The effect of N-acetylcysteine in the nucleus accumbens on neurotransmission and relapse to cocaine

Biol Psychiatry. 2012 Jun 1;71(11):978-86. doi: 10.1016/j.biopsych.2011.10.024. Epub 2011 Dec 3.


Background: Relapse to cocaine seeking has been linked with low glutamate in the nucleus accumbens core (NAcore) causing potentiation of synaptic glutamate transmission from prefrontal cortex (PFC) afferents. Systemic N-acetylcysteine (NAC) has been shown to restore glutamate homeostasis, reduce relapse to cocaine seeking, and depotentiate PFC-NAcore synapses. Here, we examine the effects of NAC applied directly to the NAcore on relapse and neurotransmission in PFC-NAcore synapses, as well as the involvement of the metabotropic glutamate receptors 2/3 (mGluR2/3) and 5 (mGluR5).

Methods: Rats were trained to self-administer cocaine for 2 weeks and following extinction received either intra-accumbens NAC or systemic NAC 30 or 120 minutes, respectively, before inducing reinstatement with a conditioned cue or a combined cue and cocaine injection. We also recorded postsynaptic currents using in vitro whole cell recordings in acute slices and measured cystine and glutamate uptake in primary glial cultures.

Results: NAC microinjection into the NAcore inhibited the reinstatement of cocaine seeking. In slices, a low concentration of NAC reduced the amplitude of evoked glutamatergic synaptic currents in the NAcore in an mGluR2/3-dependent manner, while high doses of NAC increased amplitude in an mGluR5-dependent manner. Both effects depended on NAC uptake through cysteine transporters and activity of the cysteine/glutamate exchanger. Finally, we showed that by blocking mGluR5 the inhibition of cocaine seeking by NAC was potentiated.

Conclusions: The effect of NAC on relapse to cocaine seeking depends on the balance between stimulating mGluR2/3 and mGluR5 in the NAcore, and the efficacy of NAC can be improved by simultaneously inhibiting mGluR5.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology*
  • Animals
  • Cocaine
  • Cystine / metabolism
  • Drug-Seeking Behavior / drug effects*
  • Excitatory Postsynaptic Potentials / drug effects*
  • Free Radical Scavengers / pharmacology*
  • Glutamic Acid / metabolism
  • Male
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / physiology
  • Patch-Clamp Techniques
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / drug effects
  • Receptors, Metabotropic Glutamate / metabolism
  • Recurrence
  • Synaptic Transmission / drug effects*


  • Free Radical Scavengers
  • Receptors, Metabotropic Glutamate
  • Glutamic Acid
  • Cystine
  • Cocaine
  • Acetylcysteine