Uncompetitive NMDA receptor antagonists attenuate NMDA-induced impairment of passive avoidance learning and LTP

Uncompetitive NMDA receptor antagonists attenuate NMDA-induced impairment of passive avoidance... In general, N -methyl-D-aspartate (NMDA) receptor antagonists inhibit learning and long term potentiation (LTP). However, it has been suggested that direct tonic, i.e. non-temporal, activation of NMDA receptors, in contrast to learning, may lead to an increase in synaptic “noise” and, in turn, to a loss of association detection. In the present study, a two-choice passive avoidance task and LTP in vitro (CA1 hippocampal region) were used to address this issue. Dark avoidance learning was impaired by systemic NMDA administration (starting at 25 mg/kg) that was not related to either toxic effects or state-dependent learning. NMDA-induced amnesia was antagonized by ((+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5, 10-imine maleate (MK-801) and 1-amino-3,5-dimethyladamantane (memantine), starting at low doses of 0.05 and 2.5 mg/kg, respectively, in a bell-shaped dose-response relationship. A competitive NMDA receptor antagonist CGP-39551 failed to reverse NMDA-induced amnesia. In hippocampal slices, NMDA (10 μM) depressed (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolproprionic acid (AMPA) receptor-mediated field potentials in CA1 and also caused a moderate reduction of LTP induction/expression. It was this latter effect that was antagonized by memantine (1 μM). Thus, under conditions of tonic activation of NMDA receptors, uncompetitive NMDA receptor antagonists can paradoxically reverse deficits in learning and synaptic plasticity. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neuropharmacology Elsevier

Uncompetitive NMDA receptor antagonists attenuate NMDA-induced impairment of passive avoidance learning and LTP

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Publisher
Elsevier
Copyright
Copyright © 1997 Elsevier Ltd
ISSN
0028-3908
eISSN
1873-7064
DOI
10.1016/S0028-3908(97)00070-1
Publisher site
See Article on Publisher Site

Abstract

In general, N -methyl-D-aspartate (NMDA) receptor antagonists inhibit learning and long term potentiation (LTP). However, it has been suggested that direct tonic, i.e. non-temporal, activation of NMDA receptors, in contrast to learning, may lead to an increase in synaptic “noise” and, in turn, to a loss of association detection. In the present study, a two-choice passive avoidance task and LTP in vitro (CA1 hippocampal region) were used to address this issue. Dark avoidance learning was impaired by systemic NMDA administration (starting at 25 mg/kg) that was not related to either toxic effects or state-dependent learning. NMDA-induced amnesia was antagonized by ((+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5, 10-imine maleate (MK-801) and 1-amino-3,5-dimethyladamantane (memantine), starting at low doses of 0.05 and 2.5 mg/kg, respectively, in a bell-shaped dose-response relationship. A competitive NMDA receptor antagonist CGP-39551 failed to reverse NMDA-induced amnesia. In hippocampal slices, NMDA (10 μM) depressed (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolproprionic acid (AMPA) receptor-mediated field potentials in CA1 and also caused a moderate reduction of LTP induction/expression. It was this latter effect that was antagonized by memantine (1 μM). Thus, under conditions of tonic activation of NMDA receptors, uncompetitive NMDA receptor antagonists can paradoxically reverse deficits in learning and synaptic plasticity.

Journal

NeuropharmacologyElsevier

Published: Jul 1, 1997

References

  • Depletion of cortical cholecystokinin levels after excitotoxin injection into the nucleus basalis: sensitivity to MK-801
    Bandopadhyay, R.; Debelleroche, J.
  • Excitatory amino acid neurotransmission: NMDA receptors and Hebb-type synaptic plasticity
    Cotman, C.W.; Monaghan, D.T.
  • Discriminative stimulus effects of excitatory amino acid agonists in rats
    Grech, D.M.; Lunn, W.H.W.; Balster, R.L.
  • Involvement of N -methyl-D-aspartate (NMDA) receptors in noncompetitive NMDA receptor antagonist-induced hyperlocomotion in mice
    Irifune, M.; Shimizu, T.; Nomoto, M.; Fukuda, T.
  • Nitric oxide inhibitors facilitate the induction of hippocampal long-term potentiation by modulating NMDA responses
    Kato, K.; Zorumski, C.F.
  • NMDA receptor antagonists can enhance or impair learning performance in animals
    Mondadori, C.; Weiskrantz, L.; Buerki, H.; Petschke, F.; Fagg, G.E.

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