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.1999 May;127(1):131-8.
doi: 10.1038/sj.bjp.0702543.

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

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

S Liachenko et al. Br J Pharmacol.1999 May.

Abstract

The synaptic concentrations of glutamate and gamma-aminobutyric acid (GABA) are modulated by their release and re-uptake. The effects of general anaesthetics on these two processes remain unclear. This study evaluates the effects of isoflurane, a clinically important anaesthetic, on glutamate and GABA release and re-uptake in superfused mouse cerebrocortical slices. Experiments consisted of two 1.5-min exposures to 40 mM KCl in 30 min intervals. During the second exposure, different concentrations of isoflurane 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 first KCl-evoked increases in glutamate and GABA were used to determine the isoflurane concentration-response curves. The results can be described as a sum of two independent processes, corresponding to the inhibitions of release and re-uptake, respectively. The EC50 values for the inhibitions of release and re-uptake were 295+/-16 and 805+/-43 microM for glutamate, and 229+/-13 and 520+/-25 microM for GABA, respectively. Addition of PDC did not significantly affect glutamate release but shifted the re-uptake curve to the left (EC50= 315+/-20 microM). Nipecotic acid completely blocked GABA uptake, rendering isoflurane inhibition of GABA re-uptake undetectable. Our data suggest that isoflurane inhibits both the release and re-uptake of neurotransmitters and that the inhibitions occur at different EC50's. For GABA, both EC50's are within the clinical concentration range. The net anaesthetic effect on extracellular concentrations of neurotransmitters, particularly GABA, depends on the competition between inhibition of release and that of re-uptake.

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Figures

Figure 1
Figure 1
Representative profiles of glutamate outflow from mouse cerebrocortical slices after two consecutive 1.5-min exposures to 40 mM KCl in the absence (a) and presence (b) of 0.3 mM L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC), a selective glutamate re-uptake inhibitor. All samples were collected in 1.5 min. The time interval between the two KCl exposures was 30 min. The shaded areas represent K+-evoked increases in glutamate outflow above the mean basal level. The integration of the shaded areas is used to calculate the ratio of the second to first K+-evoked glutamate outflow.
Figure 2
Figure 2
Representative profiles of GABA outflow from mouse cerebrocortical slices after two consecutive 1.5-min exposures to 40 mM KCl in the absence (a) and presence (b) of 1 mM nipecotic acid, a GABA re-uptake inhibitor. All samples were collected in 1.5 min. The time interval between the two KCl exposures was 30 min. The shaded areas represent K+-evoked increases in GABA outflow above the mean basal level. The integration of the shaded areas is used to calculate the ratio of the second to first K+-evoked GABA outflow.
Figure 3
Figure 3
Effects of the re-uptake inhibitors on the ratios of the second to first K+-evoked glutamate and GABA outflow in superfused mouse cerebrocortical slices. L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC, 0.3 mM) or nipecotic acid (1 mM) was introduced into the superfusion chamber 4.5 min before the second 1.5-min exposure to 40 mM KCl.*Significantly different from other groups (P<0.01, one-way ANOVA with Student-Neuman-Keuls multiple comparisons).
Figure 4
Figure 4
Effects of isoflurane on the K+-evoked outflow of glutamate (a) and GABA (b) in the absence (open circles) and presence (filled circles) of their respective re-uptake inhibitors: 0.3 mM of L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) for glutamate, and 1 mM of nipecotic acid for GABA. Solid lines are best fit to the data using the equation, which consists of two independent components corresponding to the inhibition of release (dashed lines) and inhibition of re-uptake (dotted lines). The EC50 values are listed in Table 1. Note that PDC reduced the isoflurane EC50 for the inhibition of glutamate re-uptake, whereas nipecotic acid eliminated the component for the isoflurane inhibition of GABA re-uptake.
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