Effects of intravenous anesthetic agents on glutamate release - A role forGABA(A) receptor-mediated inhibition

Background Many anesthetic agents are known to enhance the alpha(1)beta(2)g amma(2s) gamma-aminobutyric acid type A (GABA(A)) chloride current; however , they also depress excitatory neurotransmission. The authors evaluated two hypotheses: intravenous anesthetic agents inhibit glutamate release and an y observed inhibition may be secondary to GABA, receptor activation. Methods: Cerebrocortical slices were prepared front Wistar rats. After perf usion in oxygenated Krebs buffer for 60 min at 37 degrees C, samples for gl utamate assay were obtained at 2-min intervals, After 6 min, a 2-min pulse of 46 mM K+ was applied to the slices (S-1); this was repeated after 30 min (S-2). Bicuculline (1-100 mu M) was applied when the S, 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 S-2. Perfusate glutamate concentrations were measured fluorometrically, and the area under the glutamate release curves was expressed as a ratio (S-2/S-1), Results: Potassium (46 mM) evoked a monophasic release of glutamate during S-1 and S-2, with a mean control S-2/S-1 ratio of 1.07 +/- 0.33 (mean +/- S D, n = 96). Ketamine and thiopental produced a concentration-dependent inhi bition of K+-evoked glutamate release with half-maximum inhibition of relea se values of 18.2 and 10.9 mu M, respectively. Release was also inhibited b y propofol, Bicuculline produced a concentration dependent reversal of thio pental Inhibition of glutamate release with a half-maximum reversal of the agonist effect of 10.3 mu M Bicuculline also reversed the effects of propof ol but not those of ketamine, Conclusions: The authors' data indicate that thiopental, propofol, and keta mine inhibit K+-evoked glutamate release from rat cerebrocortical slices. T he inhibition produced by thiopental and propofol is mediated by activation of GABA(A) receptors, revealing a subtle interplay between GABA-releasing (GABAergic) and glutamatergic transmission in anesthetic action.