title: The effect of N-acetylcysteine in the nucleus accumbens on neurotransmission and relapse to cocaine.
abstract: 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.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA. kupchik@musc.edu
authors.forename: Yonatan M
authors.initials: YM
authors.lastname: Kupchik
authors.forename: Khaled
authors.initials: K
authors.lastname: Moussawi
authors.forename: Xing-Chun
authors.initials: XC
authors.lastname: Tang
authors.forename: Xiusong
authors.initials: X
authors.lastname: Wang
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Kalivas
authors.forename: Rosalia
authors.initials: R
authors.lastname: Kolokithas
authors.forename: Katelyn B
authors.initials: KB
authors.lastname: Ogburn
authors.forename: Peter W
authors.initials: PW
authors.lastname: Kalivas
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D003042:Cocaine; D003553:Cystine / Q000378:metabolism; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000378:metabolism; D012008:Recurrence; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D016166:Free Radical Scavengers; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; D003553:Cystine; D003042:Cocaine; D000111:Acetylcysteine