title: Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking.
abstract: BACKGROUND
  The cystine-glutamate exchanger is downregulated after chronic cocaine, resulting in reduced extracellular levels of nucleus accumbens glutamate. The importance of cocaine-induced loss of glutamate homeostasis is revealed by N-acetylcysteine restoring cystine-glutamate exchange and attenuating reinstatement to cocaine seeking. Another regulator of extracellular glutamate is the glial glutamate transporter GLT-1. We hypothesized that cocaine self-administration reduces GLT-1 and that GLT-1 upregulation inhibits cocaine seeking.
  
  
  METHODS
  We measured [(3)H] glutamate uptake and protein expression of GLT-1 and xCT, the catalytic subunit of the cystine-glutamate exchanger, following cocaine self-administration and 3 weeks of extinction training. We also examined the affect of ceftriaxone (previously shown to increase GLT-1) and N-acetylcysteine treatment on the expression of GLT-1 and xCT. Ceftriaxone was also tested for the capacity to inhibit cue- and cocaine-induced relapse.
  
  
  RESULTS
  Cocaine self-administration reduced glutamate uptake and the expression of both GLT-1 and xCT. Ceftriaxone restored GLT-1 and xCT levels and prevented cue- and cocaine-induced reinstatement of drug seeking. N-acetylcysteine also restored GLT-1 and xCT levels.
  
  
  CONCLUSIONS
  These results indicate that glutamate transport and cystine-glutamate exchange may be coregulated and provide further evidence that targeting glutamate homeostasis is a potential method for treating cocaine relapse.
authors.affiliation: Department of Neurosciences, Medical University of South, Carolina, Charleston, South Carolina 29425, USA. knackst@musc.edu
authors.forename: Lori A
authors.initials: LA
authors.lastname: Knackstedt
authors.forename: Roberto I
authors.initials: RI
authors.lastname: Melendez
authors.forename: Peter W
authors.initials: PW
authors.lastname: Kalivas
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D002443:Ceftriaxone / Q000494:pharmacology / Q000627:therapeutic use*; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D003216:Conditioning, Operant / Q000187:drug effects; D003553:Cystine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration / Q000379:methods; D013997:Time Factors; D014316:Tritium / Q000378:metabolism
chemical_list: D000975:Antioxidants; D018765:Dopamine Uptake Inhibitors; D027342:Excitatory Amino Acid Transporter 2; D014316:Tritium; D018698:Glutamic Acid; D003553:Cystine; D002443:Ceftriaxone; D003042:Cocaine; C030905:N-monoacetylcystine