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

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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.

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Acknowledgments

This work was supported by the National Institutes of Health grants DA017328 (DAB), DA025617 (DAB), DK074734 (SC), as well as by The Brain and Behavior Research Fund (DAB).

Disclosure

David A. Baker owns shares in Promentis Pharmaceuticals, a company developing novel antipsychotic agents. Promentis did not sponsor or otherwise support the experiments contained in this manuscript.

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  1. Department of Biomedical Sciences, Marquette University, Suite 446, 561 N. 15th St, Milwaukee, WI, 53233, USA

    Victoria Lutgen, Krista Qualmann, Jon Resch, Linghai Kong, SuJean Choi & David A. Baker

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  1. Victoria Lutgen
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  2. Krista Qualmann
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Lutgen, V., Qualmann, K., Resch, J. et al. Reduction in phencyclidine induced sensorimotor gating deficits in the rat following increased system xc − activity in the medial prefrontal cortex. Psychopharmacology 226, 531–540 (2013). https://doi.org/10.1007/s00213-012-2926-3

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