Dual actions of volatile anesthetics on GABAA IPSCS

Molecular determinants for the action of general anesthetics at recombinant α2β3γ2γ‐aminobutyric acidA receptors

“…On wild-type a 2 b 3 c 2 receptors en¯urane had a potentiating effect, though smaller compared to the action of the other anesthetics tested and compared to other reports (Mihic et al 1997). The relatively small potentiation we observed might be due to the fact that en¯urane has a dual action on GABA A receptors, with maximal potentiations achieved at concentrations much lower (100 lM) than the one used in our study (1 mM) (Antkowiak and Heck 1997;Banks and Pearce 1999). In both point-mutated receptors, a 2 b 3(N265M) c 2 and a 2 b 3(M286W) c 2 , the modulation by en¯urane is signi®cantly reduced, indicating that both amino acid residues in TM2 and TM3 are important for en¯urane modulation of GABA-induced currents.…”

“…Fresh solutions were prepared every hour. Based on other studies in which a similar application method was used, we expect only a small loss of enflurane of approximately 10% and 15% (Antkowiak and Heck 1997; Banks and Pearce 1999), which would affect recordings from wild type and mutant receptors in the same way.…”

Sevoflurane potentiates and blocks GABA-induced currents through recombinant alpha1beta2gamma2 GABAA receptors: implications for an enhanced GABAergic transmission

“…Isoflurane increased the affinity of GABA, but depressed the maximum GABA response at the GABA A R [8]. A similar dual effect of volatile anaesthetics was found in rat pyramidal cells, where they reduced the amplitude, but prolonged the decay of miniature inhibitory postsynaptic currents (IPSCs) dose dependently [9]. In dissociated hippocampal neurons, sevoflurane caused an increase in apparent affinity of GABA, and was supposed to exhibit a blocking effect as suggested by 'hump currents' [10].…”

Neocortex is the major target of sedative concentrations of volatile anaesthetics: strong depression of firing rates and increase of GABAA receptor‐mediated inhibition

“…We found that at two concentrations representing the lower and upper limit, respectively, of published MAC awake values, IPSCs were prolonged by approximately 20% and 45%, respectively. These values are in good agreement with those of (Jones & Harrison 1993) and (Banks & Pearce 1999), who reported that at concentrations slightly above MAC awake isoflurane and enflurane enhanced GABA A receptor‐mediated currents in the hippocampus in vitro by approximately 50%. We note that the relation between the enhancement of GABA A currents and the depression of firing rates found in the present study is excellent for all anaesthetics at the lower concentration (an increase of charge transfer of 19–23% corresponds to a depression of firing rates by 52–53%) but diverges somewhat at the higher concentration, particularly in the case of halothane.…”

“…Remarkably, despite the different pharmacological approaches to inducing ongoing activity the above‐mentioned reports point to GABA A receptors as a major molecular target of anaesthetics in the cortex. GABA A receptor‐mediated synaptic transmission in cortex had indeed earlier been found to be enhanced by anaesthetics (Jones & Harrison, 1993; Franks & Lieb, 1994; Franks & Lieb, 1998; Banks & Pearce, 1999; Eger II et al ., 2001; Nishikawa & MacIver, 2001), yet mainly at concentrations close to those inducing immobility. Immobility, however, requires anaesthetic doses far higher than those producing sedation and hypnosis (Stoelting et al ., 1970).…”