Studies on the toxicity of 6-hydroxydopa and hydrogen peroxide in the central nervous system.
Item
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Title
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Studies on the toxicity of 6-hydroxydopa and hydrogen peroxide in the central nervous system.
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Identifier
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AAI9020755
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identifier
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9020755
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Creator
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Evans, Jacqueline Meryl.
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Contributor
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Adviser: Gerald Cohen
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Date
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1990
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Neuroscience
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Abstract
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The effects of hydrogen peroxide production on central catecholamine neurons were explored using two independent means of peroxide production. In the first set of experiments the peroxide-generating catecholamine neurotoxin 6-hydroxydopa (6-OH-DOPA, 2,4,5-trihydroxyphenylalanine) was studied. 6-OH-DOPA destroys central and peripheral noradrenergic neurons while sparing dopaminergic neurons. Previous studies indicated that 6-OH-DOPA toxicity is mediated by the formation of 6-hydroxydopamine (6-OHDA, 2,4,5-trihydroxyphenylethylamine).;The levels of 6-OH-DOPA and 6-OHDA in mouse brain were measured after systemic administration of 6-OH-DOPA. Levels of 6-OHDA in mouse striatum were remarkably stable. Experiments with reserpine indicated that the stability of 6-OHDA was largely dependent upon storage in synaptic vesicles. 6-OHDA levels were increased after inhibition of monoamine oxidase, inhibition of peripheral decarboxylase, or after inhibition of axonal uptake. These data are in accord with the strong localization of the decarboxylase to catecholamine terminals and suggest that 6-OH-DOPA is converted to 6-OHDA within catecholamine nerve terminals.;Administration of a neurotoxic dose of 6-OH-DOPA caused a near total reduction in both cortical norepinephrine levels and synaptosomal uptake of {dollar}\sp 3{dollar}H-norepinephrine, whereas striatal dopamine levels and uptake of {dollar}\sp 3{dollar}H-dopamine remained unchanged. At the same time, 6-OHDA levels were 8.8-fold higher in the striatum (5.54 ug/g) than in the frontal cortex (0.63 ug/g). These data showed that striatal dopamine neurons were resistant to 6-OH-DOPA-induced toxicity despite the presence of sizable amounts of 6-OHDA.;In a second set of experiments mice were treated with reserpine in order to enhance peroxide production by monoamine oxidase. Reserpinization caused a prolonged decrease in striatal dopamine levels; however, synaptosomal uptake of {dollar}\sp 3{dollar}H-dopamine and {dollar}\sp 3{dollar}H-mazindol binding were unaltered. A significant (10.9 %) decrease in striatal tyrosine hydroxylase activity at one week after reserpine may however partially explain the long-lasting decrease in dopamine levels. Additional data provide evidence for a possible role of monoamine oxidase in the return of striatal dopamine levels after reserpine.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
