title: A shift in the role of glutamatergic signaling in the nucleus accumbens core with the development of an addicted phenotype.
abstract: BACKGROUND
  While dopamine signaling in the nucleus accumbens (NAc) plays a well-established role in motivating cocaine use in early nonaddicted stages, recent evidence suggests that other signaling pathways may be critical once addiction has developed. Given the importance of glutamatergic signaling in the NAc for drug seeking and relapse, here we examined its role in motivating cocaine self-administration under conditions known to produce either a nonaddicted or an addicted phenotype.
  
  
  METHODS
  Following acquisition, male and female Sprague Dawley rats were given either short access (three fixed-ratio 1 sessions, 20 infusions/day) or extended 24-hour access (10 days; 4 trials/hour; up to 96 infusions/day) to cocaine. Following a 14-day abstinence period, motivation for cocaine was assessed under a progressive-ratio schedule, and once stable, the effects of intra-NAc infusions of the glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate/kainate receptor antagonist CNQX (0, .01, .03, .1 μg/side) were determined. As an additional measure for the development of an addicted phenotype, separate groups of rats were screened under an extinction/cue-induced reinstatement procedure following abstinence from short-access versus extended-access self-administration.
  
  
  RESULTS
  Motivation for cocaine and levels of extinction and reinstatement responding were markedly higher following extended-access versus short-access self-administration, confirming the development of an addicted phenotype in the extended-access group. CNQX dose-dependently reduced motivation for cocaine in the extended-access group but was without effect in the short-access group.
  
  
  CONCLUSIONS
  These results suggest that the role of glutamatergic signaling in the NAc, though not essential for motivating cocaine use in nonaddicted stages, becomes critical once addiction has developed.
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Doyle
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia.
authors.forename: Carolina
authors.initials: C
authors.lastname: Ramôa
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia.
authors.forename: Garrett
authors.initials: G
authors.lastname: Garber
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia.
authors.forename: Joshua
authors.initials: J
authors.lastname: Newman
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia.
authors.forename: Zeeshan
authors.initials: Z
authors.lastname: Toor
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia. Electronic address: wlynch@virginia.edu.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Lynch
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D003216:Conditioning, Operant / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects; D005260:Female; D018698:Glutamic Acid / Q000502:physiology*; D008297:Male; D009042:Motivation / Q000187:drug effects / Q000502:physiology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors; D012055:Reinforcement Schedule; D012646:Self Administration
chemical_list: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D003042:Cocaine; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors
keywords: CNQX; cocaine; extended access; glutamate; motivation; nucleus accumbens