Hauger R L, Millan M A, Lorang M, Harwood J P, Aguilera G
Veterans Administration Medical Center, La Jolla, California 92103.
Endocrinology. 1988 Jul;123(1):396-405. doi: 10.1210/endo-123-1-396.
The regulation of pituitary and brain CRF receptors and corticotroph responses during stress were studied in rats subjected to prolonged immobilization. Plasma ACTH levels showed the characteristic biphasic changes, with a rapid 23-fold increase in 15 min, followed by a decrease to about twice the basal levels after 6-h immobilization. In contrast, plasma corticosterone levels were markedly elevated throughout the duration of the stress. Pituitary CRF receptor content, measured by binding of [125I]Tyr-ovine CRF to pituitary membrane-rich fractions, was unchanged after 2.5 h, but was reduced by 28 +/- 2.7% (+/- SE) and 47.6 +/- 1.1% after 18 and 48 h of immobilization, respectively. These results were confirmed by autoradiography in slide-mounted frozen pituitary sections. In contrast, no changes in CRF receptor content were observed in brain areas, including olfactory bulb, frontoparietal cortex, hippocampus, amygdala, and lateral septum. A concomitant decrease in immunoreactive (ir) CRF content in the median eminence of rats immobilized for 48 h is consistent with the hypothesis that increased release of CRF into the portal circulation occurs during chronic stress. Despite pituitary CRF receptor loss and reduced in vitro responses to CRF, the increases in plasma ACTH and corticosterone in vivo after ether exposure or CRF injection were greater and more prolonged in rats immobilized for 48 h than in nonimmobilized controls. The decrease in pituitary CRF receptors was accompanied by decreased CRF-stimulated cAMP and ACTH release in cultured pituitary cells from 48-h restrained rats. However, concomitant incubation of cells with CRF and vasopressin restored cAMP and ACTH responses to control levels, suggesting that the simultaneous release of both regulators from the hypothalamus determines the plasma ACTH level. These findings indicate that the decrease in plasma ACTH during the adaptation phase to stress is accompanied by decreases in pituitary CRF receptors. However, the enhanced pituitary response to a superimposed stress or CRF injection implies that the decrease in plasma ACTH levels during prolonged stress may be due to adaptive changes at the central level. These findings emphasize the importance of the integrated actions of CRF and other regulators in the control of the pituitary adrenal-axis during stress.
在长期固定的大鼠中研究了应激期间垂体和脑促肾上腺皮质激素释放因子（CRF）受体的调节以及促肾上腺皮质激素细胞的反应。血浆促肾上腺皮质激素（ACTH）水平呈现典型的双相变化，在15分钟内迅速增加23倍，随后在固定6小时后降至基础水平的约两倍。相比之下，在整个应激期间血浆皮质酮水平显著升高。通过[125I]酪氨酸 - 羊CRF与富含垂体膜的组分结合来测量垂体CRF受体含量，在2.5小时后未发生变化，但在固定18小时和48小时后分别降低了28±2.7%（±标准误）和47.6±1.1%。这些结果在载玻片上的冷冻垂体切片的放射自显影中得到证实。相比之下，在包括嗅球、额顶叶皮质、海马、杏仁核和外侧隔在内的脑区中未观察到CRF受体含量的变化。固定48小时的大鼠正中隆起中免疫反应性（ir）CRF含量的相应减少与以下假设一致，即在慢性应激期间CRF向门脉循环的释放增加。尽管垂体CRF受体减少且体外对CRF的反应降低，但在乙醚暴露或CRF注射后，固定48小时的大鼠体内血浆ACTH和皮质酮的增加比未固定的对照大鼠更大且更持久。垂体CRF受体的减少伴随着来自48小时束缚大鼠的培养垂体细胞中CRF刺激的环磷酸腺苷（cAMP）和ACTH释放的减少。然而，细胞与CRF和血管加压素的同时孵育将cAMP和ACTH反应恢复到对照水平，表明这两种调节因子从下丘脑的同时释放决定了血浆ACTH水平。这些发现表明，在适应应激阶段血浆ACTH的减少伴随着垂体CRF受体的减少。然而，垂体对叠加应激或CRF注射的反应增强意味着长期应激期间血浆ACTH水平的降低可能是由于中枢水平的适应性变化。这些发现强调了CRF和其他调节因子在应激期间控制垂体 - 肾上腺轴中的综合作用的重要性。
