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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