，但没有接触酒精。总治疗时间为8天。所有动物均配备有留置颈静脉插管，用于监测血液酒精水平（巴尔斯）以及药物暴露过程中ACTH和皮质酮的释放。由于存在旋转装置，动物的运动不会受到这些插管的限制或阻碍。在第9天早晨，在基础条件下或暴露于神经源性（轻度电足电击）或全身性[iv脂多糖（LPS）]刺激下将动物断头。室旁核神经元的反应，即早期基因（IEG）c-fos和NGFI-B的mRNA浓度的变化，和血浆促肾上腺皮质激素水平的测定前和期间内毒素血症或electrofootshocks.Results：在没有酒精的情况下，血浆促肾上腺皮质激素和皮质酮保持在基础水平，表明没有环境引起的压力。在暴露于酒精的大鼠中，巴尔斯是一致的和可预测的，我们的目标峰值约为200 mg%。在药物治疗期结束时，对照组和酒精治疗组大鼠垂体前叶CRF和VP受体mRNA水平无显著差异。与此相反，酒精治疗分别减少CRF和增加VP存储在外部带的正中隆起。它还增加了PVN的大细胞（m）部分中的NGFI-B和c-fos转录物，但在基础条件下（即，在没有电击或LPS的情况下）。暴露于这些应激源后，另一方面，所有组的大鼠显示血浆ACTH水平显着增加，以及上调其PVN神经元的反应，如pPVN IEGs转录的变化所示。然而，这些激素和神经元的反应显着钝化在动物预处理与alcohol.Conclusions：总的来说，我们的研究结果表明，减少PVN神经元的激活代表了一个重要的机制的能力，长期的酒精治疗钝化ACTH反应休克或内毒素血症。此外，我们开发的新的酒精输送系统是实用和可靠的，并且具有显著的优点，即它能够在动物的药物暴露期间测量循环激素水平。
Background: We have previously shown that long-term alcohol treatment blunts the ACI-H response to alcohol itself, as well as to other stresses, and is accompanied by decreased pituitary responsiveness to vasopressin (VP), but nut corticotropin-releasing Factor (CRF). The present work aims to determine the relevance of changes in CRF and VP receptors in the pituitary gland and/or peptide stores of CRF neurons in the paraventricular nucleus (PVN) of the hypothalamus, the areas that are most directly involved in ACTH release.Methods: intact male rats were exposed to alcohol using a new vapor delivery system which enables individual rat housing in boxes. Alcohol treatment was delivered for 6 hr once daily (0700-1300), after which the rats were returned to their home cages where they had free access to food and water. Control rats were kept in similar boxes, but not exposed to alcohol. Total treatment time was 8 days. All animals were equipped with indwelling jugular cannulae that were used to monitor blood alcohol levels (BALs) as well as ACTH and corticosterone release throughout drug exposure. Due to the presence of a swivel, the animals' movements were not restricted or hindered by the presence of these cannulae. On the morning of day 9, the animals were decapitated under basal conditions or exposed to a neurogenic (mild electrofootshocks) or systemic [iv lipopolysaccharide (LPS)] stimulus. PVN neuronal responses, indicated by changes in mRNA concentrations of the immediate early genes (IEGs) c-fos and NGFI-B, and plasma ACTH levels were measured before and during endotoxemia or electrofootshocks.Results: In the absence of alcohol, plasma ACTH and corticosterone remained at basal levels, indicating the absence of environment-induced stress. In rats exposed to alcohol, BALs were consistent and predictable, and we targeted peak values of about 200 mg%. At the end of the drug treatment period, there were no significant differences between CRF and VP receptor mRNA levels in the anterior pituitary of control and alcohol-treated rats. In contrast, alcohol treatment respectively decreased CRF and increased VP stores in the external zone of the median eminence. It also increased NGFI-B and c-fos transcripts in the magnocellular (m) portion of the PVN, but not the parvicellular (p) division of this nucleus under basal conditions (i.e., in the absence of shocks or LPS). After exposure to these stressors, on the other hand, all groups of rats showed significant increases in plasma ACTH levels as well as up-regulation of their PVN neuronal response, as indicated by changes in pPVN IEGs transcripts. However, these hormonal and neuronal responses were significantly blunted in animals pretreated with alcohol.Conclusions: Collectively, our results suggest that decreased PVN neuronal activation represents an important mechanism of the ability of long-term alcohol treatment to blunt the ACTH response to shocks or endotoxemia. In addition, the new system of alcohol delivery that we developed is practical and reliable, and has the significant advantage that it enables measurement of circulating hormone levels during drug exposure of the animals.