Article date: 1989/2/7
PubMed ID: 2714367
Journal name: European journal of pharmacology (ISSN: 0014-2999)
Intravenous administration of 2-[2-methoxyethoxy]-ethyl 8-[cis-2-n-octylcyclopropyl]-octanoate (A2C) was found to disorder brain membranes but did not produce intoxication or anesthesia in mice. The abilities of A2C and an anesthetic (benzyl alcohol) to inhibit [35S]t-butylbicyclophosphorothionate (TBPS) binding, and modify gamma-aminobutyric acid (GABA) receptor-mediated 36Cl- influx into brain vesicles were then compared. Both of the perturbants inhibited [35S]TBPS binding at the same concentrations at which they reduced membrane order; however, the anesthetic was nearly 4 times more effective in reducing [35S]TBPS binding than was A2C. Muscimol-stimulated 36Cl- uptake was enhanced by benzyl alcohol at a concentration which produced little or no change in membrane order. Concentrations of both A2C and benzyl alcohol which reduced membrane order inhibited muscimol-stimulated 36Cl- influx. Similarly, membrane order and muscimol-activated 36Cl- uptake were reduced in brain vesicles prepared from mice which had received A2C in vivo. The effects of anesthetics on the GABAA receptor-chloride channel complex were analyzed by a two site model of action in which a 'perturbant' site is responsible for decreased 36Cl- uptake; but a distinct 'anesthetic' site is responsible for augmentation of chloride flux and anesthesia.
Author List: Buck K J, Allan A M, 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: Benzyl Alcohols; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Chlorides; Radioisotopes; Stearates; Stearic Acids; Muscimol; Chlorine; A(2)C; gamma-Aminobutyric Acid; tert-butylbicyclophosphorothionate;
Mesh terms: Anesthesia; Animals; Benzyl Alcohols/pharmacology; Brain Chemistry/drug effects; Bridged Bicyclo Compounds/metabolism; Bridged Bicyclo Compounds, Heterocyclic; Chlorides/metabolism; Chlorine; Male; Membrane Fluidity/drug effects; Membranes/drug effects; Mice; Mice, Inbred ICR; Muscimol/pharmacology; Radioisotopes; Stearates/pharmacology; Stearic Acids/pharmacology; Synaptosomes/drug effects; Temperature; gamma-Aminobutyric Acid/metabolism;