title: Functional alterations in cerebral GABAA receptor complex associated with formation of alcohol dependence: analysis using GABA-dependent 36Cl- influx into neuronal membrane vesicles.
abstract: The effect of alcohol dependence induced by ethanol inhalation on GABA-dependent 36Cl- influx into membrane vesicles prepared from the mouse brain has been examined. Ethanol, flunitrazepam and salsolinol induced a significant facilitation of the GABA-dependent 36Cl- influx into membrane vesicles obtained from the normal mouse brain. Ethanol inhalation induced the facilitation of GABA-dependent 36Cl- influx at 3-12 hr after the initiation of inhalation, but this facilitation returned to a normal level within 12 hr. In membrane vesicles obtained from the brain of an alcohol-dependent mouse at 7 days after the initiation of ethanol inhalation, not only was there a significant decrease of the GABA-dependent 36Cl- influx but there occurred also the disappearance of the activating effects of ethanol, flunitrazepam and salsolinol on the influx. This decrease in GABA-dependent 36Cl- influx was found to be recovered within 8 hr after the withdrawal of ethanol inhalation. On the other hand, behavioural withdrawal signs such as tonic-clonic convulsions with grimaces and heads thrown back appeared at 8 hr after the withdrawal of ethanol inhalation and continued for 8-16 hr. These results suggest that the observed functional deteriorations at cerebral GABAA receptors such as the decrease of GABA-dependent 36Cl- influx and the disappearance of the activating effects of ethanol, flunitrazepam and salsolinol on the influx may contribute to the preparation of the exhibition of ethanol withdrawal signs and/or the establishment of functional tolerance to alcohol, but are not directly related to the exhibition of alcohol withdrawal signs.
authors.affiliation: Department of Pharmacology, Kyoto Prefectural University of Medicine, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kuriyama
authors.forename: T
authors.initials: T
authors.lastname: Ueha
mesh_terms: D000280:Administration, Inhalation; D000430:Alcohol Withdrawal Delirium / Q000503:physiopathology; D000437:Alcoholism / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000503:physiopathology; D001643:Bridged Bicyclo Compounds / Q000493:pharmacokinetics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides / Q000378:metabolism*; D005445:Flunitrazepam / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009118:Muscimol / Q000493:pharmacokinetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D013570:Synaptic Membranes / Q000187:drug effects* / Q000502:physiology; D013572:Synaptic Vesicles / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides; D011963:Receptors, GABA-A; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; C046308:tert-butylbicyclo-2-benzoate