Fluidization of brain membranes by A2C does not produce anesthesia and does not augment muscimol-stimulated 36Cl- influx.
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.