Animal Models for Schizophrenia: A Brief Overview

  • Miyako Furuta
  • Hiroshi Kunugi


Schizophrenia is a devastating disorder affecting approximately 1% of the population worldwide. Since the pathogenesis and pathophysiology of the illness are largely unknown, and current treatment strategies are far from ideal, it is crucial to develop biomarkers, new drugs, and prevention strategies. To this end, the importance of animal models is growing rapidly. The validity of animal models of human diseases should be evaluated by three dimensions: face, constructive, and predictive validity. Behavioral tests to assess the face validity are summarized. Dopamine agonists and N-methyl-D-aspartate (NMDA) receptor antagonists have been most extensively studied with respect to their producing schizophrenia-like behavioral abnormalities. Neurodevelopmental animal models of schizophrenia are based on experimentally induced disruption of brain development during pre- or perinatal period that results in altered brain neurochemistry and aberrant schizophrenia-like behaviors. The genetically engineered mouse is a powerful tool to examine the possible mechanisms of genes giving susceptibility to schizophrenia by affecting certain endophenotypes. Here we provide a brief overview of these animal models of schizophrenia, particularly those of rodents.


Negative Symptom Dopamine Agonist Latent Inhibition NMDA Receptor Antagonist Behavioral Sensitization 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Disrupted-in-schizophrenia 1


Latent inhibition


Metabotropic glutamate receptor




Neuronal PAS domain protein


NMDA R1 subunit


Neuregulin 1




Prepulse inhibition


Ventral hippocampus


  1. Adler CM, Goldberg TE, Malhotra AK, Pickar D, Breier A (1998) Effects of ketamine on thought disorder, working memory, and semantic memory in healthy volunteers. Biol Psychiatr 43:811–816.CrossRefGoogle Scholar
  2. Adler CM, Malhotra AK, Elman I, Goldberg T, Egan M, Pickar D, Breier A (1999) Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. Am J Psychiatr156:1646–1649.PubMedGoogle Scholar
  3. Allen RM, Young SJ (1978) Phencyclidine-induced psychosis. Am J Psychiatr 135:1081–1084.PubMedGoogle Scholar
  4. American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th ed, American Psychiatric Association, Washington, D.C.Google Scholar
  5. Andersen JD, Pouzet B (2004).Spatial memory deficits induced by perinatal treatment of rats with PCP and reversal effect of D-serine. Neuropsychopharmacology 29(6):1080–1090.PubMedCrossRefGoogle Scholar
  6. Bakshi VP, Geyer MA (1995) Antagonism of phencyclidine-induced deficits in prepulse inhibition by the putative atypical antipsychotic olanzapine. Psychopharmacology122:198–201.PubMedCrossRefGoogle Scholar
  7. Bakshi VP, Geyer MA (1998) Multiple limbic regions mediate the disruption of prepulse inhibition produced in rats by the noncompetitive NMDA antagonist dizocilpine. J Neurosci 18:8394–8401PubMedGoogle Scholar
  8. Bakshi VP, Swerdlow NR, Geyer MA (1994) Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response. J Pharmacol Exp Ther 271:787–794.PubMedGoogle Scholar
  9. Boksa P (2004) Animal models of obstetric complications in relation to schizophrenia. Brain Res Brain Res Rev 45:1–17.PubMedCrossRefGoogle Scholar
  10. Boksa P, El-Khodor BF (2003) Birth insult interacts with stress at adulthood to alter dopaminergic function in animal models: possible implications for schizophrenia and other disorders. Neurosci Biobehav Rev 27:91–101.PubMedCrossRefGoogle Scholar
  11. Braff DL (1993) Information processing and attention dysfunctions in schizophrenia. Schizophr Bull 19:233–259PubMedGoogle Scholar
  12. Braff DL, Geyer MA, Swerdlow NR (2001) Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl). 156: 234–258.CrossRefGoogle Scholar
  13. 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
  14. Brake WG, Noel MB, Boksa P, Gratton A (1997) Influence of perinatal factors on the nucleus accumbens dopamine response to repeated stress during adulthood: an electrochemical study in the rat. Neuroscience 77:1067–1076.PubMedCrossRefGoogle Scholar
  15. Brown RW, Bardo MT, Mace DD, Phillips SB, Kraemer PJ (2000) D-amphetamine facilitation of morris water task performance is blocked by eticlopride and correlated with increased dopamine synthesis in the prefrontal cortex. Behav Brain Res 114:135–143.PubMedCrossRefGoogle Scholar
  16. Cannon TD, Rosso IM (2002) Levels of analysis in etiological research on schizophrenia. Dev Psychopathol 14: 653–66; Review.PubMedCrossRefGoogle Scholar
  17. Clapcote SJ, Roder JC (2006) Deletion polymorphism of Disc1 is common to all 129 mouse substrains: implications for gene-targeting studies of brain function. Genetics; 173:2407–2410.PubMedCrossRefGoogle Scholar
  18. Clapcote SJ, Lipina TV, Millar JK, Mackie S, Christie S, Ogawa F, Lerch JP, Trimble K, Uchiyama M, Sakuraba Y, Kaneda H, Shiroishi T, Houslay MD, Henkelman RM, Sled JG, Gondo Y, Porteous DJ, Roder JC (2007) Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 54:387–402.PubMedCrossRefGoogle Scholar
  19. Coghill EL, Hugill A, Parkinson N, Davison C, Glenister P, Clements S, Hunter J, Cox RD, Brown SD (2002) A gene-driven approach to the identification of ENU mutants in the mouse. Nat Genet 30:255–256.PubMedCrossRefGoogle Scholar
  20. Creese I, Iversen SD (1973) Blockage of amphetamine induced motor stimulation and stereotypy in the adult rat following neonatal treatment with 6-hydroxydopamine. Brain Res 55:369–382.PubMedCrossRefGoogle Scholar
  21. Creese I, Burt DR, Snyder SH (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192:481–483.PubMedCrossRefGoogle Scholar
  22. Danysz W, Wroblewski JT, Costa E (1988) Learning impairment in rats by N-methyl-D-aspartate receptor antagonists. Neuropharmacology 27:653–656.PubMedCrossRefGoogle Scholar
  23. Deutsch SI, Mastropaolo J, Rosse RB (1998) Neurodevelopmental consequences of early exposure to phencyclidine and related drugs. Clin Neuropharmacol 21:320–332.PubMedGoogle Scholar
  24. Dunn LA, Atwater GE, Kilts CD (1993) Effects of antipsychotic drugs on latent inhibition: sensitivity and specificity of an animal behavioral model of clinical drug action. Psychopharmacology (Berl) 112:315–323.CrossRefGoogle Scholar
  25. Duncan GE, Moy SS, Perez A, Eddy DM, Zinzow WM, Lieberman JA, Snouwaert JN, Koller BH (2004) Deficits in sensorimotor gating and tests of social behavior in a genetic model of reduced NMDA receptor function. Behav Brain Res 153:507–519.PubMedCrossRefGoogle Scholar
  26. Duncan GE, Moy SS, Lieberman JA, Koller BH (2006a) Typical and atypical antipsychotic drug effects on locomotor hyperactivity and deficits in sensorimotor gating in a genetic model of NMDA receptor hypofunction. Pharmacol Biochem Behav 85:481–491.CrossRefGoogle Scholar
  27. Duncan GE, Moy SS, Lieberman JA, Koller BH (2006b) Effects of haloperidol, clozapine, and quetiapine on sensorimotor gating in a genetic model of reduced NMDA receptor function. Psychopharmacology (Berl) 184:190–200.CrossRefGoogle Scholar
  28. Eckerman DA, Gordon WA, Edwards JD, MacPhail RC, Gage MI (1980) Effects of scopolamine, pentobarbital, and amphetamine on radial arm maze performance in the rat. Pharmacol Biochem Behav12:595–602.PubMedCrossRefGoogle Scholar
  29. El-Khodor BF, Boksa P (1998) Birth insult increases amphetamine-induced behavioral responses in the adult rat. Neuroscience 87:893–904.PubMedCrossRefGoogle Scholar
  30. El-Khodor BF, Boksa P (2000) Transient birth hypoxia increases behavioral responses to repeated stress in the adult rat. Behav Brain Res 107:171–175.PubMedCrossRefGoogle Scholar
  31. El-Khodor B, Boksa P (2001) Caesarean section birth produces long term changes in dopamine D1 receptors and in stress-induced regulation of D3 and D4 receptors in the rat brain. Neuropsychopharmacology 25:423–439.PubMedCrossRefGoogle Scholar
  32. El-Khodor BF, Boksa P (2002) Birth insult and stress interact to alter dopamine transporter binding in rat brain. Neuroreport 13:201–206.PubMedCrossRefGoogle Scholar
  33. Ellenbroek BA, Cools AR (2002) Apomorphine susceptibility and animal models for psychopathology: genes and environment, Behav Genet 32:349–361.PubMedCrossRefGoogle Scholar
  34. Ennaceur A (1994) Effects of amphetamine and medial septal lesions on acquisition and retention of radial maze learning in rats. Brain Res 636:277–285.PubMedCrossRefGoogle Scholar
  35. Erbel-Sieler C, Dudley C, Zhou Y, Wu X, Estill SJ, Han T, Diaz-Arrastia R, Brunskill EW, Potter SS, McKnight SL (2004) Behavioral and regulatory abnormalities in mice deficient in the NPAS1 and NPAS3 transcription factors. Proc Natl Acad Sci U S A 101:13648–13653.PubMedCrossRefGoogle Scholar
  36. Feldon J, Weiner I (1991) The latent inhibition model of schizophrenic attention disorder. Haloperidol and sulpiride enhance rats' ability to ignore irrelevant stimuli. Biol Psychiatr 29:635–646.CrossRefGoogle Scholar
  37. Fioravanti M, Carlone O, Vitale B, Cinti ME, Clare L (2005) A meta-analysis of cognitive deficits in adults with a diagnosis of schizophrenia. Neuropsychol Rev 15:73–95.PubMedCrossRefGoogle Scholar
  38. Fradley RL, O'Meara GF, Newman RJ, Andrieux A, Job D, Reynolds DS (2005) STOP knockout and NMDA NR1 hypomorphic mice exhibit deficits in sensorimotor gating. Behav Brain Research163:257–264.CrossRefGoogle Scholar
  39. Gerber DJ, Hall D, Miyakawa T, Demars S, Gogos JA, Karayiorgou M, Tonegawa S (2003) Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit. Proc Natl Acad Sci U S A 100: 8987–8992.PubMedCrossRefGoogle Scholar
  40. 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) 156:117–154.CrossRefGoogle Scholar
  41. Geyer MA, McIlwain KL, Paylor R (2002) Mouse genetic models for prepulse inhibition: an early review. Mol Psychiatr 7:1039–53.CrossRefGoogle Scholar
  42. Gothelf D, Soreni N, Nachman RP, Tyano S, Hiss Y, Reiner O, Weizman A (2000) Evidence for the involvement of the hippocampus in the pathophysiology of schizophrenia. Eur Neuropsychopharmacol 10:389–395.PubMedCrossRefGoogle Scholar
  43. Graham FK (1975) The more or less startling effects of weak prestimulation. Psychophysiology 12: 238–248.PubMedCrossRefGoogle Scholar
  44. Gray NS, Hemsley DR, Gray JA (1992). Abolition of latent inhibition in acute, but not chronic, schizophrenics. Neurol Psychiatr Brain Res 1: 83–89.Google Scholar
  45. Greengard P (2001) The neurobiology of dopamine signaling. Biosci Rep 21:247–269.PubMedCrossRefGoogle Scholar
  46. Green MF (1996) What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatr 153:321–330.PubMedGoogle Scholar
  47. Handelmann GE, Contreras PC, O'Donohue TL (1987) Selective memory impairment by phencyclidine in rats. Eur J Pharmacol 140:69–73.PubMedCrossRefGoogle Scholar
  48. Hashimoto R, Numakawa T, Ohnishi T, Kumamaru E, Yagasaki Y, Ishimoto T, Mori T, Nemoto K, Adachi N, Izumi A, Chiba S, Noguchi H, Suzuki T, Iwata N, Ozaki N, Taguchi T, Kamiya A, Kosuga A, Tatsumi M, Kamijima K, Weinberger DR, Sawa A, Kunugi H (2006) Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling. Hum Mol Genet 15: 3024–3033.PubMedCrossRefGoogle Scholar
  49. Heale V, Harley C (1990) MK-801 and AP5 impair acquisition, but not retention, of the Morris milk maze. Pharmacol Biochem Behav 36:145–149.PubMedCrossRefGoogle Scholar
  50. Hikida T, Jaaro-Peled H, Seshadri S, Oishi K, Hookway C, Kong S, Wu D, Xue R, Andradé M, Tankou S, Mori S, Gallagher M, Ishizuka K, Pletnikov M, Kida S, Sawa A (2007) Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci U S A 104:14501–14506.PubMedCrossRefGoogle Scholar
  51. Hijzen TH, Broersen LM, Slangen JL (1991) Effects of subchronic d-amphetamine on prepulse and gap inhibition of the acoustic startle reflex in rats. Biol Psychiatr 1119–1128.Google Scholar
  52. Hoffman HS, Searle JL (1968) Acoustic and temporal factors in the evocation of startle. J Acoust Soc Am 43:269–282.PubMedCrossRefGoogle Scholar
  53. Hodgkinson CA, Goldman D, Jaeger J, Persaud S, Kane JM, Lipsky RH, Malhotra AK (2004) Disrupted in schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet 75:862–872.PubMedCrossRefGoogle Scholar
  54. Hori H, Noguchi H, Hashimoto R, Nakabayashi T, Omori M, Takahashi S, Tsukue R, Anami K, Hirabayashi N, Harada S, Saitoh O, Iwase M, Kajimoto O, Takeda M, Okabe S, Kunugi H (2006) Antipsychoticmedication and cognitive function in schizophrenia. Schizophr Res 86:138–146.PubMedCrossRefGoogle Scholar
  55. Imre G, Fokkema DS, Den Boer JA, Ter Horst GJ (2006) Dose-response characteristics of ketamine effect on locomotion, cognitive function and central neuronal activity. Brain Res Bull 69:338–345.PubMedCrossRefGoogle Scholar
  56. Jacobs PS, Taylor BM, Bardgett ME (2000) Maturation of locomotor and Fos responses to the NMDA antagonists, PCP and MK-801. Brain Res Dev Brain Res 122:91–95.PubMedCrossRefGoogle Scholar
  57. Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatr148:1301–1308.PubMedGoogle Scholar
  58. Jentsch JD, Tran A, Le D, Youngren KD, Roth RH (1997) Subchronic phencyclidine administration reduces mesoprefrontal dopamine utilization and impairs prefrontal corticaldependent cognition in the rat. Neuropsychopharmacology 17:92–99.PubMedCrossRefGoogle Scholar
  59. Jones KW, Bauerle LM, DeNoble VJ (1990) Differential effects of sigma and phencyclidine receptor ligands on learning. Eur J Pharmacol 179: 97–102.PubMedCrossRefGoogle Scholar
  60. Kalivas PW, Hooks MS, Sorg B (1993) The pharmacology and neural circuitry of sensitization to psychostimulants. Behav Pharmacol 4:315–334PubMedCrossRefGoogle Scholar
  61. Kamnasaran D, Muir WJ, Ferguson-Smith MA, Cox DW (2003) Disruption of the neuronal PAS3 gene in a family affected with schizophrenia. J Med Genet 40:325–332.PubMedCrossRefGoogle Scholar
  62. Karl T, Duffy L, Scimone A, Harvey RP, Schofield PR (2007) Altered motor activity, exploration and anxiety in heterozygous neuregulin 1 mutant mice: implications for understanding schizophrenia. Genes Brain Behav 6:677–687.PubMedCrossRefGoogle Scholar
  63. Keefe RS, Silva SG, Perkins DO, Lieberman JA (1999) The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis. Schizophr Bull 25:201–222.PubMedGoogle Scholar
  64. Keefe RS, Eesley CE, Poe MP (2005) Defining a cognitive function decrement in schizophrenia. Biol Psychiatr 57:688–691.CrossRefGoogle Scholar
  65. Keith VA, Mansbach RS, Geyer MA (1991) Failure of haloperidol to block the effects of phencyclidine and dizocilpine on prepulse inhibition of startle. Biol Psychiatr 30:557–566.CrossRefGoogle Scholar
  66. Kesner RP, Hardy JD, Novak JM (1983) Phencyclidine and behavior: II. Active avoidance learning and radial arm maze performance. Pharmacol Biochem Behav 18:351–356.PubMedCrossRefGoogle Scholar
  67. Kumari V, Cotter PA, Mulligan OF, Checkley SA, Gray NS, Hemsley DR (1999) Thornton JC, Corr PJ, Toone BK, Gray JA: Effects of d-amphetamine and haloperidol on latent inhibition in healthy male volunteers. J Psychopharmacol 13:398–405.PubMedCrossRefGoogle Scholar
  68. Kunugi H, Takei N, Murray RM, Saito K, Nanko S (1996) Small head circumference at birth in schizophrenia. Schizophr Res 20:165–170.PubMedCrossRefGoogle Scholar
  69. Kunugi H, Nanko S, Murray RM (2001) Obstetric complications and schizophrenia: prenatal underdevelopment and subsequent neurodevelopmental impairment. Br J Psychiatr Suppl 40:25–9.CrossRefGoogle Scholar
  70. Kunugi H, Tanaka M, Hori H, Hashimoto R, Saitoh O, Hironaka N (2007) Prepulse inhibition of acoustic startle in Japanese patients with chronic schizophrenia. Neurosci Res 59:23–28.PubMedCrossRefGoogle Scholar
  71. Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA (2001) Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 25:455–467.PubMedCrossRefGoogle Scholar
  72. Li Z, Kim CH, Ichikawa J, Meltzer HY (2003) Effect of repeated administration of phencyclidine on spatial performance in an eight-arm radial maze with delay in rats and mice. Pharmacol Biochem Behav 75:335–340.PubMedCrossRefGoogle Scholar
  73. Lipska BK, Weinberger DR (1993) Delayed effects of neonatal hippocampal damage on haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviors in the rat. Brain Res Dev Brain Res 75:213–222PubMedCrossRefGoogle Scholar
  74. Lipska BK, Weinberger DR (2000) To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology 23:223–239.PubMedCrossRefGoogle Scholar
  75. Lipska BK, Jaskiw GE, Weinberger DR (1993) Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: a potential animal model of schizophrenia. Neuropsychopharmacology 9:67–75.PubMedGoogle Scholar
  76. Lubow RE (1997) Latent inhibition as a measure of learned inattention: some problems and solutions. Behav Brain Res 88: 75–83; Review.PubMedCrossRefGoogle Scholar
  77. Lubow RE, Gewirtz JC (1995) Latent inhibition in humans: data, theory, and implications for schizophrenia. Psychol Bull 117:87–103; Review.PubMedCrossRefGoogle Scholar
  78. Lubow RE, Moore AU (1959) Latent inhibition: The effect of non-reinforced preexposure to the conditioned stimulus. J Comp Physiol Psychol 52:415–419.PubMedCrossRefGoogle Scholar
  79. Mansbach RS, Geyer MA (1989) Effects of phencyclidine and phencyclidine biologs on sensorimotor gating in the rat. Neuropsychopharmacology 2: 299–308.PubMedCrossRefGoogle Scholar
  80. Mansbach RS, Geyer MA, Braff DL (1988) Dopaminergic stimulation disrupts sensorimotor gating in the rat. Psychopharmacology (Berl) 94:507–514.CrossRefGoogle Scholar
  81. Marquis JP, Goulet S, Doré FY (2003) Schizophrenia-like syndrome inducing agent phencyclidine failed to impair memory for temporal order in rats. Neurobiol Learn Mem. 80:158–167.PubMedCrossRefGoogle Scholar
  82. Marquis JP, Audet MC, Doré FY, Goulet S (2007) Delayed alternation performance following subchronic phencyclidine administration in rats depends on task parameters. Prog Neuropsychopharmacol Biol Psychiatr 31:1108–1112.CrossRefGoogle Scholar
  83. McNeil TF, Cantor-Graae E (2000) Neuromotor markers of risk for schizophrenia. Aust N Z J Psychiatry 34: 86–90; Review.Google Scholar
  84. Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA, Devon RS, Clair DM, Muir WJ, Blackwood DH, Porteous DJ (2000) Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 9:1415–1423.PubMedCrossRefGoogle Scholar
  85. Miyakawa T, Leiter LM, Gerber DJ, Gainetdinov RR, Sotnikova TD, Zeng H, Caron MG, Tonegawa S (2003) Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Proc Natl Acad Sci U S A 100: 8987–8992.PubMedCrossRefGoogle Scholar
  86. Mohn AR, Gainetdinov RR, Caron MG, Koller BH (1999) Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 98: 427–436.PubMedCrossRefGoogle Scholar
  87. Moghaddam B, Adams BW (1998) Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281: 1349–1352.PubMedCrossRefGoogle Scholar
  88. Morrens M, Hulstijn W, Lewi PJ, De Hert M, Sabbe BG (2006) Stereotypy in schizophrenia. Schizophr Res 84: 397–404.PubMedCrossRefGoogle Scholar
  89. Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Meth 11: 47–60.CrossRefGoogle Scholar
  90. Murray RM, Lewis SW (1987) Is schizophrenia a neurodevelopmental disorder? Br Med J 295:681–682.CrossRefGoogle Scholar
  91. Murray TK, Ridley RM (1997) The effect of dizocilpine (MK-801) on conditional discrimination learning in the rat. Behav Pharmacol 8: 383–388.PubMedCrossRefGoogle Scholar
  92. Myhrer T (2003) Neurotransmitter systems involved in learning and memory in the rat: a meta-analysis based on studies of four behavioral tasks. Brain Res Brain Res Rev 41: 268–287; Review.PubMedCrossRefGoogle Scholar
  93. Myin-Germeys I, Delespaul P, van Os J (2005) Behavioural sensitization to daily life stress in psychosis. Psychol Med 35:733–741.PubMedCrossRefGoogle Scholar
  94. Noda Y, Yamada K, Furukawa H, Nabeshima T (1995) Enhancement of immobility in a forced swimming test by subacute or repeated treatment with phencyclidine: a new model of schizophrenia. Br J Pharmacol 116: 2531–2537.PubMedGoogle Scholar
  95. Noda Y, Mamiya T, Furukawa H, Nabeshima T (1997) Effects of antidepressants on phencyclidine-induced enhancement of immobility in a forced swimming test in mice. Eur J Pharmacol 324:135–140.PubMedCrossRefGoogle Scholar
  96. Norton N, Williams HJ, Williams NM, Spurlock G, Zammit S, Jones G, Jones S, Owen R, O'Donovan MC, Owen MJ (2003) Mutation screening of the Homer gene family and association analysis in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 120: 18–21.CrossRefGoogle Scholar
  97. O'Tuathaigh CM, O'Connor AM, O'Sullivan GJ, Lai D, Harvey R, Croke DT, Waddington JL (2007) Disruption to social dyadic interactions but not emotional/anxiety-related behaviour in mice with heterozygous ‘knockout’ of the schizophrenia risk gene neuregulin-1. Prog Neuropsychopharmacol Biol Psychiatr (Epub ahead of print)Google Scholar
  98. Packard MG, White NM (1989) Memory facilitation produced by dopamine agonists: role of receptor subtype and mnemonic requirements. Pharmacol Biochem Behav 33: 511–518.PubMedCrossRefGoogle Scholar
  99. Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev 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 13:1102–1107.PubMedCrossRefGoogle Scholar
  100. Picada J.N., Henriques J.A. and Roesler R (2003) An oxidized form of apomorphine fails to induce stereotypy. Schizophr. Res 63:199–200.PubMedCrossRefGoogle Scholar
  101. Pierce RC, Kalivas PW (1997) A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Res Brain Res Rev 25: 192–216.PubMedCrossRefGoogle Scholar
  102. Porsolt RD, Bertin A, Jalfre M (1978) “Behavioural despair” in rats and mice: strain differences and the effects of imipramine. Eur J Pharmacol 51: 291–294.PubMedCrossRefGoogle Scholar
  103. Powell CM, Miyakawa T (2006) Schizophrenia-Relevant Behavioral Testing in Rodent Models: A Uniquely Human Disorder? Biol Psychiatr 59: 1198–1207.CrossRefGoogle Scholar
  104. Randrup A, Munkvad I (1974) Pharmacology and physiology of stereotyped behavior. J Psychiatr Res 11: 1–10.PubMedCrossRefGoogle Scholar
  105. Ridley RM (1994) The psychology of perserverative and stereotyped behaviour. Prog Neurobiol 44: 221–231.PubMedCrossRefGoogle Scholar
  106. Robinson TE, Becker JB (1986) Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res 396:157–198.PubMedCrossRefGoogle Scholar
  107. Sams-Dodd F (1996) Phencyclidine-induced stereotyped behaviour and social isolation in rats: a possible animal model of schizophrenia. Behav Pharmacol 7: 3–23.PubMedGoogle Scholar
  108. Sams-Dodd F (1998a) Effects of continuous D-amphetamine and phencyclidine administration on social behaviour, stereotyped behaviour, and locomotor activity in rats. Neuropsychopharmacology 19:18–25.CrossRefGoogle Scholar
  109. Sams-Dodd F, Lipska BK, Weinberger DR (1997) Neonatal lesions of the rat ventral hippocampus result in hyperlocomotion and deficits in social behaviour in adulthood. Psychopharmacology (Berl) 132:303–310.CrossRefGoogle Scholar
  110. Sato M, Chen C-C, Akiyama K, Otsuki S (1983) Acute exacerbation of paranoid psychotic state after long-term abstinence in patients with previous methamphetamine psychosis. Biol Psychiatr 18:429–440.Google Scholar
  111. Solomon PR, Crider A, Winkelman JW, Turi A, Kamer RM, Kaplan LJ (1981) Disrupted latent inhibition in the rat with chronic amphetamine or haloperidol-induced supersensitivity: relationship to schizophrenic attention disorder. Biol Psychiatr 16: 519–537.Google Scholar
  112. Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT, Hjaltason O, Birgisdottir B, Jonsson H, Gudnadottir VG, Gudmundsdottir E, Bjornsson A, Ingvarsson B, Ingason A, Sigfusson S, Hardardottir H, Harvey RP, Lai D, Zhou M, Brunner D, Mutel V, Gonzalo A, Lemke G, Sainz J, Johannesson G, Andresson T, Gudbjartsson D, Manolescu A, Frigge ML, Gurney ME, Kong A, Gulcher JR, Petursson H, Stefansson K (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71:877–892.PubMedCrossRefGoogle Scholar
  113. Swerdlow NR, Geyer MA (1998) Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia. Schizophr Bull 24: 285–301.PubMedGoogle Scholar
  114. Swerdlow NR, Braff DL, Taaid N, Geyer MA (1994) Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients. Arch Gen Psychiatr 51: 139–154.PubMedCrossRefGoogle Scholar
  115. Szumlinski KK, Lominac KD, Kleschen MJ, Oleson EB, Dehoff MH, Schwarz MK, Seeburg PH, Worley PF, Kalivas PW (2005) Behavioral and neurochemical phenotyping of Homer1 mutant mice: possible relevance to schizophrenia. Genes Brain Behav 4:273–288.PubMedCrossRefGoogle Scholar
  116. Takao K, Yamasaki N, Miyakawa T (2007) Impact of brain-behavior phenotypying of genetically-engineered mice on research of neuropsychiatric disorders. Neurosci Res 58:124–132.PubMedCrossRefGoogle Scholar
  117. Thornton AE, Van Snellenberg JX, Sepehry AA, Honer W (2006) The impact of atypical antipsychotic medications on long-term memory dysfunction in schizophrenia spectrum disorder: a quantitative review. J. Psychopharmacol 20: 335–346.PubMedCrossRefGoogle Scholar
  118. Ujike H (2002) Stimulant-induced psychosis and schizophrenia: the role of sensitization. Curr Psychiatr Rep 4:177–184.CrossRefGoogle Scholar
  119. Vaillancourt C, Boksa P (2000) Birth insult alters dopamine-mediated behavior in a precocial species, the guinea pig. Implications for schizophrenia. Neuropsychopharmacology 23: 654–666.PubMedCrossRefGoogle Scholar
  120. Verma A, Moghaddam B (1996) NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: modulation by dopamine. J Neurosci 16: 373–379.PubMedGoogle Scholar
  121. 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 107:535–550.PubMedCrossRefGoogle Scholar
  122. Warburton EC, Joseph MH, Feldon J, Weiner I, Gray JA (1994) Antagonism of amphetamine-induced disruption of latent inhibition in rats by haloperidol and ondansetron: implications for a possible antipsychotic action of ondansetron. Psychopharmacology (Berl) 114: 657–664.CrossRefGoogle Scholar
  123. Wass C, Archer T, Pålsson E, Fejgin K, Klamer D, Engel JA, Svensson L (2006) Effects of phencyclidine on spatial learning and memory: nitric oxide-dependent mechanisms. Behav Brain Res 171:147–153.PubMedCrossRefGoogle Scholar
  124. Weinberger DR (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatr 44: 660–669.PubMedCrossRefGoogle Scholar
  125. Weiner I, Lubow RE, Feldon J (1984) Abolition of the expression but not the acquisition of latent inhibition by chronic amphetamine in rats. Psychopharmacology (Berl) 83:194–199.CrossRefGoogle Scholar
  126. Weiner I, Lubow RE, Feldon J (1988) Disruption of latent inhibition by acute administration of low doses of amphetamine. Pharmacol Biochem Behav 30: 871–878.PubMedCrossRefGoogle Scholar
  127. Weiner I, Shadach E, Barkai R, Feldon J (1997) Haloperidol- and clozapine-induced enhancement of latent inhibition with extended conditioning: implications for the mechanism of action of neuroleptic drugs. Neuropsychopharmacology 16: 42–50.PubMedCrossRefGoogle Scholar
  128. Wolff MC, Leander JD (2003) Comparison of the effects of antipsychotics on a delayed radial maze task in the rat. Psychopharmacology (Berl) 168: 410–416.CrossRefGoogle Scholar
  129. Yuii K, Suzuki M, Kurachi M (2007) Stress sensitization in schizophrenia. Ann N Y Acad Sci 1113: 276–290.PubMedCrossRefGoogle Scholar
  130. Zeng H, Chattarji S, Barbarosie M, Rondi-Reig L, Philpot BD, Miyakawa T, Bear MF, Tonegawa S (2001) Forebrain-specific calcineurin knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory. Cell 107: 617–629.PubMedCrossRefGoogle Scholar
  131. Zhang HT, Huang Y, Suvarna NU, Deng C, Crissman AM, Hopper AT, De Vivo M, Rose GM, O'Donnell JM (2005) Effects of the novel PDE4 inhibitors MEM1018 and MEM1091 on memory in the radial-arm maze and inhibitory avoidance tests in rats. Psychopharmacology (Berl) 179: 613–619.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Miyako Furuta
    • 1
  • Hiroshi Kunugi
    • 1
  1. 1.Department of Mental Disorder ResearchInstitute of Neuroscience, National Center of Neurology and PsychiatryKodaira, TokyoJapan

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