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

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Background:Many anesthetic agents are known to enhance the α1β2γ2Sγ-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 37°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 μM) was applied when the S1 response returned to basal level, and 10 min later, thiopental (1–300 μM), propofol (10 μM), or ketamine (30 μM) 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 μM, 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 μM. Bicuculline also reversed the effects of propofol but not those of ketamine.Conclusions:The authors’ data indicate that thiopental, propofol, and ketamine inhibit K+-evoked glutamate release from rat cerebrocortical slices. The inhibition produced by thiopental and propofol is mediated by activation of GABAA receptors, revealing a subtle interplay between GABA-releasing (GABAergic) and glutamatergic transmission in anesthetic action.A antagonist; mechanisms of anesthesia; neurotransmitter release; rat cerebrocortical slices.)

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