, Volume 206, Issue 4, pp 623–630 | Cite as

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

  • Takashi Uehara
  • Tomiki Sumiyoshi
  • Tomonori Seo
  • Hiroko Itoh
  • Tadasu Matsuoka
  • Michio Suzuki
  • Masayoshi Kurachi
Original Investigation



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.


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.


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.


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.


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.


NMDA receptor MK-801 Neonatal Prepulse inhibition Locomotor activity Rat Animal model Schizophrenia 



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).


  1. 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) 192:303–316CrossRefGoogle Scholar
  2. 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 90:569–577PubMedCrossRefGoogle Scholar
  3. 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
  4. 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 4:477–488PubMedCrossRefGoogle Scholar
  5. Braff DL, Grillon C, Geyer MA (1992) Gating and habituation of the startle reflex in schizophrenic patients. Arch Gen Psychiatry 49:206–215PubMedGoogle Scholar
  6. Braff DL, Swerdlow NR, Geyer MA (1999) Symptom correlates of prepulse inhibition deficits in male schizophrenic patients. Am J Psychiatry 156:596–602PubMedGoogle Scholar
  7. 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 26:441–455PubMedCrossRefGoogle Scholar
  8. 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 80:591–596PubMedCrossRefGoogle Scholar
  9. 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 32:1014–1023PubMedCrossRefGoogle Scholar
  10. Graham FK (1975) Presidential Address, 1974. The more or less startling effects of weak prestimulation. Psychophysiology 12:238–248PubMedCrossRefGoogle Scholar
  11. 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 18:1706–1710PubMedCrossRefGoogle Scholar
  12. Hoffman HS, Searle JL (1968) Acoustic and temporal factors in the evocation of startle. J Acoust Soc Am 43:269–282PubMedCrossRefGoogle Scholar
  13. Japha K, Koch M (1999) Picrotoxin in the medial prefrontal cortex impairs sensorimotor gating in rats: reversal by haloperidol. Psychopharmacology (Berl) 144:347–354CrossRefGoogle Scholar
  14. Jentsch JD, Roth RH (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20:201–225PubMedCrossRefGoogle Scholar
  15. 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 254:406–414PubMedCrossRefGoogle Scholar
  16. Krase W, Koch M, Schnitzler HU (1993) Glutamate antagonists in the reticular formation reduce the acoustic startle response. Neuroreport 4:13–16PubMedCrossRefGoogle Scholar
  17. Kurachi M (2003a) Pathogenesis of schizophrenia: part I. Symptomatology, cognitive characteristics and brain morphology. Psychiatry Clin Neurosci 57:3–8PubMedCrossRefGoogle Scholar
  18. Kurachi M (2003b) Pathogenesis of schizophrenia: part II. Temporo-frontal two-step hypothesis. Psychiatry Clin Neurosci 57:9–15PubMedCrossRefGoogle Scholar
  19. Moghaddam B, Jackson ME (2003) Glutamatergic animal models of schizophrenia. Ann N Y Acad Sci 1003:131–137PubMedCrossRefGoogle Scholar
  20. 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) 190:43–49CrossRefGoogle Scholar
  21. Roberts GW (1991) Schizophrenia: a neuropathological perspective. Br J Psychiatry 158:8–17PubMedCrossRefGoogle Scholar
  22. 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 355:5–8PubMedCrossRefGoogle Scholar
  23. 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) 197:457–464CrossRefGoogle Scholar
  24. Siever LJ, Davis KL (2004) The pathophysiology of schizophrenia disorders: perspectives from the spectrum. Am J Psychiatry 161:398–413PubMedCrossRefGoogle Scholar
  25. 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 445:130–136PubMedCrossRefGoogle Scholar
  26. Stefani MR, Moghaddam B (2003) Distinct contributions of glutamate receptor subtypes to cognitive set-shifting abilities in the rat. Ann N Y Acad Sci 1003:464–467PubMedCrossRefGoogle Scholar
  27. Stefani MR, Moghaddam B (2005) Transient N-methyl-d-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia. Biol Psychiatry 57:433–436PubMedCrossRefGoogle Scholar
  28. Stefani MR, Groth K, Moghaddam B (2003) Glutamate receptors in the rat medial prefrontal cortex regulate set-shifting ability. Behav Neurosci 117:728–737PubMedCrossRefGoogle Scholar
  29. 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 364:124–129PubMedCrossRefGoogle Scholar
  30. 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 128:2109–2122PubMedCrossRefGoogle Scholar
  31. 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) 156:194–215CrossRefGoogle Scholar
  32. 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 99:770–780PubMedCrossRefGoogle Scholar
  33. 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 860:77–86PubMedCrossRefGoogle Scholar
  34. 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 989:112–116PubMedCrossRefGoogle Scholar
  35. 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 356:21–24PubMedCrossRefGoogle Scholar
  36. 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 61:391–400PubMedCrossRefGoogle Scholar
  37. 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 8:148–156CrossRefGoogle Scholar
  38. 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 107:535–550PubMedCrossRefGoogle Scholar
  39. 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 153:1370–1379PubMedCrossRefGoogle Scholar
  40. Weinberger DR (1995) Neurodevelopmental perspectives on schizophrenia. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology; the fourth generation of progress. Raven, New York, pp 1171–1183Google Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Takashi Uehara
    • 1
    • 2
    • 3
  • Tomiki Sumiyoshi
    • 1
    • 3
  • Tomonori Seo
    • 1
  • Hiroko Itoh
    • 1
  • Tadasu Matsuoka
    • 1
  • Michio Suzuki
    • 1
    • 3
  • Masayoshi Kurachi
    • 2
    • 3
  1. 1.Department of NeuropsychiatryUniversity of Toyama Graduate School of Medicine and Pharmaceutical SciencesToyamaJapan
  2. 2.Department of Psychiatric Early InterventionUniversity of Toyama Graduate School of Medicine and Pharmaceutical SciencesToyamaJapan
  3. 3.Core Research for Evolutional Science and TechnologyJapan Science and Technology CorporationTokyoJapan

Personalised recommendations