Dose-dependent enhancement of in vivo GABA(A)-benzodiazepine receptor binding by isoflurane.
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.
Gyulai
F E
FE
Department of Anesthesiology and Critical Care Medicine, University of Pittsburgh School of Medicine, Pennsylvania 15213, USA. gyulaife@anes.upmc.edu
Mintun
M A
MA
Firestone
L L
LL
D000328:Adult; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D001812:Blood-Brain Barrier; D002560:Cerebrovascular Circulation / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005442:Flumazenil / Q000378:metabolism; D006801:Humans; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D011485:Protein Binding; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism
D018685:Anesthetics, Inhalation; D002712:Chlorides; D011963:Receptors, GABA-A; D005442:Flumazenil; D007530:Isoflurane