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[ <sup>11</sup>C]flumazenil binding is increased in a dose-dependent manner with tiagabine-induced elevations in GABA levels

Frankle, WG and Cho, RY and Mason, NS and Chen, CM and Himes, M and Walker, C and Lewis, DA and Mathis, CA and Narendran, R (2012) [ <sup>11</sup>C]flumazenil binding is increased in a dose-dependent manner with tiagabine-induced elevations in GABA levels. PLoS ONE, 7 (2).

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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 [ 11C]flumazenil associated with increases in extracellular GABA induced via GABA membrane transporter (GAT1) blockade with tiagabine. GAT1 blockade resulted in significant increases in [ 11C]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 [ 11C]flumazenil binding observed with PET is directly correlated with tiagabine dose. [ 11C]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) [ 11C]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 [ 11C]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. © 2012 Frankle et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Frankle, WG
Cho, RYryc2@pitt.eduRYC2
Mason, NSmasons@pitt.eduMASONS
Chen, CM
Himes, M
Walker, C
Lewis, DAtnplewis@pitt.eduTNPLEWIS
Mathis, CAmathis@pitt.eduMATHIS
Narendran, Rran29@pitt.eduRAN29
ContributionContributors NameEmailPitt UsernameORCID
Date: 27 February 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 2
DOI or Unique Handle: 10.1371/journal.pone.0032443
Refereed: Yes
Other ID: NLM PMC3288104
PubMed Central ID: PMC3288104
PubMed ID: 22384252
Date Deposited: 03 Aug 2012 15:45
Last Modified: 22 Jun 2021 13:55


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