CORTICOSTERONE, BRAIN MINERALOCORTICOID-RECEPTORS (MRS) AND THE ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS - THE LEWIS RAT AS AN EXAMPLE OF INCREASED CENTRAL MR-CAPACITY AND A HYPORESPONSIVE HPA-AXIS
CORTICOSTERONE, BRAIN MINERALOCORTICOID-RECEPTORS (MRS) AND THE ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS - THE LEWIS RAT AS AN EXAMPLE OF INCREASED CENTRAL MR-CAPACITY AND A HYPORESPONSIVE HPA-AXIS
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DOI：
10.1016/0306-4530(95)00003-7
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发表时间：
1995-01-01
影响因子：
3.7
通讯作者：
DEKLOET, ER
中科院分区：
文献类型：
--
作者：
OITZL, MS;VANHAARST, AD;DEKLOET, ER
在这项研究中，我们报告了雄性 LEW 和 Wistar 大鼠之间调节下丘脑-垂体-肾上腺 (HPA) 轴的大脑和外周元件的一系列差异。我们发现：（i）大脑（海马、下丘脑）和垂体中盐皮质激素受体（MR）和糖皮质激素受体（GR）的不同特性：LEW 大鼠海马和下丘脑中 MR 的能力增加，而垂体中糖皮质激素受体 GR 的能力降低。海马中 MR 和 GR 的结合亲和力 (Kd) 相当。 (ii) 在 LEW 大鼠下丘脑室旁核中检测到较低浓度的促肾上腺皮质激素释放激素 (CRH) mRNA。 (iii) LEW 和 Wistar 大鼠的肾上腺重量相似；然而，LEW 大鼠却做到了。肾上腺皮质细胞减少约30%。在体外，使肾上腺皮质细胞接受增加剂量的 ACTH(1-24)，导致 LEW 大鼠体内皮质酮的释放量减少约 60%。 (iv) LEW 大鼠逃脱了地塞米松抑制，显示内源性 ACTH 基础水平增加，但与静脉注射 5 ng ACTH(1-24) 相比，皮质酮释放量相当。 (v) LEW 大鼠对多种刺激有反应：乙醚麻醉下的肾上腺切除术、新环境、尾部切口和约束或免疫挑战，其循环 ACTH 和皮质酮血浆水平低于 Wistar 大鼠。 (vi) LEW 大鼠夜间 ACTH 和皮质酮水平低于 Wistar 大鼠，但早上没有差异。在 LEW 大鼠中，晚上通过中枢注射特异性 MR 拮抗剂 RU28318 来阻断大脑 MR，导致 ACTH 和皮质酮的循环水平增加。 (vii)一天肾上腺切除的LEW大鼠中皮质类固醇结合蛋白的水平较低，表明游离皮质酮水平较高。 (viii) LEW 大鼠的胸腺比 Wistar 大鼠小。综上所述，受体结合数据对应于 LEW 大鼠对压力的神经内分泌反应性降低。我们认为，LEW 大鼠中枢 MR/GR 平衡的转变，即增强 MR 介导的皮质酮作用，是该大鼠品系低反应性 HPA 轴的中枢调节机制。下丘脑中 CRH mRNA 水平较低，ACTH 和皮质酮对各种刺激的反应水平较低，以及肾上腺对外源性 ACTH 反应低下，显然是皮质酮通过中枢 MR 进行终生抑制作用的结果。
In this study we report a series of differences in brain and peripheral elements regulating the hypothalamic-pituitary-adrenal (HPA) axis between male LEW and Wistar rats. We found: (i) differential properties of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the brain (hippocampus, hypothalamus) and pituitary: LEW rats displayed an increased capacity of MRs in the hippocampus and hypothalamus and a decreased capacity of glucocorticoid receptors GRs in the pituitary. The binding affinity (Kd) for MRs and GRs in the hippocampus was comparable. (ii) Lower concentrations of corticotropin releasing hormone (CRH) mRNA were detected in the nucleus paraventicularis of the hypothalamus of LEW rats. (iii) Adrenal weight was similar in LEW and Wistar rats; however, LEW rats had. about 30% less adrenocortical cells. Subjecting adrenocortical cells to increasing doses of ACTH(1-24) in vitro resulted in about a 60% smaller release of corticosterone in LEW rats. (iv) LEW rats escaped dexamethasone suppression showing increased basal levels of endogenous ACTH, but responded with a comparable release of corticosterone to the IV injection of 5 ng ACTH(1-24). (v) LEW rats responded to a variety of stimuli: adrenalectomy under ether anaesthesia, a novel environment, a tail nick and restraint or an immunological challenge, with lower circulating ACTH and corticosterone plasma levels than Wistar rats. (vi) Evening levels of ACTH and corticosterone were lower in LEW than Wistar rats but did not differ in the morning. Blockade of brain MRs in the evening by a central injection of the specific MR antagonist RU28318 in LEW rats resulted in increased circulating levels of ACTH and corticosterone. (vii) Levels of corticosteroid-binding proteins were lower in one-day adrenalectomized LEW rats, indicating higher levels of free corticosterone. (viii) LEW rats had a smaller thymus than Wistar rats. Taken together, the receptor binding data correspond to a decreased neuroendocrine responsiveness of LEW rats to stress. We suggest that the shift in the central MR/GR balance of LEW rats, i.e. augmented MR-mediated effects of corticosterone, is the central regulating mechanism of the hyporeactive HPA axis in this rat strain. Lower levels of CRH mRNA in the hypothalamus and lower levels of ACTH and corticosterone in response to various stimuli, as well as the hyporesponsive adrenals to exogenous ACTH, are apparently the consequences of the life-long suppressive action of corticosterone via central MRs.