MECHANISMS OF NEUROENDOCRINE REGULATION

调查的重点是监管的机制 应激时的下丘脑和垂体功能。这些研究已经 明确的下丘脑-垂体-肾上腺反应的不同类型 不同慢性应激范式的适应过程中的轴心：a) 促肾上腺皮质激素对初级应激的脱敏，但高反应性 对一种新的刺激，b)对初级刺激的持续ACTH反应 和对新刺激的高反应性，以及c)轻微的ACTH反应 主要刺激和降低对一种新压力的敏感性。至 确定这种差异反应的机制，下丘脑 ACTH分泌的主要调节因子的表达和分泌， 对促肾上腺皮质激素释放激素(CRH)和加压素(VP)进行研究 在不同的应激范式中。一个主要的发现是激活了 慢性应激过程中的HPA轴伴随着 为垂体提供VP的小细胞加压素能系统 门脉血。另一方面，通过渗透压升高全身VP水平 刺激不能增强CRH对ACTH分泌的影响 CRH受体调节。在脑垂体水平上，ACTH反应增加 与POMC mRNA水平的升高有关，但与 CRH受体水平和垂体反应性之间的关系。上一首 研究表明，α-1肾上腺素能受体很重要 压力引起的正中隆起松解的中介物。延拓 在这些研究中，使用电子显微镜免疫细胞化学技术， 研究表明，α1-肾上腺素能激动剂能刺激CRH从 含VP的CRH神经元亚群。提供更多研究 两种证据表明，长期的，但不是急性中枢的 α1肾上腺素能受体激活可增加大鼠脑内CRH基因的表达 下丘脑。首先，重复注射α1受体激动剂， 甲氧胺，每6小时注射一次，持续24小时，但不是在单次注射后4小时， 导致下丘脑室旁核CRH基因表达显著增加，第二， 中枢α1-肾上腺素能阻断CRH基因的表达 在24小时应激后观察到，但在4小时应激后观察不到。研究是 正在进行中以确定多个 神经递质与下丘脑调节有关。

Investigation has focused on the mechanism of regulation of the hypothalamic and pituitary function during stress. These studies have defined distinct types of responses of the hypothalamic-pituitary-adrenal axis during adaptation in different chronic stress paradigms: a) desensitization of the ACTH to the primary stress, but hyperresponsiveness to a novel stimulus, b) sustained ACTH response to the primary stimulus and hyperresponsivenes to a novel stimulus, and c) minor ACTH responses to the primary stimulus and reduced sensitivity to a novel stress. To determine the mechanism of this differential responses, the hypothalamic expression and secretion of the major regulators of ACTH secretion, corticotropin releasing hormone (CRH) and vasopressin (VP), were studied in the various stress paradigms. A major finding was that activation of the HPA axis during chronic stress is accompanied by activation of the parvicellular vasopressinergic system, which provides VP to the pituitary portal blood. On the other hand, increasing systemic VP levels by osmotic stimulation failed to potentiate the effects of CRH on ACTH secretion and CRH receptor regulation. At the pituitary level, increased ACTH responses were associated to increases in POMC mRNA levels, but no relationship was found between CRH receptor levels and pituitary responsiveness. Previous studies demonstrated that alpha-1 adrenergic receptors are important mediators of stress-induced release from the median eminence. Extension of these studies, using electron microscopy immunocytochemical techniques, showed that alpha1-adrenergic agonists stimulate CRH release from the subpopulation of VP-containing CRH neurons. Additional studies provided two types of evidence indicating that long term, but not acute central alpha1-adrenergic receptor activation increases CRH mRNA in the hypothalamus. First, repeated injection of the alpha1-receptor agonist, methoxamine, every 6 hr for 24 hr, but not 4 hr after a single injection, resulted in significant increases in CRH mRNA in the PVN, and second, central alpha1-adrenergic blockade prevented the increases in CRH mRNA observed after 24 hr stress, but not those after 4 hr stress. Studies are in progress to determine the precise role of the multiple neurotransmitters implicated in hypothalamic regulation.