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

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

TRANSPORTATION PLANNING MADE THE TITANS\u27 NEW STADIUM A SUCCESS

The opening of the Tennessee Titans\u27 Adelphia Coliseum in Nashville, Tennessee, brought an extensive amount of automobile, pedestrian, shuttle-bus, and charter-bus movement within the vicinity of the stadium and within Nashville\u27s central business district (CBD). In this feature, the final in a series of three on Nashville, the authors describe the detailed traffic- and parking-management plans implemented to ensure safe and efficient traffic and pedestrian mobility before and after stadium events. The major components of the plan include specific vehicular and pedestrian routing for both pregame and postgame, designated parking plan for reserved and nonreserved parking, an extensive CBD shuttle and park-and-ride shuttle-bus plan, signing and street-closure recommendations, and police fixed-post locations. The plan also included provisions for local neighborhood management such as access and parking control, enforcement and security, cleanup, and the implementation of a citizen\u27s hotline. Other issues addressed in the plan included coordination with other downtown events, a scaled-back plan for smaller events, and a multifaceted public-information plan to effectively communicate the details of the plan to all stadium attendees and affected parties

Evaluation of dopamine D₂/₃ specific binding in the cerebellum for the positron emission tomography radiotracer [¹¹C]FLB 457:implications for measuring cortical dopamine release

In a recent PET study we demonstrated the ability to measure amphetamine-induced DA release in the human cortex with the dopamine D(2/3) radioligand [(11)C]FLB 457. As previous studies in animals have shown that a relatively high fraction of the [(11)C]FLB 457 signal in the cerebellum represents specific binding to D(2/3) receptors, there was concern that the use of the cerebellum as a measure of nonspecific binding (i.e., reference region) to derive [(11)C]FLB 457 binding potential (BP(ND)) would bias cortical dopamine release measurements. Thus, we evaluated the fractional contribution of specific binding to D(2/3) receptors in the human cerebellum for [(11)C]FLB 457. Six healthy human subjects (5M/1F) were studied twice with [(11)C]FLB 457, once at baseline and again following a single oral dose of 15 mg of aripiprazole, a D(2/3) partial agonist. [(11)C]FLB 457 distribution volume (V(T)) was estimated using kinetic analysis in the cortical regions of interest and potential reference regions. The change in [(11)C]FLB 457 V(T) following aripiprazole ranged from −33 to −42% in the cortical regions of interest (ROIs). The aripiprazole-induced change in [(11)C]FLB 457 V(T) in three potential reference regions suggests significant specific binding the cerebellum (CER, −17 ± 12%), but not pons (PON, −10 ± 10%) and centrum semiovale (CESVL, −3 ± 12%). Nevertheless, a re-analysis of the published [(11)C]FLB 457 test-retest and amphetamine studies suggests that the use of the PON V(T) and CESVL V(T) as an estimate of nonspecific binding to derive [(11)C]FLB 457 BP(ND) in dopamine release studies is unlikely to be successful because it leads to less reproducible outcome measures, which in turn diminishes the ability to measure dopamine release in the cortex. D(2/3) blocking studies with aripiprazole and [(11)C]FLB 457 suggest specific binding to D(2/3) receptors in the cerebellum. These data also suggest that the contribution of specific binding to D(2/3) receptors in the cerebellum is lower than that in the cortical ROIs and that CER V(T) is mostly representative of nonspecific binding. Nevertheless, caution is advised when using reference tissue methods that rely solely on the cerebellum signal as an input function to quantify [(11)C]FLB 457 BP(ND)