title: Reduction in phencyclidine induced sensorimotor gating deficits in the rat following increased system xc⁻ activity in the medial prefrontal cortex.
abstract: BACKGROUND
  Aspects of schizophrenia, including deficits in sensorimotor gating, have been linked to glutamate dysfunction and/or oxidative stress in the prefrontal cortex. System xc(-), a cystine-glutamate antiporter, is a poorly understood mechanism that contributes to both cellular antioxidant capacity and glutamate homeostasis.
  
  
  OBJECTIVE
  Our goal was to determine whether increased system xc(-) activity within the prefrontal cortex would normalize a rodent measure of sensorimotor gating.
  
  
  METHODS
  In situ hybridization was used to map messenger RNA (mRNA) expression of xCT, the active subunit of system xc(-), in the prefrontal cortex. Prepulse inhibition was used to measure sensorimotor gating; deficits in prepulse inhibition were produced using phencyclidine (0.3-3 mg/kg, sc). N-Acetylcysteine (10-100 μM) and the system xc(-) inhibitor (S)-4-carboxyphenylglycine (CPG, 0.5 μM) were used to increase and decrease system xc(-) activity, respectively. The uptake of (14)C-cystine into tissue punches obtained from the prefrontal cortex was used to assay system xc(-) activity.
  
  
  RESULTS
  The expression of xCT mRNA in the prefrontal cortex was most prominent in a lateral band spanning primarily the prelimbic cortex. Although phencyclidine did not alter the uptake of (14)C-cystine in prefrontal cortical tissue punches, intraprefrontal cortical infusion of N-acetylcysteine (10-100 μM) significantly reduced phencyclidine- (1.5 mg/kg, sc) induced deficits in prepulse inhibition. N-Acetylcysteine was without effect when coinfused with CPG (0.5 μM), indicating an involvement of system xc(-).
  
  
  CONCLUSIONS
  These results indicate that phencyclidine disrupts sensorimotor gating through system xc(-) independent mechanisms, but that increasing cystine-glutamate exchange in the prefrontal cortex is sufficient to reduce behavioral deficits produced by phencyclidine.
authors.affiliation: Department of Biomedical Sciences, Marquette University, Suite 446, 561 N. 15th St, Milwaukee, WI 53233, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Lutgen
authors.forename: Krista
authors.initials: K
authors.lastname: Qualmann
authors.forename: Jon
authors.initials: J
authors.lastname: Resch
authors.forename: Linghai
authors.initials: L
authors.lastname: Kong
authors.forename: Sujean
authors.initials: S
authors.lastname: Choi
authors.forename: David A
authors.initials: DA
authors.lastname: Baker
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000494:pharmacology; D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism*; D026922:Amino Acid Transport Systems, Acidic; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020233:Gait Disorders, Neurologic / Q000209:etiology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D017403:In Situ Hybridization; D008297:Male; D010622:Phencyclidine / Q000008:administration & dosage / Q000633:toxicity; D017397:Prefrontal Cortex / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle; D012559:Schizophrenia / Q000503:physiopathology*; D055139:Sensory Gating / Q000502:physiology*
chemical_list: D000111:Acetylcysteine; D027182:Amino Acid Transport System y+; D026922:Amino Acid Transport Systems, Acidic; D001565:Benzoates; D005998:Glycine; D010622:Phencyclidine; D012333:RNA, Messenger; C079693:4-carboxyphenylglycine; C000723960:Slc7a11 protein, rat