Benzodiazepine agonist and inverse agonist actions on GABAA receptor-operated chloride channels. I. Acute effects of ethanol
- Univ. of Colorado Health Sciences Center, Denver (USA)
Acute exposure to ethanol was found to enhance the ability of a benzodiazepine (BZ) inverse agonist, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), to reduce muscimol-activated 36Cl- uptake by membranes isolated from mouse cerebral cortex. Pretreatment in vivo with a hypnotic dose of ethanol (but not a subhypnotic dose), or exposure to a corresponding concentration in vitro, was effective. This increase in sensitivity of gamma-aminobutyric acid receptor-operated chloride channels to the actions of DMCM was due to an increase in both the potency and efficacy of DMCM. Sensitization to DMCM was reversible and was not observed 24 hr after a single injection of ethanol. Pretreatment with ethanol (10, 50 and 100 mM) in vitro produced sensitization to DMCM in a concentration-dependent manner, similar to that produced by in vivo exposure; this increase in sensitivity did not develop if the membranes were pretreated with ethanol at 0 degrees C. Similarly, in vitro exposure to pentobarbital (200 microM) or flunitrazepam (1 microM) enhanced the actions of the inverse agonist Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5a)(1,4)BZ-3- carboxylate). Acute ethanol exposure did not alter low-affinity gamma-aminobutyric acidA receptor binding or muscimol action, or the ability of a BZ agonist, flunitrazepam, to augment muscimol-activated chloride flux. Ethanol exposure did not alter (3H)flumazenil (Ro15-1788) binding to central BZ receptors, its displacement by DMCM or allosteric modulation of DMCM binding by muscimol (muscimol-shift).
- OSTI ID:
- 6721301
- Journal Information:
- Journal of Pharmacology and Experimental Therapeutics; (USA), Vol. 253:2; ISSN 0022-3565
- Country of Publication:
- United States
- Language:
- English
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59 BASIC BIOLOGICAL SCIENCES
AMINOBUTYRIC ACID
RECEPTORS
CHLORIDES
MEMBRANE TRANSPORT
ETHANOL
BIOLOGICAL EFFECTS
ACUTE EXPOSURE
BIOCHEMICAL REACTION KINETICS
BRAIN
CELL MEMBRANES
DOSE-RESPONSE RELATIONSHIPS
INTRAPERITONEAL INJECTION
MEMBRANE PROTEINS
MICE
TRACER TECHNIQUES
TRANQUILIZERS
TRITIUM COMPOUNDS
ALCOHOLS
AMINO ACIDS
ANIMALS
AUTONOMIC NERVOUS SYSTEM AGENTS
BODY
CARBOXYLIC ACIDS
CELL CONSTITUENTS
CENTRAL NERVOUS SYSTEM
CENTRAL NERVOUS SYSTEM AGENTS
CHLORINE COMPOUNDS
DRUGS
HALIDES
HALOGEN COMPOUNDS
HYDROGEN COMPOUNDS
HYDROXY COMPOUNDS
INJECTION
INTAKE
ISOTOPE APPLICATIONS
KINETICS
MAMMALS
MEMBRANES
NERVOUS SYSTEM
NEUROREGULATORS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PROTEINS
PSYCHOTROPIC DRUGS
REACTION KINETICS
RODENTS
VERTEBRATES
560300* - Chemicals Metabolism & Toxicology
550201 - Biochemistry- Tracer Techniques