Article date: 1990/5/1
PubMed ID: 2160008
Journal name: The Journal of pharmacology and experimental therapeutics (ISSN: 0022-3565)
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 BZ agonists. In contrast, coupling between BZ inverse agonist sites and the chloride channel is increased.(ABSTRACT TRUNCATED AT 250 WORDS)
Author List: Buck K J, Harris R A
Publication Types: Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.
Substances mentioned in the article: Azides; Carbolines; Chloride Channels; Chlorides; Convulsants; GABA Antagonists; Membrane Proteins; Pyridazines; Receptors, GABA-A; Tritium; Benzodiazepines; methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; Ethanol; Flunitrazepam; Ro 15-4513; gabazine;
Mesh terms: Animals; Azides/metabolism; Benzodiazepines/metabolism; Brain/drug effects; Carbolines/metabolism; Chloride Channels; Chlorides/metabolism; Convulsants/metabolism; Ethanol/blood; Flunitrazepam/metabolism; GABA Antagonists; Male; Membrane Proteins/metabolism; Mice; Mice, Inbred ICR; Pyridazines/metabolism; Receptors, GABA-A/drug effects; Substance Withdrawal Syndrome/metabolism; Tritium;