Suzdak P D, Swedberg M D, Andersen K E, Knutsen L J, Braestrup C
Department of Receptor Neurochemistry, Novo Nordisk A/S, Maaloev, Denmark.
Life Sci. 1992;51(24):1857-68. doi: 10.1016/0024-3205(92)90037-p.
The in vivo binding of 3H-Tiagabine to the central GABA uptake carrier in mouse brain was characterized. 3H-Tiagabine in vivo bound to a single class of binding sites with a Kd = 72.5 nM and a Bmax = 640 pmol/g tissue. 3H-Tiagabine binding in vivo was regionally distributed within the CNS, and showed a good correlation with 3H-Tiagabine binding in vitro. Pharmacological characterization of 3H-Tiagabine binding in vivo revealed a binding site exhibiting specificity for GABA uptake inhibitors. Experiments examining the in vivo receptor occupancy of the GABA uptake carrier for a series of GABA uptake inhibitors revealed that 20-30% of the GABA uptake sites were occupied at the ED50 for inhibiting DMCM-induced clonic convulsions, while a 50-62% receptor occupancy in vivo was needed to inhibit rotarod performance. These data suggest that 3H-Tiagabine in vivo binding may be a useful method for assessing GABA uptake inhibitor penetration into the CNS, and may be a useful tool for studying the physiological regulation of the GABA uptake carrier.
对3H-噻加宾在小鼠脑内与中枢γ-氨基丁酸（GABA）摄取载体的体内结合特性进行了表征。3H-噻加宾在体内与一类单一的结合位点结合，解离常数（Kd）为72.5 nM，最大结合容量（Bmax）为640 pmol/g组织。3H-噻加宾在体内的结合在中枢神经系统内呈区域分布，并且与体外3H-噻加宾的结合表现出良好的相关性。对3H-噻加宾在体内结合的药理学表征揭示了一个对GABA摄取抑制剂具有特异性的结合位点。对一系列GABA摄取抑制剂的GABA摄取载体体内受体占有率的实验研究表明，在抑制二甲基环己基甲酰胺（DMCM）诱导的阵挛性惊厥的半数有效剂量（ED50）时，20 - 30%的GABA摄取位点被占据，而在体内需要50 - 62%的受体占有率才能抑制旋转棒试验表现。这些数据表明，3H-噻加宾在体内的结合可能是评估GABA摄取抑制剂渗透入中枢神经系统的一种有用方法，并且可能是研究GABA摄取载体生理调节的一种有用工具。
