Concentration‐dependent isoflurane effects on depolarization‐evoked glutamate and GABA outflows from mouse brain slices

Abstract

1 The synaptic concentrations of glutamate and g-aminobutyric acid (GABA) are modulated by their release and re-uptake. The e ects of general anaesthetics on these two processes remain unclear. This study evaluates the e ects of iso¯urane, a clinically important anaesthetic, on glutamate and GABA release and re-uptake in superfused mouse cerebrocortical slices. 2 Experiments consisted of two 1.5-min exposures to 40 mM KCl in 30 min intervals. During the second exposure, di erent concentrations of iso¯urane with and without 0.3 mM L-transpyrrolidine-2,4-dicarboxylic acid (PDC, a competitive inhibitor of glutamate uptake transporter) or 1 mM nipecotic acid (a competitive inhibitor of GABA uptake transporter) were introduced. The ratios of the second to ®rst KCl-evoked increases in glutamate and GABA were used to determine the iso¯urane concentration-response curves.3 The results can be described as a sum of two independent processes, corresponding to the inhibitions of release and re-uptake, respectively. The EC 50 values for the inhibitions of release and re-uptake were 295+16 and 805+43 mM for glutamate, and 229+13 and 520+25 mM for GABA, respectively. Addition of PDC did not signi®cantly a ect glutamate release but shifted the re-uptake curve to the left (EC 50 =315+20 mM). Nipecotic acid completely blocked GABA uptake, rendering iso¯urane inhibition of GABA re-uptake undetectable. 4 Our data suggest that iso¯urane inhibits both the release and re-uptake of neurotransmitters and that the inhibitions occur at di erent EC 50 's. For GABA, both EC 50 's are within the clinical concentration range. The net anaesthetic e ect on extracellular concentrations of neurotransmitters, particularly GABA, depends on the competition between inhibition of release and that of re-uptake.

Selective Depression by General Anesthetics of Glutamate Versus GABA Release from Isolated Cortical Nerve Terminals

“…Previous studies support the conclusion that clinically relevant concentrations of volatile anesthetics do not affect K ϩ -evoked excitatory amino acid release (Minchin, 1981;Kendall and Minchin, 1982;Lingamaneni et al, 2001) or GABA release (Minchin, 1981;Kendall and Minchin, 1982;Lecharney et al, 1995;Salford et al, 1997;Lingamaneni et al, 2001). Inhibition of K ϩ -evoked release of glutamate (Miao et al, 1995;Liachenko et al, 1999) or GABA Liachenko et al, 1999) by isoflurane has been reported. Interpretation of results obtained in brain slices (Liachenko et al, 1999), however, is (Buggy et al, 2000).…”

“…Inhibition of K ϩ -evoked release of glutamate (Miao et al, 1995;Liachenko et al, 1999) or GABA Liachenko et al, 1999) by isoflurane has been reported. Interpretation of results obtained in brain slices (Liachenko et al, 1999), however, is (Buggy et al, 2000). Failure to compare anesthetic effects on release evoked by additional secretagogues (Lingamaneni et al, 2001) makes it difficult to interpret results obtained only with elevated KCl.…”

Isoflurane Inhibits the Neurotransmitter Release Machinery

“…Simulations suggested that the effects of isoflurane on the electrical properties of neurons can account for between 62 and 78% of the inhibitory effects of isoflurane on excitatory post synaptic currents (Wu et al 2004). In contrast with the studies from Hemmings, Richards, and Wu, other groups have reported more robust dose-dependent inhibition of KCl-evoked neurotransmitter release by clinically relevant concentrations of isoflurane (Larsen et al 1994;Liachenko et al 1999;Miao et al 1995). Larsen et al, for example, reported ϳ0.33, 1, and 2 MAC isoflurane inhibited KCl-evoked glutamate release from rat hippocampal slices by 31, 42, and 51%, respectively (Larsen et al 1994).…”

REAL-TIME IN VIVO NEUROTRANSMITTER MEASUREMENTS USING ENZYME-BASED CERAMIC MICROELECTRODE ARRAYS: WHAT WE HAVE LEARNED ABOUT GLUTAMATE SIGNALING

“…Anesthesia has been shown to alter mostly tonic glutamate levels and in some circumstances phasic glutamate release dynamics (Liachenko et al, 1998(Liachenko et al, , 1999Rutherford et al, 2007). Recordings in freely moving animals allow for monitoring glutamate neurotransmission without the effects of anesthesia.…”