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

Yonatan M. Kupchik*, Khaled Moussawi, Xing Chun Tang, Xiusong Wang, Benjamin C. Kalivas, Rosalia Kolokithas, Katelyn B. Ogburn, Peter W. Kalivas

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

113 Scopus citations


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.

Original languageAmerican English
Pages (from-to)978-986
Number of pages9
JournalBiological Psychiatry
Issue number11
StatePublished - 1 Jun 2012
Externally publishedYes

Bibliographical note

Funding Information:
This research was supported by United States Public Health Association Grants DA015369 , DA012513 , and DA003906 . XW is currently affiliated with the Program in Neuroscience, Washington State University, Pullman, Washington.


  • Addiction
  • N-acetylcysteine
  • cocaine
  • mGluR2/3
  • mGluR5
  • nucleus accumbens


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