Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse

Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):385-90. doi: 10.1073/pnas.1011265108. Epub 2010 Dec 20.


Cocaine addiction remains without an effective pharmacotherapy and is characterized by an inability of addicts to inhibit relapse to drug use. Vulnerability to relapse arises from an enduring impairment in cognitive control of motivated behavior, manifested in part by dysregulated synaptic potentiation and extracellular glutamate homeostasis in the projection from the prefrontal cortex to the nucleus accumbens. Here we show in rats trained to self-administer cocaine that the enduring cocaine-induced changes in synaptic potentiation and glutamate homeostasis are mechanistically linked through group II metabotropic glutamate receptor signaling. The enduring cocaine-induced changes in measures of cortico-accumbens synaptic and glial transmission were restored to predrug parameters for at least 2 wk after discontinuing chronic treatment with the cystine prodrug, N-acetylcysteine. N-acetylcysteine produced these changes by inducing an enduring restoration of nonsynaptic glutamatergic tone onto metabotropic glutamate receptors. The long-lasting pharmacological restoration of cocaine-induced glutamatergic adaptations by chronic N-acetylcysteine also caused enduring inhibition of cocaine-seeking in an animal model of relapse. These data mechanistically link nonsynaptic glutamate to cocaine-induced adaptations in excitatory transmission and demonstrate a mechanism to chronically restore prefrontal to accumbens transmission and thereby inhibit relapse in an animal model.

Publication types

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

MeSH terms

  • Acetylcysteine / pharmacology*
  • Animals
  • Chromatography, High Pressure Liquid
  • Cocaine-Related Disorders / drug therapy*
  • Glutamic Acid / metabolism
  • Homeostasis / drug effects
  • Homeostasis / physiology
  • Long-Term Potentiation / drug effects*
  • Microdialysis
  • Nucleus Accumbens / physiology
  • Patch-Clamp Techniques
  • Prefrontal Cortex / physiology
  • Rats
  • Receptors, Metabotropic Glutamate / metabolism*
  • Secondary Prevention
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Synaptic Transmission / drug effects*


  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • Glutamic Acid
  • Acetylcysteine