Karanth S, Linthorst A C, Stalla G K, Barden N, Holsboer F, Reul J M
Max Planck Institute of Psychiatry, Clinical Institute, Department of Neuroendocrinology, Munich, Germany.
Endocrinology. 1997 Aug;138(8):3476-85. doi: 10.1210/endo.138.8.5331.
Recently, a transgenic mouse with impaired glucocorticoid receptor (GR) function was created to serve as an animal model for the study of neuroendocrine changes occurring in stress-related disorders, such as major depression. Here, we investigated the hypothalamic-pituitary-adrenocortical (HPA) axis changes in these transgenic mice. There were no significant differences between basal early morning plasma ACTH and corticosterone levels in normal and transgenic mice. When animals were exposed to a mild stressor, an enhanced response in plasma ACTH was observed in the transgenic mice, whereas plasma corticosterone responses were not different. In view of these differences in plasma ACTH and corticosterone responses, we directed our studies toward the regulation of ACTH secretion on the hypothalamic-hypophyseal level in vitro. Therefore, an in vitro model, the pituitary-hypothalamic complex (PHc) was developed and its ACTH release profile was compared with that of the pituitary (PI) alone. The basal ACTH release by PHc and PI from normal and transgenic mice was similar. Regardless of the strain under study, the basal ACTH release by PI was significantly lower than the release by PHc. Stimulation of tissues with either high K+ (56 mM) or CRH (10 or 20 nM) produced an enhanced ACTH release from both PHc and PI, whereas the response in PI was larger than that in PHC. Moreover, the responses to these stimuli were markedly enhanced in tissues from transgenic mice. In tissues of normal mice, corticosterone inhibited both basal and CRH-stimulated ACTH release more potently in PHc than in PI. Furthermore, the feedback capacity of corticosterone to restrain both basal and CRH-stimulated ACTH release was highly impaired in tissues of transgenic mice, whereas the feedback in PHc appeared to be more affected than that in the PI of these animals. In conclusion, the in vitro data on PHc and PI revealed intrahypothalamic mechanisms operating 1) to fine-tune stimulus-evoked ACTH responses; and 2) to facilitate the negative feedback action of glucocorticoids. Moreover, in the transgenic tissues, the impaired GR function was found to cause augmented stimulus-evoked ACTH responses and an impaired glucocorticoid feedback efficacy which appeared to be mainly defective at the hypothalamic level. Thus, in the transgenic mice with life-long central GR dysfunction we found impaired negative feedback combined with "normal" (i.e. noncompensated) in vivo plasma corticosterone responses. This is a condition with potentially grave pathophysiological consequences and, therefore, this transgenic animal may be regarded as a valuable model for the study of functional glucocorticoid insufficiency at the central nervous system level.
最近，一种糖皮质激素受体（GR）功能受损的转基因小鼠被培育出来，作为研究应激相关疾病（如重度抑郁症）中发生的神经内分泌变化的动物模型。在此，我们研究了这些转基因小鼠下丘脑-垂体-肾上腺皮质（HPA）轴的变化。正常小鼠和转基因小鼠清晨基础血浆促肾上腺皮质激素（ACTH）和皮质酮水平之间没有显著差异。当动物暴露于轻度应激源时，转基因小鼠血浆ACTH反应增强，而血浆皮质酮反应没有差异。鉴于血浆ACTH和皮质酮反应的这些差异，我们将研究方向转向体外下丘脑-垂体水平上ACTH分泌的调节。因此，开发了一种体外模型，即垂体-下丘脑复合体（PHc），并将其ACTH释放情况与单独的垂体（PI）进行比较。正常小鼠和转基因小鼠的PHc和PI的基础ACTH释放相似。无论研究的是哪种品系，PI的基础ACTH释放均显著低于PHc的释放。用高钾（56 mM）或促肾上腺皮质激素释放激素（CRH，10或20 nM）刺激组织均可使PHc和PI的ACTH释放增加，而PI的反应大于PHc。此外，转基因小鼠组织对这些刺激的反应明显增强。在正常小鼠组织中，皮质酮对PHc基础和CRH刺激的ACTH释放的抑制作用比PI更强。此外，转基因小鼠组织中皮质酮抑制基础和CRH刺激的ACTH释放的反馈能力严重受损，而这些动物的PHc中的反馈似乎比PI中的反馈受影响更大。总之，关于PHc和PI的体外数据揭示了下丘脑内存在的机制，这些机制1）用于微调刺激诱发的ACTH反应；2）促进糖皮质激素的负反馈作用。此外，在转基因组织中，发现GR功能受损会导致刺激诱发的ACTH反应增强以及糖皮质激素反馈效能受损，这似乎主要在下丘脑水平存在缺陷。因此，在具有终身中枢GR功能障碍的转基因小鼠中，我们发现负反馈受损以及体内血浆皮质酮反应“正常”（即未代偿）。这是一种可能具有严重病理生理后果的情况，因此，这种转基因动物可被视为研究中枢神经系统水平功能性糖皮质激素不足的有价值模型。
