文摘
Rationale Aspects of schizophrenia, including deficits in sensorimotor gating, have been linked to glutamate dysfunction and/or oxidative stress in the prefrontal cortex. System xc ?/sup>, a cystine–glutamate antiporter, is a poorly understood mechanism that contributes to both cellular antioxidant capacity and glutamate homeostasis. Objectives Our goal was to determine whether increased system xc ?/sup> 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 ?/sup>, in the prefrontal cortex. Prepulse inhibition was used to measure sensorimotor gating; deficits in prepulse inhibition were produced using phencyclidine (0.3-?mg/kg, sc). N-Acetylcysteine (10-00?μM) and the system xc ?/sup> inhibitor (S)-4-carboxyphenylglycine (CPG, 0.5?μM) were used to increase and decrease system xc ?/sup> activity, respectively. The uptake of 14C-cystine into tissue punches obtained from the prefrontal cortex was used to assay system xc ?/sup> 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 14C-cystine in prefrontal cortical tissue punches, intraprefrontal cortical infusion of N-acetylcysteine (10-00?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 ?/sup>. Conclusions These results indicate that phencyclidine disrupts sensorimotor gating through system xc ?/sup> independent mechanisms, but that increasing cystine–glutamate exchange in the prefrontal cortex is sufficient to reduce behavioral deficits produced by phencyclidine.