Mechanism of inhibition by ethanol of NMDA and AMPA receptor channel functions in cultured rat cortical neurons

被引：0
作者：
Wirkner K. [1 ]
Eberts C. [1 ]
Poelchen W. [1 ]
Allgaier C. [1 ]
Illes P. [1 ]
机构：
[1] Rudolf-Boehm-Institut F. Pharmakol., Toxikologie der Universitat, Hartelstrasse 16-18
来源：
Naunyn-Schmiedeberg's Archives of Pharmacology | 2000年 / 362卷 / 6期
关键词：
Ligand-activated cationic channel; Noncompetitive antagonism; Open-channel block; Patch-clamp;
D O I：
10.1007/s002100000262
中图分类号：
学科分类号：
摘要：
The effect and mode of action of ethanol on N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors of rat cortical neurons in primary culture were compared by means of the patch-clamp technique. The maxima of the concentration-response curves for both NMDA and AMPA were markedly depressed by ethanol without an apparent shift of the curves to the right. Ethanol inhibited the effects of NMDA and AMPA concentration-dependently and equally well. Excitatory amino acid (EAA) currents were depressed to the largest extent when ethanol was continuously superfused during and between agonist applications; a smaller inhibitory effect was observed when ethanol was intermittently superfused during agonist applications only. There was no inhibition by ethanol, when its superfusion was between two agonist applications. According to expectations, the analysis of the ratios of plateau to peak currents failed to suggest a use-dependent blockade by ethanol. In addition, comparison of the voltage-current curves of NMDA and AMPA in the absence and presence of ethanol indicated a voltage-independent effect and no change in the reversal potential of the two agonists. Finally, the measurement of activation and deactivation time constants for the ethanol-induced inhibition of NMDA and AMPA responses confirms the failure of ethanol to cause an open-channel block. In conclusion, these findings as a whole indicate that ethanol inhibits NMDA and AMPA currents by a noncompetitive mechanism. The mode of action appears to be similar for both NMDA and AMPA; under the conditions of the present study, a selective interference with structural motifs of the NMDA receptor is unlikely.
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页码：568 / 576
页数：8
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  • [1] Benveniste, M., Clements, J., Vyklicky, L., Mayer, M.L., A kinetic analysis of the modulation of N-methyl-D-aspartic acid receptors by glycine in mouse cultured hippocampal neurones (1990) J Physiol (Lond), 428, pp. 333-357
  • [2] Brann, D.W., Glutamate: A major excitatory transmitter in neuroendocrine regulation (1995) Neuroendocrinology, 61, pp. 213-225
  • [3] Buller, A.L., Larson, H.C., Morrisett, R.A., Monaghan, D.T., Glycine modulates ethanol inhibition of heteromeric N-methyl-D-aspartate receptors expressed in Xenopus oocytes (1995) Mol Pharmacol, 48, pp. 717-723
  • [4] Cebers, G., Cebere, A., Zharkovsky, A., Liljequist, S., Glycine does not reverse the inhibitory actions of ethanol on NMDA receptor functions in cerebellar granule cells (1996) Naunyn-Schmiedeberg's Arch Pharmacol, 354, pp. 736-745
  • [5] Chen, H.S.V., Lipton, S.A., Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: Uncompetitive antagonism (1997) J Physiol (Lond), 499, pp. 27-46
  • [6] Chu, B., Anantharam, V., Treistman, S.N., Ethanol inhibition of recombinant heteromeric NMDA channels in the presence and absence of modulators (1995) J Neurochem, 65, pp. 140-148
  • [7] Collingridge, G.L., Singer, W., Excitatory amino acid receptors and synaptic plasticity (1990) Trends Pharmacol Sci, 11, pp. 290-296
  • [8] Dildy-Mayfield, J.E., Harris, R.A., Comparison of ethanol sensitivity of rat brain kainate, D, L-α-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid and N-methyl-D-aspartate receptors expressed in Xenopus oocytes (1992) J Pharmacol Exp Ther, 262, pp. 487-494
  • [9] Dildy-Mayfield, J.E., Harris, R.A., Ethanol inhibits kainate responses of glutamate receptors expressed in Xenopus oocytes: Role of calcium and protein kinase C (1995) J Neurosci, 15, pp. 3162-3171
  • [10] Dingledine, R., Borges, K., Bowie, D., Traynelis, S.F., The glutamate receptor ion channels (1999) Pharmacol Rev, 51, pp. 7-61
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