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.
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