Abstract
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.
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Acknowledgements
MH71672 (DAB), MH53327 (JMW), MH-45212 (VH), MH64673 (VH), and a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression (DAB). We thank Hideyo Sato for donating mxCT cDNA.
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Dr James Meador-Woodruff is the editor in chief of Neuropsychopharmacology and the ACNP website and receives a stipend from ACNP for these services. The remaining authors do not have a conflict of interest or any relationship with outside organizations to disclose.
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Baker, D., Madayag, A., Kristiansen, L. et al. Contribution of Cystine–Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine. Neuropsychopharmacol 33, 1760–1772 (2008). https://doi.org/10.1038/sj.npp.1301532
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DOI: https://doi.org/10.1038/sj.npp.1301532
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