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

Abstract

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. Our goal was to determine whether increased system xc(-) 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 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. 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(-). 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.