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Neonatal phencyclidine administration and post-weaning social isolation as a dual-hit model of ‘schizophrenia-like’ behaviour in the rat

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Abstract

Rationale

Schizophrenia is a debilitating disorder comprising positive, negative and cognitive deficits with a poorly defined neurobiological aetiology; therefore, animal models with greater translational reliability are essential to develop improved therapies.

Objectives

This study combines two developmental challenges in rats, neonatal phencyclidine (PCP) injection and subsequent rearing in social isolation from weaning, to attempt to produce more robust behavioural deficits with greater translational relevance to schizophrenia than either challenge alone.

Methods

Forty-two male Lister-hooded rat pups received the N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine (PCP, 10 mg/kg, s.c.), or vehicle on post-natal day (PND) 7, 9 and 11 and were weaned on PND 23 into group housing (saline-treated n = 11 or PCP-treated n = 10) or isolation (saline n = 10 or PCP n = 11). Six weeks post-weaning, novelty- and PCP-induced (3.2 mg/kg) locomotor activity, novel object discrimination, prepulse inhibition of acoustic startle and contextual memory in a conditioned emotion response (CER) were recorded.

Results

Isolation rearing alone significantly elevated baseline locomotor activity and induced visual recognition memory impairment in novel object discrimination. Neonatal PCP treatment did not induce locomotor sensitisation to a subsequent acute PCP injection, but it impaired prepulse inhibition when combined with isolation rearing. CER freezing behaviour was significantly reduced by isolation rearing but an even greater effect occurred when combined with neonatal PCP treatment.

Conclusions

Neonatal PCP and isolation rearing both produce behavioural deficits in adult rats, but combined treatment caused a wider range of more severe cognitive impairments, providing a more comprehensive preclinical model to determine the neurobiological aetiology of schizophrenia than either treatment alone.

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References

  • Akkerman S, Blokland A, Reneerkens O, van Goethem NP, Bollen E, Gijselaers HJ, Lieben CK, Steinbusch HW, Prickaerts J (2012) Object recognition testing: methodological considerations on exploration and discrimination measures. Behav Brain Res 232:335–347

    Article  PubMed  Google Scholar 

  • Anagnostaras SG, Maren S, Sage JR, Goodrich S, Fanselow MS (1999) Scopolamine and Pavlovian fear conditioning in rats: dose-effect analysis. Neuropsychopharmacology 21:731–744

    Article  CAS  PubMed  Google Scholar 

  • Anastasio NC, Johnson KM (2008a) Atypical anti-schizophrenic drugs prevent changes in cortical N-methyl-D-aspartate receptors and behavior following sub-chronic phencyclidine administration in developing rat pups. Pharmacol Biochem Behav 90:569–577

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Anastasio NC, Johnson KM (2008b) Differential regulation of the NMDA receptor by acute and sub-chronic phencyclidine administration in the developing rat. J Neurochem 104:1210–1218

    Article  CAS  PubMed  Google Scholar 

  • Andersen JD, Pouzet B (2004) Spatial memory deficits induced by perinatal treatment of rats with PCP and reversal effect of D-serine. Neuropsychopharmacology 29:1080–1090

    Article  CAS  PubMed  Google Scholar 

  • Ashby DM, Habib D, Dringenberg HC, Reynolds JN, Beninger RJ (2010) Subchronic MK-801 treatment and post-weaning social isolation in rats: differential effects on locomotor activity and hippocampal long-term potentiation. Behav Brain Res 212:64–70

    Article  CAS  PubMed  Google Scholar 

  • Athos J, Impey S, Pineda VV, Chen X, Storm DR (2002) Hippocampal CRE-mediated gene expression is required for contextual memory formation. Nat Neurosci 5:1119–1120

    Article  CAS  PubMed  Google Scholar 

  • Atkins CM, Selcher JC, Petraitis JJ, Trzaskos JM, Sweatt JD (1998) The MAPK cascade is required for mammalian associative learning. Nat Neurosci 1:602–609

    Article  CAS  PubMed  Google Scholar 

  • Bakshi VP, Geyer MA (1999) Ontogeny of isolation rearing-induced deficits in sensorimotor gating in rats. Physiol Behav 67:385–392

    Article  CAS  PubMed  Google Scholar 

  • Barch DM, Carter CS (2008) Measurement issues in the use of cognitive neuroscience tasks in drug development for impaired cognition in schizophrenia: a report of the second consensus building conference of the CNTRICS initiative. Schizophr Bull 34:613–618

    Article  PubMed Central  PubMed  Google Scholar 

  • Barch DM, Carter CS, Arnsten A, Buchanan RW, Cohen JD, Geyer M, Green MF, Krystal JH, Nuechterlein K, Robbins T, Silverstein S, Smith EE, Strauss M, Wykes T, Heinssen R (2009) Selecting paradigms from cognitive neuroscience for translation into use in clinical trials: proceedings of the third CNTRICS meeting. Schizophr Bull 35:109–114

    Article  PubMed Central  PubMed  Google Scholar 

  • 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 14:83–144

    CAS  PubMed  Google Scholar 

  • Beninger RJ, Beuk J, Banasikowski TJ, van Adel M, Boivin GA, Reynolds JN (2010) Subchronic phencyclidine in rats: alterations in locomotor activity, maze performance, and GABA(A) receptor binding. Behav Pharmacol 21:1–10

    Article  CAS  PubMed  Google Scholar 

  • Bianchi M, Fone KF, Azmi N, Heidbreder CA, Hagan JJ, Marsden CA (2006) Isolation rearing induces recognition memory deficits accompanied by cytoskeletal alterations in rat hippocampus. Eur J Neurosci 24:2894–2902

    Article  CAS  PubMed  Google Scholar 

  • Bloomfield C, French SJ, Jones DN, Reavill C, Southam E, Cilia J, Totterdell S (2008) Chandelier cartridges in the prefrontal cortex are reduced in isolation reared rats. Synapse 62:628–631

    Article  CAS  PubMed  Google Scholar 

  • Boctor SY, Ferguson SA (2010) Altered adult locomotor activity in rats from phencyclidine treatment on postnatal days 7, 9 and 11, but not repeated ketamine treatment on postnatal day 7. Neurotoxicology 31:42–54

    Article  CAS  PubMed  Google Scholar 

  • Boctor SY, Wang C, Ferguson SA (2008) Neonatal PCP is more potent than ketamine at modifying preweaning behaviors of Sprague-Dawley rats. Toxicol Sci 106:172–179

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bolton MM, Heaney CF, Sabbagh JJ, Murtishaw AS, Magcalas CM, Kinney JW (2012) Deficits in emotional learning and memory in an animal model of schizophrenia. Behav Brain Res 233:35–44

    Article  PubMed Central  PubMed  Google Scholar 

  • Braff DL, Geyer MA (1990) Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry 47:181–188

    Article  CAS  PubMed  Google Scholar 

  • Carter CS, Barch DM, Buchanan RW, Bullmore E, Krystal JH, Cohen J, Geyer M, Green M, Nuechterlein KH, Robbins T, Silverstein S, Smith EE, Strauss M, Wykes T, Heinssen R (2008) Identifying cognitive mechanisms targeted for treatment development in schizophrenia: an overview of the first meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia Initiative. Biol Psychiatry 64:4–10

    Article  PubMed Central  PubMed  Google Scholar 

  • Cilia J, Reavill C, Hagan JJ, Jones DN (2001) Long-term evaluation of isolation-rearing induced prepulse inhibition deficits in rats. Psychopharmacology (Berl) 156:327–337

    Article  CAS  Google Scholar 

  • Cilia J, Hatcher PD, Reavill C, Jones DN (2005) Long-term evaluation of isolation-rearing induced prepulse inhibition deficits in rats: an update. Psychopharmacology (Berl) 180:57–62

    Article  CAS  Google Scholar 

  • Coelho CA, Ferreira TL, Soares JC, Oliveira MG (2013) Hippocampal NMDA receptor blockade impairs CREB phosphorylation in amygdala after contextual fear conditioning. Hippocampus 23:545–551

    Article  CAS  Google Scholar 

  • Coyle JT (2012) NMDA receptor and schizophrenia: a brief history. Schizophr Bull 38:920–926

    Article  PubMed Central  PubMed  Google Scholar 

  • Day-Wilson KM, Jones DN, Southam E, Cilia J, Totterdell S (2006) Medial prefrontal cortex volume loss in rats with isolation rearing-induced deficits in prepulse inhibition of acoustic startle. Neuroscience 141:1113–1121

    Article  CAS  PubMed  Google Scholar 

  • Del Arco A, Zhu S, Terasmaa A, Mohammed AH, Fuxe K (2004) Hyperactivity to novelty induced by social isolation is not correlated with changes in D2 receptor function and binding in striatum. Psychopharmacology (Berl) 171:148–155

    Article  CAS  Google Scholar 

  • Deutsch SI, Mastropaolo J, Rosse RB (1998) Neurodevelopmental consequences of early exposure to phencyclidine and related drugs. Clin Neuropharmacol 21:320–332

    CAS  PubMed  Google Scholar 

  • du Bois TM, Newell KA, Han M, Deng C, Huang XF (2009) Perinatal PCP treatment alters the developmental expression of prefrontal and hippocampal muscarinic receptors. Prog Neuropsychopharmacol Biol Psychiatry 33:37–40

    Article  PubMed  CAS  Google Scholar 

  • Enomoto T, Noda Y, Mouri A, Shin EJ, Wang D, Murai R, Hotta K, Furukawa H, Nitta A, Kim HC, Nabeshima T (2005) Long-lasting impairment of associative learning is correlated with a dysfunction of N-methyl-D-aspartate-extracellular signaling-regulated kinase signaling in mice after withdrawal from repeated administration of phencyclidine. Mol Pharmacol 68:1765–1774

    CAS  PubMed  Google Scholar 

  • Fabricius K, Helboe L, Fink-Jensen A, Wortwein G, Steiniger-Brach B, Sotty F (2010) Increased dopaminergic activity in socially isolated rats: an electrophysiological study. Neurosci Lett 482:117–122

    Article  CAS  PubMed  Google Scholar 

  • Fabricius K, Helboe L, Fink-Jensen A, Wortwein G, Steiniger-Brach B (2011) Pharmacological characterization of social isolation-induced hyperactivity. Psychopharmacology (Berl) 215:257–266

    Article  CAS  Google Scholar 

  • Fanselow MS (2000) Contextual fear, gestalt memories, and the hippocampus. Behav Brain Res 110:73–81

    Article  CAS  PubMed  Google Scholar 

  • Fitzgerald ML, Mackie K, Pickel VM (2013) The impact of adolescent social isolation on dopamine D2 and cannabinoid CB1 receptors in the adult rat prefrontal cortex. Neuroscience 235:40–50

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fone KCF, Porkess MV (2008) Behavioural and neurochemical effects of post-weaning social isolation in rodents—relevance to developmental neuropsychiatric disorders. Neurosci Biobehav Rev 32:1087–1102

    Article  CAS  PubMed  Google Scholar 

  • Fulford AJ, Marsden CA (1998) Effect of isolation-rearing on conditioned dopamine release in vivo in the nucleus accumbens of the rat. J Neurochem 70:384–390

    Article  CAS  PubMed  Google Scholar 

  • Gilabert-Juan J, Belles M, Saez AR, Carceller H, Zamarbide S, Molto MD, Nacher J (2013) A “double hit” murine model for schizophrenia shows alterations in the structure and neurochemistry of the medial prefrontal cortex and the hippocampus. Neurobiol Dis 59:126–140

    Article  CAS  PubMed  Google Scholar 

  • 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. Psychopharmacology (Berl) 202:287–293

    Article  CAS  Google Scholar 

  • 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 53:119–127

    Article  CAS  PubMed  Google Scholar 

  • Gresack JE, Risbrough VB, Scott CN, Coste S, Stenzel-Poore M, Geyer MA, Powell SB (2010) Isolation rearing-induced deficits in contextual fear learning do not require CRF(2) receptors. Behav Brain Res 209:80–84

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hall FS, Wilkinson LS, Humby T, Inglis W, Kendall DA, Marsden CA, Robbins TW (1998) Isolation rearing in rats: pre- and postsynaptic changes in striatal dopaminergic systems. Pharmacol Biochem Behav 59:859–872

    Article  CAS  PubMed  Google Scholar 

  • Harte MK, Powell SB, Swerdlow NR, Geyer MA, Reynolds GP (2007) Deficits in parvalbumin and calbindin immunoreactive cells in the hippocampus of isolation reared rats. J Neural Transm 114:893–898

    Article  CAS  PubMed  Google Scholar 

  • Harvey PD, McClure MM (2006) Pharmacological approaches to the management of cognitive dysfunction in schizophrenia. Drugs 66:1465–1473

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Hawken ER, Delva NJ, Beninger RJ (2013) Increased drinking following social isolation rearing: implications for polydipsia associated with schizophrenia. PLoS One 8:e56105

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hemsley DR (2005) The development of a cognitive model of schizophrenia: placing it in context. Neurosci Biobehav Rev 29:977–988

    Article  PubMed  Google Scholar 

  • Herbener ES (2009) Impairment in long-term retention of preference conditioning in schizophrenia. Biol Psychiatry 65:1086–1090

    Article  PubMed Central  PubMed  Google Scholar 

  • Hewitt KN, Shah YB, Prior MJ, Morris PG, Hollis CP, Fone KC, Marsden CA (2005) Behavioural and pharmacological magnetic resonance imaging assessment of the effects of methylphenidate in a potential new rat model of attention deficit hyperactivity disorder. Psychopharmacology (Berl) 180:716–723

    Article  CAS  Google Scholar 

  • Hickey AJ, Reynolds JN, Beninger RJ (2012) Post-weaning social isolation and subchronic NMDA glutamate receptor blockade: effects on locomotor activity and GABA signaling in the rat suggest independent mechanisms. Pharmacol Biochem Behav 101:231–238

    Article  CAS  PubMed  Google Scholar 

  • Horiguchi M, Huang M, Meltzer HY (2011) The role of 5-hydroxytryptamine 7 receptors in the phencyclidine-induced novel object recognition deficit in rats. J Pharmacol Exp Ther 338:605–614

    Article  CAS  PubMed  Google Scholar 

  • Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull 35:549–562

    Article  PubMed Central  PubMed  Google Scholar 

  • Jentsch JD, Tran A, Le D, Youngren KD, Roth RH (1997) Subchronic phencyclidine administration reduces mesoprefrontal dopamine utilization and impairs prefrontal cortical-dependent cognition in the rat. Neuropsychopharmacology 17:92–99

    Article  CAS  PubMed  Google Scholar 

  • Jentsch JD, Taylor JR, Roth RH (1998) Subchronic phencyclidine administration increases mesolimbic dopaminergic system responsivity and augments stress- and psychostimulant-induced hyperlocomotion. Neuropsychopharmacology 19:105–113

    Article  CAS  PubMed  Google Scholar 

  • Jones GH, Hernandez TD, Kendall DA, Marsden CA, Robbins TW (1992) Dopaminergic and serotonergic function following isolation rearing in rats: study of behavioural responses and postmortem and in vivo neurochemistry. Pharmacol Biochem Behav 43:17–35

    Article  CAS  PubMed  Google Scholar 

  • Jones CA, Brown AM, Auer DP, Fone KC (2011) The mGluR2/3 agonist LY379268 reverses post-weaning social isolation-induced recognition memory deficits in the rat. Psychopharmacology (Berl) 214:269–283

    Article  CAS  Google Scholar 

  • Kaalund SS, Riise J, Broberg BV, Fabricius K, Karlsen AS, Secher T, Plath N, Pakkenberg B (2013) Differential expression of parvalbumin in neonatal phencyclidine-treated rats and socially isolated rats. J Neurochem 124:548–557

    Article  CAS  PubMed  Google Scholar 

  • Keefe RS (2007) Cognitive deficits in patients with schizophrenia: effects and treatment. J Clin Psychiatry 68(Suppl 14):8–13

    PubMed  Google Scholar 

  • King MV, Sleight AJ, Woolley ML, Topham IA, Marsden CA, Fone KC (2004) 5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation—an effect sensitive to NMDA receptor antagonism. Neuropharmacology 47:195–204

    Article  CAS  PubMed  Google Scholar 

  • King MV, Seeman P, Marsden CA, Fone KC (2009) Increased dopamine D2High receptors in rats reared in social isolation. Synapse 63:476–483

    Article  CAS  PubMed  Google Scholar 

  • Konradi C, Yang CK, Zimmerman EI, Lohmann KM, Gresch P, Pantazopoulos H, Berretta S, Heckers S (2011) Hippocampal interneurons are abnormal in schizophrenia. Schizophr Res 131:165–173

    Article  PubMed Central  PubMed  Google Scholar 

  • Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214

    Article  CAS  PubMed  Google Scholar 

  • Li M, He W, Chen J (2011) Time course of prepulse inhibition disruption induced by dopamine agonists and NMDA antagonists: effects of drug administration regimen. Pharmacol Biochem Behav 99:509–518

    Article  CAS  PubMed  Google Scholar 

  • Lim AL, Taylor DA, Malone DT (2011) Isolation rearing in rats: effect on expression of synaptic, myelin and GABA-related immunoreactivity and its utility for drug screening via the subchronic parenteral route. Brain Res 1381:52–65

    Article  CAS  PubMed  Google Scholar 

  • Liu F, Zou X, Sadovova N, Zhang X, Shi L, Guo L, Qian F, Wen Z, Patterson TA, Hanig JP, Paule MG, Slikker W Jr, Wang C (2010) Changes in gene expression after phencyclidine administration in developing rats: a potential animal model for schizophrenia. Int J Dev Neurosci 29:351–358

    Article  PubMed  CAS  Google Scholar 

  • Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, Breier A (1997) Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 17:141–150

    Article  CAS  PubMed  Google Scholar 

  • Mandillo S, Rinaldi A, Oliverio A, Mele A (2003) Repeated administration of phencyclidine, amphetamine and MK-801 selectively impairs spatial learning in mice: a possible model of psychotomimetic drug-induced cognitive deficits. Behav Pharmacol 14:533–544

    Article  CAS  PubMed  Google Scholar 

  • Maren S (2001) Neurobiology of Pavlovian fear conditioning. Annu Rev Neurosci 24:897–931

    Article  CAS  PubMed  Google Scholar 

  • Maren S, Fanselow MS (1997) Electrolytic lesions of the fimbria/fornix, dorsal hippocampus, or entorhinal cortex produce anterograde deficits in contextual fear conditioning in rats. Neurobiol Learn Mem 67:142–149

    Article  CAS  PubMed  Google Scholar 

  • McIntosh AL, Ballard TM, Steward LJ, Moran PM, Fone KC (2013) The atypical antipsychotic risperidone reverses the recognition memory deficits induced by post-weaning social isolation in rats. Psychopharmacology (Berl) 228:31–42

    Article  CAS  Google Scholar 

  • McLean S, Grayson B, Harris M, Protheroe C, Woolley M, Neill J (2010a) Isolation rearing impairs novel object recognition and attentional set shifting performance in female rats. J Psychopharmacol 24:57–63

    Article  PubMed  Google Scholar 

  • McLean SL, Neill JC, Idris NF, Marston HM, Wong EH, Shahid M (2010b) Effects of asenapine, olanzapine, and risperidone on psychotomimetic-induced reversal-learning deficits in the rat. Behav Brain Res 214:240–247

    Article  CAS  PubMed  Google Scholar 

  • Meffre J, Chaumont-Dubel S, Mannoury la Cour C, Loiseau F, Watson DJ, Dekeyne A, Seveno M, Rivet JM, Gaven F, Deleris P, Herve D, Fone KC, Bockaert J, Millan MJ, Marin P (2012) 5-HT(6) receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia. EMBO Mol Med 4:1043–1056

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Meng Q, Li N, Han X, Shao F, Wang W (2010) Peri-adolescence isolation rearing alters social behavior and nociception in rats. Neurosci Lett 480:25–29

    Article  CAS  PubMed  Google Scholar 

  • Millan MJ, Agid Y, Brune M, Bullmore ET, Carter CS, Clayton NS, Connor R, Davis S, Deakin B, DeRubeis RJ, Dubois B, Geyer MA, Goodwin GM, Gorwood P, Jay TM, Joels M, Mansuy IM, Meyer-Lindenberg A, Murphy D, Rolls E, Saletu B, Spedding M, Sweeney J, Whittington M, Young LJ (2012) Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov 11:141–168

    Article  CAS  PubMed  Google Scholar 

  • Nagai T, Murai R, Matsui K, Kamei H, Noda Y, Furukawa H, Nabeshima T (2009) Aripiprazole ameliorates phencyclidine-induced impairment of recognition memory through dopamine D1 and serotonin 5-HT1A receptors. Psychopharmacology (Berl) 202:315–328

    Article  CAS  Google Scholar 

  • Nakatani-Pawlak A, Yamaguchi K, Tatsumi Y, Mizoguchi H, Yoneda Y (2009) Neonatal phencyclidine treatment in mice induces behavioral, histological and neurochemical abnormalities in adulthood. Biol Pharm Bull 32:1576–1583

    Article  CAS  PubMed  Google Scholar 

  • Napolitano A, Shah K, Schubert MI, Porkess V, Fone KC, Auer DP (2013) In vivo neurometabolic profiling to characterize the effects of social isolation and ketamine-induced NMDA antagonism: a rodent study at 7.0 T. Schizophr Bull. doi:10.1093/schbul/sbt067

  • Nestler EJ, Hyman SE (2010) Animal models of neuropsychiatric disorders. Nat Neurosci 13:1161–1169

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • NICE (2009) Schizophrenia: core interventions in the treatment and management of schizophrenia in adults in primary and secondary care. National Institute for Health and Clinical Excellence Clinical Guidelines. NICE, London, pp 1-41

  • Owen F, Cross AJ, Crow TJ, Longden A, Poulter M, Riley GJ (1978) Increased dopamine-receptor sensitivity in schizophrenia. Lancet 2:223–226

    Article  CAS  PubMed  Google Scholar 

  • Powell SB, Swerdlow NR, Pitcher LK, Geyer MA (2002) Isolation rearing-induced deficits in prepulse inhibition and locomotor habituation are not potentiated by water deprivation. Physiol Behav 77:55–64

    Article  CAS  PubMed  Google Scholar 

  • Powell SB, Zhou X, Geyer MA (2009) Prepulse inhibition and genetic mouse models of schizophrenia. Behav Brain Res 204:282–294

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Quan MN, Tian YT, Xu KH, Zhang T, Yang Z (2010) Post weaning social isolation influences spatial cognition, prefrontal cortical synaptic plasticity and hippocampal potassium ion channels in Wistar rats. Neuroscience 169:214–222

    Article  CAS  PubMed  Google Scholar 

  • Radonjic NV, Jakovcevski I, Bumbasirevic V, Petronijevic ND (2013) Perinatal phencyclidine administration decreases the density of cortical interneurons and increases the expression of neuregulin-1. Psychopharmacology (Berl) 227:673–683

    Article  CAS  Google Scholar 

  • Redrobe JP, Elster L, Frederiksen K, Bundgaard C, de Jong IE, Smith GP, Bruun AT, Larsen PH, Didriksen M (2012) Negative modulation of GABAA alpha5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats. Psychopharmacology (Berl) 221:451–468

    Article  CAS  Google Scholar 

  • Rodefer JS, Murphy ER, Baxter MG (2005) PDE10A inhibition reverses subchronic PCP-induced deficits in attentional set-shifting in rats. Eur J Neurosci 21:1070–1076

    Article  PubMed  Google Scholar 

  • Roseman AS, McGregor C, Thornton JE (2012) Estradiol attenuates the cognitive deficits in the novel object recognition task induced by sub-chronic phencyclidine in ovariectomized rats. Behav Brain Res 233:105–112

    Article  CAS  PubMed  Google Scholar 

  • Rung JP, Carlsson A, Ryden Markinhuhta K, Carlsson ML (2005) (+)-MK-801 induced social withdrawal in rats; a model for negative symptoms of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 29:827–832

    Article  CAS  PubMed  Google Scholar 

  • Rushe TM, Woodruff PW, Murray RM, Morris RG (1999) Episodic memory and learning in patients with chronic schizophrenia. Schizophr Res 35:85–96

    Article  CAS  PubMed  Google Scholar 

  • Sabbagh JJ, Heaney CF, Bolton MM, Murtishaw AS, Kinney JW (2012) Examination of ketamine-induced deficits in sensorimotor gating and spatial learning. Physiol Behav 107:355–363

    Article  CAS  PubMed  Google Scholar 

  • Schafe GE, Atkins CM, Swank MW, Bauer EP, Sweatt JD, LeDoux JE (2000) Activation of ERK/MAP kinase in the amygdala is required for memory consolidation of pavlovian fear conditioning. J Neurosci 20:8177–8187

    CAS  PubMed  Google Scholar 

  • Schrijver NC, Bahr NI, Weiss IC, Wurbel H (2002) Dissociable effects of isolation rearing and environmental enrichment on exploration, spatial learning and HPA activity in adult rats. Pharmacol Biochem Behav 73:209–224

    Article  CAS  PubMed  Google Scholar 

  • Schubert MI, Porkess MV, Dashdorj N, Fone KC, Auer DP (2009) Effects of social isolation rearing on the limbic brain: a combined behavioral and magnetic resonance imaging volumetry study in rats. Neuroscience 159:21–30

    Article  CAS  PubMed  Google Scholar 

  • Seeman P (2011) All roads to schizophrenia lead to dopamine supersensitivity and elevated dopamine D2(high) receptors. CNS Neurosci Ther 17:118–132

    Article  CAS  PubMed  Google Scholar 

  • Sestito RS, Trindade LB, de Souza RG, Kerbauy LN, Iyomasa MM, Rosa ML (2011) Effect of isolation rearing on the expression of AMPA glutamate receptors in the hippocampal formation. J Psychopharmacol 25:1720–1729

    Article  CAS  PubMed  Google Scholar 

  • Sharp FR, Tomitaka M, Bernaudin M, Tomitaka S (2001) Psychosis: pathological activation of limbic thalamocortical circuits by psychomimetics and schizophrenia? Trends Neurosci 24:330–334

    Article  CAS  PubMed  Google Scholar 

  • Sigurdsson T, Doyere V, Cain CK, LeDoux JE (2007) Long-term potentiation in the amygdala: a cellular mechanism of fear learning and memory. Neuropharmacology 52:215–227

    Article  CAS  PubMed  Google Scholar 

  • Sircar R (2003) Postnatal phencyclidine-induced deficit in adult water maze performance is associated with N-methyl-D-aspartate receptor upregulation. Int J Dev Neurosci 21:159–167

    Article  CAS  PubMed  Google Scholar 

  • Snigdha S, Neill JC, McLean SL, Shemar GK, Cruise L, Shahid M, Henry B (2011) Phencyclidine (PCP)-induced disruption in cognitive performance is gender-specific and associated with a reduction in brain-derived neurotrophic factor (BDNF) in specific regions of the female rat brain. J Mol Neurosci 43:337–345

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Swerdlow NR, Braff DL, Masten VL, Geyer MA (1990) Schizophrenic-like sensorimotor gating abnormalities in rats following dopamine infusion into the nucleus accumbens. Psychopharmacology (Berl) 101:414–420

    Article  CAS  Google Scholar 

  • Thomson DM, McVie A, Morris BJ, Pratt JA (2010) Dissociation of acute and chronic intermittent phencyclidine-induced performance deficits in the 5-choice serial reaction time task: influence of clozapine. Psychopharmacology (Berl) 213:681–695

    Article  CAS  Google Scholar 

  • Toua C, Brand L, Moller M, Emsley RA, Harvey BH (2010) The effects of sub-chronic clozapine and haloperidol administration on isolation rearing induced changes in frontal cortical N-methyl-D-aspartate and D1 receptor binding in rats. Neuroscience 165:492–499

    Article  CAS  PubMed  Google Scholar 

  • Uehara T, Sumiyoshi T, Seo T, Itoh H, Matsuoka T, Suzuki M, Kurachi M (2009) Long-term effects of neonatal MK-801 treatment on prepulse inhibition in young adult rats. Psychopharmacology (Berl) 206:623–630

    Article  CAS  Google Scholar 

  • Vale AL, Montgomery AM (1997) Social interaction: responses to chlordiazepoxide and the loss of isolation-reared effects with paired-housing. Psychopharmacology (Berl) 133:127–132

    Article  CAS  Google Scholar 

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

    Article  PubMed Central  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Wang CZ, Yang SF, Xia Y, Johnson KM (2008) Postnatal phencyclidine administration selectively reduces adult cortical parvalbumin-containing interneurons. Neuropsychopharmacology 33:2442–2455

    Article  CAS  PubMed  Google Scholar 

  • Watson DJ, Loiseau F, Ingallinesi M, Millan MJ, Marsden CA, Fone KC (2012a) Selective blockade of dopamine D3 receptors enhances while D2 receptor antagonism impairs social novelty discrimination and novel object recognition in rats: a key role for the prefrontal cortex. Neuropsychopharmacology 37:770–786

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Watson DJ, Marsden CA, Millan MJ, Fone KC (2012b) Blockade of dopamine D(3) but not D(2) receptors reverses the novel object discrimination impairment produced by post-weaning social isolation: implications for schizophrenia and its treatment. Int J Neuropsychopharmacol 15:471–484

    Article  CAS  PubMed  Google Scholar 

  • Weiss IC, Feldon J (2001) Environmental animal models for sensorimotor gating deficiencies in schizophrenia: a review. Psychopharmacology (Berl) 156:305–326

    Article  CAS  Google Scholar 

  • Weiss IC, Domeney AM, Heidbreder CA, Moreau JL, Feldon J (2001) Early social isolation, but not maternal separation, affects behavioral sensitization to amphetamine in male and female adult rats. Pharmacol Biochem Behav 70:397–409

    Article  CAS  PubMed  Google Scholar 

  • Weiss IC, Pryce CR, Jongen-Relo AL, Nanz-Bahr NI, Feldon J (2004) Effect of social isolation on stress-related behavioural and neuroendocrine state in the rat. Behav Brain Res 152:279–295

    Article  CAS  PubMed  Google Scholar 

  • Wiley JL, Buhler KG, Lavecchia KL, Johnson KM (2003) Pharmacological challenge reveals long-term effects of perinatal phencyclidine on delayed spatial alternation in rats. Prog Neuropsychopharmacol Biol Psychiatry 27:867–873

    Article  CAS  PubMed  Google Scholar 

  • Wilkinson LS, Killcross SS, Humby T, Hall FS, Geyer MA, Robbins TW (1994) Social isolation in the rat produces developmentally specific deficits in prepulse inhibition of the acoustic startle response without disrupting latent inhibition. Neuropsychopharmacology 10:61–72

    Article  CAS  PubMed  Google Scholar 

  • Wongwitdecha N, Marsden CA (1996) Social isolation increases aggressive behaviour and alters the effects of diazepam in the rat social interaction test. Behav Brain Res 75:27–32

    Article  CAS  PubMed  Google Scholar 

  • Woods S, Clarke NN, Layfield R, Fone KC (2012) 5-HT(6) receptor agonists and antagonists enhance learning and memory in a conditioned emotion response paradigm by modulation of cholinergic and glutamatergic mechanisms. Br J Pharmacol 167:436–449

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang ZJ, Reynolds GP (2002) A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia. Schizophr Res 55:1–10

    Article  PubMed  Google Scholar 

  • Zhang R, He J, Zhu S, Zhang H, Wang H, Adilijiang A, Kong L, Wang J, Kong J, Tan Q, Li XM (2012) Myelination deficit in a phencyclidine-induced neurodevelopmental model of schizophrenia. Brain Res 1469:136–143

    Article  CAS  PubMed  Google Scholar 

  • Zhao X, Sun L, Jia H, Meng Q, Wu S, Li N, He S (2009) Isolation rearing induces social and emotional function abnormalities and alters glutamate and neurodevelopment-related gene expression in rats. Prog Neuropsychopharmacol Biol Psychiatry 33:1173–1177

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Mr Ian Topham for technical assistance. This work was supported by the BBSRC (to PLRG) and the University of Nottingham.

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The authors declare no conflicts of interest.

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  1. School of Life Sciences, Medical School, Queen’s Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK

    Philip LR Gaskin, Stephen PH Alexander & Kevin CF Fone

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  1. Philip LR Gaskin
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  2. Stephen PH Alexander
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  3. Kevin CF Fone
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Correspondence to Kevin CF Fone.

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Gaskin, P.L., Alexander, S.P. & Fone, K.C. Neonatal phencyclidine administration and post-weaning social isolation as a dual-hit model of ‘schizophrenia-like’ behaviour in the rat. Psychopharmacology 231, 2533–2545 (2014). https://doi.org/10.1007/s00213-013-3424-y

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  • DOI: https://doi.org/10.1007/s00213-013-3424-y

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