Psychopharmacology

, Volume 221, Issue 3, pp 451–468 | Cite as

Negative modulation of GABAA α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats

  • John P. Redrobe
  • Lisbeth Elster
  • Kristen Frederiksen
  • Christoffer Bundgaard
  • Inge E. M. de Jong
  • Garrick P. Smith
  • Anne Techau Bruun
  • Peter H. Larsen
  • Michael Didriksen
Original Investigation

Abstract

Rationale

A growing body of evidence suggests that negative modulation of γ-aminobutyric acid (GABA) GABAA α5 receptors may be a promising strategy for the treatment of certain facets of cognitive impairment; however, selective modulators of GABAA α5 receptors have not yet been tested in “schizophrenia-relevant” cognitive assay/model systems in animals.

Objectives

The objectives of this study were to investigate the potential of RO4938581, a negative modulator of GABAA α5 receptors, and to attenuate cognitive impairments induced following sub-chronic (sub-PCP) and early postnatal PCP (neo-PCP) administration in the novel object recognition (NOR) and intra-extradimensional shift (ID/ED) paradigms in rats. Complementary in vitro, ex vivo and in vivo studies were performed to confirm negative modulatory activity of RO4938581 and to investigate animal model validity, concept validity and potential side effect issues, respectively.

Results

In vitro studies confirmed the reported negative modulatory activity of RO4938581, whilst immunohistochemical analyses revealed significantly reduced parvalbumin-positive cells in the prefrontal cortex of sub-PCP- and neo-PCP-treated rats. RO4938581 (1 mg/kg) ameliorated both sub-PCP- and neo-PCP-induced cognitive deficits in NOR and ID/ED performance, respectively. In contrast, QH-II-066 (1 and 3 mg/kg), a GABAA α5 receptor positive modulator, impaired cognitive performance in the NOR task when administered to vehicle-treated animals. Additional studies revealed that both RO4938581 (1 mg/kg) and QH-II-066 (1 and 3 mg/kg) attenuated amphetamine-induced hyperactivity in rats.

Conclusions

Taken together, these novel findings suggest that negative modulation of GABAA α5 receptors may represent an attractive treatment option for the cognitive impairments, and potentially positive symptoms, associated with schizophrenia.

Keywords

GABA alpha5 receptors Negative allosteric modulator Sub-chronic PCP Early postnatal PCP Novel object recognition Attentional set shifting Cognition Rat 

References

  1. Aleman A, Hijman R, de Haan EH, Kahn RS (1999) Memory impairment in schizophrenia: a meta-analysis. Am J Psychiatry 156:1358–1366PubMedGoogle Scholar
  2. Arnt J (1995) Differential effects of classical and newer antipsychotics on the hypermotility induced by two dose levels of d-amphetamine. Eur J Pharmacol 283:55–62PubMedCrossRefGoogle Scholar
  3. Atack JR (2010) Preclinical and clinical pharmacology of the GABAA receptor alpha5 subtype-selective inverse agonist alpha5IA. Pharmacol Ther 125:11–26PubMedCrossRefGoogle Scholar
  4. Atack JR (2011) GABAA receptor subtype-selective modulators. II. α5-Selective inverse agonists for cognition enhancement. Curr Top Med Chem 11:1203–1214PubMedCrossRefGoogle Scholar
  5. Atack JR, Bayley PJ, Seabrook GR, Wafford KA, McKernan RM, Dawson GR (2006) L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for alpha5-containing GABAA receptors. Neuropharmacology 51:1023–1029PubMedCrossRefGoogle Scholar
  6. Ballard TM, Knoflach F, Prinssen E, Borroni E, Vivian JA, Basile J, Gasser R, Moreau JL, Wettstein JG, Buettelmann B, Knust H, Thomas AW, Trube G, Hernandez MC (2009) RO4938581, a novel cognitive enhancer acting at GABAA alpha5 subunit-containing receptors. Psychopharmacology 202:207–223PubMedCrossRefGoogle Scholar
  7. Barch DM, Braver TS, Carter CS, Poldrack RA, Robbins TW (2009) CNTRICS final task selection: executive control. Schizophr Bull 35:115–135PubMedCrossRefGoogle Scholar
  8. Bartos M, Vida I, Jonas P (2007) Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat Rev Neurosci 8:45–56PubMedCrossRefGoogle Scholar
  9. Bayer SA, Altman J, Russo RJ, Zhang X (1993) Timetables of neurogenesis in the human brain based on experimentally determined patterns in the rat. Neurotoxicology 14:83–144PubMedGoogle Scholar
  10. Beasley CL, Reynolds GP (1997) Parvalbumin-immunoreactive neurons are reduced in the prefrontal cortex of schizophrenics. Schizophr Res 24:349–355PubMedCrossRefGoogle Scholar
  11. Belelli D, Harrison NL, Maguire J, Macdonald RL, Walker MC, Cope DW (2009) Extrasynaptic GABAA receptors: form, pharmacology, and function. J Neurosci 29:12757–12763PubMedCrossRefGoogle Scholar
  12. Berg EA (1948) A simple objective technique for measuring flexibility in thinking. J Gen Psychol 39:15–22PubMedCrossRefGoogle Scholar
  13. Birrell JM, Brown VJ (2000) Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci 20:4320–4324PubMedGoogle Scholar
  14. Broberg BV, Dias R, Glenthøj BY, Olsen CK (2008) Evaluation of a neurodevelopmental model of schizophrenia—early postnatal PCP treatment in attentional set-shifting. Behav Brain Res 190:160–163PubMedCrossRefGoogle Scholar
  15. Broberg BV, Glenthøj BY, Dias R, Larsen DB, Olsen CK (2009) Reversal of cognitive deficits by an ampakine (CX516) and sertindole in two animal models of schizophrenia: sub-chronic and early postnatal PCP treatment in attentional set-shifting. Psychopharmacology 206:631–640PubMedCrossRefGoogle Scholar
  16. Brown MW, Warburton EC, Aggleton JP (2010) Recognition memory: material, processes, and substrates. Hippocampus 20:1228–1244PubMedCrossRefGoogle Scholar
  17. Buchanan RW, Keefe RS, Lieberman JA, Barch DM, Csernansky JG, Goff DC, Gold JM, Green MF, Jarskog LF, Javitt DC, Kimhy D, Kraus MS, McEvoy JP, Mesholam-Gately RI, Seidman LJ, Ball MP, McMahon RP, Kern RS, Robinson J, Marder SR (2011) A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia. Biol Psychiatry 69:442–449PubMedCrossRefGoogle Scholar
  18. Cho RY, Konecky RO, Carter CS (2006) Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia. Proc Natl Acad Sci USA 103:19878–19883PubMedCrossRefGoogle Scholar
  19. Clancy B, Darlington RB, Finlay BL (2001) Translating developmental time across mammalian species. Neuroscience 105:7–17PubMedCrossRefGoogle Scholar
  20. Clare L, McKenna PJ, Mortimer AM, Baddeley AD (1993) Memory in schizophrenia: what is impaired and what is preserved? Neuropsychologia 31:1225–1241PubMedCrossRefGoogle Scholar
  21. Clark RE, Zola SM, Squire LR (2000) Impaired recognition memory in rats after damage to the hippocampus. J Neurosci 20:8853–8860PubMedGoogle Scholar
  22. Cochran SM, Kennedy M, McKerchar CE, Steward LJ, Pratt JA, Morris BJ (2003) Induction of metabolic hypofunction and neurochemical deficits after chronic intermittent exposure to phencyclidine: differential modulation by antipsychotic drugs. Neuropsychopharmacology 28:265–275PubMedCrossRefGoogle Scholar
  23. Collinson N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, Sur C, Smith A, Otu FM, Howell O, Atack JR, McKernan RM, Seabrook GR, Dawson GR, Whiting PJ, Rosahl TW (2002) Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosci 22:5572–5580PubMedGoogle Scholar
  24. Cooke SF, Bliss TV (2005) Long-term potentiation and cognitive drug discovery. Curr Opin Investig Drugs 6:25–34PubMedGoogle Scholar
  25. Damgaard T, Larsen DB, Hansen SL, Grayson B, Neill JC, Plath N (2010) Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors reverses sub-chronic PCP-induced deficits in the novel object recognition task in rats. Behav Brain Res 207:144–150PubMedCrossRefGoogle Scholar
  26. Dawson GR, Maubach KA, Collinson N, Cobain M, Everitt BJ, MacLeod AM, Choudhury HI, McDonald LM, Pillai G, Rycroft W, Smith AJ, Sternfeld F, Tattersall FD, Wafford KA, Reynolds DS, Seabrook GR, Atack JR (2006) An inverse agonist selective for alpha5 subunit-containing GABAA receptors enhances cognition. J Pharmacol Exp Ther 316:1335–1345PubMedCrossRefGoogle Scholar
  27. Dere E, Huston JP, De Souza Silva MA (2007) The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents. Neurosci Biobehav Rev 31:673–704PubMedCrossRefGoogle Scholar
  28. Deutsch SI, Mastropaolo J, Rosse RB (1998) Neurodevelopmental consequences of early exposure to phencyclidine and related drugs. Clin Neuropharmacol 21:320–332PubMedGoogle Scholar
  29. Egerton A, Reid L, McKerchar CE, Morris BJ, Pratt JA (2005) Impairment in perceptual attentional set-shifting following PCP administration: a rodent model of set-shifting deficits in schizophrenia. Psychopharmacology 179:77–84PubMedCrossRefGoogle Scholar
  30. Elliott R, McKenna PJ, Robbins TW, Sahakian BJ (1995) Neuropsychological evidence for frontostriatal dysfunction in schizophrenia. Psychol Med 25:619–630PubMedCrossRefGoogle Scholar
  31. Ennaceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats. 1: Behavioural data. Behav Brain Res 31:47–59PubMedCrossRefGoogle Scholar
  32. Ferrarelli F, Massimini M, Peterson MJ, Riedner BA, Lazar M, Murphy MJ, Huber R, Rosanova M, Alexander AL, Kalin N, Tononi G (2008) Reduced evoked gamma oscillations in the frontal cortex in schizophrenia patients: a TMS/EEG study. Am J Psychiatry 165:996–1005PubMedCrossRefGoogle Scholar
  33. Fett AK, Viechtbauer W, Dominguez MD, Penn DL, van Os J, Krabbendam L (2011) The relationship between neurocognition and social cognition with functional outcomes in schizophrenia: a meta-analysis. Neurosci Biobehav Rev 35:573–588PubMedCrossRefGoogle Scholar
  34. Gerdjikov TV, Rudolph U, Keist R, Mohler H, Feldon J, Yee BK (2008) Hippocampal alpha 5 subunit-containing GABA A receptors are involved in the development of the latent inhibition effect. Neurobiol Learn Mem 89:87–94PubMedCrossRefGoogle Scholar
  35. Gill KM, Lodge DJ, Cook JM, Aras S, Grace AA (2011) A novel α5GABA(A)R-positive allosteric modulator reverses hyperactivation of the dopamine system in the MAM model of schizophrenia. Neuropsychopharmacology 36:1903–1911. doi:10.1038/npp.2011.76 PubMedCrossRefGoogle Scholar
  36. Gilmour G, Dix S, Fellini L, Gastambide F, Plath N, Steckler T, Talpos J, Tricklebank M (in press) NMDA receptors, cognition and schizophrenia—testing the validity of the NMDA receptor hypofunction hypothesis. Neuropharmacology. doi:10.1016/j.neuropharm.2011.03.015
  37. Glykys J, Mann EO, Mody I (2008) Which GABA(A) receptor subunits are necessary for tonic inhibition in the hippocampus? J Neurosci 28:1421–1426PubMedCrossRefGoogle Scholar
  38. Goetghebeur P, Dias R (2009) Comparison of haloperidol, risperidone, sertindole, and modafinil to reverse an attentional set-shifting impairment following subchronic PCP administration in the rat: a back translational study. Pyschopharmacology 202:287–293CrossRefGoogle Scholar
  39. Goetghebeur PJ, Lerdrup L, Sylvest A, Dias R (2010) Erythropoietin reverses the attentional set-shifting impairment in a rodent schizophrenia disease-like model. Psychopharmacology 212:635–642PubMedCrossRefGoogle Scholar
  40. Grace AA (2011) Dopamine system dysregulation by the hippocampus: implications for the pathophysiology and treatment of schizophrenia. Neuropharmacology. doi:10.1016/j.neuropharm.2011.05.011
  41. Green MF, Bracha HS, Satz P, Christenson CD (1994) Preliminary evidence for an association between minor physical anomalies and second trimester neurodevelopment in schizophrenia. Psychiatry Res 53:119–127PubMedCrossRefGoogle Scholar
  42. Green MF, Nuechterlein KH, Gold JM, Barch DM, Cohen J, Essock S, Fenton WS, Frese F, Goldberg TE, Heaton RK, Keefe RS, Kern RS, Kraemer H, Stover E, Weinberger DR, Zalcman S, Marder SR (2004) Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria. Biol Psychiatry 56:301–307PubMedCrossRefGoogle Scholar
  43. Hadingham KL, Wingrove PB, Wafford KA, Bain C, Kemp JA, Palmer KJ, Wilson AW, Wilcox AS, Sikela JM, Ragan CI, Whiting PJ (1993) Role of the beta subunit in determining the pharmacology of human gamma-aminobutyric acid type A receptors. Mol Pharmacol 44:1211–1218PubMedGoogle Scholar
  44. Harvey PD, Keefe RSE (2001) Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. Am J Psychiatry 158:176–184PubMedCrossRefGoogle Scholar
  45. Hasan A, Nitsche MA, Rein B, Schneider-Axmann T, Guse B, Gruber O, Falkai P, Wobrock T (2011) Dysfunctional long-term potentiation-like plasticity in schizophrenia revealed by transcranial direct current stimulation. Behav Brain Res 224:15–22PubMedCrossRefGoogle Scholar
  46. Hauser J, Rudolph U, Keist R, Mohler H, Feldon J, Yee BK (2005) Hippocampal alpha5 subunit-containing GABAA receptors modulate the expression of prepulse inhibition. Mol Psychiatry 10:201–207PubMedCrossRefGoogle Scholar
  47. Haut MW, Cahill J, Cutlip WD, Stevenson JM, Makela EH, Bloomfield SM (1996) On the nature of Wisconsin card sorting test performance in schizophrenia. Psychiatry Res 65:15–22PubMedCrossRefGoogle Scholar
  48. Heckers S, Curran T, Goff D, Rauch SL, Fischman AJ, Alpert NM, Schacter DL (2000) Abnormalities in the thalamus and prefrontal cortex during episodic object recognition in schizophrenia. Biol Psychiatry 48:651–657PubMedCrossRefGoogle Scholar
  49. Hetem LA, Danion JM, Diemunsch P, Brandt C (2000) Effect of a subanesthetic dose of ketamine on memory and conscious awareness in healthy volunteers. Psychopharmacology 152:283–288PubMedCrossRefGoogle Scholar
  50. Honey GD, O'Loughlin C, Turner DC, Pomarol-Clotet E, Corlett PR, Fletcher PC (2006) The effects of a subpsychotic dose of ketamine on recognition and source memory for agency: implications for pharmacological modelling of core symptoms of schizophrenia. Neuropsychopharmacology 31:413–423PubMedCrossRefGoogle Scholar
  51. Huang Q, Zhang W, Liu R, McKernan RM, Cook JM (1996) Benzo-fused benzodiazepines employed as topological probes for the study of benzodiazepine receptor subtypes. Med Chem Res 6:384–391Google Scholar
  52. Huang Q, He X, Ma C, Liu R, Yu S, Dayer CA, Wenger GR, McKernan R, Cook JM (2000) Pharmacophore/receptor models for GABAA/BzR subtypes (α1β3γ2, α5β3γ2, and α6β3γ2) via a comprehensive ligand-mapping approach. J Med Chem 43:71–95PubMedCrossRefGoogle Scholar
  53. Hutton SB, Puri BK, Duncan LJ, Robbins TW, Barnes TRE, Joyce EM (1998) Executive function in first-episode schizophrenia. Psychol Med 28:463–473PubMedCrossRefGoogle Scholar
  54. Idris N, Neill J, Grayson B, Bang-Andersen B, Witten LM, Brennum LT, Arnt J (2010) Sertindole improves sub-chronic PCP-induced reversal learning and episodic memory deficits in rodents: involvement of 5-HT(6) and 5-HT(2A) receptor mechanisms. Psychopharmacology 208:23–36PubMedCrossRefGoogle Scholar
  55. Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vockler J, Dikranian K et al (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283:70–74PubMedCrossRefGoogle Scholar
  56. Jenkins TA, Elliott JJ, Ardis TC, Cahir M, Reynolds GP, Bell R, Cooper SJ (2010) Effect of subchronic phencyclidine administration on sucrose preference and hippocampal parvalbumin immunoreactivity in the rat. Behav Brain Res 208:479–483PubMedCrossRefGoogle Scholar
  57. Jentsch JD, Roth RH (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20:201–225PubMedCrossRefGoogle Scholar
  58. Kalvass JC, Maurer TS (2002) Influence of nonspecific brain and plasma binding on CNS exposure: implications for rational drug discovery. Biopharm Drug Dispos 23:327–338PubMedCrossRefGoogle Scholar
  59. Keefe RS, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, Meltzer HY, Green MF, Capuano G, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Davis CE, Hsiao JK, Lieberman JA, CATIE Investigators, Neurocognitive Working Group (2007) Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial. Arch Gen Psychiatry 64:633–647PubMedCrossRefGoogle Scholar
  60. Knust H, Achermann G, Ballard T, Buettelmann B, Gasser R, Fischer H, Hernandez MC, Knoflach F, Koblet A, Stadler H, Thomas AW, Trube G, Waldmeier P (2009) The discovery and unique pharmacological profile of RO4938581 and RO4882224 as potent and selective GABAA alpha5 inverse agonists for the treatment of cognitive dysfunction. Bioorg Med Chem Lett 19:5940–5944PubMedCrossRefGoogle Scholar
  61. Lahti AC, Koffel B, LaPorte D, Tamminga CA (1995) Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology 13:9–19PubMedCrossRefGoogle Scholar
  62. Leeson VC, Robbins TW, Matheson E, Hutton SB, Ron MA, Barnes TR, Joyce EM (2009) Discrimination learning, reversal, and set-shifting in first-episode schizophrenia: stability over 6 years and specific associations with medication type and disorganization syndrome. Biol Psychiatry 66:586–593PubMedCrossRefGoogle Scholar
  63. Lewis DA, Cho RY, Carter CS, Eklund K, Forster S, Kelly MA, Montrose D (2008) Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia. Am J Psychiatry 165:1585–1593PubMedCrossRefGoogle Scholar
  64. Manns JR, Stark CEL, Squire LR (2000) The visual paired-comparison task as a measure of declarative memory. Proc Natl Acad Sci USA 97:12375–12379PubMedCrossRefGoogle Scholar
  65. Martin LJ, Oh GH, Orser BA (2009) Etomidate targets alpha5 gamma-aminobutyric acid subtype A receptors to regulate synaptic plasticity and memory blockade. Anesthesiology 111:1025–1035PubMedCrossRefGoogle Scholar
  66. McKernan RM, Whiting PJ (1996) Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci 19:139–143PubMedCrossRefGoogle Scholar
  67. McKernan RM, Wafford K, Quirk K, Hadingham KL, Harley EA, Ragan CI, Whiting PJ (1995) The pharmacology of the benzodiazepine site of the GABA-A receptor is dependent on the type of gamma-subunit present. J Recept Signal Transduct Res 15:173–183PubMedCrossRefGoogle Scholar
  68. McLean SL, Beck JP, Woolley ML, Neill JC (2008) A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional setshifting in female rats. Behav Brain Res 189:152–158Google Scholar
  69. McLean SL, Grayson B, Idris NF, Lesage AS, Pemberton DJ, Mackie C, Neill JC (2010) Activation of alpha7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks in rats: implications for therapy of cognitive dysfunction in schizophrenia. Eur Neuropsychopharmacol 21:333–343PubMedCrossRefGoogle Scholar
  70. Möhler H (2009) Role of GABAA receptors in cognition. Biochem Soc Trans 37:1328–1333PubMedCrossRefGoogle Scholar
  71. Murray GK, Cheng F, Clark L, Barnett JH, Blackwell AD, Fletcher PC, Robbins TW, Bullmore ET, Jones PB (2008) Reinforcement and reversal learning in first-episode psychosis. Schizophr Bull 34:848–855PubMedCrossRefGoogle Scholar
  72. Neill JC, Barnes S, Cook S, Grayson B, Idris NF, McLean SL, Snigdha S, Rajagopal L, Harte MK (2010) Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism. Pharmacol Ther 128:419–432PubMedCrossRefGoogle Scholar
  73. Nutt D (2006) GABAA receptors: subtypes, regional distribution, and function. J Clin Sleep Med 2:S7–S11PubMedGoogle Scholar
  74. Nutt DJ, Besson M, Wilson SJ, Dawson GR, Lingford-Hughes AR (2007) Blockade of alcohol's amnestic activity in humans by an alpha5 subtype benzodiazepine receptor inverse agonist. Neuropharmacology 53:810–8220PubMedCrossRefGoogle Scholar
  75. O’Tuathaigh CM, Waddington JL (2010) Mutant mouse models: phenotypic relationships to domains of psychopathology and pathobiology in schizophrenia. Schizophr Bull 36:243–245PubMedCrossRefGoogle Scholar
  76. Pantelis C, Barber FZ, Barnes TR, Nelson HE, Owen AM, Robbins TW (1999) Comparison of set-shifting ability in patients with chronic schizophrenia and frontal lobe damage. Schizophr Res 37:251–270PubMedCrossRefGoogle Scholar
  77. Pedersen CS, Goetghebeur P, Dias R (2009) Chronic infusion of PCP via osmotic mini-pumps: a new rodent model of cognitive deficit in schizophrenia characterized by impaired attentional set-shifting (ID/ED) performance. J Neurosci Methods 185:66–69PubMedCrossRefGoogle Scholar
  78. Pratt JA, Winchester C, Egerton A, Cochran SM, Morris BJ (2008) Modelling prefrontal cortex deficits in schizophrenia: implications for treatment. Br J Pharmacol 153(Suppl 1):S465–S470PubMedGoogle Scholar
  79. Rezvani AH (2006) Involvement of the NMDA system in learning and memory. In: Levin ED, Buccafusco JJ (eds) Animal models of cognitive impairment, Chapter 4. CRC, Boca Raton 37–48Google Scholar
  80. Rodefer JS, Murphy ER, Baxter MG (2005) PDE10A inhibition reverses PCP-induced deficits in attentional set-shifting in rats. Eur J Neurosci 21:1070–1076PubMedCrossRefGoogle Scholar
  81. Rodefer JS, Nguyen TN, Karlsson JJ, Arnt J (2008) Reversal of subchronic PCP-induced deficits in attentional set shifting in rats by sertindole and a 5-HT6 receptor antagonist: comparison among antipsychotics. Neuropsychopharmacology 33:2657–2666PubMedCrossRefGoogle Scholar
  82. Sahakian BJ, Morris RG, Evenden JL, Heald A, Levy R, Philpot M, Robbins TW (1988) A comparative study of visuospatial memory and learning in Alzheimer-type dementia and Parkinson's disease. Brain 111:695–718PubMedCrossRefGoogle Scholar
  83. Sharma T, Antonova L (2003) Cognitive function in schizophrenia: deficits, functional consequences, and future treatment. Psychiatr Clin North Am 26:25–40PubMedCrossRefGoogle Scholar
  84. Sieghart W, Sperk G (2002) Subunit composition, distribution and function of GABA(A) receptor subtypes. Curr Top Med Chem 2:795–816PubMedCrossRefGoogle Scholar
  85. Skolnick P, Hu RJ, Cook CM, Hurt SD, Trometer JD, Liu R, Huang Q, Cook JM (1997) [3H]RY 80: a high-affinity, selective ligand for gamma-aminobutyric acidA receptors containing alpha-5 subunits. J Pharmacol Exp Ther 283:488–493PubMedGoogle Scholar
  86. 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 pimivanserin (ACP 103), a 5-hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther 332:622–631PubMedCrossRefGoogle Scholar
  87. Sotty F, Damgaard T, Montezinho LP, Mørk A, Olsen CK, Bundgaard C, Husum H (2009a) Antipsychotic-like effect of retigabine [N-(2-Amino-4-(fluorobenzylamino)-phenyl)carbamic acid ester], a KCNQ potassium channel opener, via modulation of mesolimbic dopaminergic neurotransmission. J Pharmacol Exp Ther 328:951–962PubMedCrossRefGoogle Scholar
  88. Sotty F, Montezinho LP, Steiniger-Brach B, Nielsen J (2009b) Phosphodiesterase 10A inhibition modulates the sensitivity of the mesolimbic dopaminergic system to d-amphetamine: involvement of the D1-regulated feedback control of midbrain dopamine neurons. J Neurochem 109:766–775PubMedCrossRefGoogle Scholar
  89. Tek C, Gold J, Blaxton T, Wilk C, McMahon RP, Buchanan RW (2002) Visual perceptual and working memory impairments in schizophrenia. Arch Gen Psychiatry 59:146–153PubMedCrossRefGoogle Scholar
  90. Thierry AM, Gioanni Y, Dégénétais E, Glowinski J (2000) Hippocampo-prefrontal cortex pathway: anatomical and electrophysiological characteristics. Hippocampus 10:411–419PubMedCrossRefGoogle Scholar
  91. Towers SK, Gloveli T, Traub RD, Driver JE, Engel D, Fradley R, Rosahl TW, Maubach K, Buhl EH, Whittington MA (2004) Alpha 5 subunit-containing GABAA receptors affect the dynamic range of mouse hippocampal kainate-induced gamma frequency oscillations in vitro. J Physiol 559:721–728PubMedGoogle Scholar
  92. Turner DC, Clark L, Pomarol-Clotet E, McKenna P, Robbins TW, Sahakian BJ (2004) Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia. Neuropsychopharmacology 29:1363–1373PubMedCrossRefGoogle Scholar
  93. Uhlhaas PJ, Haenschel C, Nikolić D, Singer W (2008) The role of oscillations and synchrony in cortical networks and their putative relevance for the pathophysiology of schizophrenia. Schizophr Bull 34:927–943PubMedCrossRefGoogle Scholar
  94. Wang XJ (2010) Neurophysiological and computational principles of cortical rhythms in cognition. Physiol Rev 90:1195–1268PubMedCrossRefGoogle Scholar
  95. Wang CZ, Johnson KM (2005) Differential effects of acute and subchronic administration on phencyclidine-induced neurodegeneration in the perinatal rat. J Neurosci Res 81:284–292PubMedCrossRefGoogle Scholar
  96. Wang C, McInnis J, Ross-Sanchez M, Shinnick-Gallagher P, Wiley JL, Johnson KM (2001) Long-term behavioral and neurodegenerative effects of perinatal phencyclidine administration: implications for schizophrenia. Neuroscience 107:535–550PubMedCrossRefGoogle Scholar
  97. Waters KA, Burnham KE, O’Connor D, Dawson GR, Dias R (2005) Assessment of modafinil on attentional processes in a five-choice serial reaction time test in the rat. J Psychopharmacol 19:149–158PubMedCrossRefGoogle Scholar
  98. Wilson C, Terry AV Jr (2010) Neurodevelopmental animal models of schizophrenia: role in novel drug discovery and development. Clin Schizophr Relat Psychoses 4:124–137PubMedCrossRefGoogle Scholar
  99. Winters BD, Saksida LM, Bussey TJ (2008) Object recognition memory: neurobiological mechanisms of encoding, consolidation and retrieval. Neurosci Biobehav Rev 32:1055–1070PubMedCrossRefGoogle Scholar
  100. Young JW, Powell SB, Risbrough V, Marston HM, Geyer MA (2009) Using the MATRICS to guide development of a preclinical cognitive test battery for research in schizophrenia. Pharmacol Ther 122:150–202PubMedCrossRefGoogle Scholar
  101. Zhang ZJ, Reynolds GP (2002) A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia. Schizophr Res 55:1–10PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • John P. Redrobe
    • 1
  • Lisbeth Elster
    • 2
  • Kristen Frederiksen
    • 2
  • Christoffer Bundgaard
    • 2
  • Inge E. M. de Jong
    • 2
  • Garrick P. Smith
    • 2
  • Anne Techau Bruun
    • 2
  • Peter H. Larsen
    • 2
  • Michael Didriksen
    • 2
  1. 1.Synaptic Transmission I, Neuroscience Research DK, H. Lundbeck A/SValbyDenmark
  2. 2.Neuroscience Research DK, H. Lundbeck A/SValbyDenmark

Personalised recommendations