Isoflurane alters the amount of dopamine transporter expressed on the plasma membrane in humans.
BACKGROUND
Isoflurane increases extracellular dopamine concentration and causes trafficking of the dopamine transporter (DAT) in transfected cells. Also, the binding potentials of highly specific positron-emitting DAT ligands are altered by isoflurane in rhesus monkeys. The purpose of this study was to determine the dose-response curve for isoflurane altering the binding potential of one of these ligands ([F-18]FECNT) in humans.


METHODS
Twenty human volunteers underwent positron emission tomography using [F-18]FECNT. All subjects were scanned while awake and then again after assignment to one of four groups (n = 5 each): awake-control, propofol-control, or light or deep isoflurane anesthesia as defined by Bispectral Index monitoring. Bispectral Index values in the light anesthesia group were 40 +/- 7 (end-tidal isoflurane, 1.02 +/- 0.08) versus 27 +/- 10 (end-tidal isoflurane, 1.6 +/- 0.3) in the deep anesthesia group. The within-subject percent change in putamen binding potential between the awake and second scans was determined for each subject, averaged within groups, and compared across groups.


RESULTS
The [F-18]FECNT binding potential exhibited a biphasic shape as a function of anesthetic dose. The binding potential for the second scan in the awake-control and propofol-control groups was significantly less than the initial scan; for the light anesthesia group, the binding potential was significantly increased during anesthesia, and no change was detected between the two scans in the deeper anesthesia group.


CONCLUSIONS
Isoflurane causes a dose-dependent change in the [F-18]FECNT binding potential for DAT consistent with isoflurane causing trafficking of the DAT between the plasma membrane and the cell interior. Concentrations of isoflurane below minimum alveolar concentration causes DAT to be trafficked to the plasma membrane from the cell interior, but no net trafficking occurs at higher concentrations. The data are most easily explained if isoflurane alters the amount of functionally expressed DAT through an indirect pathway. This phenomena should be more fully explored to help make the next generation of anesthetics more mechanistically specific and to reduce undesired side effects.
Votaw
John R
JR
Department of Radiology, Emory University School of Medicine, Atlanta, Georgia, USA. votaw@commander.eushc.org
Byas-Smith
Michael G
MG
Voll
Ronald
R
Halkar
Raghu
R
Goodman
Mark M
MM
D000328:Adult; D000758:Anesthesia; D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000494:pharmacology*; D002245:Carbon Dioxide / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006207:Half-Life; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007530:Isoflurane / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D026901:Membrane Transport Proteins / Q000096:biosynthesis*; D008875:Middle Aged; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009662:Nortropanes; D010092:Oximetry; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals
C410211:2-carbomethoxy-3-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane; D018685:Anesthetics, Inhalation; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009662:Nortropanes; D019275:Radiopharmaceuticals; C493214:SLC6A3 protein, human; D002245:Carbon Dioxide; D007530:Isoflurane