[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 [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.

Differences between magnetoencephalographic (MEG) spectral profiles of drugs acting on GABA at synaptic and extrasynaptic sites: A study in healthy volunteers

“…The elimination half-lives of these two drugs is similar at approximately 1.5e2.0 h in fasting subjects. The 15 mg dose of tiagabine study was chosen because it could be administered as standard tablet doses, is very similar to the 16 mg used in a PET study by Frankle et al (2012) and is identical with that used in several ongoing imaging studies by our group (Muthukumaraswamy et al, 2013b;Stokes et al, 2014) which have shown that GABA levels are increased.…”

Detecting a dexmedetomidine-evoked reduction of noradrenaline release in the human brain with the alpha2C-adrenoceptor PET ligand [11C]ORM-13070

“…The low dose, which caused the same peripherally detected sympatholytic effects as the high dose, was not expected to reach significant a 2C -AR occupancy. The sedative and sympatholytic effects of dexmedetomidine are primarily mediated via the a 2A -AR subtype (Bucheler et al, 2002;Gertler et al, 2001). In experimental animals, the sedative effects of dexmedetomidine and the dexmedetomidine-induced reductions in noradrenaline release in the brain follow very similar dose-response patterns; dexmedetomidine has been found to reduce noradrenaline turnover in the brain, an effect which is absent in knock-out mice devoid of a 2A -ARs (L€ ahdesm€ aki et al 2003).…”

“…Dexmedetomidine is a potent a 2 -AR agonist that is clinically used as a sedative-anesthetic agent (Gertler et al, 2001). Dexmedetomidine infusion causes a decrease in blood pressure and heart rate, which is thought to be the result of activation of autoinhibitory a 2A -ARs in the CNS, causing decreased sympathetic nervous system activity.…”

News and views on in-vivo imaging of neurotransmission using PET and MRI

“…[ 11 C]flumazenil, and [ 11 C]Ro15-4513 as a PET ligand with high affinity for α5-subunit-containing GABA A receptors with detecting either small changes 38 or markedly reductions 39 . These differences might also be explained by [ 11 C]flumazenil acting as a weak partial agonist and [ 11 C]Ro15-4513 being a partial inverse agonist at the benzodiazepine binding site 2 .…”