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CNS & Neurological Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Nitric Oxide-GAPDH Transcriptional Signaling Mediates Behavioral Actions of Cocaine

Author(s): Maged M. Harraz and Solomon H. Snyder

Volume 14, Issue 6, 2015

Page: [757 - 763] Pages: 7

DOI: 10.2174/1871527314666150529150143

Price: $65

Abstract

Psychotropic actions of cocaine are generally thought to involve its blockade of monoamine transporters leading to increased synaptic levels of monoamines, especially dopamine. Subsequent intracellular events have been less well characterized. We describe a signaling system wherein lower behavioral stimulant doses of cocaine, as well as higher neurotoxic doses, activate a cascade wherein nitric oxide nitrosylates glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to generate a complex with the ubiquitin-E3-ligase Siah1 which translocates to the nucleus. With lower cocaine doses, nuclear GAPDH augments CREB signaling, while at higher doses p53 signaling is enhanced. The drug CGP3466B very potently blocks GAPDH nitrosylation, hindering both signaling cascades and inhibits both behavioral activating and neurotoxic effects of cocaine. This system affords potentially novel approaches to the therapy of cocaine abuse.

Keywords: Addiction, CGP3466B, cocaine, GAPDH, neurotoxicity, nitric oxide, nitrosylation.


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