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.
Similar content being viewed by others
REFERENCES
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).
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).
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).
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).
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).
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).
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).
D. P. Cain, “Testing the NMDA, long-term potentiation, and cholinergic hypotheses of spatial learning,” Neurosci. Biobehav. Rev., 22, 181 (1998).
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).
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).
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).
J. T. Coyle, “The glutamatergic dysfunction hypothesis for schizophrenia,” Harv. Rev. Psychiatry, 3, 241 (1997).
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).
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).
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).
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).
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).
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).
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).
D. T Monagham and C. W. Cotman, “Distribution of NMDA sensitive L-[3H]glutamate binding sites in rat brain,” J. Neurosci., 5, 2909 (1985).
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).
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).
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).
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).
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).
S. M. Rothman and J. W. Olney, “Excitotoxicity and the NMDA receptor,” Trends Neurosci., 10, 299 (1987).
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).
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).
D. R. Weinberger, “From neuropathology to neurodevelopment,” Lancet, 26, No. 346(18974), 552 (1995).
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).
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).
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).
D. F. Wozniak, J. W. Olney, L. Kettinger, et al., “Behavioral effects of MK-801 in the rat,” Psychopharmacology, 101, 47 (1990).
Author information
Authors and Affiliations
Rights 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
Issue Date:
DOI: https://doi.org/10.1023/A:1021761512252