Abstract
Cocaine's behavioral-stimulant effects derive from potentiation of synaptic signaling by dopamine and serotonin leading to transcriptional alterations in postsynaptic cells. We report that a signaling cascade involving nitric oxide (NO) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mediates cocaine's transcriptional and behavioral actions. Lower, behavioral-stimulant doses enhance the cAMP response element-binding (CREB) signaling system, while higher, neurotoxic doses stimulate the p53 cytotoxic system. The drug CGP3466B, which potently and selectively blocks GAPDH nitrosylation and GAPDH-Siah binding, prevents these actions as well as behavioral effects of cocaine providing a strategy for anticocaine therapy.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Behavior, Animal / drug effects*
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Central Nervous System Stimulants / pharmacology*
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Cocaine / pharmacology*
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Dose-Response Relationship, Drug
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Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / drug effects
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Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Nitric Oxide / metabolism*
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Nitric Oxide Synthase Type I / drug effects
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Nitric Oxide Synthase Type I / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Transcription, Genetic / drug effects
Substances
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Central Nervous System Stimulants
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Nitric Oxide
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Nitric Oxide Synthase Type I
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Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
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Cocaine