Dose-dependent enhancement of in vivo GABA(A)-benzodiazepine receptor binding by isoflurane.
Publication/Presentation Date
9-1-2001
Abstract
BACKGROUND: Abundant in vitro and animal model data suggest the postsynaptic gamma-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.
Volume
95
Issue
3
First Page
585
Last Page
593
ISSN
0003-3022
Published In/Presented At
Gyulai, F. E., Mintun, M. A., & Firestone, L. L. (2001). Dose-dependent enhancement of in vivo GABA(A)-benzodiazepine receptor binding by isoflurane. Anesthesiology, 95(3), 585–593. https://doi.org/10.1097/00000542-200109000-00008
Disciplines
Anesthesiology | Medicine and Health Sciences
PubMedID
11575528
Department(s)
Department of Anesthesiology
Document Type
Article