Ethanol modulation of the gamma-aminobutyric acidA- and glycine- activated Cl- current in cultured mouse neurons

LG Aguayo and FC Pancetti

Laboratory of Neuropharmacology, Catholic University at Valparaiso, Chile.

The effects of ethanol on the GABA (gamma-aminobutyric acid)A-activated Cl- current were studied in cultured mouse hippocampal and cortical neurons using whole-cell techniques. Ethanol (0.25-200 mM) reversibly potentiated the current in 68 of the 131 hippocampal neurons examined. Ethanol also potentiated a strychnine-sensitive glycine-activated Cl- current in hippocampal and spinal neurons. Ethanol (40 mM) enhanced the maximal response to GABA without changing the Hill coefficient (1.2) or the affinity of the receptor for GABA (EC50 = 15 vs. 14 microM). We found neurons with distinct sensitivities to ethanol, and even concentrations of 425 and 850 mM further potentiated the response induced by GABA and glycine. Ethanol was able to potentiate the GABAA current even after removing Ca++ from the external solution. The protein kinase C activator phorbol, 12 myristate, 13 acetate inhibited the amplitude of the GABA current by 73 +/- 7% of control; however, 4- alpha-phorbol, 12 myristate, 13 acetate, its inactive analog, had no effects. In addition, 2 min of preapplication of 1 microM phorbol, 12 myristate, 13 acetate reduced the ethanol-potentiation from 140 +/- 8 to 122 +/- 6%. Recordings of GABA- and glycine-activated Cl- currents showed that low concentrations of ethanol can differentially affect these receptors in a single neuron. This suggests that the GABAergic effect of ethanol is not mediated by a nonspecific change and that different mechanisms might account for the potentiation of these two ligand-activated Cl- channels by ethanol. In addition, the absence of saturation with high concentrations suggests that ethanol modulates these receptor-ion channel complexes by acting in several sites, one of which might control the state of receptor phosphorylation.

Volume 270, Issue 1, pp. 61-69, 07/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				C. Dubois, H. Houchi, M. Naassila, M. Daoust, and O. Pierrefiche Blunted response to low oxygen of rat respiratory network after perinatal ethanol exposure: involvement of inhibitory control J. Physiol., March 1, 2008; 586(5): 1413 - 1427. [Abstract] [Full Text] [PDF]

				S. Koyama, M. S. Brodie, and S. B. Appel Ethanol Inhibition of M-Current and Ethanol-Induced Direct Excitation of Ventral Tegmental Area Dopamine Neurons J Neurophysiol, March 1, 2007; 97(3): 1977 - 1985. [Abstract] [Full Text] [PDF]

				J.-H. Ye, F. Wang, K. Krnjevic, W. Wang, Z.-G. Xiong, and J. Zhang Presynaptic Glycine Receptors on GABAergic Terminals Facilitate Discharge of Dopaminergic Neurons in Ventral Tegmental Area J. Neurosci., October 13, 2004; 24(41): 8961 - 8974. [Abstract] [Full Text] [PDF]

				I. A. Lobo, M. P. Mascia, J. R. Trudell, and R. A. Harris Channel Gating of the Glycine Receptor Changes Accessibility to Residues Implicated in Receptor Potentiation by Alcohols and Anesthetics J. Biol. Chem., August 6, 2004; 279(32): 33919 - 33927. [Abstract] [Full Text] [PDF]

				E. D. Eggers and A. J. Berger Mechanisms for the Modulation of Native Glycine Receptor Channels by Ethanol J Neurophysiol, June 1, 2004; 91(6): 2685 - 2695. [Abstract] [Full Text] [PDF]

				B. van Zundert, F. J. Alvarez, J. C. Tapia, H. H. Yeh, E. Diaz, and L. G. Aguayo Developmental-Dependent Action of Microtubule Depolymerization on the Function and Structure of Synaptic Glycine Receptor Clusters in Spinal Neurons J Neurophysiol, February 1, 2004; 91(2): 1036 - 1049. [Abstract] [Full Text] [PDF]

				E. Sanna, M. C. Mostallino, F. Busonero, G. Talani, S. Tranquilli, M. Mameli, S. Spiga, P. Follesa, and G. Biggio Changes in GABAA Receptor Gene Expression Associated with Selective Alterations in Receptor Function and Pharmacology after Ethanol Withdrawal J. Neurosci., December 17, 2003; 23(37): 11711 - 11724. [Abstract] [Full Text] [PDF]

				L. Ziskind-Conhaim, B.-X. Gao, and C. Hinckley Ethanol Dual Modulatory Actions on Spontaneous Postsynaptic Currents in Spinal Motoneurons J Neurophysiol, February 1, 2003; 89(2): 806 - 813. [Abstract] [Full Text] [PDF]

				J. P. Dilger The effects of general anaesthetics on ligand-gated ion channels Br. J. Anaesth., July 1, 2002; 89(1): 41 - 51. [Abstract] [Full Text] [PDF]

				M. Melis, R. Camarini, M. A. Ungless, and A. Bonci Long-Lasting Potentiation of GABAergic Synapses in Dopamine Neurons after a Single In Vivo Ethanol Exposure J. Neurosci., March 15, 2002; 22(6): 2074 - 2082. [Abstract] [Full Text] [PDF]

				G. S. Findlay, M. J. Wick, M. P. Mascia, D. Wallace, G. W. Miller, R. A. Harris, and Y. A. Blednov Transgenic Expression of a Mutant Glycine Receptor Decreases Alcohol Sensitivity of Mice J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 526 - 534. [Abstract] [Full Text] [PDF]

				J. H. Ye, L. Tao, L. Zhu, and J. J. McArdle Ethanol Inhibition of Glycine-Activated Responses in Neurons of Ventral Tegmental Area of Neonatal Rats J Neurophysiol, November 1, 2001; 86(5): 2426 - 2434. [Abstract] [Full Text] [PDF]

				J. H. Ye, L. Tao, J. Ren, R. Schaefer, P. L. Liu, D. A. Schiller, and J. J. McArdle Ethanol Potentiation of Glycine-Induced Responses in Dissociated Neurons of Rat Ventral Tegmental Area J. Pharmacol. Exp. Ther., January 1, 2001; 296(1): 77 - 83. [Abstract] [Full Text]

				E. D. Eggers, J. A. O'Brien, and A. J. Berger Developmental Changes in the Modulation of Synaptic Glycine Receptors by Ethanol J Neurophysiol, November 1, 2000; 84(5): 2409 - 2416. [Abstract] [Full Text] [PDF]

				B. van Zundert, F. A. Albarran, and L. G. Aguayo Effects of Chronic Ethanol Treatment on gamma -Aminobutyric AcidA and Glycine Receptors in Mouse Glycinergic Spinal Neurons J. Pharmacol. Exp. Ther., October 1, 2000; 295(1): 423 - 429. [Abstract] [Full Text]

				Z. Nie, S. G. Madamba, and G. R. Siggins Ethanol Enhances gamma -Aminobutyric Acid Responses in a Subpopulation of Nucleus Accumbens Neurons: Role of Metabotropic Glutamate Receptors J. Pharmacol. Exp. Ther., May 1, 2000; 293(2): 654 - 661. [Abstract] [Full Text]

				I. C. Gibson and A. J. Berger Effect of Ethanol Upon Respiratory-Related Hypoglossal Nerve Output of Neonatal Rat Brain Stem Slices J Neurophysiol, January 1, 2000; 83(1): 333 - 342. [Abstract] [Full Text] [PDF]

				S. A. Forman and Q. Zhou Novel Modulation of a Nicotinic Receptor Channel Mutant Reveals that the Open State Is Stabilized by Ethanol Mol. Pharmacol., January 1, 1999; 55(1): 102 - 108. [Abstract] [Full Text]

				M. D. Krasowski, S. E. Finn, Q. Ye, and N. L. Harrison Trichloroethanol Modulation of Recombinant GABAA, Glycine and GABA rho 1 Receptors J. Pharmacol. Exp. Ther., March 1, 1998; 284(3): 934 - 942. [Abstract] [Full Text]

				Q. Ye, V. V. Koltchine, S. J. Mihic, M. P. Mascia, M. J. Wick, S. E. Finn, N. L. Harrison, and R. A. Harris Enhancement of Glycine Receptor Function by Ethanol Is Inversely Correlated with Molecular Volume at Position alpha 267 J. Biol. Chem., February 6, 1998; 273(6): 3314 - 3319. [Abstract] [Full Text] [PDF]

				R. K. Freund and M. R. Palmer Beta Adrenergic Sensitization of gamma -Aminobutyric Acid Receptors to Ethanol Involves a Cyclic AMP/Protein Kinase A Second-Messenger Mechanism J. Pharmacol. Exp. Ther., March 1, 1997; 280(3): 1192 - 1200. [Abstract] [Full Text]