The neurokinins and locomotor sensitization to cocaine.
Item
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Title
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The neurokinins and locomotor sensitization to cocaine.
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Identifier
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AAI9959196
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identifier
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9959196
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Creator
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Kraft, Madelyne.
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Contributor
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Adviser: Jesus A. Angulo
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Date
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2000
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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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This research is an attempt to better understand the role of striatal, neurokinins substance P (SP) and neurokinin A (NKA), in acute cocaine-induced hyperactivity and locomotor sensitization, the escalating locomotor response to chronic, intermittent exposure to an unchanging cocaine dose. We found that preprotachykinin-A mRNA (PPT-A), the precursor for SP and NKA, measured by in situ hybridization, is upregulated in the dorsalateral striatum, in response to chronic, intermittent cocaine exposure. These increases in PPT-A mRNA were significantly reduced in rats coexposed to cocaine and MK-801, an NMDA receptor antagonist known to block the development of locomotor sensitization and associated neurochemical changes. Tissue levels of substance P, measured by radioimmunoassay showed no statistically significant changes in response to a time course of chronic cocaine administration. There was however, a trend toward reduced levels in the substantia nigra in response to acute cocaine suggesting increased utilization. Reductions were no longer observed after chronic exposure or a cocaine challenge, conceivably the result of compensatory increases in substance P expression suggested by the increases in PPT-A mRNA levels.;Two neurokinin receptors, NK-1 and NK-3 which have the highest affinity for SP and NKA respectively, have different distributions and are localized to separate neural populations in the striatum and substantia, nigra. We found that the blockade of NK-1 receptors by systemic administration of non-peptide antagonists LY306740 and CP099994 prior to acute cocaine administration attenuated hyperactivity induced by cocaine but the NK-3 antagonist, PD161182, had no effect. NK-1 blockade however had no effect on the development or expression of locomotor sensitization to cocaine. These findings suggest that endogenous neurokinins acting at NK-1 receptors are necessary for the full expression of acute cocaine-induced hyperactivity but do not play a role in sensitization.;NK-3 receptor blockade, by the NK-3 antagonist PD 161182, had no effect on cocaine-induced hyperactivity but robustly enhanced the expression of locomotor sensitization. These findings suggest that endogenous neurokinins, acting at the NK-3 receptor, play a homeostatic role by reducing the escalating locomotor activity associated with locomotor sensitization.
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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.
