Contribution of cystine-glutamate antiporters to the psychotomimetic effects of phencyclidine.
Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine-glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine-glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystine-glutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine-glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine-glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine-glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP.
Baker
David A
DA
Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53233, USA. david.baker@mu.edu
Madayag
Aric
A
Kristiansen
Lars V
LV
Meador-Woodruff
James H
JH
Haroutunian
Vahram
V
Raju
Ilangovan
I
D000111:Acetylcysteine / Q000627:therapeutic use*; D000368:Aged; D000369:Aged, 80 and over; D000596:Amino Acids / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000187:drug effects; D005260:Female; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007398:Interpersonal Relations; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D017551:Microdialysis / Q000379:methods; D010622:Phencyclidine; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D014966:Xanthenes / Q000494:pharmacology
D000596:Amino Acids; D016166:Free Radical Scavengers; C114624:LY 341495; D014966:Xanthenes; C453101:carboxyphenylglycine; D018698:Glutamic Acid; D010622:Phencyclidine; D005998:Glycine; D000111:Acetylcysteine