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. 1985 Feb;84(2):381–391. doi: 10.1111/j.1476-5381.1985.tb12922.x

Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex.

N L Harrison, M A Simmonds
PMCID: PMC1987274  PMID: 2858237

Abstract

Coronal sections of rat brain (500 micron thick) were trimmed to form 'wedges' of tissue consisting of cerebral cortex and corpus callosum. When these slices were placed in a two-compartment bath, the cortical tissue could be depolarized, relative to the corpus callosum, by superfusions of high K+, or by amino acids such as L-glutamate, L-aspartate, quisqualate, kainate and N-methyl D-aspartate (NMDA). Responses to NMDA were reduced by magnesium ions, by the organic antagonists (-)-2-amino 5-phosphonovalerate (APV) and 2-amino 7-phosphonoheptanoate (APH), and by the dissociative anaesthetic ketamine. In this preparation, all these antagonists shifted the NMDA dose-response curve to the right in a parallel manner. A Schild plot for Mg2+ had a slope significantly less than unity, indicative of a non-competitive action, whilst Schild plots for (-)-APV, APH and ketamine appeared linear and had slopes of approximately 1. Analysis of the results of combination experiments suggested that the presumed competitive antagonists, (-)-APV and APH, share a common site of action as NMDA antagonists, and that this site is distinct from that at which ketamine exerts its action. The action of Mg2+ is clearly different from that of either (-)-APV or ketamine. It is concluded that ketamine is a non-competitive antagonist of NMDA and may act at an allosteric site on the NMDA receptor complex to influence its function.

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Selected References

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  1. Anis N. A., Berry S. C., Burton N. R., Lodge D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharmacol. 1983 Jun;79(2):565–575. doi: 10.1111/j.1476-5381.1983.tb11031.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ault B., Evans R. H., Francis A. A., Oakes D. J., Watkins J. C. Selective depression of excitatory amino acid induced depolarizations by magnesium ions in isolated spinal cord preparations. J Physiol. 1980 Oct;307:413–428. doi: 10.1113/jphysiol.1980.sp013443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barker J. L., McBurney R. N., Mathers D. A. Convulsant-induced depression of amino acid responses in cultured mouse spinal neurones studied under voltage clamp. Br J Pharmacol. 1983 Dec;80(4):619–629. doi: 10.1111/j.1476-5381.1983.tb10051.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. CRAWFORD J. M., CURTIS D. R. THE EXCITATION AND DEPRESSION OF MAMMALIAN CORTICAL NEURONES BY AMINO ACIDS. Br J Pharmacol Chemother. 1964 Oct;23:313–329. doi: 10.1111/j.1476-5381.1964.tb01589.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Collingridge G. L., Kehl S. J., McLennan H. The antagonism of amino acid-induced excitations of rat hippocampal CA1 neurones in vitro. J Physiol. 1983 Jan;334:19–31. doi: 10.1113/jphysiol.1983.sp014477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Croucher M. J., Collins J. F., Meldrum B. S. Anticonvulsant action of excitatory amino acid antagonists. Science. 1982 May 21;216(4548):899–901. doi: 10.1126/science.7079744. [DOI] [PubMed] [Google Scholar]
  7. Crunelli V., Forda S., Kelly J. S. Blockade of amino acid-induced depolarizations and inhibition of excitatory post-synaptic potentials in rat dentate gyrus. J Physiol. 1983 Aug;341:627–640. doi: 10.1113/jphysiol.1983.sp014829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Davies J., Watkins J. C. Actions of D and L forms of 2-amino-5-phosphonovalerate and 2-amino-4-phosphonobutyrate in the cat spinal cord. Brain Res. 1982 Mar 11;235(2):378–386. doi: 10.1016/0006-8993(82)91017-4. [DOI] [PubMed] [Google Scholar]
  9. Evans R. H., Francis A. A., Jones A. W., Smith D. A., Watkins J. C. The effects of a series of omega-phosphonic alpha-carboxylic amino acids on electrically evoked and excitant amino acid-induced responses in isolated spinal cord preparations. Br J Pharmacol. 1982 Jan;75(1):65–75. doi: 10.1111/j.1476-5381.1982.tb08758.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. KRNJEVIC K., PHILLIS J. W. Iontophoretic studies of neurones in the mammalian cerebral cortex. J Physiol. 1963 Feb;165:274–304. doi: 10.1113/jphysiol.1963.sp007057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Monaghan D. T., Holets V. R., Toy D. W., Cotman C. W. Anatomical distributions of four pharmacologically distinct 3H-L-glutamate binding sites. Nature. 1983 Nov 10;306(5939):176–179. doi: 10.1038/306176a0. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Olverman H. J., Jones A. W., Watkins J. C. L-glutamate has higher affinity than other amino acids for [3H]-D-AP5 binding sites in rat brain membranes. Nature. 1984 Feb 2;307(5950):460–462. doi: 10.1038/307460a0. [DOI] [PubMed] [Google Scholar]
  15. Padjen A. L., Smith P. A. The role of the electrogenic sodium pump in the glutamate afterhyperpolarization of frog spinal cord. J Physiol. 1983 Mar;336:433–451. doi: 10.1113/jphysiol.1983.sp014589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Pennefather P., Quastel D. M. Modification of dose-response curves by effector blockade and uncompetitive antagonism. Mol Pharmacol. 1982 Sep;22(2):369–380. [PubMed] [Google Scholar]
  17. Simmonds M. A. Classification of some GABA antagonists with regard to site of action and potency in slices of rat cuneate nucleus. Eur J Pharmacol. 1982 Jun 4;80(4):347–358. doi: 10.1016/0014-2999(82)90080-2. [DOI] [PubMed] [Google Scholar]
  18. Simmonds M. A. Presynaptic actions of gamma-aminobutyric acid and some antagonists in a slice preparation of cuneate nucleus. Br J Pharmacol. 1978 Jul;63(3):495–502. doi: 10.1111/j.1476-5381.1978.tb07803.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Watkins J. C., Evans R. H. Excitatory amino acid transmitters. Annu Rev Pharmacol Toxicol. 1981;21:165–204. doi: 10.1146/annurev.pa.21.040181.001121. [DOI] [PubMed] [Google Scholar]

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