Article date: 1989/6/1
PubMed ID: 2479037
Journal name: Pharmacology, biochemistry, and behavior (ISSN: 0091-3057)
Chronic treatment with benzodiazepine receptor agonists increases sensitivity to the convulsant action of FG 7142, an inverse agonist. We investigated whether or not changes in the number and function of GABA-gated chloride channels accompanies this increased sensitivity. Diazepam, 5 mg.kg-1, was administered to mice daily for five days, and mice were then tested with a single injection of FG 7142, 40 mg.kg-1, at several intervals thereafter. At 24 hours after the last diazepam dose, 10 of 15 mice had clonic seizures following FG 7142 and four of the remaining five had myoclonic jerks. At 48 hours, only one of six mice developed a clonic seizure, and none were observed in mice tested at 96 or 144 hours. Muscimol-stimulated chloride flux was reduced in cortical synaptosomes from diazepam-treated mice at 24 hours but not at 48 or 96 hours. However, the binding of [35S]TBPS, a ligand closely associated with the chloride channel, was unchanged at 24 hours. These results suggest that a transient diminution in GABA-gated chloride channel function; unaccompanied by a reduction in channel number, may underlie the sensitization to the convulsant action of FG 7142 observed after withdrawal from chronic diazepam treatment.
Author List: Lewin E, Peris J, Bleck V, Zahniser N R, 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: Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Carbolines; Chlorides; Ion Channels; Muscimol; FG 7142; tert-butylbicyclophosphorothionate; Diazepam;
Mesh terms: Animals; Brain/drug effects; Bridged Bicyclo Compounds/metabolism; Bridged Bicyclo Compounds, Heterocyclic; Carbolines/pharmacology; Chlorides/metabolism; Diazepam/pharmacology; Dose-Response Relationship, Drug; Drug Synergism; Ion Channels/drug effects; Kindling, Neurologic/drug effects; Mice; Mice, Inbred ICR; Muscimol/pharmacology;