Document Detail


Reduction in phencyclidine induced sensorimotor gating deficits in the rat following increased system xc⁻ activity in the medial prefrontal cortex.
MedLine Citation:
PMID:  23192314     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Victoria Lutgen; Krista Qualmann; Jon Resch; Linghai Kong; Sujean Choi; David A Baker
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-29
Journal Detail:
Title:  Psychopharmacology     Volume:  226     ISSN:  1432-2072     ISO Abbreviation:  Psychopharmacology (Berl.)     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-11     Completed Date:  2013-08-29     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  7608025     Medline TA:  Psychopharmacology (Berl)     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  531-40     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Acetylcysteine / administration & dosage,  pharmacology
Amino Acid Transport System y+ / genetics,  metabolism*
Amino Acid Transport Systems, Acidic
Animals
Benzoates / pharmacology
Disease Models, Animal
Dose-Response Relationship, Drug
Gait Disorders, Neurologic / etiology
Glycine / analogs & derivatives,  pharmacology
In Situ Hybridization
Male
Phencyclidine / administration & dosage,  toxicity
Prefrontal Cortex / metabolism*
RNA, Messenger / metabolism
Rats
Rats, Sprague-Dawley
Schizophrenia / physiopathology*
Sensory Gating / physiology*
Startle Reaction
Grant Support
ID/Acronym/Agency:
DA017328/DA/NIDA NIH HHS; DA025617/DA/NIDA NIH HHS; DK074734/DK/NIDDK NIH HHS; R01 DA017328/DA/NIDA NIH HHS; R01 DA025617/DA/NIDA NIH HHS; R01 DK074734/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Amino Acid Transport System y+; 0/Amino Acid Transport Systems, Acidic; 0/Benzoates; 0/RNA, Messenger; 0/xCT protein, rat; 7292-81-1/4-carboxyphenylglycine; J1DOI7UV76/Phencyclidine; TE7660XO1C/Glycine; WYQ7N0BPYC/Acetylcysteine
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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