Potentiation of GABAA receptor activity by volatile anaesthetics is reduced by α5GABAA receptor-preferring inverse agonists I. Lecker, Y. Yin, D.S. Wang,

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Presentation transcript:

Potentiation of GABAA receptor activity by volatile anaesthetics is reduced by α5GABAA receptor-preferring inverse agonists I. Lecker, Y. Yin, D.S. Wang, B.A. Orser British Journal of Anaesthesia Volume 110, Pages i73-i81 (June 2013) DOI: 10.1093/bja/aet038 Copyright © 2013 The Author(s) Terms and Conditions

Fig 1 L-655,708 inhibits currents evoked by low, but not high, concentrations of GABA in neurones from Swiss white mice. Summarized data show that L-655,708 (L6) has a concentration-dependent inhibitory effect on currents evoked by GABA (0.1 and 1 µM) but no effect on currents evoked by GABA (10 and 100 µM) (n=5–6). **P<0.01 vs GABA. Data are mean (sem). British Journal of Anaesthesia 2013 110, i73-i81DOI: (10.1093/bja/aet038) Copyright © 2013 The Author(s) Terms and Conditions

Fig 2 L-655,708 inhibits GABA-evoked currents in neurones from wild-type but not Gabra5−/− mice. (a) and (b) The effects of L-655,708 (L6) on currents evoked by GABA (0.5 µM). (c) and (d) Summarized data showing the concentration-dependent effects of L-655,708 on GABA-evoked current (n=6). **P<0.01 vs GABA. Data are mean (sem). British Journal of Anaesthesia 2013 110, i73-i81DOI: (10.1093/bja/aet038) Copyright © 2013 The Author(s) Terms and Conditions

Fig 3 L-655,708 attenuates the potentiating effects of sevoflurane in neurones from wild-type but not Gabra5−/− mice. (a) and (b) The effects of L-655,708 (L6) on sevoflurane (SEVO, 266 μM)-mediated enhancement of currents evoked by GABA (0.5 μM). (c) and (d) The concentration-dependent effects of L-655,708 on sevoflurane-mediated enhancement of GABA-evoked current are shown (n=6). **P<0.01 vs GABA+SEVO. Data are mean (sem). British Journal of Anaesthesia 2013 110, i73-i81DOI: (10.1093/bja/aet038) Copyright © 2013 The Author(s) Terms and Conditions

Fig 4 L-655,708 decreases the potency of sevoflurane for increasing GABAA receptor activity in neurones from Swiss white mice. (a) The effects of L-655,708 (L6, 50 nM) on sevoflurane (SEVO)-mediated enhancement of currents evoked by GABA (0.5 µM). As shown previously,39 a tail current was observed during drug washout at higher concentrations of sevoflurane (6, 8, and 10 mM). (b) The corresponding concentration–response plots for sevoflurane potentiation of GABA-evoked current in the absence or presence of L-655,708 (L6). L-655,708 increased the EC50 from 1.9 (0.1) to 2.4 (0.2) (P<0.05, n=6) without affecting the maximal response. Application of sevoflurane (10 mM) caused a decrease in current, which is consistent with previous studies.39 Data points for sevoflurane (10 mM) were excluded from the curve-fitting analyses. Data are mean (sem). British Journal of Anaesthesia 2013 110, i73-i81DOI: (10.1093/bja/aet038) Copyright © 2013 The Author(s) Terms and Conditions

Fig 5 L-655,708 inhibits the potentiating effects of isoflurane on GABA currents in neurones from Swiss white mice. (a) The effects of L-655,708 (L6) on isoflurane (ISO, 250 µM)-mediated enhancement of currents evoked by GABA (0.5 µM). (b) Summarized data showing the concentration-dependent inhibitory effects of L-655,708 on isoflurane-mediated enhancement of GABA-evoked currents (n=6). **P<0.01, ***P<0.001 vs GABA+ISO. Data are mean (sem). British Journal of Anaesthesia 2013 110, i73-i81DOI: (10.1093/bja/aet038) Copyright © 2013 The Author(s) Terms and Conditions

Fig 6 MRK-016 attenuates the potentiating effects of sevoflurane and isoflurane in neurones from Swiss white mice. (a) and (b) The effects of MRK-016 (MRK) on sevoflurane (SEVO, 266 μM) and isoflurane (ISO, 250 μM) enhancement of currents evoked by GABA (0.5 μM). (c) and (d) Summarized data showing the concentration-dependent inhibitory effects of MRK-016 on sevoflurane- and isoflurane-mediated enhancement of GABA current (n=6). *P<0.05, **P<0.01, ***P<0.001 vs GABA+SEVO or GABA+ISO. Data are mean (sem). British Journal of Anaesthesia 2013 110, i73-i81DOI: (10.1093/bja/aet038) Copyright © 2013 The Author(s) Terms and Conditions

Fig 7 L-655,708 and MRK-016 inhibit GABA-evoked currents in neurones from Swiss white mice. (a) and (b) The effects of L-655,708 (L6) and MRK-016 (MRK) on currents evoked by GABA (0.5 µM). (c) and (d) Summarized data showing the concentration-dependent inhibitory effects of L-655,708 and MRK-016 on GABA-evoked current (n=6). *P<0.05, **P<0.01, and ***P<0.001 vs GABA. Data are mean (sem). British Journal of Anaesthesia 2013 110, i73-i81DOI: (10.1093/bja/aet038) Copyright © 2013 The Author(s) Terms and Conditions