van Haarst A D, Oitzl M S, de Kloet E R
Division of Medical Pharmacology, Leiden-Amsterdam Center for Drug Research, The Netherlands.
Neurochem Res. 1997 Nov;22(11):1323-8. doi: 10.1023/a:1022010904600.
In the present study the effects of intracerebroventricular (i.c.v.) and intrahippocampal administration of corticosteroid antagonists on basal hypothalamic-pituitary-adrenal (HPA) activity around the diurnal peak were compared in male Wistar rats. In two separate experiments the glucocorticoid receptor (GR) antagonist RU 38486 and the mineralocorticoid receptor (MR) antagonist RU 28318 were tested. One hour after GR antagonist injection, significant increases in plasma ACTH and corticosterone levels were observed in the i.c.v. treated rats, when compared to vehicle. In contrast, a significant decrease in ACTH levels, and a slight, but non-significant decrease in corticosterone concentrations were attained one hour after intrahippocampal injection of the GR antagonist. Injection of the MR antagonist, on the other hand, resulted in enhanced ACTH and corticosterone levels irrespective of the site of injection. These findings suggest that negative feedback inhibition at the circadian peak involves hippocampal MRs and extrahippocampal (hypothalamic) GRs. The latter feedback inhibition overrides a positive feedback influence exerted by endogenous corticosteroids through hippocampal GRs.
在本研究中，比较了在雄性Wistar大鼠中，脑室内（i.c.v.）和海马内注射皮质类固醇拮抗剂对昼夜高峰前后基础下丘脑-垂体-肾上腺（HPA）活性的影响。在两个独立实验中，对糖皮质激素受体（GR）拮抗剂RU 38486和盐皮质激素受体（MR）拮抗剂RU 28318进行了测试。与注射赋形剂的大鼠相比，在注射GR拮抗剂1小时后，脑室内给药的大鼠血浆促肾上腺皮质激素（ACTH）和皮质酮水平显著升高。相反，海马内注射GR拮抗剂1小时后，ACTH水平显著降低，皮质酮浓度略有下降，但不显著。另一方面，无论注射部位如何，注射MR拮抗剂都会导致ACTH和皮质酮水平升高。这些发现表明，昼夜高峰时的负反馈抑制涉及海马MRs和海马外（下丘脑）GRs。后者的反馈抑制作用超过了内源性皮质类固醇通过海马GRs产生的正反馈影响。
