Document Type

Article

Language

eng

Format of Original

10 p.

Publication Date

4-2013

Publisher

Springer

Source Publication

Psychopharmacology

Source ISSN

0033-3158

Original Item ID

doi: 10.1007/s00213-012-2926-3

Abstract

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 , 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 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 14C-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 14C-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.

Comments

Accepted version. Psychopharmacology, Vol. 226, No. 3 (April 2013): 531-540. DOI. © Springer 2013. Used with permission.

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