Reduction in phencyclidine induced sensorimotor gating deficits in the rat following increased system xc − activity in the medial prefrontal cortex
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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.
KeywordsSchizophrenia Prefrontal cortex Prepulse inhibition Phencyclidine Sensorimotor gating Glutamate System xc− Nonvesicular Cystine–glutamate antiporter
This work was supported by the National Institutes of Health grants DA017328 (DAB), DA025617 (DAB), DK074734 (SC), as well as by The Brain and Behavior Research Fund (DAB).
David A. Baker owns shares in Promentis Pharmaceuticals, a company developing novel antipsychotic agents. Promentis did not sponsor or otherwise support the experiments contained in this manuscript.
- Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Judd F, Katz F, Katz P, Ording-Jespersen S, Little J, Conus P, Cuenod M, Do KQ, Bush AI (2008) N-acetyl cysteine as a glutathione precursor for schizophrenia—a double-blind, randomized, placebo-controlled trial. Biol Psychiatry 64:361–368PubMedCrossRefGoogle Scholar
- Berk M, Munib A, Dean O, Malhi GS, Kohlmann K, Schapkaitz I, Jeavons S, Katz F, Anderson-Hunt M, Conus P, Hanna B, Otmar R, Ng F, Copolov DL, Bush AI (2011) Qualitative methods in early-phase drug trials: broadening the scope of data and methods from an RCT of N-acetylcysteine in schizophrenia. J Clin Psychiatry 72:909–913PubMedCrossRefGoogle Scholar
- Bridges RJ (2012) System x(c) (−) cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharmacol 165:20–34Google Scholar
- das Neves Duarte JM, Kulak A, Gholam-Razaee MM, Cuenod M, Gruetter R, Do KQ (2012) N-Acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development. Biol Psychiatry 71:1006–1014Google Scholar
- Gysin R, Kraftsik R, Boulat O, Bovet P, Conus P, Comte-Krieger E, Polari A, Steullet P, Preisig M, Teichmann T, Cuenod M, Do KQ (2011) Genetic dysregulation of glutathione synthesis predicts alteration of plasma thiol redox status in schizophrenia. Antioxid Redox Signal 15:2003–2010PubMedCrossRefGoogle Scholar
- Javitt DC, Schoepp D, Kalivas PW, Volkow ND, Zarate C, Merchant K, Bear MF, Umbricht D, Hajos M, Potter WZ, Lee CM (2011) Translating glutamate: from pathophysiology to treatment. Sci Transl Med 3: 102mr2Google Scholar
- Kupchik YM, Moussawi K, Tang XC, Wang X, Kalivas BC, Kolokithas R, Ogburn KB, Kalivas PW (2011) The Effect of n-acetylcysteine in the nucleus accumbens on neurotransmission and relapse to cocaine. Biol PsychiatryGoogle Scholar
- Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, New YorkGoogle Scholar
- Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic, New YorkGoogle Scholar
- Potkin SG, Turner JA, Brown GG, McCarthy G, Greve DN, Glover GH, Manoach DS, Belger A, Diaz M, Wible CG, Ford JM, Mathalon DH, Gollub R, Lauriello J, O’Leary D, van Erp TG, Toga AW, Preda A, Lim KO (2009) Working memory and DLPFC inefficiency in schizophrenia: the FBIRN study. Schizophr Bull 35:19–31PubMedCrossRefGoogle Scholar
- Seib TM, Patel SA, Bridges RJ (2011) Regulation of the System x(−) (C) cystine/glutamate exchanger by intracellular glutathione levels in rat astrocyte primary cultures. Glia 59:1387–1401Google Scholar