Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 5 December 1986:
Vol. 234. no. 4781, pp. 1243 - 1247
DOI: 10.1126/science.3022383
Prev | Table of Contents | Next

Articles

Science, Vol 234, Issue 4781, 1243-1247
Copyright © 1986 by American Association for the Advancement of Science

articles

A selective imidazobenzodiazepine antagonist of ethanol in the rat

PD Suzdak, Glowa JR, JN Crawley, RD Schwartz, P Skolnick, and SM Paul

Ethanol, at pharmacologically relevant concentrations of 20 to 100 mM, stimulates gamma-aminobutyric (GABA) receptor-mediated uptake of 36Cl-labeled chlorine into isolated brain vesicles. One drug that acts at GABA-benzodiazepine receptors, the imidazobenzodiazepine Ro15-4513, has been found to be a potent antagonist of ethanol-stimulated 36Cl- uptake into brain vesicles, but it fails to antagonize either pentobarbital- or muscimol-stimulated 36Cl- uptake. Pretreatment of rats with Ro15-4513 blocks the anticonflict activity of low doses of ethanol (but not pentobarbital) as well as the behavioral intoxication observed with higher doses of ethanol. The effects of Ro15-4513 in antagonizing ethanol-stimulated 36Cl- uptake and behavior are completely blocked by benzodiazepine receptor antagonists. However, other benzodiazepine receptor inverse agonists fail to antagonize the actions of ethanol in vitro or in vivo, suggesting a novel interaction of Ro15-4513 with the GABA receptor-coupled chloride ion channel complex. The identification of a selective benzodiazepine antagonist of ethanol-stimulated 36Cl- uptake in vitro that blocks the anxiolytic and intoxicating actions of ethanol suggests that many of the neuropharmacologic actions of ethanol may be mediated via central GABA receptors.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Antagonism of the Ethanol-Like Discriminative Stimulus Effects of Ethanol, Pentobarbital, and Midazolam in Cynomolgus Monkeys Reveals Involvement of Specific GABAA Receptor Subtypes.
C. M. Helms, L. S. M. Rogers, and K. A. Grant (2009)
J. Pharmacol. Exp. Ther. 331, 142-152
   Abstract »    Full Text »    PDF »
{gamma}-Aminobutyric Acid Type A Receptors and Alcoholism: Intoxication, Dependence, Vulnerability, and Treatment..
J. H. Krystal, J. Staley, G. Mason, I. L. Petrakis, J. Kaufman, R. A. Harris, J. Gelernter, and J. Lappalainen (2006)
Arch Gen Psychiatry 63, 957-968
   Abstract »    Full Text »    PDF »
From the Cover: Ethanol potently and competitively inhibits binding of the alcohol antagonist Ro15-4513 to {alpha}4/6beta3{delta} GABAA receptors.
H. J. Hanchar, P. Chutsrinopkun, P. Meera, P. Supavilai, W. Sieghart, M. Wallner, and R. W. Olsen (2006)
PNAS 103, 8546-8551
   Abstract »    Full Text »    PDF »
From the Cover: Low-dose alcohol actions on {alpha}4beta3{delta} GABAA receptors are reversed by the behavioral alcohol antagonist Ro15-4513.
M. Wallner, H. J. Hanchar, and R. W. Olsen (2006)
PNAS 103, 8540-8545
   Abstract »    Full Text »    PDF »
Alcohol-sensitive GABA receptors and alcohol antagonists.
S. M. Paul (2006)
PNAS 103, 8307-8308
   Full Text »    PDF »
Deletion of GABAA Receptor alpha 1 Subunit-containing Receptors Alters Responses to Ethanol and Other Anesthetics.
J. E. Kralic, M. Wheeler, K. Renzi, C. Ferguson, T. K. O'Buckley, A. C. Grobin, A. L. Morrow, and G. E. Homanics (2003)
J. Pharmacol. Exp. Ther. 305, 600-607
   Abstract »    Full Text »    PDF »
Withdrawal from Chronic Intermittent Ethanol Treatment Changes Subunit Composition, Reduces Synaptic Function, and Decreases Behavioral Responses to Positive Allosteric Modulators of GABAA Receptors.
E. Cagetti, J. Liang, I. Spigelman, and R. W. Olsen (2003)
Mol. Pharmacol. 63, 53-64
   Abstract »    Full Text »    PDF »
The GABAA Receptor alpha 1 Subtype in the Ventral Pallidum Regulates Alcohol-Seeking Behaviors.
S. C. Harvey, K. L. Foster, P. F. McKay, M. R. Carroll, R. Seyoum, J. E. Woods II, C. Grey, C. M. Jones, S. McCane, R. Cummings, et al. (2002)
J. Neurosci. 22, 3765-3775
   Abstract »    Full Text »    PDF »
Daily Treatment with Diazepam Differentially Modifies Sensitivity to the Effects of gamma -Aminobutyric AcidA Modulators on Schedule-Controlled Responding in Rhesus Monkeys.
L. R. McMahon and C. P. France (2002)
J. Pharmacol. Exp. Ther. 300, 1017-1025
   Abstract »    Full Text »    PDF »
GABAA Receptors Containing {alpha}5 Subunits in the CA1 and CA3 Hippocampal Fields Regulate Ethanol-Motivated Behaviors: An Extended Ethanol Reward Circuitry.
H. L. June, S. C. Harvey, K. L. Foster, P. F. McKay, R. Cummings, M. Garcia, D. Mason, C. Grey, S. McCane, L. S. Williams, et al. (2001)
J. Neurosci. 21, 2166-2177
   Abstract »    Full Text »    PDF »
Neuroactive Steroid 3alpha -Hydroxy-5alpha -Pregnan-20-One Modulates Electrophysiological and Behavioral Actions of Ethanol.
M. J. VanDoren, D. B. Matthews, G. C. Janis, A. C. Grobin, L. L. Devaud, and A. L. Morrow (2000)
J. Neurosci. 20, 1982-1989
   Abstract »    Full Text »    PDF »
Ion Channels in Presynaptic Nerve Terminals and Control of Transmitter Release.
A. Meir, S. Ginsburg, A. Butkevich, S. G. Kachalsky, I. Kaiserman, R. Ahdut, S. Demirgoren, and R. Rahamimoff (1999)
Physiol Rev 79, 1019-1088
   Abstract »    Full Text »    PDF »
Flunitrazepam Has an Inverse Agonistic Effect on Recombinant alpha 6beta 2gamma 2-GABAA Receptors via a Flunitrazepam-binding Site.
C. A. E. Hauser, C. H. R. Wetzel, B. Berning, F. M. Gerner, and R. Rupprecht (1997)
J. Biol. Chem. 272, 11723-11727
   Abstract »    Full Text »    PDF »
Gene Knockout of the alpha 6 Subunit of the gamma -Aminobutyric Acid Type A Receptor: Lack of Effect on Responses to Ethanol, Pentobarbital, and General Anesthetics.
G. E. Homanics, C. Ferguson, J. J. Quinlan, J. Daggett, K. Snyder, C. Lagenaur, Z.-P. Mi, X.-H. Wang, D. R. Grayson, and L. L. Firestone (1997)
Mol. Pharmacol. 51, 588-596
   Abstract »    Full Text »
Beta Adrenergic Sensitization of gamma -Aminobutyric Acid Receptors to Ethanol Involves a Cyclic AMP/Protein Kinase A Second-Messenger Mechanism.
R. K. Freund and M. R. Palmer (1997)
J. Pharmacol. Exp. Ther. 280, 1192-1200
   Abstract »    Full Text »
A Man With Alcoholism and HIV Infection.
S. E. Hyman (1995)
JAMA 274, 837-843
   Abstract »    PDF »
The effect of Ro 15-4513, an inverse agonist at the benzodiazepine receptor, on the exploratory response to novelty in the playground maze.
B. Nicholls, J. Mellanby, and S. Smith (1994)
J Psychopharmacol 8, 32-39
   Abstract »    PDF »
Effect of Flumazenil in a Model of Acute Alcohol Intoxication in Rats.
P. Lheureux, J. Fontaine, and R. Askenasi (1993)
Human and Experimental Toxicology 12, 177-180
   Abstract »    PDF »
Review articles : Alcohol and palliative care.
D. Kerr (1992)
Palliative Medicine 6, 185-201
   Abstract »    PDF »
Genetic differences in the ethanol sensitivity of GABAA receptors expressed in Xenopus oocytes.
K. Wafford, D. Burnett, T. Dunwiddie, and R. Harris (1990)
Science 249, 291-293
   Abstract »    PDF »
Antagonizing the behavioural effects of drugs: a discussion with specific reference to benzodiazepines and alcohol.
R. G. Lister (1989)
J Psychopharmacol 3, 21-28
   Abstract »    PDF »
Is ethanol antagonist Ro15-4513 selective for ethanol?.
K. Britton, C. Ehlers, and G. Koob (1988)
Science 239, 648-650
   PDF »
Response: Is Ethanol Antagonist Rol5-4513 Selective for Ethanol?.
P. D. SUZDAK, J. R. GLOWA, J. N. CRAWLEY, P. SKOLNICK, and S. M. PAUL (1988)
Science 239, 649-650
   PDF »
Alcohol Withdrawal and Noradrenergic Function.
M. LINNOILA, I. MEFFORD, D. NUTT, and B. ADINOFF (1987)
Ann Intern Med 107, 875-889
   Abstract »    PDF »
Classification of GABA and benzodiazepine receptors.
B. Meldrum (1987)
J Psychopharmacol 1, 1-5
   PDF »
The emerging pharmacology of ethanol.
F. E. Bloom (1987)
J Psychopharmacol 1, 227-236
   Abstract »    PDF »
New drug counters alcohol intoxication.
G Kolata (1986)
Science 234, 1198-1199
   PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)