, Volume 226, Issue 3, pp 531–540 | Cite as

Reduction in phencyclidine induced sensorimotor gating deficits in the rat following increased system xc activity in the medial prefrontal cortex

  • Victoria Lutgen
  • Krista Qualmann
  • Jon Resch
  • Linghai Kong
  • SuJean Choi
  • David A. BakerEmail author
Original Investigation



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.


Schizophrenia 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.


  1. Angulo MC, Kozlov AS, Charpak S, Audinat E (2004) Glutamate released from glial cells synchronizes neuronal activity in the hippocampus. J Neurosci 24:6920–6927PubMedCrossRefGoogle Scholar
  2. Araque A, Li N, Doyle RT, Haydon PG (2000) SNARE protein-dependent glutamate release from astrocytes. Neuroscience 20:666–673PubMedGoogle Scholar
  3. Baker DA, Xi ZX, Shen H, Swanson CJ, Kalivas PW (2002) The origin and neuronal function of in vivo nonsynaptic glutamate. J Neurosci 22:9134–9141PubMedGoogle Scholar
  4. Baker DA, Madayag A, Kristiansen LV, Meador-Woodruff JH, Haroutunian V, Raju I (2008) Contribution of cystine–glutamate antiporters to the psychotomimetic effects of phencyclidine. Neuropsychopharmacology 33:1760–1772PubMedCrossRefGoogle Scholar
  5. Bakshi VP, Swerdlow NR, Geyer MA (1994) Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response. J Pharmacol Exp Ther 271:787–794PubMedGoogle Scholar
  6. Bannai S (1984) Induction of cystine and glutamate transport activity in human fibroblasts by diethyl maleate and other electrophilic agents. J Biol Chem 259:2435–2440PubMedGoogle Scholar
  7. Bannai S (1986) Exchange of cystine and glutamate across plasma membrane of human fibroblasts. J Biol Chem 261:2256–2263PubMedGoogle Scholar
  8. Bannai S, Kitamura E (1980) Transport interaction of L-cystine and L-glutamate in human diploid fibroblasts in culture. J Biol Chem 255:2372–2376PubMedGoogle Scholar
  9. Battaglia G, Monn JA, Schoepp DD (1997) In vivo inhibition of veratridine-evoked release of striatal excitatory amino acids by the group II metabotropic glutamate receptor agonist LY354740 in rats. Neurosci Lett 229:161–164PubMedCrossRefGoogle Scholar
  10. 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
  11. 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
  12. Berman KF, Zec RF, Weinberger DR (1986) Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. II. Role of neuroleptic treatment, attention, and mental effort. Arch Gen Psychiatry 43:126–135PubMedCrossRefGoogle Scholar
  13. Bezzi P, Carmignoto G, Pasti L, Vesce S, Rossi D, Rizzini BL, Pozzan T, Volterra A (1998) Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391:281–285PubMedCrossRefGoogle Scholar
  14. Braff DL, Geyer MA (1990) Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry 47:181–188PubMedCrossRefGoogle Scholar
  15. Braff D, Stone C, Callaway E, Geyer M, Glick I, Bali L (1978) Prestimulus effects on human startle reflex in normals and schizophrenics. Psychophysiology 15:339–343PubMedCrossRefGoogle Scholar
  16. 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
  17. Bridges R, Lutgen V, Lobner D, Baker DA (2012) Thinking outside the cleft to understand synaptic activity: contribution of the cystine–glutamate antiporter (system xc ) to normal and pathological glutamatergic signaling. Pharmacol Rev 64:780–802PubMedCrossRefGoogle Scholar
  18. Bunney WE, Bunney BG (2000) Evidence for a compromised dorsolateral prefrontal cortical parallel circuit in schizophrenia. Brain Res Brain Res Rev 31:138–146PubMedCrossRefGoogle Scholar
  19. Cabungcal JH, Preissmann D, Delseth C, Cuenod M, Do KQ, Schenk F (2007) Transitory glutathione deficit during brain development induces cognitive impairment in juvenile and adult rats: relevance to schizophrenia. Neurobiol Dis 26:634–645PubMedCrossRefGoogle Scholar
  20. Chen HH, Stoker A, Markou A (2010) The glutamatergic compounds sarcosine and N-acetylcysteine ameliorate prepulse inhibition deficits in metabotropic glutamate 5 receptor knockout mice. Psychopharmacology (Berl) 209:343–350CrossRefGoogle Scholar
  21. Cho Y, Bannai S (1990) Uptake of glutamate and cysteine in C-6 glioma cells and in cultured astrocytes. J Neurochem 55:2091–2097PubMedCrossRefGoogle Scholar
  22. Cilia J, Hatcher P, Reavill C, Jones DN (2007) (+/−) Ketamine-induced prepulse inhibition deficits of an acoustic startle response in rats are not reversed by antipsychotics. J Psychopharmacol 21:302–311PubMedCrossRefGoogle Scholar
  23. Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262:689–695PubMedCrossRefGoogle Scholar
  24. 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
  25. Deserno L, Sterzer P, Wustenberg T, Heinz A, Schlagenhauf F (2012) Reduced prefrontal–parietal effective connectivity and working memory deficits in schizophrenia. J Neurosci 32:12–20PubMedCrossRefGoogle Scholar
  26. Do KQ, Trabesinger AH, Kirsten-Kruger M, Lauer CJ, Dydak U, Hell D, Holsboer F, Boesiger P, Cuenod M (2000) Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci 12:3721–3728PubMedCrossRefGoogle Scholar
  27. Franzen G, Ingvar DH (1975) Absence of activation in frontal structures during psychological testing of chronic schizophrenics. J Neurol Neurosurg Psychiatry 38:1027–1032PubMedCrossRefGoogle Scholar
  28. Garey LJ, Ong WY, Patel TS, Kanani M, Davis A, Mortimer AM, Barnes TR, Hirsch SR (1998) Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J Neurol Neurosurg Psychiatry 65:446–453PubMedCrossRefGoogle Scholar
  29. Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl) 156:117–154CrossRefGoogle Scholar
  30. Glantz LA, Lewis DA (2000) Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 57:65–73PubMedCrossRefGoogle Scholar
  31. Goghari VM, Sponheim SR, MacDonald AW 3rd (2010) The functional neuroanatomy of symptom dimensions in schizophrenia: a qualitative and quantitative review of a persistent question. Neurosci Biobehav Rev 34:468–486PubMedCrossRefGoogle Scholar
  32. Graham FK (1974) Presidential Address, (1975). The more or less startling effects of weak prestimulation. Psychophysiology 12:238–248CrossRefGoogle Scholar
  33. 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
  34. Ingvar DH, Franzen G (1974) Abnormalities of cerebral blood flow distribution in patients with chronic schizophrenia. Acta Psychiatr Scand 50:425–462PubMedCrossRefGoogle Scholar
  35. Jackson ME, Homayoun H, Moghaddam B (2004) NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex. Proc Natl Acad Sci USA 101:8467–8472PubMedCrossRefGoogle Scholar
  36. Janaky R, Ogita K, Pasqualotto BA, Bains JS, Oja SS, Yoneda Y, Shaw CA (1999) Glutathione and signal transduction in the mammalian CNS. J Neurochem 73:889–902PubMedCrossRefGoogle Scholar
  37. Japha K, Koch M (1999) Picrotoxin in the medial prefrontal cortex impairs sensorimotor gating in rats: reversal by haloperidol. Psychopharmacology (Berl) 144:347–354CrossRefGoogle Scholar
  38. 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
  39. Kau KS, Madayag A, Mantsch JR, Grier MD, Abdulhameed O, Baker DA (2008) Blunted cystine–glutamate antiporter function in the nucleus accumbens promotes cocaine-induced drug seeking. Neuroscience 155:530–537PubMedCrossRefGoogle Scholar
  40. Koch M, Bubser M (1994) Deficient sensorimotor gating after 6-hydroxydopamine lesion of the rat medial prefrontal cortex is reversed by haloperidol. Eur J Neurosci 6:1837–1845PubMedCrossRefGoogle Scholar
  41. Kranich O, Dringen R, Sandberg M, Hamprecht B (1998) Utilization of cysteine and cysteine precursors for the synthesis of glutathione in astroglial cultures: preference for cystine. Glia 22:11–18PubMedCrossRefGoogle Scholar
  42. Kulak A, Cuenod M, Do KQ (2012) Behavioral phenotyping of glutathione-deficient mice: relevance to schizophrenia and bipolar disorder. Behav Brain Res 226:563–570PubMedCrossRefGoogle Scholar
  43. Kumari V, Fannon D, Geyer MA, Premkumar P, Antonova E, Simmons A, Kuipers E (2008) Cortical grey matter volume and sensorimotor gating in schizophrenia. Cortex 44:1206–1214PubMedCrossRefGoogle Scholar
  44. 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
  45. Li M, He E, Volf N (2011) Time course of the attenuation effect of repeated antipsychotic treatment on prepulse inhibition disruption induced by repeated phencyclidine treatment. Pharmacol Biochem Behav 98:559–569PubMedCrossRefGoogle Scholar
  46. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209–1223PubMedCrossRefGoogle Scholar
  47. Lobner D, Lipton P (1993) Intracellular calcium levels and calcium fluxes in the CA1 region of the rat hippocampal slice during in vitro ischemia: relationship to electrophysiological cell damage. J Neurosci 13:4861–4871PubMedGoogle Scholar
  48. Majic T, Rentzsch J, Gudlowski Y, Ehrlich S, Juckel G, Sander T, Lang UE, Winterer G, Gallinat J (2011) COMT Val108/158Met genotype modulates human sensory gating. Neuroimage 55:818–824PubMedCrossRefGoogle Scholar
  49. Marino MJ, Wittmann M, Bradley SR, Hubert GW, Smith Y, Conn PJ (2001) Activation of group I metabotropic glutamate receptors produces a direct excitation and disinhibition of GABAergic projection neurons in the substantia nigra pars reticulata. J Neurosci 21:7001–7012PubMedGoogle Scholar
  50. Matsuzawa D, Obata T, Shirayama Y, Nonaka H, Kanazawa Y, Yoshitome E, Takanashi J, Matsuda T, Shimizu E, Ikehira H, Iyo M, Hashimoto K (2008) Negative correlation between brain glutathione level and negative symptoms in schizophrenia: a 3 T 1H-MRS study. PLoS One 3:e1944PubMedCrossRefGoogle Scholar
  51. Moghaddam B, Adams BW (1998) Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281:1349–1352PubMedCrossRefGoogle Scholar
  52. Moghaddam B, Javitt D (2012) From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37:4–15PubMedCrossRefGoogle Scholar
  53. Moran MM, McFarland K, Melendez RI, Kalivas PW, Seamans JK (2005) Cystine/glutamate exchange regulates metabotropic glutamate receptor presynaptic inhibition of excitatory transmission and vulnerability to cocaine seeking. J Neurosci 25:6389–6393PubMedCrossRefGoogle Scholar
  54. Morris BJ, Cochran SM, Pratt JA (2005) PCP: from pharmacology to modelling schizophrenia. Curr Opin Pharmacol 5:101–106PubMedCrossRefGoogle Scholar
  55. Moussawi K, Pacchioni A, Moran M, Olive MF, Gass JT, Lavin A, Kalivas PW (2009) N-Acetylcysteine reverses cocaine-induced metaplasticity. Nat Neurosci 12:182–189PubMedCrossRefGoogle Scholar
  56. Moussawi K, Zhou W, Shen H, Reichel CM, See RE, Carr DB, Kalivas PW (2011) Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse. Proc Natl Acad Sci USA 108:385–390PubMedCrossRefGoogle Scholar
  57. Oberheim NA, Wang X, Goldman S, Nedergaard M (2006) Astrocytic complexity distinguishes the human brain. Trends Neurosci 29:547–553PubMedCrossRefGoogle Scholar
  58. Ogita K, Enomoto R, Nakahara F, Ishitsubo N, Yoneda Y (1995) A possible role of glutathione as an endogenous agonist at the N-methyl-D-aspartate recognition domain in rat brain. J Neurochem 64:1088–1096PubMedCrossRefGoogle Scholar
  59. Oranje B, Van Oel CJ, Gispen-De Wied CC, Verbaten MN, Kahn RS (2002) Effects of typical and atypical antipsychotics on the prepulse inhibition of the startle reflex in patients with schizophrenia. J Clin Psychopharmacol 22:359–365PubMedCrossRefGoogle Scholar
  60. Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG (1994) Glutamate-mediated astrocyte-neuron signalling. Nature 369:744–747PubMedCrossRefGoogle Scholar
  61. Pasti L, Zonta M, Pozzan T, Vicini S, Carmignoto G (2001) Cytosolic calcium oscillations in astrocytes may regulate exocytotic release of glutamate. J Neurosci 21:477–484PubMedGoogle Scholar
  62. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, New YorkGoogle Scholar
  63. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic, New YorkGoogle Scholar
  64. Piani D, Fontana A (1994) Involvement of the cystine transport system xc in the macrophage-induced glutamate-dependent cytotoxicity to neurons. J Immunol 152:3578–3585PubMedGoogle Scholar
  65. Poskanzer KE, Yuste R (2011) Astrocytic regulation of cortical UP states. Proc Natl Acad Sci USA 108:18453–18458PubMedCrossRefGoogle Scholar
  66. 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
  67. Pow DV (2001) Visualising the activity of the cystine–glutamate antiporter in glial cells using antibodies to aminoadipic acid, a selectively transported substrate. Glia 34:27–38PubMedCrossRefGoogle Scholar
  68. Raffa M, Atig F, Mhalla A, Kerkeni A, Mechri A (2011) Decreased glutathione levels and impaired antioxidant enzyme activities in drug-naive first-episode schizophrenic patients. BMC Psychiatry 11:124PubMedCrossRefGoogle Scholar
  69. Rajkowska G, Selemon LD, Goldman-Rakic PS (1998) Neuronal and glial somal size in the prefrontal cortex: a postmortem morphometric study of schizophrenia and Huntington disease. Arch Gen Psychiatry 55:215–224PubMedCrossRefGoogle Scholar
  70. Sagara JI, Miura K, Bannai S (1993) Maintenance of neuronal glutathione by glial cells. J Neurochem 61:1672–1676PubMedCrossRefGoogle Scholar
  71. Schwabe K, Brosda J, Wegener N, Koch M (2005) Clozapine enhances disruption of prepulse inhibition after sub-chronic dizocilpine- or phencyclidine-treatment in Wistar rats. Pharmacol Biochem Behav 80:213–219PubMedCrossRefGoogle Scholar
  72. 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
  73. Shimosato K, Marley RJ, Saito T (1995) Differential effects of NMDA receptor and dopamine receptor antagonists on cocaine toxicities. Pharmacol Biochem Behav 51:781–788PubMedCrossRefGoogle Scholar
  74. Steullet P, Neijt HC, Cuenod M, Do KQ (2006) Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: relevance to schizophrenia. Neuroscience 137:807–819PubMedCrossRefGoogle Scholar
  75. Swerdlow NR, Braff DL, Geyer MA, Koob GF (1986) Central dopamine hyperactivity in rats mimics abnormal acoustic startle response in schizophrenics. Biol Psychiatry 21:23–33PubMedCrossRefGoogle Scholar
  76. Swerdlow NR, Geyer MA, Braff DL (2001) Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology (Berl) 156:194–215CrossRefGoogle Scholar
  77. Swerdlow NR, Light GA, Cadenhead KS, Sprock J, Hsieh MH, Braff DL (2006) Startle gating deficits in a large cohort of patients with schizophrenia: relationship to medications, symptoms, neurocognition, and level of function. Arch Gen Psychiatry 63:1325–1335PubMedCrossRefGoogle Scholar
  78. Swerdlow NR, Weber M, Qu Y, Light GA, Braff DL (2008) Realistic expectations of prepulse inhibition in translational models for schizophrenia research. Psychopharmacology (Berl) 199:331–388CrossRefGoogle Scholar
  79. van Veelen NM, Vink M, Ramsey NF, Kahn RS (2010) Left dorsolateral prefrontal cortex dysfunction in medication-naive schizophrenia. Schizophr Res 123:22–29PubMedCrossRefGoogle Scholar
  80. Wilmsmeier A, Ohrmann P, Suslow T, Siegmund A, Koelkebeck K, Rothermundt M, Kugel H, Arolt V, Bauer J, Pedersen A (2010) Neural correlates of set-shifting: decomposing executive functions in schizophrenia. J Psychiatry Neurosci 35:321–329PubMedCrossRefGoogle Scholar
  81. Ye ZC, Wyeth MS, Baltan-Tekkok S, Ransom BR (2003) Functional hemichannels in astrocytes: a novel mechanism of glutamate release. J Neurosci 23:3588–3596PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Victoria Lutgen
    • 1
  • Krista Qualmann
    • 1
  • Jon Resch
    • 1
  • Linghai Kong
    • 1
  • SuJean Choi
    • 1
  • David A. Baker
    • 1
    Email author
  1. 1.Department of Biomedical SciencesMarquette UniversityMilwaukeeUSA

Personalised recommendations