The role of neurokinin-1 receptor in the pathogenesis of methamphetamine-induced striatal neurotoxicity in the murine brain.
Item
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Title
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The role of neurokinin-1 receptor in the pathogenesis of methamphetamine-induced striatal neurotoxicity in the murine brain.
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Identifier
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AAI3047278
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identifier
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3047278
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Creator
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Yu, Jing.
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Contributor
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Adviser: Jesus A. Angulo
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Date
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2002
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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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Methamphetamine (METH) is an addictive substance that also causes extensive neural degeneration in the central nervous system. Because METH augments striatal substance P levels, we hypothesized that signaling through the neurokinin-1 (NK-1) receptor by substance P initiates the neurotoxic cascade. To determine the role of NK-1 receptor in METH-induced neurotoxicity, we tested the effects of the selective NK-1 receptor antagonists WIN-51,708 and L-733,060 on several markers of dopaminergic terminal toxicity in the mouse striatum (namely, dopamine transporters, dopamine content, tyrosine hydroxylase, and glial fibrillary acidic protein). Male mice received four intraperitoneal injections of METH (5 or 10 mg/kg of body weight) at 2-hour intervals and were sacrificed 3--28 days after the treatment. Exposure to METH resulted in severe depletion of dopamine transporters, tissue dopamine content and tyrosine hydroxylase, as well as prominent expression of glial fibrillary acidic protein in the striatum. Administration of either NK-1 receptor antagonist 30 min prior to the 1 st and 4th injection of METH prevented the loss of dopamine transporters assessed by autoradiography and Western blotting, the depletion of tissue dopamine assessed by High Pressure Liquid Chromatography, the reduction of tyrosine hydroxylase protein levels as well as the induction of glial fibrillary acidic protein determined by Western blotting. The immunohistological studies also demonstrated that the pretreatment of NK-1 receptor antagonist partially protected against METH-induced loss of tyrosine hydroxylase immunoreactive fibers and induction of astrogliosis. Meanwhile, we have provided the direct histological evidence, using Fluoro-Jade B staining, that METH also caused postsynaptic neuronal degeneration, which could be blocked by the pretreatment of NK-1 receptor antagonist. Pretreatment with NK-1 receptor antagonist had no effect on METH-induced hyperthermia. Exposure of mice to either of the NK-1 receptor antagonists alone was without effect on all of these markers. These results provide the first pharmacological evidence that tachykinins, particularly substance P acting through NK-1 receptors, play a crucial role in the pathogenesis of striatal neurotoxicity induced by METH. This finding could lead to novel therapeutic strategies to offset drug addictions as well as in the treatment of a number of disorders including Parkinson's and Huntington's diseases.
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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.
