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[11C]flumazenil Binding Is Increased in a Dose-Dependent Manner with Tiagabine-Induced Elevations in GABA Levels

Author

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  • W Gordon Frankle
  • Raymond Y Cho
  • N Scott Mason
  • Chi-Min Chen
  • Michael Himes
  • Christopher Walker
  • David A Lewis
  • Chester A Mathis
  • Rajesh Narendran

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 [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.

Suggested Citation

  • W Gordon Frankle & Raymond Y Cho & N Scott Mason & Chi-Min Chen & Michael Himes & Christopher Walker & David A Lewis & Chester A Mathis & Rajesh Narendran, 2012. "[11C]flumazenil Binding Is Increased in a Dose-Dependent Manner with Tiagabine-Induced Elevations in GABA Levels," PLOS ONE, Public Library of Science, vol. 7(2), pages 1-9, February.
  • Handle: RePEc:plo:pone00:0032443
    DOI: 10.1371/journal.pone.0032443
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    References listed on IDEAS

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    2. Vikaas S. Sohal & Feng Zhang & Ofer Yizhar & Karl Deisseroth, 2009. "Parvalbumin neurons and gamma rhythms enhance cortical circuit performance," Nature, Nature, vol. 459(7247), pages 698-702, June.
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