Does GABA have a role in anesthesia?

Abstract

Anesthetics may exert their effects through a GABA mechanism. Halothane causes dose-related inhibition of (1- 14C) GABA degradation to 14CO 2 by rat brain cortex slices. This is accompanied by reduced synthesis and turnover of acetylcholine and Krebs cycle intermediates. Anesthetic agents as a group inhibit the transformation of (1- 14C) GABA to 14CO 2 by rat brain synaptosomes at clinically relevant concentrations. The dose required for 10% inhibition (ID 10) correlates well with the pharmacologie 50% effective dose (ED 50). Volatile anesthetics inhibit overall GABA metabolism but do not significantly alter the individual steps of GABA uptake, GABA release or GABA transaminase activity. The known inhibition by volatile anesthetics of Complex I in electron transport leads to reduced NADH oxidation and decreased GABA catabolism. Thiopental inhibits GABA-transaminase with a ID 10 similar to its ED 50 but does not affect either synaptosomal uptake or release of GABA. Midazolam, a water-soluble benzodiazepine, exerts its effect by inhibition of GABA uptake by synaptosomes but it also causes GABA release at higher concentrations. Further experiments show that the tranquilizer, chlorpromazine, also gives a ID 10-ED 50 correlation and this ID 10 effect is based on uptake inhibition. In summary, anesthetics inhibit three sites: Complex I (volatile anesthetics), GABA-transaminase (anesthetic barbiturates) or GABA uptake (water-soluble benzodiazepines and chlorpromazine). Each may cause accumulation of GABA in the synaptic cleft, the direct demonstration of which is presently not within our technical capability. This interpretation is consistant with neurophysiological findings.