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

Ferenc E. Gyulai, Mark A. Mintun, Leonard L. Firestone

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


Background: Abundant in vitro and animal model data suggest the postsynaptic γ-aminobutyric acid receptor type A (GABAA-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 GABAA-R site, they provide sensitive probes for the GABAA-R. Availability of the 11C-labeled benzodiazepine ligand, flumazenil, allowed us to quantitatively test in humans whether the volatile anesthetic isoflurane affects GABAA-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 GABAA-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 GABAA-R is involved in the mechanism of action of isoflurane in the living human brain.

Original languageEnglish (US)
Pages (from-to)585-593
Number of pages9
Issue number3
StatePublished - 2001
Externally publishedYes


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