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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS018150-04
Application #
3398226
Study Section
Neurology A Study Section (NEUA)
Project Start
1981-08-01
Project End
1986-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
4
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Harik, S I; Mitchell, M J; Kalaria, R N (1989) Ouabain binding in the human brain. Effects of Alzheimer's disease and aging. Arch Neurol 46:951-4
Kikano, G E; LaManna, J C; Harik, S I (1989) Brain perfusion in acute and chronic hyperglycemia in rats. Stroke 20:1027-31
Kalaria, R N; Harik, S I (1989) Abnormalities of the glucose transporter at the blood-brain barrier and in brain in Alzheimer's disease. Prog Clin Biol Res 317:415-21
Moufarrij, N A; Harik, S I (1989) The effect of locus ceruleus lesion on water, sodium and potassium content of the rat cerebral cortex. Neurol Res 11:97-100
Riachi, N J; LaManna, J C; Harik, S I (1989) Entry of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into the rat brain. J Pharmacol Exp Ther 249:744-8
Kalaria, R N; Stockmeier, C A; Harik, S I (1989) Brain microvessels are innervated by locus ceruleus noradrenergic neurons. Neurosci Lett 97:203-8
Homayoun, P; Lust, W D; Harik, S I (1989) Effect of several vasoactive agents on guanylate cyclase activity in isolated rat brain microvessels. Neurosci Lett 107:273-8
Harik, S I; LaManna, J C (1988) Vascular perfusion and blood-brain glucose transport in acute and chronic hyperglycemia. J Neurochem 51:1924-9
Harik, S I; Gravina, S A; Kalaria, R N (1988) Glucose transporter of the blood-brain barrier and brain in chronic hyperglycemia. J Neurochem 51:1930-4
Kalaria, R N; Mitchell, M J; Harik, S I (1988) Monoamine oxidases of the human brain and liver. Brain 111 ( Pt 6):1441-51

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