Effects of MPTP, MPP(+) and Adreno-Medullin on Dopamine Metabolism in the Rat Corpus Striatum
Chang, Geen-Dong
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https://hdl.handle.net/2142/71457
Description
Title
Effects of MPTP, MPP(+) and Adreno-Medullin on Dopamine Metabolism in the Rat Corpus Striatum
Author(s)
Chang, Geen-Dong
Issue Date
1988
Doctoral Committee Chair(s)
Ramirez, Victor D.
Department of Study
Physiology and Biophysics
Discipline
Physiology
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Neuroscience
Abstract
Self-administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a contaminant on illicit narcotic drugs, causes parkinsonism symptoms in drug addicts. Also, systemic injections of very low doses of MPTP in non-human primates produces selective destruction of the nigrostriatal dopamine neuron and severe motor impairments. That peripheral administration of a single substance selectively destroys the nigrostriatal dopaminergic system and produces symptoms and pathology comparable to parkinsonism has ignited a lot of interest in basic research of Parkinson's disease. For example, the search of MPTP-like substances, possibly neurotoxic herbicides or industrial pollutants, in the environment may provide an environmental link to the etiology of Parkinson's disease. Furthermore, the MPTP-treated primate model has made possible studies of the basal ganglia function in the progression of Parkinson's disease, which are technically or ethically infeasible in human subjects. On the other hand, tremendous efforts have been made to elucidate the mechanism, especially the neurotoxicity and selectivity, of MPTP action. So far, several neurotoxic reactions caused by MPTP and 1-methyl-4-phenylpyridine (MPP$\sp+$), an active metabolite of MPTP, have been demonstrated. First, oxidation of MPTP catalyzed by monoamine oxidase can generate hydrogen peroxide and other active oxygen species, which might then initiate oxidative damage to the cells. Also, MPTP and MPP$\sp+$ may affect dopamine metabolism which then leads to persistent depletion of dopamine. Recently, as a means to study recovery of dopamine function in a mouse model of Parkinson's disease induced by MPTP, adrenal medulla fragments were inserted directly into the striatum of the MPTP-lesioned animals. Therefore, it was of interest to examine the effects of MPTP and MPP$\sp+$ and of adrenal extract on dopamine metabolism in the corpus striatum. This thesis presents evidence that (1) both MPTP and MPP$\sp+$ have potent effects on stimulating DA release from the corpus striatum and on inhibiting DA catabolism in vitro and in vivo, (2) the majority of extracellular dopamine is taken up by the terminals and oxidized into 3,4-dihydroxyphenylacetic acid (DOPAC) and (3) a glycoprotein, tentatively named adrenomedullin, is present in the adrenal gland and has potent dopamine-releasing activity in the corpus striatum.
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