Sybirska E, Seibyl J P, Bremner J D, Baldwin R M, al-Tikriti M S, Bradberry C, Malison R T, Zea-Ponce Y, Zoghbi S, During M
Department of Psychiatry, Yale University School of Medicine, West Haven, CT.
Neuropharmacology. 1993 Jul;32(7):671-80. doi: 10.1016/0028-3908(93)90080-m.
SPECT imaging with [123I]iomazenil was used to measure benzodiazepine (BZ) neuroreceptor occupancy of the agonist lorazepam administered at therapeutically relevant doses in humans and supratherapeutic doses in monkeys. Lorazepam at therapeutic doses (0.03 mg/kg, i.v.) administered 90 min after the bolus injection of [123I]iomazenil had no statistically significant effect (P > 0.12) on the washout rates of regional brain activities compared to that in control subjects, although human subjects demonstrated marked sedation from the lorazepam. In baboons, the effects of higher doses of lorazepam (cumulative 0.5 mg/kg) were examined in a stepwise displacement paradigm. The in vivo potency was expressed as the ED50 (or dose required to displace 50% of receptor bound activity) and was equal to 0.34 +/- 0.01 mg/kg (mean +/- SD, n = 12). Log-logit analyses of displacement data corrected for endogenous washout showed that therapeutic doses of lorazepam were associated with < 3% BZ receptor occupancy. To examine if endogenous GABA modulates potency of the BZ agonist, the ED50 of lorazepam was compared with and without concurrent administration of tiagabine, a GABA reuptake inhibitor. These experiments were designed to measure an in vivo GABA shift of agonist potency. In vivo microdialysis demonstrated that tiagabine (up to 1 mg/kg, i.v.) increased extracellular GABA levels up to 200% of baseline, but these doses had only a minimal enhancement of lorazepam's potency to displace [123I]iomazenil. This study strongly suggests that single therapeutically relevant doses of lorazepam occupy a relatively small percentage (i.e. < 3%) of BZ receptors and that BZ binding sites have a significant (i.e. > 97%) receptor reserve.
使用[123I]艾司西酞普兰进行单光子发射计算机断层扫描（SPECT）成像，以测量在人类中给予治疗相关剂量以及在猴子中给予超治疗剂量的激动剂劳拉西泮后苯二氮䓬（BZ）神经受体占有率。在静脉推注[123I]艾司西酞普兰90分钟后给予治疗剂量（0.03mg/kg，静脉注射）的劳拉西泮，与对照组相比，区域脑活动的清除率没有统计学上的显著影响（P>0.12），尽管人类受试者表现出明显的劳拉西泮镇静作用。在狒狒中，采用逐步置换范式研究了更高剂量劳拉西泮（累积0.5mg/kg）的作用。体内效力以半数有效剂量（ED50，即置换50%受体结合活性所需的剂量）表示，等于0.34±0.01mg/kg（平均值±标准差，n=12）。对经内源性清除校正的置换数据进行对数-对数几率分析表明，治疗剂量的劳拉西泮与<3%的BZ受体占有率相关。为了研究内源性γ-氨基丁酸（GABA）是否调节BZ激动剂的效力，比较了同时给予和不给予GABA再摄取抑制剂噻加宾时劳拉西泮的ED50。这些实验旨在测量激动剂效力的体内GABA移位。体内微透析表明，噻加宾（高达1mg/kg，静脉注射）可使细胞外GABA水平升高至基线的200%，但这些剂量对劳拉西泮置换[123I]艾司西酞普兰的效力仅有最小程度的增强。这项研究强烈表明，单剂量治疗相关的劳拉西泮占据相对较小比例（即<3%）的BZ受体，且BZ结合位点具有显著的（即>97%）受体储备。
