N-Acetylcysteine reverses cocaine-induced metaplasticity

Nat Neurosci. 2009 Feb;12(2):182-9. doi: 10.1038/nn.2250. Epub 2009 Jan 11.

Abstract

Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry crucial for regulating motivated behavior. We found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentiation (LTP) and long-term depression (LTD) in the nucleus accumbens core subregion after stimulation of the prefrontal cortex. N-acetylcysteine (NAC) treatment prevents relapse in animal models and craving in humans by activating cystine-glutamate exchange and thereby stimulating extrasynaptic metabotropic glutamate receptors (mGluR). NAC treatment of rats restored the ability to induce LTP and LTD by indirectly stimulating mGluR2/3 and mGluR5, respectively. Our findings show that cocaine self-administration induces metaplasticity that inhibits further induction of synaptic plasticity, and this impairment can be reversed by NAC, a drug that also prevents relapse.

Publication types

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

MeSH terms

  • Acetylcysteine / pharmacology*
  • Animals
  • Behavior, Animal / drug effects
  • Cocaine-Related Disorders / drug therapy*
  • Cocaine-Related Disorders / physiopathology*
  • Disease Models, Animal
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Free Radical Scavengers / pharmacology*
  • Long-Term Potentiation / drug effects
  • Long-Term Synaptic Depression / drug effects
  • Male
  • Neuronal Plasticity / drug effects*
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / physiology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiology
  • Pyridines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / physiology
  • Secondary Prevention
  • Self Administration
  • Substance Withdrawal Syndrome / drug therapy
  • Substance Withdrawal Syndrome / physiopathology

Substances

  • Excitatory Amino Acid Antagonists
  • Free Radical Scavengers
  • GRM5 protein, human
  • Grm5 protein, rat
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • 6-methyl-2-(phenylethynyl)pyridine
  • Acetylcysteine