Skip to main content
Log in

Behavioral Analysis of the Consequences of Chronic Blockade of NMDA-Type Glutamate Receptors in the Early Postnatal Period in Rats

  • Published:
Neuroscience and Behavioral Physiology Aims and scope Submit manuscript

Abstract

Considering data on the possible glutamatergic nature of the pathogenesis of schizophrenia, we attempted to model cognitive derangements in animals by chronic blockade of NMDA glutamate receptors. Wistar rats received daily s.c. injections of the non-competitive NMDA glutamate receptor antagonist MK-801 (0.05 mg/kg) from days 7 to day 49 of postnatal life. One day after the antagonist injections given on days 27 and 28 of life, animals of the experimental group showed decreased levels of spontaneous movement and orientational-investigative activity as compared with controls, where there was no change in the elevated locomotor reaction produced in response to the direct action of MK-801. These animals showed decreases in the level of anxiety (on day 40 of life) and derangement in spatial learning with food reinforcement (days 50–54 of life). It is suggested that early neonatal blockade of NMDA glutamate receptors leads to the development in animals of disturbances to situational perception and assessment of incoming sensory information.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

REFERENCES

  1. V. G. Bashkatova and K. S. Raevskii, “Nitric oxide in the mechanisms of brain damage induced by the neurotoxic actions of glutamate,” Biokhimiya, 63, No. 7, 1020 (1998).

    Google Scholar 

  2. Methods for Studying the Embryotoxic Actions of Pharmacological Substances and Their Effects on Reproductive Function [in Russian], Pharmacology Committee, Directorate for New Therapeutic Agents and Medical Technologies, Ministry of Health of the USSR, Moscow (1986).

  3. K. S. Raevskii, V. G. Bashkatova, and A. F. Vanin, “The role of nitric oxide in glutamatergic brain pathology,” Vestn. Ross. Akad. Med. Nauk., No. 4, 11 (2000).

  4. N. B. Saul'skaya and A. I. Gorbachevskaya, “Conditioned reflex selection of dopamine in the nucleus accumbens after lesioning of the hippocampal formation in rats,” Ros. Fiziol. Zh. im. I. M. Sechenova, 83, No. 1-2, 76 (1997).

    Google Scholar 

  5. M. Ahlander, I. Misane, P. A. Schott, and S. O. Ogren, “A behavioral analysis of the spatial learning deficit induced by the NMDA receptor antagonist MK-801 (dizocilpine) in the rat,” Neuropsychopharmacology, 21, 414 (1999).

    Google Scholar 

  6. K. M. Boje and P. Skolnick, “Ontogeny of glycine-enhanced [3H]MK-801 binding to N-methyl-D-aspartate receptor-coupled ion channels,” Brain Res. Dev. Brain Res., No. 65, 51 (1992).

    Google Scholar 

  7. G. Brosnan-Watters, D. F. Wozniak, A. Nardi, and J. W. Olney, “Parallel recovery of MK-801-induced spatial learning impairment and neuronal injury in male mice,” Pharmacol. Biochem. Behav., 62, 111 (1999).

    Google Scholar 

  8. D. P. Cain, “Testing the NMDA, long-term potentiation, and cholinergic hypotheses of spatial learning,” Neurosci. Biobehav. Rev., 22, 181 (1998).

    Google Scholar 

  9. D. P. Cain, D. Saucier, and F. Boon, “Testing hypotheses of spatial learning: the role of NMDA receptors and NMDA-mediated long-term potentiation,” Behav. Brain Res., 84, 179 (1997).

    Google Scholar 

  10. Z. Caramanos and M. L. Shapiro, “Spatial memory and N-methyl-D-aspartate receptor antagonists APV and MK-801: memory impairments depend on familiarity with the environment, drug dose, and training duration,” Behav. Neurosci., 108, 30 (1994).

    Google Scholar 

  11. A. Carlsson, L. O. Hansson, N. Waters, and M. L. Carlsson, “Neurotransmitter aberrations in schizophrenia: new perspectives and therapeutic implications,” Life Sci., 61, No. 2, 75 (1997).

    Google Scholar 

  12. J. T. Coyle, “The glutamatergic dysfunction hypothesis for schizophrenia,” Harv. Rev. Psychiatry, 3, 241 (1997).

    Google Scholar 

  13. F. Facchinetti, E. Ciani, R. Dall'Olio, et al., “Structural, neurochemical and behavioural consequences of neonatal blockade of NMDA receptor through chronic treatment with CGP39551 or MK-801,” Dev. Brain Res., 74, 219 (1993).

    Google Scholar 

  14. J. A. Gorter, M. Veerman, and M. Mirmiran, “Hippocampal neuronal responsiveness to NMDA agonists and antagonists in the adult rat neonatally treated with MK-801,” Brain Res., 572, 176 (1992).

    Google Scholar 

  15. J. A. Gorter and J. P. de Bruin, “Chronic neonatal MK-801 treatment results in an impairment of spatial learning in the adult rat,” Brain Res., No. 580, 12 (1992).

    Google Scholar 

  16. G. S. Griesbach and A. Amsel, “Immediate and long-term effects of neonatal MK-801 treatment on nonspatial learning,” Proc. Natl. Acad. Sci. USA, 95, 11435 (1998).

    Google Scholar 

  17. V. Heale and C. Harley, “MK-801 and AP5 impair acquisition, but not retention, of the Morris milk maze,” Pharmacol. Biochem. Behav., 36, 145 (1990).

    Google Scholar 

  18. R. L. McLamb, L. R. Williams, K. P. Nanry, et al., “MK-801 impedes the acquisition of a spatial memory task in rats,” Pharmacol. Biochem. Behav., 37, 41 (1990).

    Google Scholar 

  19. A. R. Mohn, R. R. Gainetdinov, M. G. Caron, and B. H. Koller, “Mice with reduced NMDA receptor expression display behaviors related to schizophrenia,” Cell, 98, No. 4, 427 (1999).

    Google Scholar 

  20. D. T Monagham and C. W. Cotman, “Distribution of NMDA sensitive L-[3H]glutamate binding sites in rat brain,” J. Neurosci., 5, 2909 (1985).

    Google Scholar 

  21. S. L. Morgan and T. J. Teyler, “VDCCs and NMDARs underlie two forms of LTP in CA1 hippocampus in vivo,” J. Neurophysiol., 82, No. 2, 736 (1999).

    Google Scholar 

  22. C. M. Norris and T. C. Foster, “MK-801 improves retention in aged rats: implications for altered neural plasticity in age-related memory deficits,” Neurobiol. Learn. Mem., 71, 194 (1999).

    Google Scholar 

  23. M. Ohno and S. Watanabe, “Interactive processing between glutamatergic and cholinergic systems involved in inhibitory avoidance learning of rats,” Eur. J. Pharmacol., 312, 145 (1996).

    Google Scholar 

  24. C. G. Parsons, W. Danysz, and G. Quack, “Glutamate in CNS disorders as a target for drug development: an update,” Drug News Perspect., 11, No. 9, 523 (1998).

    Google Scholar 

  25. K. Rosenblum, M. Maroun, and G. Richter-Levin, “Frequency-dependent inhibition in the dentate gyrus is attenuated by the NMDA receptor blocker MK-801 at doses that do not yet affect long-term potentiation,” Hippocampus, 9, No. 5, 491 (1999).

    Google Scholar 

  26. S. M. Rothman and J. W. Olney, “Excitotoxicity and the NMDA receptor,” Trends Neurosci., 10, 299 (1987).

    Google Scholar 

  27. R. Sircar, “Developmental maturation of the N-methyl-D-aspartic acid receptor channel complex in postnatal rat brain,” Int. J. Dev. Neurosci., 18, 121 (2000).

    Google Scholar 

  28. S. L. Smith-Roe, K. Sadeghian, and A. E. Kelley, “Spatial learning and performance in the radial arm maze is impaired after N-methyl-D-aspartate (NMDA) receptor blockade in striatal subregions,” Behav. Neurosci., 113, 703 (1999).

    Google Scholar 

  29. D. R. Weinberger, “From neuropathology to neurodevelopment,” Lancet, 26, No. 346(18974), 552 (1995).

    Google Scholar 

  30. A. Wenzel and M. Villa, “NMDA receptor heterogeneity during postnatal development of the rat brain: Differential expression of the NR2A, NR2B, and NR2C subunit proteins,” J. Neurochem., 68, 469 (1997).

    Google Scholar 

  31. I. Q. Whishaw and R. N. Auer, “Immediate and long-lasting effects of MK-801 on motor activity, spatial navigation in a swimming pool, and EEG in the rat,” Psychopharmacology, 98, 500 (1989).

    Google Scholar 

  32. A. M. White and P. J. Best, “The effects of MK-801 in spatial working memory and within-session spatial learning,” Pharmacol. Biochem. Behav., 59, 613 (1998).

    Google Scholar 

  33. D. F. Wozniak, J. W. Olney, L. Kettinger, et al., “Behavioral effects of MK-801 in the rat,” Psychopharmacology, 101, 47 (1990).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Latysheva, N.V., Raevskii, K.S. Behavioral Analysis of the Consequences of Chronic Blockade of NMDA-Type Glutamate Receptors in the Early Postnatal Period in Rats. Neurosci Behav Physiol 33, 123–131 (2003). https://doi.org/10.1023/A:1021761512252

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1021761512252

Keywords

Navigation