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Title: Benzodiazepine agonist and inverse agonist actions on GABAA receptor-operated chloride channels. II. Chronic effects of ethanol

Mice were made tolerant to and dependent on ethanol by administration of a liquid diet. Gamma-aminobutyric acid (GABA) receptor-dependent uptake of 36Cl- by mouse cortical microsacs was used to study the actions of benzodiazepine (BZ) agonists and inverse agonists. Chronic exposure to ethanol attenuated the ability of a BZ agonist, flunitrazepam, to augment muscimol-stimulated uptake of 36Cl- and enhanced the actions of BZ inverse agonists, Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,4)-benzodiazepine - 3-carboxylate) and DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate), to inhibit GABAA receptor-operated chloride channels. Augmentation of chloride flux by pentobarbital was not reduced by chronic ethanol exposure. Attenuation of flunitrazepam efficacy was transient and returned to control levels within 6 to 24 hr after withdrawal from ethanol, but increased sensitivity to Ro15-4513 was observed as long as 8 days after withdrawal. Chronic exposure to ethanol did not alter (3H)SR 95531 (2-(3'-carbethoxy-2'propyl)-3-amino-6-p-methoxyphenylpyridazinium bromide) binding to low-affinity GABAA receptors or muscimol stimulation of chloride flux; and did not alter (3H)Ro15-4513 or (3H)flunitrazepam binding to central BZ receptors or allosteric modulation of this binding by muscimol (i.e., muscimol-shift). These results suggest that chronic exposure to ethanol reduces coupling between BZ agonist sites and the chloride channel, and may be responsible for the development of cross-tolerance between ethanol and BZmore » agonists. In contrast, coupling between BZ inverse agonist sites and the chloride channel is increased.« less
Authors:
;  [1]
  1. (Univ. of Colorado Health Sciences Center, Denver (USA))
Publication Date:
OSTI Identifier:
6721290
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Pharmacology and Experimental Therapeutics; (USA); Journal Volume: 253:2
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.; 59 BASIC BIOLOGICAL SCIENCES; AMINOBUTYRIC ACID; RECEPTORS; CHLORIDES; MEMBRANE TRANSPORT; ETHANOL; BIOLOGICAL EFFECTS; SYMPATHOLYTICS; BIOCHEMICAL REACTION KINETICS; CHLORINE 36; CHRONIC EXPOSURE; MICE; TRACER TECHNIQUES; TRITIUM COMPOUNDS; ALCOHOLS; AMINO ACIDS; ANIMALS; AUTONOMIC NERVOUS SYSTEM AGENTS; BETA DECAY RADIOISOTOPES; BETA-MINUS DECAY RADIOISOTOPES; CARBOXYLIC ACIDS; CHLORINE COMPOUNDS; CHLORINE ISOTOPES; DRUGS; ELECTRON CAPTURE RADIOISOTOPES; HALIDES; HALOGEN COMPOUNDS; HYDROGEN COMPOUNDS; HYDROXY COMPOUNDS; ISOTOPE APPLICATIONS; ISOTOPES; KINETICS; LIGHT NUCLEI; MAMMALS; MEMBRANE PROTEINS; NEUROREGULATORS; NUCLEI; ODD-ODD NUCLEI; ORGANIC ACIDS; ORGANIC COMPOUNDS; PROTEINS; RADIOISOTOPES; REACTION KINETICS; RODENTS; VERTEBRATES; YEARS LIVING RADIOISOTOPES 560300* -- Chemicals Metabolism & Toxicology; 550201 -- Biochemistry-- Tracer Techniques