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. 1996 Feb;117(4):689–697. doi: 10.1111/j.1476-5381.1996.tb15245.x

Effects of memantine and MK-801 on NMDA-induced currents in cultured neurones and on synaptic transmission and LTP in area CA1 of rat hippocampal slices.

T Frankiewicz 1, B Potier 1, Z I Bashir 1, G L Collingridge 1, C G Parsons 1
PMCID: PMC1909336  PMID: 8646415

Abstract

The effects of the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, memantine (1-amino-3,5-dimethyladamantane) and MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzocyclo-hepten-5,10-imin e maleate) were compared on synaptic transmission and long-term potentiation (LTP) in hippocampal slices and on NMDA-induced currents in cultured superior collicular neurones. 2. Memantine (10-100 microM) reversibly reduced, but did not abolish, NMDA receptor-mediated secondary population spikes recorded in area CA1 of hippocampal slices bathed in Mg(2+)-free artificial cerebrospinal fluid. 3. Memantine (100 microM) antagonized NMDA receptor-mediated excitatory postsynaptic currents recorded in area CA1 in a strongly voltage-dependent manner i.e. depressed to 11 +/- 4% of control at -35 mV and 95 +/- 5% of control at +40 mV (n = 9), with no apparent effect on response kinetics. 4. The effects of MK-801 and memantine on the induction of LTP were assessed after prolonged pre-incubations with these antagonists. When present for 6.6 +/- 0.4 h prior to tetanic stimulation, memantine blocked the induction of LTP with an IC50 of 11.6 +/- 0.53 microM. By comparison, similar long pre-incubations with MK-801 (6.4 +/- 0.4 h) blocked the induction of LTP with an IC50 of 0.13 +/- 0.02 microM. 5. Memantine and MK-801 reduced NMDA-induced currents in cultured superior colliculus neurones recorded at -70 mV with IC50s of 2.2 +/- 0.2 microM and 0.14 +/- 0.04 microM respectively. The effects of memantine were highly voltage-dependent and behaved as though the affinity decreased epsilon fold per 50 mV of depolarization (apparent delta = 0.71). In contrast, under the conditions used, MK-801 appeared to be much less voltage-dependent i.e. affinity decreased epsilon fold per 329 mV of depolarization (apparent delta = 0.15). 6. Depolarizing steps from -70 mV to +50 mV in the continuous presence of memantine (10 microM) caused a rapid relief of blockade of NMDA-induced currents from 83.7 +/- 1.9% to 21.8 +/- 1.8% (n = 5). This relief was best fitted by a double exponential function (17.2 +/- 11.7 and 698 +/- 204 ms), the faster component of which was most pronounced. 7. In conclusion, whereas MK-801 is equipotent in blocking NMDA-induced currents (at - 70 mV) and the induction of LTP, memantine is relatively less potent in blocking the induction of LTP. This is due to its rapid relief of blockade upon depolarization; a property which might explain its promising clinical profile in the treatment of chronic neurodegenerative diseases.

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Selected References

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  1. Andiné P., Sandberg M., Bågenholm R., Lehmann A., Hagberg H. Intra- and extracellular changes of amino acids in the cerebral cortex of the neonatal rat during hypoxic-ischemia. Brain Res Dev Brain Res. 1991 Dec 17;64(1-2):115–120. doi: 10.1016/0165-3806(91)90214-4. [DOI] [PubMed] [Google Scholar]
  2. Apland J. P., Cann F. J. Anticonvulsant effects of memantine and MK-801 in guinea pig hippocampal slices. Brain Res Bull. 1995;37(3):311–316. doi: 10.1016/0361-9230(95)00038-g. [DOI] [PubMed] [Google Scholar]
  3. Bashir Zafar I., Collingridge Graham L. NMDA Receptor-dependent Transient Homo- and Heterosynaptic Depression in Picrotoxin-treated Hippocampal Slices. Eur J Neurosci. 1992;4(6):485–490. doi: 10.1111/j.1460-9568.1992.tb00898.x. [DOI] [PubMed] [Google Scholar]
  4. Benveniste H., Drejer J., Schousboe A., Diemer N. H. Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem. 1984 Nov;43(5):1369–1374. doi: 10.1111/j.1471-4159.1984.tb05396.x. [DOI] [PubMed] [Google Scholar]
  5. Bliss T. V., Collingridge G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993 Jan 7;361(6407):31–39. doi: 10.1038/361031a0. [DOI] [PubMed] [Google Scholar]
  6. Bormann J. Memantine is a potent blocker of N-methyl-D-aspartate (NMDA) receptor channels. Eur J Pharmacol. 1989 Aug 3;166(3):591–592. doi: 10.1016/0014-2999(89)90385-3. [DOI] [PubMed] [Google Scholar]
  7. Boulton C. L., Irving A. J., Southam E., Potier B., Garthwaite J., Collingridge G. L. The nitric oxide--cyclic GMP pathway and synaptic depression in rat hippocampal slices. Eur J Neurosci. 1994 Oct 1;6(10):1528–1535. doi: 10.1111/j.1460-9568.1994.tb00543.x. [DOI] [PubMed] [Google Scholar]
  8. Bresink I., Danysz W., Parsons C. G., Mutschler E. Different binding affinities of NMDA receptor channel blockers in various brain regions--indication of NMDA receptor heterogeneity. Neuropharmacology. 1995 May;34(5):533–540. doi: 10.1016/0028-3908(95)00017-z. [DOI] [PubMed] [Google Scholar]
  9. Buisson A., Callebert J., Mathieu E., Plotkine M., Boulu R. G. Striatal protection induced by lesioning the substantia nigra of rats subjected to focal ischemia. J Neurochem. 1992 Sep;59(3):1153–1157. doi: 10.1111/j.1471-4159.1992.tb08358.x. [DOI] [PubMed] [Google Scholar]
  10. Chen H. S., Pellegrini J. W., Aggarwal S. K., Lei S. Z., Warach S., Jensen F. E., Lipton S. A. Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity. J Neurosci. 1992 Nov;12(11):4427–4436. doi: 10.1523/JNEUROSCI.12-11-04427.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Clements J. D., Lester R. A., Tong G., Jahr C. E., Westbrook G. L. The time course of glutamate in the synaptic cleft. Science. 1992 Nov 27;258(5087):1498–1501. doi: 10.1126/science.1359647. [DOI] [PubMed] [Google Scholar]
  12. Coan E. J., Collingridge G. L. Characterization of an N-methyl-D-aspartate receptor component of synaptic transmission in rat hippocampal slices. Neuroscience. 1987 Jul;22(1):1–8. doi: 10.1016/0306-4522(87)90192-8. [DOI] [PubMed] [Google Scholar]
  13. Coan E. J., Collingridge G. L. Effects of phencyclidine, SKF 10,047 and related psychotomimetic agents on N-methyl-D-aspartate receptor mediated synaptic responses in rat hippocampal slices. Br J Pharmacol. 1987 Jul;91(3):547–556. doi: 10.1111/j.1476-5381.1987.tb11248.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Coan E. J., Saywood W., Collingridge G. L. MK-801 blocks NMDA receptor-mediated synaptic transmission and long term potentiation in rat hippocampal slices. Neurosci Lett. 1987 Sep 11;80(1):111–114. doi: 10.1016/0304-3940(87)90505-2. [DOI] [PubMed] [Google Scholar]
  15. Collingridge G. L., Kehl S. J., McLennan H. Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus. J Physiol. 1983 Jan;334:33–46. doi: 10.1113/jphysiol.1983.sp014478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Danysz W., Gossel M., Zajaczkowski W., Dill D., Quack G. Are NMDA antagonistic properties relevant for antiparkinsonian-like activity in rats?--case of amantadine and memantine. J Neural Transm Park Dis Dement Sect. 1994;7(3):155–166. doi: 10.1007/BF02253435. [DOI] [PubMed] [Google Scholar]
  17. Danysz W., Zajaczkowski W., Parsons C.G. Modulation of learning processes by ionotropic glutamate receptor ligands. Behav Pharmacol. 1995 Aug;6(5-6):455–474. [PubMed] [Google Scholar]
  18. Davies S. N., Martin D., Millar J. D., Aram J. A., Church J., Lodge D. Differences in results from in vivo and in vitro studies on the use-dependency of N-methylaspartate antagonism by MK-801 and other phencyclidine receptor ligands. Eur J Pharmacol. 1988 Jan 12;145(2):141–151. doi: 10.1016/0014-2999(88)90225-7. [DOI] [PubMed] [Google Scholar]
  19. Dimpfel W. Effects of memantine on synaptic transmission in the hippocampus in vitro. Arzneimittelforschung. 1995 Jan;45(1):1–5. [PubMed] [Google Scholar]
  20. Ditzler K. Efficacy and tolerability of memantine in patients with dementia syndrome. A double-blind, placebo controlled trial. Arzneimittelforschung. 1991 Aug;41(8):773–780. [PubMed] [Google Scholar]
  21. Globus M. Y., Busto R., Dietrich W. D., Martinez E., Valdes I., Ginsberg M. D. Effect of ischemia on the in vivo release of striatal dopamine, glutamate, and gamma-aminobutyric acid studied by intracerebral microdialysis. J Neurochem. 1988 Nov;51(5):1455–1464. doi: 10.1111/j.1471-4159.1988.tb01111.x. [DOI] [PubMed] [Google Scholar]
  22. Globus M. Y., Busto R., Martinez E., Valdés I., Dietrich W. D., Ginsberg M. D. Comparative effect of transient global ischemia on extracellular levels of glutamate, glycine, and gamma-aminobutyric acid in vulnerable and nonvulnerable brain regions in the rat. J Neurochem. 1991 Aug;57(2):470–478. doi: 10.1111/j.1471-4159.1991.tb03775.x. [DOI] [PubMed] [Google Scholar]
  23. Grossmann W., Schütz W. Memantin und neurogene Blasenstörungen im Rahmen spastischer Zustandsbilder. Arzneimittelforschung. 1982;32(10):1273–1276. [PubMed] [Google Scholar]
  24. Görtelmeyer R., Erbler H. Memantine in the treatment of mild to moderate dementia syndrome. A double-blind placebo-controlled study. Arzneimittelforschung. 1992 Jul;42(7):904–913. [PubMed] [Google Scholar]
  25. Halliwell R. F., Peters J. A., Lambert J. J. The mechanism of action and pharmacological specificity of the anticonvulsant NMDA antagonist MK-801: a voltage clamp study on neuronal cells in culture. Br J Pharmacol. 1989 Feb;96(2):480–494. doi: 10.1111/j.1476-5381.1989.tb11841.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hashimoto N., Matsumoto T., Mabe H., Hashitani T., Nishino H. Dopamine has inhibitory and accelerating effects on ischemia-induced neuronal cell damage in the rat striatum. Brain Res Bull. 1994;33(3):281–288. doi: 10.1016/0361-9230(94)90195-3. [DOI] [PubMed] [Google Scholar]
  27. Herron C. E., Lester R. A., Coan E. J., Collingridge G. L. Frequency-dependent involvement of NMDA receptors in the hippocampus: a novel synaptic mechanism. Nature. 1986 Jul 17;322(6076):265–268. doi: 10.1038/322265a0. [DOI] [PubMed] [Google Scholar]
  28. Hessler N. A., Shirke A. M., Malinow R. The probability of transmitter release at a mammalian central synapse. Nature. 1993 Dec 9;366(6455):569–572. doi: 10.1038/366569a0. [DOI] [PubMed] [Google Scholar]
  29. Huettner J. E., Bean B. P. Block of N-methyl-D-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1307–1311. doi: 10.1073/pnas.85.4.1307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Karschin A., Aizenman E., Lipton S. A. The interaction of agonists and noncompetitive antagonists at the excitatory amino acid receptors in rat retinal ganglion cells in vitro. J Neurosci. 1988 Aug;8(8):2895–2906. doi: 10.1523/JNEUROSCI.08-08-02895.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kornhuber J., Bormann J., Hübers M., Rusche K., Riederer P. Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem brain study. Eur J Pharmacol. 1991 Apr 25;206(4):297–300. doi: 10.1016/0922-4106(91)90113-v. [DOI] [PubMed] [Google Scholar]
  32. Kornhuber J., Bormann J., Retz W., Hübers M., Riederer P. Memantine displaces [3H]MK-801 at therapeutic concentrations in postmortem human frontal cortex. Eur J Pharmacol. 1989 Aug 3;166(3):589–590. doi: 10.1016/0014-2999(89)90384-1. [DOI] [PubMed] [Google Scholar]
  33. Kornhuber J., Quack G. Cerebrospinal fluid and serum concentrations of the N-methyl-D-aspartate (NMDA) receptor antagonist memantine in man. Neurosci Lett. 1995 Aug 4;195(2):137–139. doi: 10.1016/0304-3940(95)11785-u. [DOI] [PubMed] [Google Scholar]
  34. Kornhuber J., Weller M., Schoppmeyer K., Riederer P. Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. J Neural Transm Suppl. 1994;43:91–104. [PubMed] [Google Scholar]
  35. MacDonald J. F., Nowak L. M. Mechanisms of blockade of excitatory amino acid receptor channels. Trends Pharmacol Sci. 1990 Apr;11(4):167–172. doi: 10.1016/0165-6147(90)90070-O. [DOI] [PubMed] [Google Scholar]
  36. Mayer M. L., Westbrook G. L., Guthrie P. B. Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature. 1984 May 17;309(5965):261–263. doi: 10.1038/309261a0. [DOI] [PubMed] [Google Scholar]
  37. Mitani A., Andou Y., Kataoka K. Selective vulnerability of hippocampal CA1 neurons cannot be explained in terms of an increase in glutamate concentration during ischemia in the gerbil: brain microdialysis study. Neuroscience. 1992;48(2):307–313. doi: 10.1016/0306-4522(92)90492-k. [DOI] [PubMed] [Google Scholar]
  38. Morris R. G., Anderson E., Lynch G. S., Baudry M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. 1986 Feb 27-Mar 5Nature. 319(6056):774–776. doi: 10.1038/319774a0. [DOI] [PubMed] [Google Scholar]
  39. Nowak L., Bregestovski P., Ascher P., Herbet A., Prochiantz A. Magnesium gates glutamate-activated channels in mouse central neurones. Nature. 1984 Feb 2;307(5950):462–465. doi: 10.1038/307462a0. [DOI] [PubMed] [Google Scholar]
  40. Parsons C. G., Gruner R., Rozental J., Millar J., Lodge D. Patch clamp studies on the kinetics and selectivity of N-methyl-D-aspartate receptor antagonism by memantine (1-amino-3,5-dimethyladamantan). Neuropharmacology. 1993 Dec;32(12):1337–1350. doi: 10.1016/0028-3908(93)90029-3. [DOI] [PubMed] [Google Scholar]
  41. Parsons C. G., Quack G., Bresink I., Baran L., Przegalinski E., Kostowski W., Krzascik P., Hartmann S., Danysz W. Comparison of the potency, kinetics and voltage-dependency of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vivo. Neuropharmacology. 1995 Oct;34(10):1239–1258. doi: 10.1016/0028-3908(95)00092-k. [DOI] [PubMed] [Google Scholar]
  42. Pongrácz F., Poolos N. P., Kocsis J. D., Shepherd G. M. A model of NMDA receptor-mediated activity in dendrites of hippocampal CA1 pyramidal neurons. J Neurophysiol. 1992 Dec;68(6):2248–2259. doi: 10.1152/jn.1992.68.6.2248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Rosenmund C., Clements J. D., Westbrook G. L. Nonuniform probability of glutamate release at a hippocampal synapse. Science. 1993 Oct 29;262(5134):754–757. doi: 10.1126/science.7901909. [DOI] [PubMed] [Google Scholar]
  44. Schneider E., Fischer P. A., Clemens R., Balzereit F., Fünfgeld E. W., Haase H. J. Wirkungen oraler Memantin-Gaben auf die Parkinson-Symptomatik. Ergebnisse einer placebo-kontrollierten Multicenter-Studie. Dtsch Med Wochenschr. 1984 Jun 22;109(25):987–990. doi: 10.1055/s-2008-1069311. [DOI] [PubMed] [Google Scholar]
  45. Wenk G. L., Danysz W., Mobley S. L. Investigations of neurotoxicity and neuroprotection within the nucleus basalis of the rat. Brain Res. 1994 Aug 29;655(1-2):7–11. doi: 10.1016/0006-8993(94)91590-3. [DOI] [PubMed] [Google Scholar]
  46. Wenk G. L., Danysz W., Mobley S. L. MK-801, memantine and amantadine show neuroprotective activity in the nucleus basalis magnocellularis. Eur J Pharmacol. 1995 Oct 6;293(3):267–270. doi: 10.1016/0926-6917(95)00028-3. [DOI] [PubMed] [Google Scholar]
  47. Wesemann W., Sontag K. H., Maj J. Zur Pharmakodynamik und Pharmakokinetik des Memantin. Arzneimittelforschung. 1983;33(8):1122–1134. [PubMed] [Google Scholar]
  48. Wong E. H., Kemp J. A., Priestley T., Knight A. R., Woodruff G. N., Iversen L. L. The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci U S A. 1986 Sep;83(18):7104–7108. doi: 10.1073/pnas.83.18.7104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Woodhull A. M. Ionic blockage of sodium channels in nerve. J Gen Physiol. 1973 Jun;61(6):687–708. doi: 10.1085/jgp.61.6.687. [DOI] [PMC free article] [PubMed] [Google Scholar]

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