Chronic intermittent cold stress sensitises the hypothalamic-pituitary-adrenal response to a novel acute stress by enhancing noradrenergic influence in the rat paraventricular nucleus
Chronic intermittent cold stress sensitises the hypothalamic-pituitary-adrenal response to a novel acute stress by enhancing noradrenergic influence in the rat paraventricular nucleus
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DOI：
10.1111/j.1365-2826.2005.01372.x
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发表时间：
2005-11-01
影响因子：
3.2
通讯作者：
Morilak, DA
中科院分区：
文献类型：
--
作者：
Ma, S;Morilak, DA
慢性间歇性冷应激通过新的急性应激使下丘脑-垂体-肾上腺（HPA）轴激活敏感。我们已经表明，增强去甲肾上腺素能功能的边缘前脑有助于HPA敏化。在本研究中，我们调查是否慢性间歇性寒冷也引起室旁核（PVN），HPA应激反应的主要介质的去甲肾上腺素能功能的变化。大鼠暴露于慢性间歇性寒冷（7天，每天6小时，4摄氏度）。在最后一次冷暴露后的第二天，基线血浆ACTH没有差异，但是与对照组相比，冷应激大鼠对30分钟急性固定应激的峰值ACTH反应更大。双侧PVN微量注射α（1）-肾上腺素能受体拮抗剂benoxathian可使对照组急性应激诱导的促肾上腺皮质激素（ACTH）水平降低约25%。此外，在冷应激大鼠中，所有促肾上腺皮质激素反应的敏化作用均被苯恶噻烷阻断，达到与苯恶噻烷治疗对照相当的水平。在第二项研究中，使用微透析来测量PVN中的去甲肾上腺素释放，与对照组相比，冷应激大鼠PVN中的去甲肾上腺素释放的基线或急性应激诱导的增加没有差异。因此，在第三项研究中，我们测试了慢性冷应激后突触后α（1）受体敏感性的潜在变化。与对照组相比，在冷应激大鼠的室旁核中微量注射α（1）-肾上腺素能受体激动剂苯肾上腺素，剂量依赖性激活ACTH分泌显著增强。因此，慢性间歇性冷暴露后对急性应激的致敏HPA反应至少部分归因于PVN中对α（1）-肾上腺素能受体活化的增强反应。慢性应激诱导的急性应激反应的可塑性可能是重要的应激适应，但也可能有助于与压力相关的病理生理条件。因此，了解这些适应性变化背后的神经机制可能有助于我们了解这些疾病的病因，并有助于未来开发更有效的治疗或预防策略。
Chronic intermittent cold stress sensitises activation of the hypothalamic-pituitary-adrenal (HPA) axis by novel acute stress. We have shown that enhanced noradrenergic function in limbic forebrain contributes to HPA sensitisation. In the present study, we investigated whether chronic intermittent cold also induced changes in noradrenergic function in the paraventricular nucleus (PVN), the primary mediator of the HPA stress response. Rats were exposed to chronic intermittent cold (7 days, 6 h per day, 4 degrees C). On the day after final cold exposure, there were no differences in baseline plasma ACTH, but the peak ACTH response to 30 min of acute immobilisation stress was greater in cold-stressed rats compared to controls. Bilateral microinjection of the alpha(1)-adrenergic receptor antagonist benoxathian into the PVN reduced acute stress-induced adrenocorticotrophic hormone (ACTH) levels by approximately 25% in controls. Furthermore, in cold-stressed rats, all of the sensitisation of the ACTH response was blocked by benoxathian, to a level comparable to benoxathian-treated controls. In a second study using microdialysis to measure norepinephrine release in the PVN, there were no differences in either baseline or acute stress-induced increases in norepinephrine release in the PVN of cold-stressed rats compared to controls. Thus, in a third study, we tested potential alterations in postsynaptic alpha(1)-receptor sensitivity after chronic cold stress. Dose-dependent activation of ACTH secretion by microinjection of the alpha(1)-adrenergic receptor agonist, phenylephrine, into the PVN was significantly enhanced in cold-stressed rats compared to controls. Thus, the sensitised HPA response to acute stress after chronic intermittent cold exposure is at least partly attributable to an enhanced response to alpha(1)-adrenergic receptor activation in the PVN. Chronic stress-induced plasticity in the acute stress response may be important for stress adaptation, but may also contribute to pathophysiological conditions associated with stress. Thus, understanding the neural mechanisms underlying such adaptations may help us understand the aetiology of such disorders, and contribute to the future development of more effective treatment or prevention strategies.