Dose-dependent enhancement of in vivo GABA_A-benzodiazepine receptor binding by isoflurane

Background: Abundant in vitro and animal model data suggest the postsynaptic γ-aminobutyric acid receptor type A (GABA_A-R) is an important target for volatile general anesthetics, but the relevance of these models is untested in humans. Because benzodiazepines have also been shown to act via a specific GABA_A-R site, they provide sensitive probes for the GABA_A-R. Availability of the ¹¹C-labeled benzodiazepine ligand, flumazenil, allowed us to quantitatively test in humans whether the volatile anesthetic isoflurane affects GABA_A-RS in vivo in a dose-dependent manner. Methods: ¹¹C-flumazenil positron emission tomography scans were obtained in 12 healthy subjects while awake (control condition) and anesthetized with either 1.0 or 1.5 minimum alveolar concentration isoflurane (n = 7 and 5, respectively; isoflurane conditions). Regions of interest included areas of high, intermediate, and low GABA_A-benzodiazepine site density. For each subject and experimental condition, the binding of ¹¹C-flumazenil, expressed as distribution volume (which linearly correlates to maximal binding site density and apparent ligand affinity), was obtained by curve fitting using a two-compartment model. Results: The ratio of distribution volume increased significantly in each examined region during the isoflurane conditions compared with control conditions (P < 0.01, one-tailed t test). Furthermore, the increases in ratio of distribution volume during the 1.5-minimum alveolar concentration isoflurane condition were significantly greater than those measured during 1.0 minimum alveolar concentration isoflurane inhalation (P < 0.002, one-tailed t test). Conclusions: Isoflurane exposure appeared to enhance receptor-specific ¹¹C-flumazenil binding in a dose-dependent manner. The results suggest the possibility that a conformational change of the GABA_A-R is involved in the mechanism of action of isoflurane in the living human brain.