Ethanol potentiation of GABAergic transmission in cultured spinal cord neurons involves gamma-aminobutyric acidA-gated chloride channels

AK Mehta and MK Ticku

Department of Pharmacology, University of Texas Health Science Center, San Antonio.

The interaction of ethanol with gamma-aminobutyric acid (GABA)-mediated 36-Cl-influx and its modulation by various drugs was investigated in C57 mice spinal cord cultured neurons. Ethanol (5-100 mM) potentiated the effect of GABA on 36Cl-influx; whereas at concentrations greater than or equal to 50 mM ethanol activated Cl- channels directly. The effect of ethanol was specific for GABAA receptor-gated Cl- channels, as ethanol did not potentiate glycine-induced 36Cl-influx in the same neurons. Both the enhancing and direct effects of ethanol on 36Cl- influx were blocked by GABA antagonists like bicuculline, picrotoxinin and inverse agonists of the benzodiazepine site like the imidazodiazepine R015-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H- imidazo [1,5 alpha], [1,4]benzodiazepine-3-carboxylate) and N-methyl- beta-carboline-3-carboxamide (FG-7142). Ethanol potentiating effect of GABA-induced 36Cl-influx was also reversed by methyl-6,7-dimethyl-4- ethyl-beta-carboline-3-carboxylate. The effects of the inverse agonists were blocked by the benzodiazepine receptor antagonist R015-1788. Both R015-4513 and FG-7142 reversed direct and GABA potentiating effects of ethanol effect at concentrations lower than those that exhibit inverse agonistic activity in the 36Cl-influx assay in cultured neurons. These results suggest that ethanol facilitation of GABAAergic transmission involves GABA receptor-gated Cl- channels and that this interaction may be responsible for some of the pharmacological effects of ethanol.

Volume 246, Issue 2, pp. 558-564, 08/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				J. H. Krystal, J. Staley, G. Mason, I. L. Petrakis, J. Kaufman, R. A. Harris, J. Gelernter, and J. Lappalainen {gamma}-Aminobutyric Acid Type A Receptors and Alcoholism: Intoxication, Dependence, Vulnerability, and Treatment. Arch Gen Psychiatry, September 1, 2006; 63(9): 957 - 968. [Abstract] [Full Text] [PDF]

				J. Liang, N. Zhang, E. Cagetti, C. R. Houser, R. W. Olsen, and I. Spigelman Chronic Intermittent Ethanol-Induced Switch of Ethanol Actions from Extrasynaptic to Synaptic Hippocampal GABAA Receptors J. Neurosci., February 8, 2006; 26(6): 1749 - 1758. [Abstract] [Full Text] [PDF]

				J. W. Maas Jr, S. K. Vogt, G. C. K. Chan, V. V. Pineda, D. R. Storm, and L. J. Muglia Calcium-Stimulated Adenylyl Cyclases Are Critical Modulators of Neuronal Ethanol Sensitivity J. Neurosci., April 20, 2005; 25(16): 4118 - 4126. [Abstract] [Full Text] [PDF]

				J. W. Maas Jr, R. A. Indacochea, L. M. Muglia, T. T. Tran, S. K. Vogt, T. West, A. Benz, A. A. Shute, D. M. Holtzman, S. Mennerick, et al. Calcium-Stimulated Adenylyl Cyclases Modulate Ethanol-Induced Neurodegeneration in the Neonatal Brain J. Neurosci., March 2, 2005; 25(9): 2376 - 2385. [Abstract] [Full Text] [PDF]

				M. Wallner, H. J. Hanchar, and R. W. Olsen From The Cover: Ethanol enhances {alpha}4{beta}3{delta} and {alpha}6{beta}3{delta} {gamma}-aminobutyric acid type A receptors at low concentrations known to affect humans PNAS, December 9, 2003; 100(25): 15218 - 15223. [Abstract] [Full Text] [PDF]

				J. E. Kralic, M. Wheeler, K. Renzi, C. Ferguson, T. K. O'Buckley, A. C. Grobin, A. L. Morrow, and G. E. Homanics Deletion of GABAA Receptor alpha 1 Subunit-containing Receptors Alters Responses to Ethanol and Other Anesthetics J. Pharmacol. Exp. Ther., May 1, 2003; 305(2): 600 - 607. [Abstract] [Full Text] [PDF]

				E. Cagetti, J. Liang, I. Spigelman, and R. W. Olsen Withdrawal from Chronic Intermittent Ethanol Treatment Changes Subunit Composition, Reduces Synaptic Function, and Decreases Behavioral Responses to Positive Allosteric Modulators of GABAA Receptors Mol. Pharmacol., January 1, 2003; 63(1): 53 - 64. [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]

				S. C. Steffensen, Z. Nie, J. R. Criado, and G. R. Siggins Ethanol Inhibition of N-Methyl-D-aspartate Responses Involves Presynaptic gamma -Aminobutyric AcidB Receptors J. Pharmacol. Exp. Ther., August 1, 2000; 294(2): 637 - 647. [Abstract] [Full Text]

				H. E. Criswell, T. J. McCown, Z. Ming, R. A. Mueller, and G. R. Breese Interactive Role for Neurosteroids in Ethanol Enhancement of gamma -Aminobutyric Acid-Gated Currents from Dissociated Substantia Nigra Reticulata Neurons J. Pharmacol. Exp. Ther., December 1, 1999; 291(3): 1054 - 1059. [Abstract] [Full Text]

				H. L. June, D. Zuccarelli, L. Torres, K. S. Craig, J. Delong, A. Allen, M. R. Braun, C. R. Cason, and J. M. Murphy High-Affinity Benzodiazepine Antagonists Reduce Responding Maintained by Ethanol Presentation in Ethanol-Preferring Rats J. Pharmacol. Exp. Ther., March 1, 1998; 284(3): 1006 - 1914. [Abstract] [Full Text]

				D. W. Sapp and H. H. Yeh Ethanol-GABAA Receptor Interactions: A Comparison between Cell Lines and Cerebellar Purkinje Cells J. Pharmacol. Exp. Ther., February 1, 1998; 284(2): 768 - 776. [Abstract] [Full Text]

				R. F. Tyndale, S. V. Bhave, E. Hoffmann, P. L. Hoffman, B. Tabakoff, A. J. Tobin, and R. W. Olsen Pentobarbital Decreases the gamma -Aminobutyric AcidA Receptor Subunit gamma-2 Long/Short mRNA Ratio by a Mechanism Distinct from Receptor Occupation J. Pharmacol. Exp. Ther., October 1, 1997; 283(1): 350 - 357. [Abstract] [Full Text]

				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]

				K. L. Shelton and R. L. Balster Effects of gamma -Aminobutyric Acid Agonists and N-Methyl-D-aspartate Antagonists on a Multiple Schedule of Ethanol and Saccharin Self-administration in Rats J. Pharmacol. Exp. Ther., March 1, 1997; 280(3): 1250 - 1260. [Abstract] [Full Text]

				K. Wafford, D. Burnett, T. Dunwiddie, and R. Harris Genetic differences in the ethanol sensitivity of GABAA receptors expressed in Xenopus oocytes Science, July 20, 1990; 249(4966): 291 - 293. [Abstract] [PDF]

				D. Lovinger, G White, and F. Weight Ethanol inhibits NMDA-activated ion current in hippocampal neurons Science, March 31, 1989; 243(4899): 1721 - 1724. [Abstract] [PDF]