title: [11C]flumazenil binding is increased in a dose-dependent manner with tiagabine-induced elevations in GABA levels.
abstract: Evidence indicates that synchronization of cortical activity at gamma-band frequencies, mediated through GABA-A receptors, is important for perceptual/cognitive processes. To study GABA signaling in vivo, we recently used a novel positron emission tomography (PET) paradigm measuring the change in binding of the benzodiazepine (BDZ) site radiotracer [(11)C]flumazenil associated with increases in extracellular GABA induced via GABA membrane transporter (GAT1) blockade with tiagabine. GAT1 blockade resulted in significant increases in [(11)C]flumazenil binding potential (BPND) over baseline in the major functional domains of the cortex, consistent with preclinical studies showing that increased GABA levels enhance the affinity of GABA-A receptors for BDZ ligands. In the current study we sought to replicate our previous results and to further validate this approach by demonstrating that the magnitude of increase in [(11)C]flumazenil binding observed with PET is directly correlated with tiagabine dose. [(11)C]flumazenil distribution volume (VT) was measured in 18 healthy volunteers before and after GAT1 blockade with tiagabine. Two dose groups were studied (n = 9 per group; Group I: tiagabine 0.15 mg/kg; Group II: tiagabine 0.25 mg/kg). GAT1 blockade resulted in increases in mean (± SD) [(11)C]flumazenil VT in Group II in association cortices (6.8 ± 0.8 mL g-1 vs. 7.3 ± 0.4 mL g-1;p = 0.03), sensory cortices (6.7 ± 0.8 mL g-1 vs. 7.3 ± 0.5 mL g-1;p = 0.02) and limbic regions (5.2 ± 0.6 mL g-1 vs. 5.7 ± 0.3 mL g-1;p = 0.03). No change was observed at the low dose (Group I). Increased orbital frontal cortex binding of [(11)C]flumazenil in Group II correlated with the ability to entrain cortical networks (r = 0.67, p = 0.05) measured via EEG during a cognitive control task. These data provide a replication of our previous study demonstrating the ability to measure in vivo, with PET, acute shifts in extracellular GABA.
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. franklewg@upmc.edu
authors.forename: W Gordon
authors.initials: WG
authors.lastname: Frankle
authors.forename: Raymond Y
authors.initials: RY
authors.lastname: Cho
authors.forename: N Scott
authors.initials: NS
authors.lastname: Mason
authors.forename: Chi-Min
authors.initials: CM
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Himes
authors.forename: Christopher
authors.initials: C
authors.lastname: Walker
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
authors.forename: Chester A
authors.initials: CA
authors.lastname: Mathis
authors.forename: Rajesh
authors.initials: R
authors.lastname: Narendran
mesh_terms: D000328:Adult; D002247:Carbon Isotopes / Q000494:pharmacology*; D003071:Cognition; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000379:methods; D004594:Electrophysiology; D005260:Female; D005442:Flumazenil / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D015233:Models, Statistical; D009557:Nipecotic Acids / Q000494:pharmacology*; D049268:Positron-Emission Tomography / Q000379:methods; D012044:Regression Analysis; D000078308:Tiagabine; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D002247:Carbon Isotopes; D018757:GABA Modulators; D050485:GABA Plasma Membrane Transport Proteins; D008024:Ligands; D009557:Nipecotic Acids; C493413:SLC6A1 protein, human; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D000078308:Tiagabine