Dose-dependent enhancement of in vivo GABA(A)-benzodiazepine receptor binding by isoflurane

Background: Abundant in vitro and animal model data suggest the postsynapti c gamma -aminobutyric acid receptor type A (GABA(A)-R) is an important targ et for volatile general anesthetics, but the relevance of these models Is u ntested 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 C-11-labeled benzodiazepine ligand, flumazenil, allowe d us to quantitatively test in humans whether the volatile anesthetic isofl urane affects GABA(A)-Rs in vivo in a dose-dependent manner. Methods: C-11-flumazenil positron emission tomography scans were obtained i n 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 C-11-flumazenil, express ed as distribution volume (which linearly correlates to maximal binding sit e density and apparent ligand affinity), was obtained by curve fitting usin g a two-compartment model. Results: The ratio of distribution volume increased significantly In each e xamined region during the Isoflurane conditions compared with control condi tions (P < 0.01, one-tailed t test). Furthermore, the increases in ratio of distribution volume during the 1.5-minimum alveolar concentration isoflura ne condition were significantly greater than those measured during 1.0 mini mum alveolar concentration isoflurane Inhalation (P < 0.002, one-tailed t t est). Conclusions: Isoflurane exposure appeared to enhance receptor-specific C-11 -flumazenil binding in a dose-dependent manner. The results suggest the pos sibility that a conformational change of the GABA(A)-R is Involved in the m echanism of action of isoflurane in the living human brain.