Effects of Intravenous Anesthetic Agents on Glutamate Release: A Role for GABAA Receptor-Mediated Inhibition

Background: Many anesthetic agents are known to enhance the alpha]1beta]2gamma]2Sgamma]-aminobutyric acid type A (GABAA) chloride current; however, they also depress excitatory neurotransmission. The authors evaluated two hypotheses: intravenous anesthetic agents inhibit glutamate release and any observed inhibition may be secondary to GABAA receptor activation.

Methods: Cerebrocortical slices were prepared from Wistar rats. After perfusion in oxygenated Krebs buffer for 60 min at 37degrees]C, samples for glutamate assay were obtained at 2-min intervals. After 6 min, a 2-min pulse of 46 mM K+ was applied to the slices (S1); this was repeated after 30 min (S2). Bicuculline (1-100 mu]M) was applied when the S1 response returned to basal level, and 10 min later, thiopental (1-300 mu]M), propofol (10 mu]M), or ketamine (30 mu]M) were also applied until the end of S2. Perfusate glutamate concentrations were measured fluorometrically, and the area under the glutamate release curves was expressed as a ratio (S2/S1).

Results: Potassium (46 mM) evoked a monophasic release of glutamate during S1 and S2, with a mean control S2/S1 ratio of 1.07 +/- 0.33 (mean +/- SD, n = 96). Ketamine and thiopental produced a concentration-dependent inhibition of K+-evoked glutamate release with half-maximum inhibition of release values of 18.2 and 10.9 mu]M, respectively. Release was also inhibited by propofol. Bicuculline produced a concentration dependent reversal of thiopental inhibition of glutamate release with a half-maximum reversal of the agonist effect of 10.3 mu]M. Bicuculline also reversed the effects of propofol but not those of ketamine.