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Long-term effects of neonatal MK-801 treatment on prepulse inhibition in young adult rats

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Abstract

Rationale

Blockade of N-methyl-d-asparate (NMDA) receptors has been shown to produce some of the abnormal behaviors related to symptoms of schizophrenia in rodents and human. Neonatal treatment of rats with non-competitive NMDA antagonists has been shown to induce behavioral abnormality in a later period.

Objectives

The aim of this study was to determine whether brief disruption of NMDA receptor function during a critical stage of development is sufficient to produce sensorimotor-gating deficits in the late adolescence or early adulthood in the rat.

Methods

Male pups received the NMDA receptor blocker MK-801 (0.13 or 0.20 mg/kg), or an equal volume of saline on postnatal day (PD) 7 through 10. The animals were tested twice for prepulse inhibition (PPI) and locomotor activity in pre- (PD 35-38) and post- (PD 56-59) puberty.

Results

Neonatal exposure to both doses MK-801 disrupted PPI in the adolescence and early adulthood. Low-dose MK-801 elicited long-term effects on startle amplitudes, whereas high-dose MK-801 did not. Neither dose of MK-801 showed a significant effect on spontaneous locomotor activity, whereas the high dose attenuated rearing.

Conclusions

The results of this study suggest neonatal exposure to MK-801 disrupted sensorimotor gating in the adolescence and early adulthood stages. These findings indicate that rats transiently exposed to NMDA blockers in neonatal periods are useful for the study of the pathophysiology and treatment of schizophrenia.

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References

  • Abekawa T, Ito K, Nakagawa S, Koyama T (2007) Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats. Psychopharmacology (Berl) 192:303–316

    Article  CAS  Google Scholar 

  • Anastasio NC, Johnson KM (2008) 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  PubMed  CAS  Google Scholar 

  • 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 18:8394–8401

    PubMed  CAS  Google Scholar 

  • Beninger RJ, Jhamandas A, Aujla H, Xue L, Dagnone RV, Boegman RJ, Jhamandas K (2002) Neonatal exposure to the glutamate receptor antagonist MK-801: effects on locomotor activity and pre-pulse inhibition before and after sexual maturity in rats. Neurotox Res 4:477–488

    Article  PubMed  Google Scholar 

  • Braff DL, Grillon C, Geyer MA (1992) Gating and habituation of the startle reflex in schizophrenic patients. Arch Gen Psychiatry 49:206–215

    PubMed  CAS  Google Scholar 

  • Braff DL, Swerdlow NR, Geyer MA (1999) Symptom correlates of prepulse inhibition deficits in male schizophrenic patients. Am J Psychiatry 156:596–602

    PubMed  CAS  Google Scholar 

  • Breese GR, Knapp DJ, Moy SS (2002) Integrative role for serotonergic and glutamatergic receptor mechanisms in the action of NMDA antagonists: potential relationships to antipsychotic drug actions on NMDA antagonist responsiveness. Neurosci Biobehav Rev 26:441–455

    Article  PubMed  CAS  Google Scholar 

  • Bubenikova V, Votava M, Horacek J, Palenicek T, Dockery C (2005) The effect of zotepine, risperidone, clozapine and olanzapine on MK-801-disrupted sensorimotor gating. Pharmacol Biochem Behav 80:591–596

    Article  PubMed  CAS  Google Scholar 

  • Bubenikova-Valesova V, Horacek J, Vrajova M, Hoschl C (2008) Models of schizophrenia in humans and animals based on inhibition of NMDA receptors. Neurosci Biobehav Rev 32:1014–1023

    Article  PubMed  CAS  Google Scholar 

  • Graham FK (1975) Presidential Address, 1974. The more or less startling effects of weak prestimulation. Psychophysiology 12:238–248

    Article  PubMed  CAS  Google Scholar 

  • Harris LW, Sharp T, Gartlon J, Jones DN, Harrison PJ (2003) Long-term behavioural, molecular and morphological effects of neonatal NMDA receptor antagonism. Eur J Neurosci 18:1706–1710

    Article  PubMed  Google Scholar 

  • Hoffman HS, Searle JL (1968) Acoustic and temporal factors in the evocation of startle. J Acoust Soc Am 43:269–282

    Article  PubMed  CAS  Google Scholar 

  • Japha K, Koch M (1999) Picrotoxin in the medial prefrontal cortex impairs sensorimotor gating in rats: reversal by haloperidol. Psychopharmacology (Berl) 144:347–354

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Kawasaki Y, Suzuki M, Nohara S, Hagino H, Takahashi T, Matsui M, Yamashita I, Chitnis XA, McGuire PK, Seto H, Kurachi M (2004) Structural brain differences in patients with schizophrenia and schizotypal disorder demonstrated by voxel-based morphometry. Eur Arch Psychiatry Clin Neurosci 254:406–414

    Article  PubMed  Google Scholar 

  • Krase W, Koch M, Schnitzler HU (1993) Glutamate antagonists in the reticular formation reduce the acoustic startle response. Neuroreport 4:13–16

    Article  PubMed  CAS  Google Scholar 

  • Kurachi M (2003a) Pathogenesis of schizophrenia: part I. Symptomatology, cognitive characteristics and brain morphology. Psychiatry Clin Neurosci 57:3–8

    Article  PubMed  Google Scholar 

  • Kurachi M (2003b) Pathogenesis of schizophrenia: part II. Temporo-frontal two-step hypothesis. Psychiatry Clin Neurosci 57:9–15

    Article  PubMed  Google Scholar 

  • Moghaddam B, Jackson ME (2003) Glutamatergic animal models of schizophrenia. Ann N Y Acad Sci 1003:131–137

    Article  PubMed  CAS  Google Scholar 

  • Rasmussen BA, O'Neil J, Manaye KF, Perry DC, Tizabi Y (2007) Long-term effects of developmental PCP administration on sensorimotor gating in male and female rats. Psychopharmacology (Berl) 190:43–49

    Article  CAS  Google Scholar 

  • Roberts GW (1991) Schizophrenia: a neuropathological perspective. Br J Psychiatry 158:8–17

    Article  PubMed  CAS  Google Scholar 

  • Schwabe K, Koch M (2004) Role of the medial prefrontal cortex in N-methyl-d-aspartate receptor antagonist induced sensorimotor gating deficit in rats. Neurosci Lett 355:5–8

    Article  PubMed  CAS  Google Scholar 

  • Seo T, Sumiyoshi T, Tsunoda M, Tanaka K, Uehara T, Matsuoka T, Itoh H, Kurachi M (2008) T-817MA, a novel neurotrophic compound, ameliorates phencyclidine-induced disruption of sensorimotor gating. Psychopharmacology (Berl) 197:457–464

    Article  CAS  Google Scholar 

  • Siever LJ, Davis KL (2004) The pathophysiology of schizophrenia disorders: perspectives from the spectrum. Am J Psychiatry 161:398–413

    Article  PubMed  Google Scholar 

  • Spiera RF, Davis M (1988) Excitatory amino acid antagonists depress acoustic startle after infusion into the ventral nucleus of the lateral lemniscus or paralemniscal zone. Brain Res 445:130–136

    Article  PubMed  CAS  Google Scholar 

  • Stefani MR, Moghaddam B (2003) Distinct contributions of glutamate receptor subtypes to cognitive set-shifting abilities in the rat. Ann N Y Acad Sci 1003:464–467

    Article  PubMed  Google Scholar 

  • Stefani MR, Moghaddam B (2005) Transient N-methyl-d-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia. Biol Psychiatry 57:433–436

    Article  PubMed  CAS  Google Scholar 

  • Stefani MR, Groth K, Moghaddam B (2003) Glutamate receptors in the rat medial prefrontal cortex regulate set-shifting ability. Behav Neurosci 117:728–737

    Article  PubMed  CAS  Google Scholar 

  • Sumiyoshi T, Tsunoda M, Uehara T, Tanaka K, Itoh H, Sumiyoshi C, Kurachi M (2004) Enhanced locomotor activity in rats with excitotoxic lesions of the entorhinal cortex, a neurodevelopmental animal model of schizophrenia: behavioral and in vivo microdialysis studies. Neurosci Lett 364:124–129

    Article  PubMed  CAS  Google Scholar 

  • Suzuki M, Zhou SY, Takahashi T, Hagino H, Kawasaki Y, Niu L, Matsui M, Seto H, Kurachi M (2005) Differential contributions of prefrontal and temporolimbic pathology to mechanisms of psychosis. Brain 128:2109–2122

    Article  PubMed  Google Scholar 

  • Swerdlow NR, Geyer MA, Braff DL (2001) Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology (Berl) 156:194–215

    Article  CAS  Google Scholar 

  • Takahashi M, Kakita A, Futamura T, Watanabe Y, Mizuno M, Sakimura K, Castren E, Nabeshima T, Someya T, Nawa H (2006) Sustained brain-derived neurotrophic factor up-regulation and sensorimotor gating abnormality induced by postnatal exposure to phencyclidine: comparison with adult treatment. J Neurochem 99:770–780

    Article  PubMed  CAS  Google Scholar 

  • Uehara T, Tanii Y, Sumiyoshi T, Kurachi M (2000) Neonatal lesions of the left entorhinal cortex affect dopamine metabolism in the rat brain. Brain Res 860:77–86

    Article  PubMed  CAS  Google Scholar 

  • Uehara T, Sumiyoshi T, Itoh H, Kurachi M (2003) Modulation of stress-induced dopamine release by excitotoxic damage of the entorhinal cortex in the rat. Brain Res 989:112–116

    Article  PubMed  CAS  Google Scholar 

  • Uehara T, Sumiyoshi T, Itoh H, Kurachi M (2004) Inhibition of dopamine synthesis with alpha-methyl-p-tyrosine abolishes the enhancement of methamphetamine-induced extracellular dopamine levels in the amygdala of rats with excitotoxic lesions of the entorhinal cortex. Neurosci Lett 356:21–24

    Article  PubMed  CAS  Google Scholar 

  • Uehara T, Sumiyoshi T, Matsuoka T, Itoh H, Kurachi M (2007) Effect of prefrontal cortex inactivation on behavioral and neurochemical abnormalities in rats with excitotoxic lesions of the entorhinal cortex. Synapse 61:391–400

    Article  PubMed  CAS  Google Scholar 

  • Varty GB, Higgins GA (1994) Differences between three rat strains in sensitivity to prepulse inhibition of an acoustic startle response: influence of apomorphine and phencyclidine pretreatment. J Psychopharmacol 8:148–156

    Article  CAS  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  PubMed  CAS  Google Scholar 

  • Wedzony K, Fijal K, Mackowiak M, Chocyk A, Zajaczkowski W (2008) Impact of postnatal blockade of N-methyl-d-aspartate receptors on rat behavior: a search for a new developmental model of schizophrenia. Neuroscience 153:1370–1379

    Article  PubMed  CAS  Google Scholar 

  • Weinberger DR (1995) Neurodevelopmental perspectives on schizophrenia. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology; the fourth generation of progress. Raven, New York, pp 1171–1183

    Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge the insightful comments and criticism by Dr. M. Tsunoda and Dr. K. Tanaka.

This study was supported by a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science (No. 20591363).

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Authors and Affiliations

  1. Department of Neuropsychiatry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, 2630 Sugitani, Toyama, 930-0194, Japan

    Takashi Uehara, Tomiki Sumiyoshi, Tomonori Seo, Hiroko Itoh, Tadasu Matsuoka & Michio Suzuki

  2. Department of Psychiatric Early Intervention, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan

    Takashi Uehara & Masayoshi Kurachi

  3. Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo, Japan

    Takashi Uehara, Tomiki Sumiyoshi, Michio Suzuki & Masayoshi Kurachi

Authors
  1. Takashi Uehara
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  2. Tomiki Sumiyoshi
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  3. Tomonori Seo
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  4. Hiroko Itoh
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  5. Tadasu Matsuoka
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  6. Michio Suzuki
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  7. Masayoshi Kurachi
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Correspondence to Takashi Uehara.

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Uehara, T., Sumiyoshi, T., Seo, T. et al. Long-term effects of neonatal MK-801 treatment on prepulse inhibition in young adult rats. Psychopharmacology 206, 623–630 (2009). https://doi.org/10.1007/s00213-009-1527-2

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  • DOI: https://doi.org/10.1007/s00213-009-1527-2

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