NORADRENERGIC CONTROL OF CEREBRAL OXIDATIVE METABOLISM

拟议实验的目的是继续研究 内源性脑去甲肾上腺素在控制脑缺血中的生物学作用 脑氧化代谢及其局部血管灌注， 渗透性，特别注意提供葡萄糖作为 脑代谢的主要底物。 的生理机制 去甲肾上腺素的这种影响及其意义将是 研究了 为这些研究选择的模型包括 化学损毁大鼠蓝斑核。 基因座 蓝斑是大多数（如果不是全部）去甲肾上腺素能神经递质的起源部位。 大脑皮层的神经支配 切除病灶的影响 蓝斑将使用各种生理学体内研究 方法学以及伴随的体外生物化学和药理学 和体内技术。 生理技术测量脑血 流量，大脑对葡萄糖的提取，监测大脑的氧化还原状态， 双波长反射法测定细胞色素氧化酶与局部血容量 分光光度法，和血管内皮细胞的能力，排除 大分子（如白蛋白）进入大脑。 结果 从这些实验中获得的将与定量相关 生物化学分析的儿茶酚胺神经递质，酶， 合成它们及其代谢物， 中间代谢 因为清醒动物的蓝斑， 通常在压力条件下激活，实验将探索 去甲肾上腺素耗尽的大脑皮层的异常反应 在这种紧张的情况下，通常与 代谢需求增加，如固定压力和状态 癫痫 去甲肾上腺素影响神经细胞凋亡的机制 大脑生理学将被研究， 大脑皮层中的去甲肾上腺素能受体及其药理学作用 各种去甲肾上腺素能受体激动剂和拮抗剂对这些 功能协调发展的

The aim of the proposed experiments is to continue the study of the biological role of endogenous cerebral norepinephrine in the control of brain oxidative metabolism and its local vascular perfusion and permeability with particular attention to the provision of glucose as the major substrate for brain metabolism. The physiological mechanisms underlying this influence of norepinephrine and their significance will be investigated. The models chosen for these studies include effects of chemical lesion of the nucleus locus ceruleus in the rat. The locus ceruleus is the site of origin of most, if not all, the noradrenergic innervation of the cerebral cortex. The effects of ablation of the locus ceruleus will be studied using a variety of physiological in vivo methodologies and concomitantly by biochemical and pharmacological in vitro and in vivo techniques. Physiological techniques measure cerebral blood flow, the extraction of glucose by the brain, monitoring the redox state of cytochrome oxidase and local blood volume by dual wavelength reflection spectrophotometry, and the ability of the vascular endothelium to exclude large molecules (such as albumin) from entering the brain. The results obtained from these experiments will be correlated with quantitative biochemical analyses of catecholamine neurotransmitters, the enzymes that synthesize them and their metabolites and of compounds involved in intermediary metabolism. Since the locus ceruleus, in awake animals, is ordinarily activated during stressful conditions, experiments will explore the abnormal responses of the norepinephrine-depleted cerebral cortex during such stressful conditions, that are usually associated with increased metabolic demands such as immobilization stress and status epilepticus. The mechanisms underlying the influence of norepinephrine on cerebral physiology will be investigated vis-a-vis the density of noradrenergic receptors in the cerebral cortex and the pharmacological effect of various noradrenergic receptor agonists and antagonists on these functions.