Enhancement of gamma-aminobutyric acidA receptor function and binding by the volatile anesthetic halothane
Longoni, B.; Demontis, G.C.; Olsen, R.W.
Journal of Pharmacology and Experimental Therapeutics 266(1): 153-159
1993
ISSN/ISBN: 0022-3565 PMID: 7687288 Document Number: 417619
The volatile general anesthetics halothane and enflurane increased muscimol-stimulated 36Cl- efflux via gamma-aminobutyric acid (GABA)-A receptors in rat brain cortical slices and also increased basal 36Cl- efflux in the absence of GABA agonist. The effects occurred in the clinical range of anesthetic concentrations (0.561.7 mM halothane and 0.46-1.4 mM enflurane). Both anesthetics induced a slow onset increase in basal 36Cl- efflux rate when added alone with no exogenous GABA agonist. This direct effect of halothane had a biphasic dependence on anesthetic concentrations, with a maximal effect in the range 1.1 to 1.7 mM. Replacing extracellular calcium with magnesium or blocking voltage-gated calcium entry with cobalt (200 mu-M) altered the direct halothane effect, shifting the concentration-dependence curve to the right. Halothane direct potentiation of chloride flux in the absence of GABA agonist was blocked by the GABA-A chloride channel antagonist picrotoxin but not by the GABA-A receptor antagonist bicuculline. The halothane potentiation of the muscimol response was detectable at concentrations of 0.56 mM halothane in the assay buffer, and was linear with concentration up to 2.8 mM. The effect was more pronounced at low GABA agonist concentrations, apparently due to an increase in GABA affinity. Lowering the extracellular calcium concentration to micromolar levels did not affect halothane potentiation of muscimol responses. Halothane at similar concentrations increased the high-affinity binding of (3H)muscimol to GABA-A receptor sites in rat brain cortical membranes in a calcium-independent manner. Thus, volatile anesthetics, like several other chemical classes of anesthetics, appear to enhance GABA-A-mediated inhibitory synaptic transmission via a direct effect on the postsynaptic GABA-A receptor-chloride ion channel complex. This allosteric modulation of GABA-A receptors appears to represent a unified mechanism of general anesthetic drug action.