Reduction in phencyclidine induced sensorimotor gating deficits in the rat following increased system xc- activity in the medial prefrontal cortex

Aspects of schizophrenia, including deficits in sensorimotor gating, have been linked to glutamate dysfunction and/or oxidative stress in the prefrontal cortex. System x(c) (-), a cystine-glutamate antiporter, is a poorly understood mechanism that contributes to both cellular antioxidant capacity and glutamate homeostasis. Our goal was to determine whether increased system x(c) (-) activity within the prefrontal cortex would normalize a rodent measure of sensorimotor gating. In situ hybridization was used to map messenger RNA (mRNA) expression of xCT, the active subunit of system x(c) (-), 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 mu M) and the system x(c) (-) inhibitor (S)-4-carboxyphenylglycine (CPG, 0.5 mu M) were used to increase and decrease system x(c) (-) activity, respectively. The uptake of C-14-cystine into tissue punches obtained from the prefrontal cortex was used to assay system x(c) (-) activity. 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 C-14-cystine in prefrontal cortical tissue punches, intraprefrontal cortical infusion of N-acetylcysteine (10-100 mu M) significantly reduced phencyclidine- (1.5 mg/kg, sc) induced deficits in prepulse inhibition. N-Acetylcysteine was without effect when coinfused with CPG (0.5 mu M), indicating an involvement of system x(c) (-). These results indicate that phencyclidine disrupts sensorimotor gating through system x(c) (-) independent mechanisms, but that increasing cystine-glutamate exchange in the prefrontal cortex is sufficient to reduce behavioral deficits produced by phencyclidine.