Behavioral effects of cocaine mediated by nitric oxide-GAPDH transcriptional signaling

Neuron. 2013 May 22;78(4):623-30. doi: 10.1016/j.neuron.2013.03.021.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Central Nervous System Stimulants / pharmacology*
  • Cocaine / pharmacology*
  • Dose-Response Relationship, Drug
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / drug effects
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type I / drug effects
  • Nitric Oxide Synthase Type I / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Transcription, Genetic / drug effects

Substances

  • Central Nervous System Stimulants
  • Nitric Oxide
  • Nitric Oxide Synthase Type I
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
  • Cocaine