title: Glutamate transporter GLT-1 mediates N-acetylcysteine inhibition of cocaine reinstatement.
abstract: Both pre-clinical and clinical studies indicate that N-acetylcysteine (NAC) may be useful in treating relapse to addictive drug use. Cocaine self-administration in rats reduces both cystine-glutamate exchange and glutamate transport via GLT-1 in the nucleus accumbens, and NAC treatment normalizes these two glial processes critical for maintaining glutamate homeostasis. However, it is not known if one or both of these actions by NAC is needed to inhibit relapse to cocaine seeking. To determine whether the restoration of GLT-1 and/or cystine-glutamate exchange is required for NAC to inhibit cue-induced reinstatement of cocaine seeking, we utilized the rat self-administration/extinction/reinstatement model of cocaine relapse. Rats were pre-treated in the nucleus accumbens with vivo-morpholino antisense oligomers targeting either GLT-1 or xCT (catalytic subunit of the cystine-glutamate exchanger) overlapping with daily NAC administration during extinction (100 mg/kg, i.p. for the last 5 days). Rats then underwent cue-induced reinstatement of active lever pressing in the absence of NAC, to determine if preventing NAC-induced restoration of one or the other protein was sufficient to block the capacity of chronic NAC to inhibit reinstatement. The vivo-morpholino suppression of xCT reduced cystine-glutamate exchange but did not affect NAC-induced reduction of reinstated cocaine seeking. In contrast, suppressing NAC-induced restoration of GLT-1 not only prevented NAC from inhibiting reinstatement, but augmented the capacity of cues to reinstate cocaine seeking. We hypothesized that the increased reinstatement after inhibiting NAC induction of GLT-1 resulted from increased extracellular glutamate, and show that augmented reinstatement is prevented by blocking mGluR5. Restoring GLT-1, not cystine-glutamate exchange, is a key mechanism whereby daily NAC reduces cue-induced cocaine reinstatement.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA; Department of Psychology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Reissner
authors.forename: Cassandra D
authors.initials: CD
authors.lastname: Gipson
authors.forename: Phuong K
authors.initials: PK
authors.lastname: Tran
authors.forename: Lori A
authors.initials: LA
authors.lastname: Knackstedt
authors.forename: Michael D
authors.initials: MD
authors.lastname: Scofield
authors.forename: Peter W
authors.initials: PW
authors.lastname: Kalivas
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D026922:Amino Acid Transport Systems, Acidic / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D027342:Excitatory Amino Acid Transporter 2 / Q000187:drug effects* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007266:Inhibition, Psychological; D051381:Rats; D012054:Reinforcement, Psychology; D012646:Self Administration; D027182:Amino Acid Transport System y+
chemical_list: D000111:Acetylcysteine; D026922:Amino Acid Transport Systems, Acidic; D003042:Cocaine; D018765:Dopamine Uptake Inhibitors; D027342:Excitatory Amino Acid Transporter 2; D016166:Free Radical Scavengers; C493395:Slc1a2 protein, rat; C000723960:Slc7a11 protein, rat; D027182:Amino Acid Transport System y+
keywords: Cocaine; N-acetylcysteine; cystine-glutamate exchange; glutamate; glutamate transport; mGluR5; nucleus accumbens; reinstatement