, Volume 217, Issue 1, pp 127–142 | Cite as

Effects of chronic oral treatment with aripiprazole on the expression of NMDA receptor subunits and binding sites in rat brain

  • Nina Segnitz
  • Thomas Ferbert
  • Andrea Schmitt
  • Peter Gass
  • Peter J. Gebicke-Haerter
  • Mathias ZinkEmail author
Original Investigation



The glutamatergic theory of schizophrenia proposes a dysfunction of ionotropic N-methyl-d-aspartate receptors (NMDA-R). Several therapeutic strategies address NMDA-R function and the effects of antipsychotic agents on NMDA-R expression have been described. Within the second-generation antipsychotics, the partial dopaminergic and serotonergic agonist aripiprazole (APZ) was able to counteract the behavioral effects of NMDA-R antagonists.


This study aims to investigate the effects of APZ on NMDA-R subunit expression and binding.


We treated Sprague–Dawley rats for 4 weeks or 4 months with APZ in daily oral doses of 10 and 40 mg per kilogram of body weight. Gene expression of the NMDA-R subunits NR1, NR2A, NR2B, NR2C, and NR2D, respectively, was assessed by semiquantitative radioactive in situ hybridization and in parallel receptor binding using 3H-MK-801 receptor autoradiography.


Increased expression levels of NR1 (4 weeks), NR2A (4 weeks), NR2C (4 weeks and 4 months), and NR2D (4 months) were observed in several hippocampal and cortical brain regions. The parallel reduced expression of NR2B mRNAs (4 months) resulted in a relative increase of the NR2A/NR2B ratio. Marked differences between specific brain regions, the doses of APZ, and the time points of assessment became obvious. On the receptor level, increased MK-801-binding was found after 4 weeks in the 40-mg group and after 4 months in the 10-mg group.


The effects of APZ converge in enhanced NMDA receptor expression and a shift of subunit composition towards adult-type receptors. Our results confirm the regulatory connections between dopaminergic, serotonergic, and glutamatergic neurotransmissions with relevance for cognitive and negative symptoms of schizophrenia.


Animal model Aripiprazole Antipsychotic Dopamine Glutamate NMDA Receptor Schizophrenia Serotonin 



Anterior cingulate cortex




Hippocampal subregion cornu ammonis 1


Hippocampal subregion cornu ammonis 3


Caudate nucleus and putamen


Dentate gyrus


Excitatory amino acid transporter


Fronto-parietal cortex


γ-Amino butyric acid




In situ hybridization


Messenger ribonucleic acid




NMDA receptor




Occipital cortex


Parietal cortex


Prefrontal cortex


Retrosplenial granular cortex


Standard error of the mean


Temporal cortex




Vesicular glutamate transporter 1



This work has been funded by an unrestricted grant to M. Z. by Bristol-Myers Squibb GmbH & CoKGaA and Otsuka Pharmaceuticals. M. Z. holds scientific and speaker grants of the European Research Advisory Board (ERAB), Pfizer Pharma GmbH and Bristol Myers Squibb Pharmaceuticals, AstraZeneca, and Janssen Cilag. P.G. has been speaker for Pfizer Pharma GmbH and AstraZeneca. N.S., T.F., A.S., and P.J. G.-H. have no conflicts of interest.


  1. Baier PC, Blume A, Koch J, Marx A, Fritzer G, Aldenhoff JB, Schiffelholz T (2009) Early postnatal depletion of NMDA receptor development affects behaviour and NMDA receptor expression until later adulthood in rats—a possible model for schizophrenia. Behav Brain Res 205:96–101PubMedCrossRefGoogle Scholar
  2. Belforte JE, Zsiros V, Sklar ER, Jiang Z, Yu G, Li Y, Quinlan EM, Nakazawa K (2010) Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci 13:76–83PubMedCrossRefGoogle Scholar
  3. Benes FM (2009) Neural circuitry models of schizophrenia: is it dopamine, GABA, glutamate, or something else? Biol Psychiatry 65:1003–1005PubMedCrossRefGoogle Scholar
  4. Bickel S, Javitt DC (2009) Neurophysiological and neurochemical animal models of schizophrenia: focus on glutamate. Behav Brain Res 204:352–362PubMedCrossRefGoogle Scholar
  5. Bitanihirwe BK, Lim MP, Kelley JF, Kaneko T, Woo TU (2009) Glutamatergic deficits and parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia. BMC Psychiatry 9:71PubMedCrossRefGoogle Scholar
  6. Bortolozzi A, az-Mataix L, Toth M, Celada P, Artigas F, Bortolozzi A, az-Mataix L, Toth M, Celada P, Artigas F (2007) In vivo actions of aripiprazole on serotonergic and dopaminergic systems in rodent brain. Psychopharmacol 191:745–758CrossRefGoogle Scholar
  7. Bowles TM, Levin GM (2003) Aripiprazole: a new atypical antipsychotic drug. Ann Pharmacother 37:687–694PubMedCrossRefGoogle Scholar
  8. Bruins Slot LA, Kleven MS, Newman-Tancredi A (2005) Effects of novel antipsychotics with mixed D(2) antagonist/5-HT(1A) agonist properties on PCP-induced social interaction deficits in the rat. Neuropharmacolcology 49:996–1006CrossRefGoogle Scholar
  9. Carlsson A (2006) The neurochemical circuitry of schizophrenia. Pharmacopsychiatry 39(Suppl 1):S10–S14PubMedCrossRefGoogle Scholar
  10. Cheng MC, Liao D-L, Hsiung C-A, Chen C-Y, Liao Y-C, Chen C-H (2008) Chronic treatment with aripiprazole induces differential gene expression in the rat frontal cortex. Int J Neuropsychopharmacol 11:207–216PubMedCrossRefGoogle Scholar
  11. Choi YK, Gardner MP, Tarazi FI (2009) Effects of risperidone on glutamate receptor subtypes in developing rat brain. Eur Neuropsychopharmacol 19:77–84PubMedCrossRefGoogle Scholar
  12. Corbett R, Camacho F, Woods AT, Kerman LL, Fishkin RJ, Brooks K, Dunn RW (1995) Antipsychotic agents antagonize non-competitive N-methyl-d-aspartate antagonist-induced behaviors. Psychopharmacologia 120:67–74CrossRefGoogle Scholar
  13. Corlew R, Brasier DJ, Feldman DE, Philpot BD (2008) Presynaptic NMDA receptors: newly appreciated roles in cortical synaptic function and plasticity. Neuroscientist 14:609–625PubMedCrossRefGoogle Scholar
  14. Cosi C, Waget A, Rollet K, Tesori V, Newman-Tancredi A (2005) Clozapine, ziprasidone and aripiprazole but not haloperidol protect against kainic acid-induced lesion of the striatum in mice, in vivo: role of 5-HT1A receptor activation. Brain Res 1043:32–41PubMedCrossRefGoogle Scholar
  15. Coyle JT, Tsai G, Goff D (2003) Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Ann NY Acad Sci 1003:318–327PubMedCrossRefGoogle Scholar
  16. Dahan L, Husum H, Mnie-Filali O, Arnt J, Hertel P, Haddjeri N (2009) Effects of bifeprunox and aripiprazole on rat serotonin and dopamine neuronal activity and anxiolytic behaviour. J Psychopharmacol 23:177–189PubMedCrossRefGoogle Scholar
  17. Deng X, Shibata H, Takeuchi N, Rachi S, Sakai M, Ninomiya H, Iwata N, Ozaki N, Fukumaki Y (2007) Association study of polymorphisms in the glutamate transporter genes SLC1A1, SLC1A3, and SLC1A6 with schizophrenia. Am J Med Genet B Neuropsychiatr Genet 144B:271–278PubMedCrossRefGoogle Scholar
  18. Du Bois TM, Deng C, Han M, Newell KA, Huang XF (2009) Excitatory and inhibitory neurotransmission is chronically altered following perinatal NMDA receptor blockade. Eur Neuropsychopharmacol 19:256–265PubMedCrossRefGoogle Scholar
  19. Duncan GE, Inada K, Farrington JS, Koller BH, Moy SS (2009) Neural activation deficits in a mouse genetic model of NMDA receptor hypofunction in tests of social aggression and swim stress. Brain Res 1265:186–195PubMedCrossRefGoogle Scholar
  20. El-Sayeh HG, Morganti C, Adams CE (2006) Aripiprazole for schizophrenia. Br J Psychiatry 189:102–108PubMedCrossRefGoogle Scholar
  21. Englisch S, Weinbrenner A, Inta D, Zink M (2009) Aripiprazole for the management of olanzapine-induced weight gain. Pharmacopsychiatry 42:166–167PubMedCrossRefGoogle Scholar
  22. Espinosa JS, Wheeler DG, Tsien RW, Luo L (2009) Uncoupling dendrite growth and patterning: single-cell knockout analysis of NMDA receptor 2B. Neuron 62:205–217PubMedCrossRefGoogle Scholar
  23. Farber NB (2003) The NMDA receptor hypofunction model of psychosis. Ann NY Acad Sci 1003:119–130PubMedCrossRefGoogle Scholar
  24. Fejgin K, Safonov S, Palsson E, Wass C, Engel JA, Svensson L, Klamer D (2007) The atypical antipsychotic, aripiprazole, blocks phencyclidine-induced disruption of prepulse inhibition in mice. Psychopharmacologia 191:377–385CrossRefGoogle Scholar
  25. Fitzgerald LW, Deutch AY, Gasic G, Heinemann SF, Nestler EJ (1995) Regulation of cortical and subcortical glutamate receptor subunit expression by antipsychotic drugs. J Neurosci 15:2453–2461PubMedGoogle Scholar
  26. Funk AJ, Rumbaugh G, Harotunian V, McCullumsmith RE, Meador-Woodruff JH (2009) Decreased expression of NMDA receptor-associated proteins in frontal cortex of elderly patients with schizophrenia. Neuroreport 20:1019–1022PubMedCrossRefGoogle Scholar
  27. Gaspar PA, Bustamante ML, Silva H, Aboitiz F (2009) Molecular mechanisms underlying glutamatergic dysfunction in schizophrenia: therapeutic implications. J Neurochem 111:891–900PubMedCrossRefGoogle Scholar
  28. Gielen M, Retchless BS, Mony L, Johnson JW, Paoletti P (2009) Mechanism of differential control of NMDA receptor activity by NR2 subunits. Nature. doi: 10.1038/nature07993 PubMedGoogle Scholar
  29. Gilmour G, Pioli EY, Dix SL, Smith JW, Conway MW, Jones WT, Loomis S, Mason R, Shahabi S, Tricklebank MD (2009) Diverse and often opposite behavioural effects of NMDA receptor antagonists in rats: implications for “NMDA antagonist modelling” of schizophrenia. Psychopharmacologia 205:203–216CrossRefGoogle Scholar
  30. Goebel DJ, Poosch MS (1999) NMDA receptor subunit gene expression in the rat brain: a quantitative analysis of endogenous mRNA levels of NR1Com, NR2A, NR2B, NR2C, NR2D and NR3A. Brain Res Mol Brain Res 69:164–170PubMedCrossRefGoogle Scholar
  31. Goff DC, Coyle JT (2001) The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 158:1367–1377PubMedCrossRefGoogle Scholar
  32. Gonzalez-Burgos G, Lewis DA (2008) GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia. Schizophr Bull 34:944–961PubMedCrossRefGoogle Scholar
  33. Gordon JA (2010) Testing the glutamate hypothesis of schizophrenia. Nat Neurosci 13:2–4PubMedCrossRefGoogle Scholar
  34. Guo C, Yang Y, Su Y, Si T (2010) Postnatal BDNF expression profiles in prefrontal cortex and hippocampus of a rat schizophrenia model induced by MK-801 administration. J Biomed Biotechnol 2010:783297PubMedGoogle Scholar
  35. Han M, Huang XF, Deng C (2009) Aripiprazole differentially affects mesolimbic and nigrostriatal dopaminergic transmission: implications for long-term drug efficacy and low extrapyramidal side-effects. Int J Neuropsychopharmacol. doi: 10.1017/S1461145709009948 Google Scholar
  36. Harrison PJ, Law AJ, Eastwood SL (2003) Glutamate receptors and transporters in the hippocampus in schizophrenia. Ann NY Acad Sci 1003:94–101PubMedCrossRefGoogle Scholar
  37. Harrison PJ, Weinberger DR (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 10:40–68PubMedCrossRefGoogle Scholar
  38. Henderson DC, Fan X, Copeland PM, Sharma B, Borba C, Boxill R, Freudenreich O, Cather C, Evins A, Goff DC (2009) Aripiprazole added to overweight and obese olanzapine-treated schizophrenia patients. J Clin Psychopharmacol 29:165–169PubMedCrossRefGoogle Scholar
  39. Henn FA (1995) The NMDA-receptor as a site for pathogenesis. Arch Gen Psychiatry 52:1008–1010PubMedGoogle Scholar
  40. Homayoun H, Moghaddam B (2008) Orbitofrontal cortex neurons as a common target for classic and glutamatergic antipsychotic drugs. Proc Nat Acad Sci USA 105:18041–18046PubMedCrossRefGoogle Scholar
  41. Homayoun H, Moghaddam B (2007) NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 27:11496–11500PubMedCrossRefGoogle Scholar
  42. Ibrahim HM, Hogg AJ Jr, Healy DJ, Haroutunian V, Davis KL, Meador-Woodruff JH (2000) Ionotropic glutamate receptor binding and subunit mRNA expression in thalamic nuclei in schizophrenia. Am J Psychiatry 157:1811–1823PubMedCrossRefGoogle Scholar
  43. Inoue A, Seto M, Sugita S, Hide I, Hirose T, Koga N, Kikuchi T, Nakata Y (1998) Differential effects on D2 dopamine receptor and prolactin gene expression by haloperidol and aripiprazole in the rat pituitary. Mol Brain Res 2:285–292CrossRefGoogle Scholar
  44. Jenkins TA, Harte MK, Reynolds GP (2010) Effect of subchronic phencyclidine administration on sucrose preference and hippocampal parvalbumin immunoreactivity in the rat. Neurosci Lett 471:144–147PubMedCrossRefGoogle Scholar
  45. Jordan S, Koprivica V, Dunn R, Tottori K, Kikuchi T, Altar CA (2004) In vivo effects of aripiprazole on cortical and striatal dopaminergic and serotonergic function. Eur J Pharmacol 483:45–53PubMedCrossRefGoogle Scholar
  46. Kalinichev M, Rourke C, Daniels AJ, Grizzle MK, Britt CS, Ignar DM, Jones DN (2005) Characterisation of olanzapine-induced weight gain and effect of aripiprazole vs olanzapine on body weight and prolactin secretion in female rats. Psychopharmacol 182:220–231CrossRefGoogle Scholar
  47. Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GG, Zimbroff DL, Ali MW (2002) Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 63:763–771PubMedCrossRefGoogle Scholar
  48. Kargieman L, Santana N, Mengod G, Celada P, Artigas F (2007) Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine. P Natl Acad Sci USA 104:14843–14848Google Scholar
  49. Kern RS, Green MF, Cornblatt BA, Owen JR, McQuade RD, Carson WH, Ali M, Marcus R (2006) The neurocognitive effects of aripiprazole: an open-label comparison with olanzapine. Psychopharmacol 187:312–320CrossRefGoogle Scholar
  50. Konradi C, Heckers S (2003) Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. Pharmaco Ther 97:153–179CrossRefGoogle Scholar
  51. Kristiansen LV, Huerta I, Beneyto M, Meador-Woodruff JH (2007) NMDA receptors and schizophrenia. Curr Opin Pharmacol 7:48–55PubMedCrossRefGoogle Scholar
  52. Krystal JH, Perry EB Jr, Gueorguieva R, Belger A, Madonick SH, Bi-Dargham A, Cooper TB, Macdougall L, Bi-Saab W, D’Souza DC, Krystal JH, Perry EBJ, Gueorguieva R, Belger A, Madonick SH, Bi-Dargham A, Cooper TB, Macdougall L, Bi-Saab W, D’Souza DC (2005) Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: implications for glutamatergic and dopaminergic model psychoses and cognitive function. Arch Gen Psychiatry 62:985–994PubMedCrossRefGoogle Scholar
  53. Lei G, Anastasio NC, Fu Y, Neugebauer V, Johnson KM (2009) Activation of dopamine D1 receptors blocks phencyclidine-induced neurotoxicity by enhancing N-methyl-d-aspartate receptor-mediated synaptic strength. J Neurochem 109:1017–1030PubMedCrossRefGoogle Scholar
  54. Leite JV, Guimaraes FS, Moreira FA (2008) Aripiprazole, an atypical antipsychotic, prevents the motor hyperactivity induced by psychotomimetics and psychostimulants in mice. Eur J Pharmacol 578:222–227PubMedCrossRefGoogle Scholar
  55. Li M, Budin R, Fleming AS, Kapur S (2005) Effects of novel antipsychotics, amisulpiride and aripiprazole, on maternal behavior in rats. Psychopharmacol 181:600–610CrossRefGoogle Scholar
  56. Li Z, Ichikawa J, Dai J, Meltzer HY (2004) Aripiprazole, a novel antipsychotic drug, preferentially increases dopamine release in the prefrontal cortex and hippocampus in rat brain. Eur J Pharmacol 493:75–83PubMedCrossRefGoogle Scholar
  57. Lieberman JA (2004) Dopamine partial agonists: a new class of antipsychotic. CNS Drugs 18:251–267PubMedCrossRefGoogle Scholar
  58. Lopez-Gil X, Artigas F, Adell A (2009) Role of different monoamine receptors controlling MK-801-induced release of serotonin and glutamate in the medial prefrontal cortex: relevance for antipsychotic action. Int J Neuropsychopharmacol 12:487–499PubMedCrossRefGoogle Scholar
  59. Lopez-Gil X, Artigas F, Adell A (2010) Unraveling monoamine receptors involved in the action of typical and atypical antipsychotics on glutamatergic and serotonergic transmission in prefrontal cortex. Curr Pharm Des 16:502–515PubMedCrossRefGoogle Scholar
  60. MacDonald AW III, Chafee MV (2006) Translational and developmental perspective on N-methyl-d-aspartate synaptic deficits in schizophrenia. Dev Psychopathol 18:853–876PubMedGoogle Scholar
  61. McLean SL, Idris NF, Woolley ML, Neill JC (2009) D1-like receptor activation improves PCP-induced cognitive deficits in animal models: implications for mechanisms of improved cognitive function in schizophrenia. Eur Neuropsychopharmacol 19:440–450PubMedCrossRefGoogle Scholar
  62. Meyer-Lindenberg A, Weinberger DR (2006) Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci 7:818–827PubMedCrossRefGoogle Scholar
  63. Millan MJ (2005) N-Methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives. Psychopharmacol 179:30–53CrossRefGoogle Scholar
  64. Moghaddam B, Jackson ME (2003) Glutamatergic animal models of schizophrenia. Ann NY Acad Sci 1003:131–137PubMedCrossRefGoogle Scholar
  65. Nagai T, Murai R, Matsui K, Kamei H, Noda Y, Furukawa H, Nabeshima T (2009) Aripiprazole ameliorates phencyclidine-induced impairment of recognition memory through dopamine D1 and serotonin 5-HT1A receptors. Psychopharmacol 202:315–328CrossRefGoogle Scholar
  66. Nordquist RE, Risterucci C, Moreau JL, von Kienlin M, Kunnecke B, Maco M, Freichel C, Riemer C, Spooren W (2008) Effects of aripiprazole/OPC-14597 on motor activity, pharmacological models of psychosis, and brain activity in rats. Neuropharmacol 54:405–416CrossRefGoogle Scholar
  67. Paoletti P, Neyton J (2007) NMDA receptor subunits: function and pharmacology. Curr Opin Pharmacol 7:39–47PubMedCrossRefGoogle Scholar
  68. Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreeev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD (2007) Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nat Med 13:1102–1107PubMedCrossRefGoogle Scholar
  69. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic, San DiegoGoogle Scholar
  70. Paz RD, Tardito S, Atzori M, Tseng KY (2008) Glutamatergic dysfunction in schizophrenia: from basic neuroscience to clinical psychopharmacology. Eur Neuropsychopharmacol 18:773–786PubMedCrossRefGoogle Scholar
  71. Potvin S, Stip E, Roy J-Y (2005) Toxic psychoses as pharmacological models of schizophrenia. Curr Psychiatry Rev 1:23–32CrossRefGoogle Scholar
  72. Rolls ET, Loh M, Deco G, Winterer G (2008) Computational models of schizophrenia and dopamine modulation in the prefrontal cortex. Nat Rev Neurosci 9:696–709PubMedCrossRefGoogle Scholar
  73. Roopun AK, Cunningham MO, Racca C, Alter K, Traub RD, Whittington MA (2008) Region-specific changes in gamma and beta2 rhythms in NMDA receptor dysfunction models of schizophrenia. Schizophr Bull 34:962–973PubMedCrossRefGoogle Scholar
  74. Schmitt A, Zink M, Mueller B, May B, Herb A, Jatzko A, Braus DF, Henn FA (2003a) Effects of long-term antipsychotic treatment on NMDA receptor binding and gene expression of subunits. Neurochem Res 28:235–241PubMedCrossRefGoogle Scholar
  75. Schmitt A, Zink M, Petroianu G, May B, Braus DF, Henn FA (2003b) Decreased gene expression of glial and neuronal glutamate transporters after chronic antipsychotic treatment in rat brain. Neurosci Lett 347:81–84PubMedCrossRefGoogle Scholar
  76. Segnitz N, Schmitt A, Gebicke-Härter P, Zink M (2009) Differential expression of glutamate transporter genes after chronic oral treatment with aripiprazole in rats. Neurochem Int 55:619–628PubMedCrossRefGoogle Scholar
  77. Seillier A, Giuffrida A (2009) Evaluation of NMDA receptor models of schizophrenia: divergences in the behavioral effects of sub-chronic PCP and MK-801. Behav Brain Res 204:410–415PubMedCrossRefGoogle Scholar
  78. Semba J, Sakai M, Miyoshi R, Mataga N, Fukamauchi F, Kito S (1996) Differential expression of c-fos mRNA in rat prefrontal cortex, striatum, N. accumbens and lateral septum after typical and atypical antipsychotics: an in situ hybridization study. Neurochem Int 29:435–442PubMedCrossRefGoogle Scholar
  79. Semba J, Watanabe A, Kito S, Toru M (1995) Behavioural and neurochemical effects of OPC-14597, a novel antipsychotic drug, on dopaminergic mechanisms in rat brain. Neuropharmacology 34:785–791PubMedCrossRefGoogle Scholar
  80. Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR, Roth BL, Mailman R (2003) Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacol 28:1400–1411CrossRefGoogle Scholar
  81. Shim SS, Hammonds MD, Kee BS (2008) Potentiation of the NMDA receptor in the treatment of schizophrenia: focused on the glycine site. Eur Arch Psychiatry Clin Neurosci 258:16–27PubMedCrossRefGoogle Scholar
  82. Snigdha S, Horiguchi M, Huang M, Li Z, Shahid M, Neill JC, Meltzer HY (2010) Attenuation of phencyclidine-induced object recognition deficits by the combination of atypical antipsychotic drugs and pimavanserin (ACP 103), a 5-hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther 332:622–631PubMedCrossRefGoogle Scholar
  83. Snigdha S, Neill JC (2008) Improvement of phencyclidine-induced social behaviour deficits in rats: involvement of 5-HT1A receptors. Beh Brain Res 191:26–31CrossRefGoogle Scholar
  84. Sparshatt A, Taylor D, Patel MX, Kapur S (2010) A systematic review of aripiprazole—dose, plasma concentration, receptor occupancy, and response: implications for therapeutic drug monitoring. J Clin Psychiatry 71:1447–1456PubMedCrossRefGoogle Scholar
  85. Squires RF, Saederup E (1991) A review of evidence for GABergic predominance/glutamatergic deficit as a common etiological factor in both schizophrenia and affective psychoses: more support for a continuum hypothesis of “functional” psychosis. Neurochem Res 16:1099–1111PubMedCrossRefGoogle Scholar
  86. Stephan KE, Friston KJ, Frith CD (2009) Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring. Schizophr Bull 35:509–527PubMedCrossRefGoogle Scholar
  87. Stone JM, Morrison PD, Pilowsky LS (2007) Review: glutamate and dopamine dysregulation in schizophrenia—a synthesis and selective review. J Psychopharmacol 21:440–452PubMedCrossRefGoogle Scholar
  88. Tan HY, Chen Q, Sust S, Buckholtz JW, Meyers JD, Egan MF, Mattay VS, Meyer-Lindenberg A, Weinberger DR, Callicott JH (2007) Epistasis between catechol-O-methyltransferase and type II metabotropic glutamate receptor 3 genes on working memory brain function. Proc Nat Acad Sci USA 104:12536–12541PubMedCrossRefGoogle Scholar
  89. Tarazi FI, Choi YK, Gardner M, Wong EH, Henry B, Shahid M (2009) Asenapine exerts distinctive regional effects on ionotropic glutamate receptor subtypes in rat brain. Synapse 63:413–420PubMedCrossRefGoogle Scholar
  90. Tran-Johnson TK, Sack DA, Marcus RN, Auby P, McQuade RD, Oren DA (2007) Efficacy and safety of intramuscular aripiprazole in patients with acute agitation: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 68:111–119PubMedCrossRefGoogle Scholar
  91. Ulas J, Nguyen L, Cotman CW (1993) Chronic haloperidol treatment enhances binding to NMDA receptors in rat cortex. Neuroreport 4:1049–1051PubMedCrossRefGoogle Scholar
  92. Uylings HB, Van Eden CG (1990) Qualitative and quantitative comparison of the prefrontal cortex in rat and in primates, including humans. Progr Brain Res 85:31–62CrossRefGoogle Scholar
  93. Van Eden CG, Kros JM, Uylings HB (1990) The development of the rat prefrontal cortex. Its size and development of connections with thalamus, spinal cord and other cortical areas. Progr Brain Res 85:169–183Google Scholar
  94. Van Eden CG, Rinkens A, Uylings HB (1998) Retrograde degeneration of thalamic neurons in the mediodorsal nucleus after neonatal and adult aspiration lesions of the medial prefrontal cortex in the rat. Implications for mechanisms of functional recovery. Eur J Neurosci 10:1581–1589PubMedCrossRefGoogle Scholar
  95. Van Eden CG, van Hest A, van Haaren F, Uylings HB (1994) Effects of neonatal mediodorsal thalamic lesions on structure and function of the rat prefrontal cortex. Brain Res Dev Brain Res 80:26–34PubMedGoogle Scholar
  96. Vrajova M, Stastny F, Horacek J et al (2010) Expression of the hippocampal NMDA receptor GluN1 subunit and its splicing isoforms in schizophrenia: postmortem study. Neurochem Res 35:994–1002PubMedCrossRefGoogle Scholar
  97. Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM, Nord AS, Kusenda M, Malhotra D, Bhandari A, Stray SM, Rippey CF, Roccanova P, Makarov V, Lakshmi B, Findling RL, Sikich L, Stromberg T, Merriman B, Gogtay N, Butler P, Eckstrand K, Noory L, Gochman P, Long R, Chen Z, Davis S, Baker C, Eichler EE, Meltzer PS, Nelson SF, Singleton AB, Lee MK, Rapoport JL, King MC, Sebat J (2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320:539–543PubMedCrossRefGoogle Scholar
  98. Wang HX, Gao WJ (2009) Cell type-specific development of NMDA receptors in the interneurons of rat prefrontal cortex. Neuropsychopharmacol 34:2028–2040CrossRefGoogle Scholar
  99. Wirkner K, Krause T, Koles L, Thummler S, Al-Khrasani M, Illes P (2004) D1 but not D2 dopamine receptors or adrenoceptors mediate dopamine-induced potentiation of N-methyl-d-aspartate currents in the rat prefrontal cortex. Neurosci Lett 372:89–93PubMedCrossRefGoogle Scholar
  100. Wood MD, Scott C, Clarke K, Westaway J, Davies CH, Reavill C, Hill M, Rourke C, Newson M, Jones DN, Forbes IT, Gribble A, Wood MD, Scott C, Clarke K, Westaway J, Davies CH, Reavill C, Hill M, Rourke C, Newson M, Jones DNC, Forbes IT, Gribble A (2006) Aripiprazole and its human metabolite are partial agonists at the human dopamine D2 receptor, but the rodent metabolite displays antagonist properties. Eur J Pharmacol 546:88–94PubMedCrossRefGoogle Scholar
  101. Yamamura S, Ohoyama K, Hamaguchi T, Kashimoto K, Nakagawa M, Kanehara S, Suzuki D, Matsumoto T, Motomura E, Shiroyama T, Okada M (2009a) Effects of quetiapine on monoamine, GABA, and glutamate release in rat prefrontal cortex. Psychopharmacology 206:243–258CrossRefGoogle Scholar
  102. Yamamura S, Ohoyama K, Hamaguchi T, Nakagawa M, Suzuki D, Matsumoto T, Motomura E, Tanii H, Shiroyama T, Okada M (2009b) Effects of zotepine on extracellular levels of monoamine, GABA and glutamate in rat prefrontal cortex. Brit J Pharmacol 157:656–665CrossRefGoogle Scholar
  103. Yang TT, Wang SJ (2008) Aripiprazole and its human metabolite OPC14857 reduce, through a presynaptic mechanism, glutamate release in rat prefrontal cortex: possible relevance to neuroprotective interventions in schizophrenia. Synapse 62:804–818PubMedCrossRefGoogle Scholar
  104. Zilles K, Qu MS, Kohling R, Speckmann EJ (1999) Ionotropic glutamate and GABA receptors in human epileptic neocortical tissue: quantitative in vitro receptor autoradiography. Neurosci 94:1051–1061CrossRefGoogle Scholar
  105. Zilles K, Werner L, Qu M, Schleicher A, Gross G (1991) Quantitative autoradiography of 11 different transmitter binding sites in the basal forebrain region of the rat—evidence of heterogeneity in distribution patterns. Neurosci 42:473–481CrossRefGoogle Scholar
  106. Zink M, Rapp S, Gebicke-Härter P, Henn FA, Thome J (2005) Antidepressants differentially affect expression of complexin I and II RNA in rat hippocampus. Psychopharmacol 181:560–565CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Nina Segnitz
    • 1
  • Thomas Ferbert
    • 1
  • Andrea Schmitt
    • 2
    • 3
  • Peter Gass
    • 1
  • Peter J. Gebicke-Haerter
    • 4
  • Mathias Zink
    • 1
    Email author
  1. 1.Department of Psychiatry and Psychotherapy, Central Institute of Mental HealthUniversity of HeidelbergMannheimGermany
  2. 2.Department of PsychiatryUniversity of GoettingenGoettingenGermany
  3. 3.Laboratory of Neuroscience (LIM27), Institute of PsychiatryUniversity of Sao PauloSão PauloBrazil
  4. 4.Department of Psychopharmacology, Central Institute of Mental HealthUniversity of HeidelbergMannheimGermany

Personalised recommendations