Ma S, Morilak D A
Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
J Neuroendocrinol. 2005 Nov;17(11):761-9. doi: 10.1111/j.1365-2826.2005.01372.x.
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 alpha1-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.
慢性间歇性冷应激会使下丘脑 - 垂体 - 肾上腺（HPA）轴对新的急性应激的激活变得敏感。我们已经表明，边缘前脑去甲肾上腺素能功能增强会导致HPA轴敏感化。在本研究中，我们调查了慢性间歇性冷应激是否也会引起室旁核（PVN）中去甲肾上腺素能功能的变化，PVN是HPA应激反应的主要调节因子。将大鼠暴露于慢性间歇性冷应激（7天，每天6小时，4摄氏度）。在末次冷暴露后的第二天，基础血浆促肾上腺皮质激素（ACTH）水平没有差异，但与对照组相比，冷应激大鼠对30分钟急性固定应激的ACTH峰值反应更大。向PVN双侧微量注射α（1）-肾上腺素能受体拮抗剂贝诺沙硫因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，ACTH反应的所有敏感化都被贝诺沙硫因阻断，降至与贝诺沙硫因处理的对照组相当的水平。在第二项使用微透析测量PVN中去甲肾上腺素释放的研究中，与对照组相比，冷应激大鼠PVN中基础或急性应激诱导的去甲肾上腺素释放增加没有差异。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，向PVN微量注射α（1）-肾上腺素能受体激动剂去氧肾上腺素后，冷应激大鼠ACTH分泌的剂量依赖性激活显著增强。因此，慢性间歇性冷暴露后HPA对急性应激的敏感反应至少部分归因于PVN中对α1 - 肾上腺素能受体激活的反应增强。慢性应激诱导的急性应激反应可塑性可能对应激适应很重要，但也可能导致与应激相关的病理生理状况。因此，了解这种适应背后的神经机制可能有助于我们理解此类疾病的病因，并有助于未来开发更有效的治疗或预防策略。
