Ethanol-related changes in benzodiazepine receptor ligand modulation of GABA[sub A] receptor-operated chloride channels: Relevance to ethanol tolerance and dependence

Thesis/Dissertation · Mon Jan 01 04:00:00 EST 1990

OSTI ID:7013312

Buck, K J

This study focuses on how ethanol exposure affects biochemical processes associated with the GABA[sub A] complex in the mammalian CNS, and examines the role of these changes in the development of alcohol tolerance and withdrawal. In vitro studies of control mice and those acutely or chronically exposed to alcohol were conducted. Radioligand binding using the low-affinity GABA[sub A] receptor-selective antagonist [[sup 3]H]SR95531 showed no changes in saturation binding analysis of receptor affinity or density. Muscimol-activated [sup 36]Cl[sup [minus]] flux in isolated brain membrane vesicles was not reduced by ethanol exposure. Radioligand binding, using the central BZ-selective agonist [[sup 3]H]flunitrazepam, antagonist [[sup 3]H]flumazenil, and inverse agonist [[sup 3]H]Ro15-4513, was used to measure cortical receptors; saturation binding analysis revealed no affect of ethanol on BZ receptor density or affinity and no change in allosteric modulation of BZ receptor binding by muscimol. [sup 36]Cl[sup [minus]] flux studies, used to measure BZ agonist enhancement or inverse agonist inhibition of muscimol-activated channel activity, showed attenuation of the former and increase of the latter in ethanol exposure. These results support the hypothesis that ethanol exposure results in subsensitivity of the GABA[sub A] receptor complex to BZ agonists and increased sensitivity to BZ inverse agonists. Ethanol-induced changes in the GABAergic system were examined in mice genetically selected for being resistant (WSR) or prone (WSP) to the developemnt of seizures associated with ethanol withdrawal. Ethanol-induced sensitization to BZ inverse agonist inhibition of channel activity was greater in WSP than in WSR mice. This supports the hypothesis that hypersensitivity to BZ inverse agonists is functionally related to ethanol withdrawal severity.

• Research Organization: Colorado Univ., Denver, CO (United States). Health Sciences Center
• OSTI ID: 7013312
• Country of Publication: United States
• Language: English

Related Subjects

560300* -- Chemicals Metabolism & Toxicology
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ALCOHOLS
AMINO ACIDS
AMINOBUTYRIC ACID
ANIMALS
AUTONOMIC NERVOUS SYSTEM AGENTS
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BETA-PLUS DECAY RADIOISOTOPES
BIOLOGICAL EFFECTS
CARBOXYLIC ACIDS
CENTRAL NERVOUS SYSTEM
CENTRAL NERVOUS SYSTEM AGENTS
CHLORINE 36
CHLORINE ISOTOPES
DRUGS
ELECTRON CAPTURE RADIOISOTOPES
ETHANOL
HYDROGEN ISOTOPES
HYDROXY COMPOUNDS
ISOTOPE APPLICATIONS
ISOTOPES
LIGANDS
LIGHT NUCLEI
MAMMALS
MEMBRANE PROTEINS
MICE
NERVOUS SYSTEM
NEUROREGULATORS
NUCLEI
ODD-EVEN NUCLEI
ODD-ODD NUCLEI
ORGANIC ACIDS
ORGANIC COMPOUNDS
PHARMACOLOGY
PROTEINS
PSYCHOTROPIC DRUGS
RADIOISOTOPES
RECEPTORS
RODENTS
TRACER TECHNIQUES
TRANQUILIZERS
TRITIUM
VERTEBRATES
YEARS LIVING RADIOISOTOPES