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

Victoria Lutgen; Krista Qualmann; Jon Resch; Linghai Kong; SuJean Choi; David A Baker

doi:10.1007/s00213-012-2926-3

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

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

Psychopharmacology, Vol.226(3), pp.531-540

04/2013

DOI: 10.1007/s00213-012-2926-3

PMCID: PMC3595356

PMID: 23192314

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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 14C-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 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 −.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.

Schizophrenia

Psychiatry

System x c

Neurosciences

Nonvesicular

Prefrontal cortex

Glutamate

Cystine–glutamate antiporter

Sensorimotor gating

Biomedicine

Phencyclidine

Pharmacology/Toxicology

Prepulse inhibition

Details

Title: Subtitle: Reduction in phencyclidine induced sensorimotor gating deficits in the rat following increased system xc − activity in the medial prefrontal cortex
Creators: Victoria Lutgen - Department of Biomedical Sciences Marquette University Suite 446, 561 N. 15th St Milwaukee WI 53233 USA
Krista Qualmann - Department of Biomedical Sciences Marquette University Suite 446, 561 N. 15th St Milwaukee WI 53233 USA
Jon Resch - Department of Biomedical Sciences Marquette University Suite 446, 561 N. 15th St Milwaukee WI 53233 USA
Linghai Kong - Department of Biomedical Sciences Marquette University Suite 446, 561 N. 15th St Milwaukee WI 53233 USA
SuJean Choi - Department of Biomedical Sciences Marquette University Suite 446, 561 N. 15th St Milwaukee WI 53233 USA
David A Baker - Department of Biomedical Sciences Marquette University Suite 446, 561 N. 15th St Milwaukee WI 53233 USA
Resource Type: Journal article
Publication Details: Psychopharmacology, Vol.226(3), pp.531-540
DOI: 10.1007/s00213-012-2926-3
PMID: 23192314
PMCID: PMC3595356
NLM abbreviation: Psychopharmacology (Berl)
ISSN: 0033-3158
eISSN: 1432-2072
Publisher: Springer-Verlag; Berlin/Heidelberg
Language: English
Date published: 04/2013
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984065749902771

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