Noradrenergic pathway in the brain as a stress-conveying system

下丘脑-垂体-肾上腺轴(HPA轴)在维持机体内环境平衡中起着关键作用。促肾上腺皮质激素释放激素(CRH)在HPA轴的调节中起着最重要的作用。我们最近证实，去甲肾上腺素(NE)是大脑中的主要递质之一，它能刺激下丘脑CRH基因的表达。加压素(AVP)与促肾上腺皮质激素释放激素(CRH)共存于同一神经元中。去甲肾上腺素是否在转录水平上调节CRH和/或AVP基因的表达尚不清楚。在本实验中，我们使用与基因内含子序列相对应的cRNA探针，通过原位杂交组织化学方法对PVN中的CRH和AVP hnRNA进行了定量。NE刺激CRH基因转录。时程显示去甲肾上腺素作用非常迅速，在15min内达到峰值，1小时内恢复到基线水平。而注射NE后，AVP hnRNA无明显变化。在接下来的一系列实验中，大鼠被切除肾上腺并补充小剂量皮质酮(Cort)，从而将血浆皮质酮浓度钳制在低浓度。在本实验条件下，大鼠下丘脑注射去甲肾上腺素，并与假手术对照组比较CRH/AVP hnRNA的时程变化。ADX/CORT组CRH hnRNA表达的时程与假手术组无明显差异。AVP hnRNA在ADX/CORT组升高更明显。这些结果提示，在生理条件下，AVP基因转录可能比CRH基因转录受循环糖皮质激素更敏感的调节。

Hypothalamic-pituitary-adrenal axis (HPA-axis) plays a pivotal role in maintaining the homeostatic balance of organisms. Corticotropin-releasing hormone (CRH) plays the most important role in the regulation of the HPA-axis. We demonstrated recently that norepinephrine (NE), one of the major transmitters in the brain, stimulates CRH gene expression in the hypothalamus. Vasopressin (AVP) colocalizes with CRH in an identical neuron. It has not been clear whether NE regulates CRH and/or AVP gene expression at the transcriptional level. In this experiment, we quantitated CRH and AVP hnRNA in the PVN by in situ hybridization histochemistry using cRNA probes corresponding to the intronic sequences of the genes. NE stimulated CRH gene transcription. The time course showed very rapid action of NE, reaching the peak within 15 min, and returning to the baseline within an hour. In contrast, AVP hnRNA did not change significantly after NE injection. In the next series of experiments, rats were adrenalectomized and supplemented with a low- dose corticosterone (CORT), thereby plasma CORT concentration was clamped at a low concentration. In this experimental condition, rats were given intrahypothalamic NE, and the time course of CRH/AVP hnRNA was compared to that of the sham-operated controls. The time course of CRH hnRNA in the ADX/CORT group was not greatly different from that of the sham-operated group. AVP hnRNA increased more prominently in the ADX/CORT group. These results suggest that the AVP gene transcription may be more sensitively regulated by circulating glucocorticoid than the CRH gene transcription in the physiological conditions.