Propofol and benzodiazepine modulation of GABA[subscript]AR function

grantor: University of TorontoThe general anaesthetic, propofol, has multiple effects on the GABA$\sb{\rm A}$R: it potentiates GABA-evoked responses; it activates the receptor, and it alters the kinetics of receptor desensitization. In contrast, sedative benzodiazepines only potentiate GABA-evoked responses. It is not known if the multiple effects of propofol on the GABA$\sb{\rm A}$R are mediated by distinct binding sites or which effect accounts for propofol's anaesthetic properties. The whole-cell patch clamp method was used to study the effects of benzodiazepines and propofol on GABA$\sb{\rm A}$R's present in cultured, murine hippocampal neurons. The concentration of propofol that activated the GABA$\sb{\rm A}$R (EC$\sb{50}$ = 24.3 $\pm$ 3.4 $\mu$M) was significantly greater than that which decreased receptor desensitization (EC$\sb{50}$ = 1.15 $\pm$ 0.33 $\mu$M). Furthermore, midazolam potentiated propofol-induced currents but did not alter propofol-induced changes in receptor desensitization, suggesting that receptor activation and desensitization were mediated by distinct mechanisms. Low concentrations of propofol (1 $\mu$M) and midazolam (0.5 $\mu$M) interacted in a superadditive manner to enhance GABA (0.3 $\mu$M)-evoked responses and isobolographic analysis suggested a synergistic interaction. In contrast, higher concentrations of these drugs produced an additive interaction. As low concentrations of propofol and midazolam interact synergistically to produce hypnosis and higher concentrations do not interact synergistically to induce anaesthesia, our results suggest that hypnosis and anaesthesia may be mediated by distinct changes in GABA$\sb{\rm A}$R function.M.Sc