, Volume 232, Issue 21–22, pp 4085–4097 | Cite as

PCP-based mice models of schizophrenia: differential behavioral, neurochemical and cellular effects of acute and subchronic treatments

  • Anna CastañéEmail author
  • Noemí Santana
  • Francesc Artigas
Original Investigation



N-methyl-D-aspartate receptor (NMDA-R) hypofunction has been proposed to account for the pathophysiology of schizophrenia. Thus, NMDA-R blockade has been used to model schizophrenia in experimental animals. Acute and repeated treatments have been successfully tested; however, long-term exposure to NMDA-R antagonists more likely resembles the core symptoms of the illness.


To explore whether schizophrenia-related behaviors are differentially induced by acute and subchronic phencyclidine (PCP) treatment in mice and to examine the neurobiological bases of these differences.


Subchronic PCP induced a sensitization of acute locomotor effects. Spontaneous alternation in a T-maze and novel object recognition performance were impaired after subchronic but not acute PCP, suggesting a deficit in working memory. On the contrary, reversal learning and immobility in the tail suspension test were unaffected. Subchronic PCP significantly reduced basal dopamine but not serotonin output in medial prefrontal cortex (mPFC) and markedly decreased the expression of tyrosine hydroxylase in the ventral tegmental area. Finally, acute and subchronic PCP treatments evoked a different pattern of c-fos expression. At 1 h post-treatment, acute PCP increased c-fos expression in many cortical regions, striatum, thalamus, hippocampus, and dorsal raphe. However, the increased c-fos expression produced by subchronic PCP was restricted to the retrosplenial cortex, thalamus, hippocampus, and supramammillary nucleus. Four days after the last PCP injection, c-fos expression was still increased in the hippocampus of subchronic PCP-treated mice.


Acute and subchronic PCP administration differently affects neuronal activity in brain regions relevant to schizophrenia, which could account for their different behavioral effects.


Behavior c-fos Dopamine Phencyclidine Glutamate NMDA Serotonin Schizophrenia Reversal learning Working memory 



This work has received support from the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM (13INT4 intramural project), and the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013). We thank Emilio Regli, Patricia Sariñana, and Miguel Angel López-Venegas, as well as Leticia Campa, Mireia Galofré, Noemí Jurado, and Verónica Paz for technical support.

Conflict of interest

Francesc Artigas has received consulting and educational honoraria from Lundbeck, and he is PI of a grant from Lundbeck. He is also member of the scientific advisory board of Neurolixis. The rest of authors declare no conflict of interest.


  1. Alexander GE, Crutcher MD (1990) Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 13:266–271CrossRefPubMedGoogle Scholar
  2. Amann LC, Gandal MJ, Halene TB, Ehrlichman RS, White SL, McCarren HS, Siegel SJ (2010) Mouse behavioral endophenotypes for schizophrenia. Brain Res Bull 83:147–161CrossRefPubMedGoogle Scholar
  3. Bondi C, Matthews M, Moghaddam B (2012) Glutamatergic animal models of schizophrenia. Curr Pharm Des 18:1593–1604CrossRefPubMedGoogle Scholar
  4. Boulougouris V, Glennon JC, Robbins TW (2008) Dissociable effects of selective 5-HT2A and 5-HT2C receptor antagonists on serial spatial reversal learning in rats. Neuropsychopharmacology 33:2007–2019CrossRefPubMedGoogle Scholar
  5. Brigman JL, Ihne J, Saksida LM, Bussey TJ, Holmes A (2009) Effects of subchronic phencyclidine (PCP) treatment on social behaviors, and operant discrimination and reversal learning in C57BL/6J mice. Front Behav Neurosci 3:2PubMedCentralCrossRefPubMedGoogle Scholar
  6. Bubser M, Schmidt WJ (1990) 6-Hydroxydopamine lesion of the rat prefrontal cortex increases locomotor activity, impairs acquisition of delayed alternation tasks, but does not affect uninterrupted tasks in the radial maze. Behav Brain Res 37:157–68CrossRefPubMedGoogle Scholar
  7. Carlsson M, Carlsson A (1990) Interactions between glutamatergic and monoaminergic systems within the basal ganglia: implications for schizophrenia and Parkinson’s disease. Trends Neurosci 13:272–276CrossRefPubMedGoogle Scholar
  8. Castañé A, Artigas F, Bortolozzi A (2008) The absence of 5-HT(1A) receptors has minor effects on dopamine but not serotonin release evoked by MK-801 in mice prefrontal cortex. Psychopharmacology 200:281–290CrossRefPubMedGoogle Scholar
  9. Chartoff EH, Heusner CL, Palmiter RD (2005) Dopamine is not required for the hyperlocomotor response to NMDA receptor antagonists. Neuropsychopharmacology 30:1324–1333PubMedGoogle Scholar
  10. Clarke HF, Dalley JW, Crofts HS, Robbins TW, Roberts AC (2004) Cognitive inflexibility after prefrontal serotonin depletion. Science 304:878–880CrossRefPubMedGoogle Scholar
  11. Clarke HF, Walker SC, Crofts HS, Dalley JW, Robbins TW, Roberts AC (2005) Prefrontal serotonin depletion affects reversal learning but not attentional set shifting. J Neurosci 25:532–538CrossRefPubMedGoogle Scholar
  12. Coyle JT (2006) Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26:365–384CrossRefPubMedGoogle Scholar
  13. Coyle JT, Tsai G, Goff D (2003) Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Ann N Y Acad Sci 1003:318–332CrossRefPubMedGoogle Scholar
  14. Dix S, Gilmour G, Potts S, Smith JW, Tricklebank M (2010) A within-subject cognitive battery in the rat: differential effects of NMDA receptor antagonists. Psychopharmacology 212:227–242CrossRefPubMedGoogle Scholar
  15. Dragunow M, Faull R (1989) The use of c-fos as a metabolic marker in neuronal pathway tracing. J Neurosci Methods 29:261–265CrossRefPubMedGoogle Scholar
  16. Egerton A, Reid L, McGregor S, Cochran SM, Morris BJ, Pratt JA (2008) Subchronic and chronic PCP treatment produces temporally distinct deficits in attentional set shifting and prepulse inhibition in rats. Psychopharmacology 198:37–49CrossRefPubMedGoogle Scholar
  17. Featherstone RE, Kapur S, Fletcher PJ (2007) The amphetamine-induced sensitized state as a model of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 31:1556–1571CrossRefPubMedGoogle Scholar
  18. Fellini L, Kumar G, Gibbs S, Steckler T, Talpos J (2014) Re-evaluating the PCP challenge as a pre-clinical model of impaired cognitive flexibility in schizophrenia. Eur Neuropsychopharmacol 24:1836–1849CrossRefPubMedGoogle Scholar
  19. Franklin K, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic, San Diego, CaliforniaGoogle Scholar
  20. Frohlich J, Van Horn JD (2014) Reviwing the ketamine model for schizophrenia. J Psychopharmacol 28:287–330PubMedCentralCrossRefPubMedGoogle Scholar
  21. Gerfen CR (2000) Molecular effects of dopamine on striatal-projection pathways. Trends Neurosci 23:S64–S70CrossRefPubMedGoogle Scholar
  22. Graybiel AM (1990) Neurotransmitters and neuromodulators in the basal ganglia. Trends Neurosci 13:244–254CrossRefPubMedGoogle Scholar
  23. Groenewegen HJ (2003) The basal ganglia and motor control. Neural Plast 10:107–120PubMedCentralCrossRefPubMedGoogle Scholar
  24. Hashimoto K, Fujita Y, Shimizu E, Iyo M (2005) Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of clozapine, but not haloperidol. Eur J Pharmacol 519:114–117CrossRefPubMedGoogle Scholar
  25. Hiramatsu M, Sasaki M, Nabeshima T, Kameyama T (1997) Effects of dynorphin A (1-13) on carbon monoxide-induced delayed amnesia in mice. Pharmacol Biochem Behav 56:73–79CrossRefPubMedGoogle Scholar
  26. Hiyoshi T, Kambe D, Karasawa J, Chaki S (2014) Differential effects of NMDA receptor antagonists at lower and higher doses on basal gamma band oscillation power in rat cortical electroencephalograms. Neuropharmacology 85:384–396CrossRefPubMedGoogle Scholar
  27. 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 208:23–36CrossRefPubMedGoogle Scholar
  28. Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308CrossRefPubMedGoogle Scholar
  29. Jentsch JD, Roth RH (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20:201–225CrossRefPubMedGoogle Scholar
  30. Jentsch JD, Taylor JR (2001) Impaired inhibition of conditioned responses produced by subchronic administration of phencyclidine to rats. Neuropsychopharmacology 24:66–74CrossRefPubMedGoogle Scholar
  31. Jones CA, Watson DJG, Fone KCF (2011) Animal models of schizophrenia. Br J Pharmacol 164:1162–1194PubMedCentralCrossRefPubMedGoogle Scholar
  32. Kaffman A, Krystal JH (2012) New frontiers in animal research of psychiatric illness. Methods Mol Biol 829:3–30PubMedCentralCrossRefPubMedGoogle Scholar
  33. Kantrowitz JT, Javitt DC (2010) N-methyl-D-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? Brain Res Bull 83:108–121PubMedCentralCrossRefPubMedGoogle Scholar
  34. 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. Proc Natl Acad Sci U S A 104:14843–14848PubMedCentralCrossRefPubMedGoogle Scholar
  35. Konkle AT, Bielajew C (2004) Yracing the neuroanatomical profiles of reward pathways with markers of neuronal activation. Rev Neurosci 15:383–414PubMedGoogle Scholar
  36. Krystal JH, D’Souza DC, Mathalon D, Perry E, Belger A, Hoffman R (2003) NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology 169:215–233CrossRefPubMedGoogle Scholar
  37. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD et al (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214CrossRefPubMedGoogle Scholar
  38. Landau SM, Lal R, O’Neil JP, Baker S, Jagust WJ (2009) Striatal dopamine and working memory. Cereb Cortex 19:445–454PubMedCentralCrossRefPubMedGoogle Scholar
  39. Lapin IP, Rogawski (1995) Effects of D1 and D2 dopamine receptor antagonists and catecholamine depleting agents on the locomotor stimulation induced by dizocilpine in mice. Behav Brain Res 70:145–151CrossRefPubMedGoogle Scholar
  40. López Hill X, Scorza MC (2012) Role of the anterior thalamic nucleus in the motor hyperactivity induced by systemic MK-801 administration in rats. Neuropharmacology 62:2440–2446CrossRefPubMedGoogle Scholar
  41. Luby ED, Cohen BD, Rosenbaum G, Gottlieb JS, Kelley R (1959) Study of a new schizophrenomimetic drug AMA. Arch Neurol Psychiatry 81:363–369CrossRefGoogle Scholar
  42. Ma J, Leung LS (2000) Relation between hippocampal gamma waves and behavioral disturbances induced by phencyclidine and methamphetamine. Behav Brain Res 111:1–11CrossRefPubMedGoogle Scholar
  43. Ma J, Leung LS (2007) The supramammillo-septal-hippocampal pathway mediates sensorimotor gating impairment and hyperlocomotion induced by MK-801 and ketamine in rats. Psychopharmacology 191:961–974CrossRefPubMedGoogle Scholar
  44. McLean SL, Woolley ML, Thomas D, Neill JC (2009) Role of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in the rat. Psychopharmacology 206:403–414CrossRefPubMedGoogle Scholar
  45. McLean SL, Neill JC, Idris NF, Marston HM, Wong EH, Shahid M (2010) Effects of asenapine, olanzapine, and risperidone on psychotomimetic-induced reversal-learning deficits in the rat. Behav Brain Res 214:240–247CrossRefPubMedGoogle Scholar
  46. McLean SL, Grayson B, Idris NF, Lesage AS, Pemberton DJ, Mackie C, Neill JC (2011) Activation of alpha 7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks inrats: implications for therapy of cognitive dysfunction in schizophrenia. Eur Neuropsychopharmacol 21:333–343CrossRefPubMedGoogle Scholar
  47. Moghaddam B, Javitt D (2012) From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37:4–15PubMedCentralCrossRefPubMedGoogle Scholar
  48. Mouri A, Koseki T, Narusawa S, Niwa M, Mamiya T, Kano S, Sawa A, Nabeshima T (2012) Mouse strain differences in phencyclidine-induced behavioural changes. Int J Neuropsychopharmacol 15:767–779CrossRefPubMedGoogle Scholar
  49. Murphy BL, Arnsten AF, Goldman-Rakic PS, Roth RH (1996) Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys. Proc Natl Acad Sci U S A 93:1325–1329PubMedCentralCrossRefPubMedGoogle Scholar
  50. Nagai T, Noda Y, Une T, Furukawa K, Furukawa H, Kan QM, Nabeshima T (2003) Effect of AD-5423 on animal models of schizophrenia: phencyclidine-induced behavioral changes in mice. Neuroreport 14:269–272CrossRefPubMedGoogle Scholar
  51. 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 128:419–432CrossRefPubMedGoogle Scholar
  52. Neill JC, Harte MK, Haddad PM, Lydall ES, Dwyer DM (2014) Acute and chronic effects of NMDA receptor antagonists in rodents, relevance to negative symptoms of schizophrenia: a translational link to humans. Eur Neuropsychopharmacol 24:822–823CrossRefPubMedGoogle Scholar
  53. Panagis G, Nomikos GG, Miliaressis E, Chergui K, Kastellakis A, Svensson TH, Spyraki C (1997) Ventral pallidum self-stimulation induces stimulus dependent increase in c-fos expression in reward-related brain regions. Neuroscience 77:175–186CrossRefPubMedGoogle Scholar
  54. Paoletti P, Bellone C, Zhou Q (2013) NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 14:383–400CrossRefPubMedGoogle Scholar
  55. Phillipson OT, Griffiths AC (1985) The topographic order of inputs to nucleus accumbens in the rat. Neuroscience 16:275–296CrossRefPubMedGoogle Scholar
  56. Pierce RC, Kalivas PW (1997) A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Res Brain Res Rev 25:192–221CrossRefPubMedGoogle Scholar
  57. Post RM, Rose H (1976) Increasing effects of repetitive cocaine administration in the rat. Nature 260:731–732CrossRefPubMedGoogle Scholar
  58. Robbins TW (2012) Animal models of neuropsychiatry revisited: a personal tribute to Teitelbaum. Behav Brain Res 231:337–342CrossRefPubMedGoogle Scholar
  59. Sager SM, Sharp FR, Currant T (1988) Expression of c-fos protein in brain: metabolic mapping at the cellular level. Science 240:1328–1331CrossRefGoogle Scholar
  60. Santana N, Troyano-Rodriguez E, Mengod G, Celada P, Artigas F (2011) Activation of thalamocortical networks by the N-methyl-D-aspartate receptor antagonist phencyclidine: reversal by clozapine. Biol Psychiatry 69:918–927CrossRefPubMedGoogle Scholar
  61. Seillier A, Giuffrida A (2009) Evaluation of NMDA receptor models of schizophrenia: divergences in the behavioral effects of subchronic PCP and MK-801. Behav Brain Res 204:410–415CrossRefPubMedGoogle Scholar
  62. Simon H (1981) Dopaminergic A10 neurons and frontal system. J Physiol 77:81–95Google Scholar
  63. Spielewoy C, Markou A (2003) Withdrawal from chronic phencyclidine treatment induces long-lasting depression in brain reward function. Neuropsychopharmacology 28:1106–1116PubMedGoogle Scholar
  64. Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85:367–370CrossRefPubMedGoogle Scholar
  65. Tanibuchi Y, Fujita Y, Kohno M, Ishima T, Takatsu Y, Iyo M, Hashimoto K (2009) Effects of quetiapine on phencyclidine-induced cognitive deficits in mice: a possible role of alpha1-adrenoceptors. Eur Neuropsychopharmacol 19:861–867CrossRefPubMedGoogle Scholar
  66. Thomson DM, McVie A, Morris BJ, Pratt JA (2011) Dissociation of acute and chronic intermittent phencyclidine-induced performance deficits in the 5-choice serial reaction time task: influence of clozapine. Psychopharmacology 213:681–695CrossRefPubMedGoogle Scholar
  67. Troyano-Rodríguez E, Lladó-Pelfort L, Santana N, Teruel-Martí V, Celada P, Artigas F (2014) Phencyclidine inhibits the activity of thalamic reticular gamma-aminobutyric acidergic neurons in rat brain. Biol Psychiatry 76:937–945CrossRefPubMedGoogle Scholar
  68. Väisänen J, Ihalainen J, Tanila H, Castrén E (2004) Effects of NMDA-receptor antagonist treatment on c-fos expression in rat brain areas implicated in schizophrenia. Cell Mol Neurobiol 24:769–780CrossRefPubMedGoogle Scholar
  69. van den Buuse M (2010) Modeling the positive symptoms of schizophrenia in genetically modified mice: pharmacology and methodology aspects. Schizophr Bull 36:246–270PubMedCentralCrossRefPubMedGoogle Scholar
  70. Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AF (2007) Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci 10:376–384CrossRefPubMedGoogle Scholar
  71. Williams GV, Goldman-Rakic PS (1995) Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376:572–575CrossRefPubMedGoogle Scholar
  72. Xu X, Domino EF (1994) Genetic differences in the locomotor response to single and daily doses of phencyclidine in inbred mouse strains. Behav Pharmacol 5:623–629CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Anna Castañé
    • 1
    • 2
    • 3
    Email author
  • Noemí Santana
    • 1
    • 2
    • 3
  • Francesc Artigas
    • 1
    • 2
    • 3
  1. 1.Department of Neurochemistry and NeuropharmacologyCSIC-Institut d’Investigacions Biomèdiques de Barcelona (IIBB)BarcelonaSpain
  2. 2.Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIIIMadridSpain
  3. 3.Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)BarcelonaSpain

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