Sevoflurane and Propofol Increase 11C-Flumazenil Binding to Gamma-Aminobutyric AcidA Receptors in Humans

Abstract

In Brief Based on in vitro studies and animal data, most anesthetics are supposed to act via γ-aminobutyric acid type A (GABAA) receptors. However, this fundamental characteristic has not been extensively investigated in humans. We studied 11C-flumazenil binding to GABAA receptors during sevoflurane and propofol anesthesia in the living human brain using positron emission tomography (PET). Fourteen healthy male subjects underwent 2 60-min dynamic PET studies with 11C-labeled flumazenil, awake and during anesthesia. Anesthesia was maintained with 2% end-tidal sevoflurane (n = 7) or propofol at a target plasma concentration of 9.0 ± 3.0 (mean ± sd) μg/mL (n = 7). The depth of anesthesia was measured with bispectral index (BIS). Values of regional distribution volumes (DV) of 11C-flumazenil were calculated in several brain areas using metabolite-corrected arterial plasma curves and a two-compartment model. Separate voxel-based statistical analysis using parametric DV images was performed for detailed visualization. The average BIS index was 35 ± 6 in the sevoflurane group and 28 ± 8 in the propofol group (P = 0.02). Sevoflurane increased the DV of 11C-flumazenil significantly (P < 0.05) in all brain areas studied except the pons and the white matter. In the propofol group the increases were significant (P < 0.05) in the caudatus, putamen, cerebellum, thalamus and the frontal, temporal, and parietal cortices. Furthermore, the DV increases in the frontal, occipital, parietal, and temporal cortical areas and in the putamen were statistically significantly larger in the sevoflurane than in the propofol group. Our findings support the involvement of GABAA receptors in the mechanism of action of both anesthetics in humans. IMPLICATIONS: Both sevoflurane and propofol enhanced gamma-aminobutyric acid (GABA)A receptor binding in the living human brain as assessed with 11C-labeled flumazenil and positron emission tomography, thus supporting the involvement of GABAA receptors in the mechanism of action of both volatile anesthetics and propofol.