Faculty Collaboration Database

Reduction in phencyclidine induced sensorimotor gating deficits in the rat following increased system xc⁻ activity in the medial prefrontal cortex. Psychopharmacology (Berl) 2013 Apr;226(3):531-40

Date

11/30/2012

Pubmed ID

23192314

Pubmed Central ID

PMC3595356

DOI

10.1007/s00213-012-2926-3

Scopus ID

2-s2.0-84876499468 (requires institutional sign-in at Scopus site)   14 Citations

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 (14)C-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 (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(-).

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.

Author List

Lutgen V, Qualmann K, Resch J, Kong L, Choi S, Baker DA

Author

Sujean Choi PhD in the School of Allied Health department at Marquette University

MESH terms used to index this publication - Major topics in bold

Acetylcysteine
Amino Acid Transport System y+
Amino Acid Transport Systems, Acidic
Animals
Benzoates
Disease Models, Animal
Dose-Response Relationship, Drug
Gait Disorders, Neurologic
Glycine
In Situ Hybridization
Male
Phencyclidine
Prefrontal Cortex
RNA, Messenger
Rats
Rats, Sprague-Dawley
Reflex, Startle
Schizophrenia
Sensory Gating