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

Abstract

Rationale

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.

Objectives

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.

Results

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.

Conclusions

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

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References

  1. Alexander GE, Crutcher MD (1990) Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 13:266–271

    CAS  Article  PubMed  Google 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 83:147–161

    Article  PubMed  Google Scholar 

  3. Bondi C, Matthews M, Moghaddam B (2012) Glutamatergic animal models of schizophrenia. Curr Pharm Des 18:1593–1604

    CAS  Article  PubMed  Google 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 33:2007–2019

    CAS  Article  PubMed  Google 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 3:2

    PubMed Central  Article  PubMed  Google 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 37:157–68

    CAS  Article  PubMed  Google 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 13:272–276

    CAS  Article  PubMed  Google 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 200:281–290

    Article  PubMed  Google Scholar 

  9. Chartoff EH, Heusner CL, Palmiter RD (2005) Dopamine is not required for the hyperlocomotor response to NMDA receptor antagonists. Neuropsychopharmacology 30:1324–1333

    CAS  PubMed  Google Scholar 

  10. Clarke HF, Dalley JW, Crofts HS, Robbins TW, Roberts AC (2004) Cognitive inflexibility after prefrontal serotonin depletion. Science 304:878–880

    CAS  Article  PubMed  Google 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 25:532–538

    CAS  Article  PubMed  Google Scholar 

  12. Coyle JT (2006) Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26:365–384

    CAS  Article  PubMed  Google 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 1003:318–332

    CAS  Article  PubMed  Google 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 212:227–242

    CAS  Article  PubMed  Google Scholar 

  15. Dragunow M, Faull R (1989) The use of c-fos as a metabolic marker in neuronal pathway tracing. J Neurosci Methods 29:261–265

    CAS  Article  PubMed  Google 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 198:37–49

    CAS  Article  PubMed  Google Scholar 

  17. Featherstone RE, Kapur S, Fletcher PJ (2007) The amphetamine-induced sensitized state as a model of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 31:1556–1571

    CAS  Article  PubMed  Google 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 24:1836–1849

    CAS  Article  PubMed  Google Scholar 

  19. Franklin K, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic, San Diego, California

    Google Scholar 

  20. Frohlich J, Van Horn JD (2014) Reviwing the ketamine model for schizophrenia. J Psychopharmacol 28:287–330

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  21. Gerfen CR (2000) Molecular effects of dopamine on striatal-projection pathways. Trends Neurosci 23:S64–S70

    CAS  Article  PubMed  Google Scholar 

  22. Graybiel AM (1990) Neurotransmitters and neuromodulators in the basal ganglia. Trends Neurosci 13:244–254

    CAS  Article  PubMed  Google Scholar 

  23. Groenewegen HJ (2003) The basal ganglia and motor control. Neural Plast 10:107–120

    PubMed Central  Article  PubMed  Google 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 519:114–117

    CAS  Article  PubMed  Google 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 56:73–79

    CAS  Article  PubMed  Google 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 85:384–396

    CAS  Article  PubMed  Google 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 208:23–36

    CAS  Article  PubMed  Google Scholar 

  28. Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308

    CAS  Article  PubMed  Google Scholar 

  29. Jentsch JD, Roth RH (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20:201–225

    CAS  Article  PubMed  Google Scholar 

  30. Jentsch JD, Taylor JR (2001) Impaired inhibition of conditioned responses produced by subchronic administration of phencyclidine to rats. Neuropsychopharmacology 24:66–74

    CAS  Article  PubMed  Google Scholar 

  31. Jones CA, Watson DJG, Fone KCF (2011) Animal models of schizophrenia. Br J Pharmacol 164:1162–1194

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  32. Kaffman A, Krystal JH (2012) New frontiers in animal research of psychiatric illness. Methods Mol Biol 829:3–30

    PubMed Central  CAS  Article  PubMed  Google 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 83:108–121

    PubMed Central  CAS  Article  PubMed  Google 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 104:14843–14848

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  35. Konkle AT, Bielajew C (2004) Yracing the neuroanatomical profiles of reward pathways with markers of neuronal activation. Rev Neurosci 15:383–414

    PubMed  Google 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 169:215–233

    CAS  Article  PubMed  Google 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 51:199–214

    CAS  Article  PubMed  Google Scholar 

  38. Landau SM, Lal R, O’Neil JP, Baker S, Jagust WJ (2009) Striatal dopamine and working memory. Cereb Cortex 19:445–454

    PubMed Central  Article  PubMed  Google 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 70:145–151

    CAS  Article  PubMed  Google 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 62:2440–2446

    Article  PubMed  Google Scholar 

  41. Luby ED, Cohen BD, Rosenbaum G, Gottlieb JS, Kelley R (1959) Study of a new schizophrenomimetic drug AMA. Arch Neurol Psychiatry 81:363–369

    CAS  Article  Google Scholar 

  42. Ma J, Leung LS (2000) Relation between hippocampal gamma waves and behavioral disturbances induced by phencyclidine and methamphetamine. Behav Brain Res 111:1–11

    CAS  Article  PubMed  Google 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 191:961–974

    CAS  Article  PubMed  Google 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 206:403–414

    CAS  Article  PubMed  Google 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 214:240–247

    CAS  Article  PubMed  Google 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 21:333–343

    CAS  Article  PubMed  Google Scholar 

  47. Moghaddam B, Javitt D (2012) From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37:4–15

    PubMed Central  CAS  Article  PubMed  Google 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 15:767–779

    CAS  Article  PubMed  Google 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 93:1325–1329

    PubMed Central  CAS  Article  PubMed  Google 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 14:269–272

    CAS  Article  PubMed  Google 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 128:419–432

    CAS  Article  PubMed  Google 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 24:822–823

    CAS  Article  PubMed  Google 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 77:175–186

    CAS  Article  PubMed  Google Scholar 

  54. Paoletti P, Bellone C, Zhou Q (2013) NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 14:383–400

    CAS  Article  PubMed  Google Scholar 

  55. Phillipson OT, Griffiths AC (1985) The topographic order of inputs to nucleus accumbens in the rat. Neuroscience 16:275–296

    CAS  Article  PubMed  Google 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 25:192–221

    CAS  Article  PubMed  Google Scholar 

  57. Post RM, Rose H (1976) Increasing effects of repetitive cocaine administration in the rat. Nature 260:731–732

    CAS  Article  PubMed  Google Scholar 

  58. Robbins TW (2012) Animal models of neuropsychiatry revisited: a personal tribute to Teitelbaum. Behav Brain Res 231:337–342

    CAS  Article  PubMed  Google Scholar 

  59. Sager SM, Sharp FR, Currant T (1988) Expression of c-fos protein in brain: metabolic mapping at the cellular level. Science 240:1328–1331

    Article  Google 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 69:918–927

    CAS  Article  PubMed  Google 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 204:410–415

    CAS  Article  PubMed  Google Scholar 

  62. Simon H (1981) Dopaminergic A10 neurons and frontal system. J Physiol 77:81–95

    CAS  Google Scholar 

  63. Spielewoy C, Markou A (2003) Withdrawal from chronic phencyclidine treatment induces long-lasting depression in brain reward function. Neuropsychopharmacology 28:1106–1116

    CAS  PubMed  Google Scholar 

  64. Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85:367–370

    CAS  Article  PubMed  Google 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 19:861–867

    CAS  Article  PubMed  Google 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 213:681–695

    CAS  Article  PubMed  Google 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 76:937–945

    Article  PubMed  Google 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 24:769–780

    Article  PubMed  Google Scholar 

  69. van den Buuse M (2010) Modeling the positive symptoms of schizophrenia in genetically modified mice: pharmacology and methodology aspects. Schizophr Bull 36:246–270

    PubMed Central  Article  PubMed  Google 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 10:376–384

    CAS  Article  PubMed  Google Scholar 

  71. Williams GV, Goldman-Rakic PS (1995) Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376:572–575

    CAS  Article  PubMed  Google 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 5:623–629

    CAS  Article  PubMed  Google Scholar 

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Acknowledgments

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.

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Castañé, A., Santana, N. & Artigas, F. PCP-based mice models of schizophrenia: differential behavioral, neurochemical and cellular effects of acute and subchronic treatments. Psychopharmacology 232, 4085–4097 (2015). https://doi.org/10.1007/s00213-015-3946-6

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Keywords

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