Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
PLoS One. 2012;7(2):e32443. doi: 10.1371/journal.pone.0032443. Epub 2012 Feb 27.
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 [(11)C]flumazenil associated with increases in extracellular GABA induced via GABA membrane transporter (GAT1) blockade with tiagabine. GAT1 blockade resulted in significant increases in [(11)C]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 [(11)C]flumazenil binding observed with PET is directly correlated with tiagabine dose. [(11)C]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) [(11)C]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 [(11)C]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.
证据表明，通过 GABA-A 受体介导的皮质活动在伽马波段频率上的同步是感知/认知过程的重要基础。为了在体内研究 GABA 信号，我们最近使用了一种新的正电子发射断层扫描 (PET) 范式，该范式测量了苯二氮䓬 (BDZ) 结合位点放射性示踪剂 [(11)C]氟马西尼的结合变化，这种变化与 GABA 膜转运体 (GAT1) 阻断剂噻加宾诱导的细胞外 GABA 增加有关。GAT1 阻断导致皮质主要功能区域的 [(11)C]氟马西尼结合潜能 (BPND) 相对于基线显著增加，这与临床前研究一致，表明 GABA 水平的增加增强了 GABA-A 受体对 BDZ 配体的亲和力。在本研究中，我们试图复制以前的结果，并通过证明 PET 观察到的 [(11)C]氟马西尼结合增加的幅度与噻加宾剂量直接相关，进一步验证这种方法。在 GAT1 阻断后，我们在 18 名健康志愿者中测量了 [(11)C]氟马西尼的分布容积 (VT) ，使用噻加宾。研究了两个剂量组 (每组 n = 9；组 I：噻加宾 0.15mg/kg；组 II：噻加宾 0.25mg/kg)。GAT1 阻断导致组 II 中的 [(11)C]氟马西尼 VT 在联合皮质中增加（平均值 ± SD；6.8 ± 0.8mL g-1 vs. 7.3 ± 0.4mL g-1；p = 0.03）、感觉皮质（6.7 ± 0.8mL g-1 vs. 7.3 ± 0.5mL g-1；p = 0.02）和边缘区域（5.2 ± 0.6mL g-1 vs. 5.7 ± 0.3mL g-1；p = 0.03）。低剂量组（组 I）未见变化。组 II 中眶额皮质对 [(11)C]氟马西尼的结合增加与 EEG 测量的认知控制任务期间皮质网络的同步能力（r = 0.67，p = 0.05）相关。这些数据提供了我们之前研究的复制，证明了使用 PET 在体内测量细胞外 GABA 急性变化的能力。
