[ ¹¹C]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) [ ¹¹C]flumazenil binding is increased in a dose-dependent manner with tiagabine-induced elevations in GABA levels. PLoS ONE, 7 (2).

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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. © 2012 Frankle et al.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Frankle, WG Cho, RY ryc2@pitt.edu RYC2 Mason, NS masons@pitt.edu MASONS Chen, CM Himes, M Walker, C Lewis, DA tnplewis@pitt.edu TNPLEWIS Mathis, CA mathis@pitt.edu MATHIS Narendran, R ran29@pitt.edu RAN29
Contributors:	Contribution Contributors Name Email Pitt Username ORCID Editor Hashimoto, Kenji UNSPECIFIED UNSPECIFIED UNSPECIFIED
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
URI:	http://d-scholarship.pitt.edu/id/eprint/13225

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