1. Effects of two volatile anesthetics [halothane (Hal) and enflurane (Enf)] and a volatile convulsant [hexafluorodiethyl ether (HFE)] on amino acid-induced membrane currents in neurons dissociated from the nucleus tractus solitarius of the rat were examined. The dissociated neurons were voltage clamped in the whole-cell mode of the patch-clamp technique. All drugs were applied with a microperfusion system, termed the 'Y-tube' method. 2. The glutamate (Glu)-induced excitatory response was slightly reduced by both the anesthetics. The responses to three agonists at Glu receptor were depressed by Hal (10-3 M) in the rank order of quisqualate > N-methyl-D- aspartate > kainate. HFE slightly increased the Glu response at a high concentration of 2 x 10-3 M. 3. The γ-aminobutyric acid (GABA)-induced chloride current (I(Cl)) was enhanced by both anesthetics. The dissociation constant (K(d)) for the enhancement was 2.3 x 10-4 M for Hal and 2.1 x 10- 4 M for Enf, and the Hill coefficient was 1.6 for Hal and 1.5 for Enf. HFE depressed the GABA response with a K(d) of 8.7 x 10-5 and a Hill coefficient of 0.84. 4. Hal (10-3 M) and Enf (10-3 M) decreased the K(d) of the GABA concentration-response curve from 3.5 x 10-6 to 10-6 and 1.9 x 10-6 M, respectively, without changing the maximum response or the Hill coefficient (1.5). In the presence of HFE (10-4 M), the K(d) was increased to 1.4 x 10-5 M and the Hill coefficient was slightly changed to 1.2. These findings suggest a heterotropic allosteric effect of the volatile agents. The two anesthetics were suggested to affect GABA(A) and barbiturate receptor domains but not the benzodiazepine receptor domain of the GABA receptor- chloride channel complex. 5. Hal increased the glycine (Gly)-induced I(Cl), with a K(d) of 3.7 x 10-4 M and a Hill coefficient of 1.9. Enf also enhanced the response, with a K(d) of 6.3 x 10-4 M and a Hill coefficient of 1.5. HFE had no effect on the Gly response. 6. Hal (10-3 M) and Enf (10-3 M) reduced the K(d) of the Gly concentration-response curve from 4.8 x 10-5 to 2.4 x 10-5 and 3.1 x 10-5 M, respectively, without altering the maximum response or the Hill coefficient (1.8). 7. It is concluded that anesthesia produced by Hal and Enf may be due to the enhancement of the I(Cl) evoked by GABA and Gly, which suppresses the neuronal activity in the CNS. HFE may induce convulsions by depressing the GABA-induced inhibition. 8. On the basis of the present findings that the three volatile agents, two anesthetics and a convulsant, differentially influenced the excitatory and inhibitory receptor-channel complexes on the same neuronal membrane, it may be concluded that these hydrophobic agents induce anesthesia or convulsions via interaction with receptor-channel proteins rather than via physical perturbation of the membrane lipids.
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