Summary
The effects of NMDA receptor antagonism on learning and memory were investigated using competitive (DL-2-amino-7-phosphonoheptanoate, AP7) and non-competitive (MK 801) blockers in three different learning tasks. Administration (i.p.) of drugs prior to training resulted in impaired learning performance in the place-navigation and dark-avoidance paradigms, and improved performance in the step-down passive avoidance task; however, using this treatment protocol, the possibility of druginduced non-mnemonic effects modifying learning performance could not be excluded. Drug administration immediately post-trial had no effect in the place-navigation paradigm, and improved retention performance in the dark-avoidance and step-down avoidance tasks. The similar results obtained with both types of antagonist indicate that the observed effects are indeed due to NMDA receptor blockade, and hence that such blockade modifies learning in a task-dependent manner. Exclusion of non-mnemonic effects by using the post-trial treatment regime demonstrates that NMDA antagonists facilitate learning of passive avoidance tasks.
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Aggleton JP, Hunt PR, Rawlins JNP (1986) The effects of hippocampal lesions upon spatial and non-spatial tests of working memory. Behav Brain Res 19: 133–146
Barnes CA (1988) Spatial learning and memory processes: the search for their neurobiological mechanisms in the rat. Trends Neurosci 11: 163–169
Cahusac PMB, Evans RH, Hill RG, Rodriquez RE, Smith DAS (1984) The behavioural effects of an N-methyl-aspartate receptor antagonist following application to the lumbar spinal cord of conscious rats. Neuropharmacology 23: 719–724
Chapman AG, Collins JF, Meldrum BS, Westerberg E (1983) Uptake of a novel anticonvulsant compound, 2-amino-7-phosphono-(4,5-3H)heptanoic acid, into mouse brain. Neurosci Lett 37: 75–80
Clineschmidt BV, Martin GE, Bunting PR (1982) Anti-convulsant activity of (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclohepten-5,10-imine (MK-801), a substance with potent anticonvulsant, central sympathomimetic, and apparent anxiolytic properties. Drug Devel Res 2: 123–134
Coan EJ, Saywood W, Collingridge GL (1987) MK-801 blocks NMDA receptor-mediated synaptic transmission and long term potentiation in rat hippocampal slices. Neurosci Lett 80: 111–114
Collingridge GL, Bliss TVP (1987) NMDA receptors — their role in long-term potentiation. Trends Neurosci 10: 288–293
Collingridge GL, Kehl SJ, McLennan H (1983) Excitatory amino acids in synaptic transmission in the Schaffer collateralcommissural pathway of the rat hippocampus. J Physiol 334: 33–46
Compton RP, Contreras PC, O'Donohue TL, Monahan JB (1987) The N-methyl-D-aspartate antagonist, 2-amino-7-phosphonoheptanoate, produces phencyclidine-like behavioral effects in rats. Eur J Pharmacol 136: 133–134
Compton RP, Kreiter PA, Smith RG, Harken RD, Monahan JB (1988) Determination of the pharmacokinetics of 2-amino-7-phosphonoheptanoate in rat plasma and cerebrospinal fluid. Neurosci Lett 84: 339–344
Cotman CW, Iversen LL (1987) Excitatory amino acids in the brain-focus on NMDA receptors. Trends Neurosci 10: 263–265
Evans RH, Francis AA, Jones AW, Smith DAS, Watkins JC (1982) The effects of a series of w-phosphonic alpha-carboxylic amino acids on electrically evoked and excitant amino acid-induced responses in isolated spinal cord preparations. Br J Pharmacol 75: 65–75
Fagg GE, Baud J (1988) Characterization of NMDA receptorionophore complexes in the brain. In: Lodge D (ed) Excitatory amino acids in health and disease. Wiley and Sons Ltd, Chichester, pp 63–90
Goddard GV (1986) A step nearer a neural substrate. Nature (London) 119: 721
Halliwell RF, Morris RGM (1987) Anticonvulsant doses of MK-801 fail to block long-term potentiation in vivo, or impair spatial memory in the rat. Neurosci Lett Suppl 29: S99
Harris EW, Ganong AH, Cotman CW (1984) Long-term potentiation in the hippocampus involves activation of N-methyl-Daspartate receptors. Brain Res 323: 132–137
Headley PM, Parsons CG, West DC (1987) The role of N-methylaspartate receptors in mediating responses of rat and cat spinal neurones to defined sensory stimuli. J Physiol 385: 169–188
Koeck W, Woods JH, Ornstein P (1986) Phencyclidine-like behavioral effects in pigeons induced by systemic administration of the excitatory amino acid antagonist, 2-amino-5-phosphonovalerate. Life Sci 39: 973–978
Meldrum BS (1985) Possible therapeutic applications of antagonists of excitatory amino acid neurotransmitters. Clin Sci 68: 113–122
Miller N (1951) Learnable drives and rewards. In: Stevens (ed) Handbook of experimental psychology. Wiley, New York, pp 435–472
Monaghan DT, Cotman CW (1985) Distribution of NMDA-sensitive, 1-3H-glutamate binding sites in rat brain as determined by quantitative autoradiography. J Neurosci 5: 2909–2919
Mondadori C (1981) Pharmacological modulation of memory: trends and problems. Acta Neurol Scand 64: Suppl 89
Mondadori C (1987) Pharmacology of memory. In: Mutschler E, Winterfeld E (eds) Science or art, trends in medicinal chemistry. Verlag Chemie, Weinheim New York, pp 263–279
Mondadori C, Ortmann R, Petschke F, Buerki H, D'Amato F, Meisburger JG, Fagg GE (1988) Task-dependent impairment of facilitation of learning by NMDA receptor blockade. In: Cavalheiro EA, Lehmann J, Turski L (ed) Frontiers in excitatory amino acid research. Liss Inc, New York, pp 419–426
Morris RGM (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Meth 11: 47–60
Morris RGM (1988) Elements of a hypothesis concerning the participation of hippocampal NMDA receptors in learning. In: Lodge D (ed) Excitatory amino acids in health and disease. Wiley and Sons Ltd, Chichester, pp 297–320
Morris RGM, Anderson E, Lynch GS, Baudry M (1986) Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature (Lond) 319: 774–776
Olton DS, Becker JT, Handelmann GE (1979) Hypocampus, space and memory, Behav Brain Sci 2: 316–365
Polc P (1985) 2-amino-7-phosphonoheptanoic acid depresses gamma-motoneurons and polysynaptic reflexes in the cat spinal cord. Eur J Pharmacol 117: 387–389
Salt TE (1986) Mediation of thalamic sensory input by both NMDA receptors and non-NMDA receptors. Nature (Lond) 322: 263–265
Teiler TJ, Discenna P (1987) Long-term potentiation. Ann Rev Neurosci 10: 131–161
Tricklebank MD, Singh L, Oles RJ, Wong EHF, Iversen SD (1987) A role for receptors of N-methyl-D-aspartic acid in the discriminative stimulus properties of phencycline. Eur J Pharmacol 141: 497–501
Tukey JW (1977) Exploratory data analysis. Addison-Wesley, London,p 47
Turski L, Schwarz M, Turski WA, Klockgether T, Sontag KH, Collins JF (1985) Muscle relaxant action of excitatory amino acid antagonists. Neurosci Lett 53: 321–326
Wigstroem H, Gustafsson B, Huang YY (1986) Mode of action of excitatory amino acid receptor antagonists on hippocampal long-lasting potentiation. Neuroscience 17: 1105–1115
Wong EHF, Kemp JA, Priestley T, Knight AR, Woodruff GN, Iversen LL (1986) The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci USA 83: 7104–7108
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Mondadori, C., Weiskrantz, L., Buerki, H. et al. NMDA receptor antagonists can enhance or impair learning performance in animals. Exp Brain Res 75, 449–456 (1989). https://doi.org/10.1007/BF00249896
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DOI: https://doi.org/10.1007/BF00249896