The Role of Striatal Neuropeptides on Glutamate and Methamphetamine-Induced Neurotoxicity in the Murine Brain
Item
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Title
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The Role of Striatal Neuropeptides on Glutamate and Methamphetamine-Induced Neurotoxicity in the Murine Brain
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Identifier
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d_2009_2013:24c23c263d1c:11270
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identifier
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11683
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Creator
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Afanador, Lauriaselle,
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Contributor
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Jesus A. Angulo
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Date
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2012
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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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Neurosciences | Glutamate | Methamphetamine | Neuropeptides | NPY | Somatostatin | Substance P
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Abstract
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The rising worldwide epidemic in addiction to methamphetamine (METH) and the well-documented neurological detriments it causes emphasizes the importance of elucidating the mechanisms by which METH causes widespread and prolonged damage. Also, METH's pathophysiology resembles a number of neurodegenerative diseases. Therefore a better understanding of the mechanisms involved would provide more effective therapeutic targets for the treatment of these neurological disorders.;METH toxicity is a complex interplay of various factors however a number of necessary components have been identified such as dopamine overflow (DA), glutamate signaling, and oxidative stress. Although METH-induced DA overflow is the initiating event, it is not the direct cause of damage. Oxidative stress is thought to be the mediator of METH toxicity and nitric oxide (NO) as a contributor.;We have found that substance P (SP) exacerbates METH-induced NO. Inhibition of SP signaling mitigated NO synthesis and conferred protection. Considering the role SP is playing in METH toxicity we wanted to investigate the role that other striatal neuropeptides play in these events, notably the inhibitory peptides neuropeptide Y (NPY) and somatostatin (SST).;We hypothesized that SP is augmenting NMDA signaling and thus magnifying NO production. Whereas NPY and SST would serve as a counteracting force thus dampening oxidative stress and conferring protection. Overall, our data demonstrated that SP does augment NMDA signaling as inhibition of the neurokinin-1 receptor (NK-1R) decreased NMDA-induced striatal cell loss. We found that SP was potentiating NMDA-induced NO production. Although the predominant source of NO was the inducible form of nitric oxide synthase (NOS).;In support of our hypothesis, NPY and SST proved to attenuate NO. Also, they were protective from METH-induced cell death although SST failed to protect DA terminals. However, an agonist for the NPY-Y2 receptor was successful in maintaining DA terminal viability. Of interest is that neither NPY nor SST modulated NMDA-induced NO or cell loss suggesting that their protective mechanism does not include modulation glutamate signaling within the striatum.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biology
